The Bioinformatics CRO Podcast

Episode 4 with Jason Stein

In our latest podcast, Grant talks with Jason Stein, assistant professor of genetics at UNC, about the latest omics techniques used to study schizophrenia, the role of academia and industry in drug discovery, and Jason’s unusual path to bioinformatics. (Recorded on November 5, 2020)

On The Bioinformatics CRO Podcast, we sit down with scientists to discuss interesting topics across biomedical research and to explore what made them who they are today.

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Transcript of Episode 4: Jason Stein

Grant: Welcome to The Bioinformatics CRO Podcast. I’m Grant Belgard and joining me today is Jason Stein. Jason, would you like to introduce yourself?

Jason: Sure. Hey Grant, my name is Jason Stein. I’m an assistant professor at UNC Chapel Hill, in the department of genetics and in the neuroscience center. And I’ve been here for just a little under five years.

Grant: Fantastic. So tenure review is coming up soon?

Jason: It is. 

Grant: Good times.

Jason: I submitted my materials in February. 

Grant: Fantastic. So, What’s your research program about? 

Jason: My research is to try to understand how genetic variation that’s present in human populations, influences brain developments and brain structure, and then leads to risk for neuropsychiatric disorders like autism and schizophrenia.

Jason: So we have several model systems that we use to study this. The major thing that we do is using human neural stem cells. So we have a population of human neural stem cells, each of which is genetically diverse. And then we try to see how genetic variation within our population is associated with differences in the development and the differentiation of these neural progenitor cells.

Grant: What have you found? 

Jason: Oh, so what have we found in that? So we recently put some pre-prints up in the bio archive (“Evaluating brain structure traits as endophenotypes using polygenicity and discoverability”, “Cell-type specific effects of genetic variation on chromatin accessibility during human neuronal differentiation”). 

Grant: And Grace can link those on the transcript. 

Jason: Oh, nice. Yeah. Link them up. Get that–what’s that rating system–the altimetric. Yeah. You got to get that altimetric up.

Jason: So what have we found? So we found that, there’s many sites in the genome where genetic variation influences chromatin accessibility and gene expression. So chromatin accessibility is a measure of the function in the non-coding genome, probably largely due to differences in transcription factor binding.

Jason: So the genome is more open and accessible in certain regions of the non-coding genome, and that allows transcription factors to bind. So genetic variation within those open regions can impact transcription factor binding, and then lead to differences in chromatin accessibility. We found, you know, many thousands of different sites where genetic variation affects chromatin accessibility. And interestingly, they’re very cell type specific. 

Jason: So we did, we did the study in two different cell types: progenitors and their differentiated neuronal progeny. And if you do a chromatin accessibility QTL–so you find genetic variation affecting chromatin accessibility–very few are shared between neurons and progenitors.

Jason: But if you look at expression, like eQTL, there are much more that are shared between, genetic variation, affecting gene expression between two cell types. So we thought that was really interesting. You may have more cell type specificity for chromatin accessibility than you do for gene expression.

Grant: That is weird. Why do you think that is? 

Jason: So, you don’t totally know. So these are just hypotheses. 

Grant: But speculation is good. That’s why you go on a podcast. You can speculate. 

Jason: You can say whatever you want and no one cares, right? 

Grant: No reviewers will reject this. 

Jason: So this is inspired a lot by the work of Daniel Gaffney. He had a paper in Nature, Genetics, and the basic hypothesis for this paper was–and I think was well demonstrated in this paper– that if you have genetic variation, it can impact chromatin accessibility cause it’ll impact like different transcription factors binding to a certain region. But only in the presence of other sort of helpful transcription factors are you actually getting an effect on transcription. 

Jason: So say in one cell type that that other transcription factor is not expressed, well then you can still have an effect on chromatin accessibility, but you wouldn’t have an effect on gene expression. So this stimulus dependence of eQTLs may not be there for caQTLs or maybe less so for caQTLs.

Jason: And that’s kind of a hypothesis that we’re going with. We haven’t really demonstrated it though. Cause you kind of have to do a lot of ChIPseq to demonstrate that, and that’s expensive and very hard as we’re trying to find out. Yeah. 

Grant: So what do you envision as the ultimate practical application of this broad line of work?

Jason: Yeah. Yeah. So I was on a paper with a colleague just down the hallway, Mark Zylka, and this paper was focusing on Angelman’s syndrome and Angelman’s syndrome is like one variant or a variant of large effect mutation, which creates a big change in development and behavioral changes.

Jason: And through Mark’s work for like 10 years, and other people’s work too, they found a molecular mechanism whereby you actually get decreased expression of UBE3A in the paternal chromosome. I’m not the best person to explain this, but I’m on a podcast, so I’m just going to go for it–the basis of Angelman’s syndrome is that usually it’s an imprinted locus in UBE3A in neurons. You usually get expression in just the maternal allele in neurons, but if you have a mutation in the maternal allele in neurons, then you have no expression of UBE3A in neurons.

Jason: Okay. So that’s bad. And that leads to Angelman syndrome. So why is the paternal allele not expressed? Well, his work over the last 10 years has found this molecular mechanism. So they found this long non-coding RNA that seems to silence the paternal allele. So his hypothesis: let’s turn on the paternal allele. So they did this CRISPR screen and found a region of the genome that you can target that decreases that lncRNA, that long non-coding RNA, and increases the expression of the paternal allele. So now you have some expression of UBE3A

Jason: Okay, cool. So understanding the molecular mechanism took 10 years, like a long time. So you went from mutation to understanding molecular mechanisms and now with this CRISPR design, they have an actual treatment. And it works in mice and human cells. It hasn’t worked in humans, right? So it’s not like ready to go, but you know, it’s getting there. 

Jason: And so my kind of feeling on this is the same way. If we understand how genetic variation creates risk for psychiatric diseases, then we can begin to say, okay, so we know the genetic variation–and there’s a lot of consortia that are doing this, like the Psychiatric Genomics Consortium–they’re creating risk for psychiatric diseases. Then, if we can understand what the mechanism is–that’s where we see these QTL type of papers come in– then we can sort of start to develop treatments for the diseases. 

Jason: Now it’s different from Mark’s work to the work that we’re doing, because that’s one variation of a very large effect. And the stuff that we’re working on is polygenic effects. Each of which are very small. But still, I have hope that if we can target some of these pathways, maybe multiple of these pathways, that it can lead to some alleviation of symptoms. So that’s kind of like what I envision obviously hasn’t been done yet.

Jason: So just because I envisioned it doesn’t mean that it’s going to happen, but that sort of pathway from finding a genetic variation, understanding the mechanism, developing a treatment is like something I’m hopeful for. 

Grant: Nice. What do you think is the most exciting area of work in biomedical research today? What do you think’s the most promising? 

Jason: Oh that’s a good question. I think this tech development stuff in the biomedical world is really exciting and tech development, not in a computer way, but in a biological way, like creating biological systems to solve scientific problems.

Jason: One of them being gene therapy approaches. If you can actually make a virus that contains gene editing proteins that target your gene of interest and can have some functional effects. That’s awesome. That’s really amazing. I think some other work too, like Jay Shendure. It doesn’t have an immediate practical outcome, but work that they’re doing is trying to make mutations or make recordings of cells as they perform some biological process.

Jason: So for example, they’re taking a cell as an embryo and then making a mutation sort of every time it divides. And then every time that divides, then you can create a linear trajectory of how one cell forms many other progenitor cells, which make many other progenitor cells, which then lead to the formation of an entire organism.

Jason: If you can take that same sort of idea and then move it to measuring each time a cell does something. So for example, fires an action potential, like George Church proposed. He calls it a ticker tape recording of action potentials, or you can record gene expression through development.

Jason: You’re developing technology to perform longitudinal recordings of biological processes. I think this is going to be amazing at the single cell resolution. That’ll be really cool because once you have a ticker tape, you can sort of fast forward that ticker tape and move cells quicker through a biological process or develop cells quicker, which I think will be really important. 

Grant: Cool. So Grace here is a UNC senior, just getting kind of started with her career if you were in her position, deciding what area of work and laboratory and so on to start in 2021 or 2022. What would you do? 

Jason: Yeah, well, I guess can I ask Grace first what are you interested in? What do you like doing? Because that’s kind of the most important thing. 

Grace: Yeah. I work in the lab of Dr. Ian Carroll and I work with the microbiome, which I’ve been obsessed with since probably junior year of high school. Yeah. I definitely do that in the future.

Jason: Okay. We, I mean, that’s the most important thing. Do the work that you’re passionate about because if you’re going to go into graduate school or you’re going to start being maybe a technician after undergrad–that’s what I did–then go to graduate school and then go to postdoc and walk your way along the academic path. It gets super frustrating at certain moments because science is difficult and the experiments don’t necessarily turn out as you expect them to. And so what gets you through that is like actually caring about what you’re doing.

Jason: The most important thing is that you really care and that in those sort of low lows that you’re going to have, no matter what field you go into, that you’re going to be like, “you know, I’m doing this for a reason. This sucks, but like, I’m just going to keep working at it.”

Jason: I think that’s kind of  the most important thing. Obviously, I think towards Grant’s question, he wants like, what do I think are important skills and things like that. I think having bioinformatics skills, especially for microbiome work is going to like make your life so much better and easier because instead of just doing an experiment and handing it off to somebody else, which I think is what Grant’s organization allows people to do, it allows you to do both of those things.

Jason: And having the ability to do both of those simultaneously really gives you a lot of skill sets. That will be super valuable because you’ll know because you did the experiment that like “I isolated this sample, and something was weird with this one. I don’t know if the concentration was low, but the quality control metrics didn’t look right.”

Jason: And then you see it in the data and you’re like, “okay this isn’t right. This is an outlier. I know why this is an outlier.” So you can throw that out. But if you’re only doing one of those things–like you’re only doing experiments or the bioinformatics–it becomes more difficult because then you’ve got to go back to the guy who did the experiment and go be like, “do you remember anything weird about the sample?” And they may or may not remember.

Grant: That’s a good segue to our next topic. Can you maybe tell us a bit about your path? Add some color. You know, start in Dayton, Ohio. What motivated you? What surprises did you find at different stages of your career? What do you maybe wish you had done differently? 

Jason: So, yeah, I was born and raised in Dayton, Ohio, the birthplace of aviation. Where the Grant Belgard–if you didn’t know for all those podcast listeners the T stands for The Grant Belgard–was also stationed for a little while. I went to high school at a public school. There were some pretty good science teachers that I had when I was in high school. Mr. Protrusio and Mr. Martin. If they’re listening, shout out. 

Grant: You could send them the transcript after.

Jason: If I can even remember how to spell Mr. Protrusio’s name, which I a hundred percent do not remember. They were good. They were inspirational and helped guide me along the path. 

Jason: When I went into college, I went to Northwestern. I studied at this program called the Integrated Science Program. And this was kind of an amazing place. Like we were somewhat segregated from the rest of the Northwestern population, which was kind of weird, but actually kind of good because we had our own little community. So we had the integrated science program, the ISP, house which was this little, somewhat crappy house.

Grant: Sounds like a real party house.

Jason: There were parties there. Yeah. But you know, people would study there, they would hang out there and we’d have parties there. We would have our classes there. So it was like your little community. It was only about 20 people or something like that. Coming from Dayton, we had very smart people that were at the high school, but like, there were some, really brilliant people in this ISP program.

Jason: And it was cool to just be around these people, interact with these people and have the attention of the teachers too, who were teaching these very small classes to us. So I liked it a lot and enjoyed the classes. 

Jason: One of the most useful things was they had this–I forget the name of the class–but they taught us basic computer programming skills like Unix, some Pearl. I don’t think R was even a big thing back then. So we didn’t learn R, but like a little bit of Python and things. And that was very useful because that has helped me in the future so much. I had a little bit of computational skills. 

Jason: So when I was there, I did research. But I did research in physics. So I worked at the Fermilab, which my friends called Fermi camp, which was a very weird, but kind of amazing place. So if you ever been, it’s outside of Chicago in Batavia, Illinois, and they have these roaming Buffalo that are just around on this large cut area and underneath there’s a particle accelerator, which was then the largest particle accelerator in the world before the large hadron collider. And they shot particles at each other and then they got a whole bunch of data and they needed some way to visualize that data. 

Jason: And to be honest, I had no idea what I was doing, but they were like, “can you program a website to make all these graphs?” And I was like, “cool, sure.” So I worked on that and I didn’t probably do a great job, but they seemed to want to keep me around. So that was good. That was really good. 

Jason: So then after that, I didn’t know what I wanted to do. I did all kinds of stuff. I took the LSAT, the GRE, the MCAT, because I didn’t know.

Grant: You were really undecided.

Jason: I was very undecided. And then, I ended up applying to a position at NIH and working in the intramural program in Bethesda for two years under Andreas Meyer-Lindenberg. And we would scan people with schizophrenia, like do MRI scans of people with schizophrenia and their siblings, and then analyze the data as well.

Grant: Was it on the main campus?

Jason: Yeah. It was on the main campus, building 10. Yeah and it was a great experience. There was again, a really good environment there. Like there were a whole bunch of people, right out of college that were interested in science, good people, friends and stuff. They were all working there at the same time. We were called IRTAs, which is intramural research training awards. Yeah. Weren’t you in IRTA, Grant? 

Grant: I was in the GPP, so in grad school I was flying back and forth between Oxford and NIH, but I was at an offsite location around Twin Brook, where the intramural sequencing facility was.

Jason: Oh, cool. 

Grant: So it was kind of a cutting edge of the genome technology branch. 

Jason: Oh, nice. Very cool. Twin Brooks, so that’s not too far, but it’s like just not on the main campus. 

Grant: Yeah, it’s on the red line. So it was close enough. 

Jason: Nice. 

Grant: You didn’t have to fight as bad traffic. 

Jason: What year did we overlap? What years were you there? 

Grant: 2008 through 2012, but not really full time, except 2010 through 2012, but I would pop back and forth for like a week at a time. 

Jason: Okay, cool. We probably did overlap just like a tiny bit then. Okay. Yeah. So I scanned people with psychiatric disorders. That was really interesting. My computational skills were super valuable to those people. They found them valuable. 

Jason: You know, one thing I really hated was calling subjects. Like a big part of our job was recruitment, which means that you get on the phone and you say, “Hi, my name’s Jason. I’m calling from the NIH.”

Grant: Did you start robocalls spamming them? 

Jason: I didn’t, I didn’t make that. I should have made that. It would have made everyone’s life easier. So we had those assignments, recruitment assignments, scanning assignments, and then we would also do analysis, and I wrote scripts to make everyone else’s analysis easier. And then I was like, “if I do this, will you call my subjects?” And they’re like, “sure.” So that was great because I really hated doing that.

Grant: Motivation.

Jason: Yeah. So I worked for Andreas Meyer-Lindenberg, who’s now in Germany, but then was at the NIMH and he told me that I should work with Paul Thompson at UCLA for graduate school. And so basically, I applied to several places for graduate school, but I emailed Paul beforehand and I was like, “Hey, Andreas told me I should work with you. Can I work with you?” And then he called me and basically said, “sure, you can work with me.”

Grant: So, weather it had nothing to do with it. 

Jason: No, actually I was pretty anti-LA the beginning. You know, LA has a bad rap. 

Grant: You’re like the anti Neil.

Jason: Neil is totally the opposite. I think growing up in West Virginia, Neil must have really hated it.

Jason: So yeah, I was not into LA. And I was like, “Oh, this place is lame, but you know, whatever. The neuroscience is supposed to be good.” But I eventually grew to really appreciate it. There’s a lot of good things there, especially hiking. Hiking is pretty amazing there. And so close to the city.

Grant: And did the weather grow on you? I mean, would you have considered taking a position in Chicago afterwards? 

Jason: Oh, a hundred percent. Yeah. I like Chicago, actually. I don’t mind the Chicago weather and I very much appreciate changes in seasons. Like here in North Carolina, it’s beautiful. Like I love the springtime, which you don’t get. Grace is agreeing with me. Springtime here is amazing. Like you just get blooming of everything after the winter. It’s just such a contrast. So beautiful. So nice. 

Grant: Yeah. Florida is just one big, hot, hurricane season. 

Jason: It’s very muggy down there. Yeah. So I worked with Paul Thompson. 

Grant: Tell us a little bit about Paul Thompson. 

Jason: Paul Thomas is an interesting human. He is a very brilliant man, very, very smart in mainly math and figuring out topologies of brain structures. He really led. He did really an amazing job at that and he is highly motivated to publish papers and you can see from his publication record. I think he’s in the thousands of papers (1250 Publications). So that was interesting. 

Jason: His lab environment was also kind of weird in the sense that we didn’t have lab meetings. There was no room. He was getting grants like crazy and recruiting many students and post-docs, and we were all shoved into his office.

Jason: There were like eight people maybe in his office. And I remember I was sitting on one side of a desk. And then on the other side of a desk, there was somebody else, like just facing you. Now that you think with COVID protocols, you’re just like breathing into the face of someone else. It was just crazy.

Jason: It was a good experience because Paul had access to so much data, and he really needed people that were willing to analyze the data. So he was really looking for people to analyze that data. And this was also at the time that GWAS was starting. I started grad school, I think in 2007, and 2007 was one of the first welcomes to GWAS.

Jason: There were a lot of candidate gene studies, which are, for those who don’t know, this sort of old school thing you don’t do now, versions of association studies. 

Grant: All BS. 

Jason: All BS. None of it has ever replicated. I would say that. The need for doing GWAS and large consortia was clearly there, but those didn’t really exist yet for brain structure traits like for things you can measure with MRI. That’s basically what I got involved in. So, Paul met with this guy, Nick Martin from Australia, who was one of our collaborators, over dinner. They basically said like, “Hey, we should form a consortium.” And then I was basically the one to lead that consortium, which eventually we called the Enigma consortium: Enhancing neuroimaging genetics through meta analysis. 

Grant: Who came up with the acronym? 

Jason: Paul came up with the acronym, which is a great acronym, but also the wrong side. You know, like if you think about it, like he keeps saying, it’s like the code breaking for the brain, which is great. I kind of like that, but it’s the wrong site. It’s the Nazi side that came up with the name. Like we should call it like Bletchley or something, something more positive, but unfortunately it’s Enigma. I mean, nobody remembers that. So I think it’s kind of great. 

Grant: Nobody knows history. 

Jason: Nobody knows history. It’s a great name. So yeah, I ended up leading this consortium and along with people from Australia, Sarah Medland, people from Holland, and they would all fly to LA and we would do all of this stuff together. It was a good experience because we were one of two consortia that were doing this at the time. We found a bunch of genetic associations to bring structure.

Grant: And then?

Jason: And then, I finished with Paul, although I didn’t really finish. I was still working with Paul on all these Enigma projects, but I was looking for a postdoc. I was trying to find a postdoc that I could not just find genetic variants associated with different traits, but what to do next.

Jason: And so I read some papers online about what to do next. And it seemed like things were converging towards using STEM cells to model variance. And I was like, “okay, cool. I want to use STEM cells to model variance. I have zero experience in wet lab biology. I don’t know how to hold a pipette. I don’t know how to run a Western blot. How can I do this? I need somebody who values computational experience and will allow me in a postdoc to like transition a little bit and learn some new things.” And so I emailed Dr. Daniel Geshwind.

Grant: I’m trying to  get him on. He said he had to listen to a few first

Jason: Did he? That’s funny. So yeah, maybe he’ll listen to this. So he wrote a Nature paper with Jenna Konopka, basically about hypothesis discovery research. Instead of all the classic wet lab scientists who were poo-pooing like, “Oh, you’re just on a fishing expedition. All bioinformatics work is a fishing expedition,” which was pretty prominent back in 2011. That’s what they would say. 

Jason: He was like, “Okay, there is hypothesis-generating research and that’s what we do. And we generate new hypotheses. And then we can validate those hypotheses, test them with model systems.” And I was like, “Cool. That makes sense. You’re not, poo-pooing all of the giant amount of work that all of this discovery science is doing.”

Jason: So then I tried to apply to his lab and I emailed him once. No response. I emailed him a second time. Maybe I got a response. I don’t really remember.

Grant: Three letters

Jason: Yeah. It never worked. Then a third time I was like, “Dan do you want to meet me or not” And then he’s like, “Oh yeah that’s fine.” And then we talked and I think this was when he was in London, maybe at the Institute of psychiatry. And so it was very difficult to get an appointment with him. But eventually I got an appointment with him. He allowed me to be a postdoc and yeah. That is where I met the Grant Belgard. 

Grant: So tell us about Dan.

Jason: I don’t know. What do you want to know about Dan? He’s a very brilliant man. He has a million projects running simultaneously. Somehow he knows and can provide useful insight to each of those different projects. He also promised me that I could meet Bob Dylan if I got a paper in a fancy journal and that has not happened. His neighbor is Bob Dylan. So I’m still waiting for that. And I hope that happens soon. 

Grant: You’re on the spot, Dan.

Jason: Yeah, I would really like to meet Bob Dylan. I think that that would be–other than meeting Grant–really a defining feature of my life.

Grant: So, what did you do in Dan’s lab? 

Jason: So in Dan’s lab, I worked with this other postdoc named Luis. Who’s now an assistant professor at UCLA. Luis and I formed a team, which we call team middle earth because we had the middle bay and we’re both nerds. And we basically did everything together. So Luis is a very brilliant molecular and cell biologist. He was trained at Harvard. He’s the most careful scientist you will ever meet. And he knew nothing about bioinformatics and was very curious about bioinformatics.  And I knew nothing about wet lab biology and he knew everything. So he taught me everything I know about wet lab biology. And then I taught him a little bit about bioinformatics and how to code. And I think mainly like how to interpret what the possible confounds are for bioinformatics experiments and stuff. 

Jason: That combination was amazing. I can’t speak for him, but it really helped me out. Like really helped me develop into a much, much, much better scientist because now I have more skillsets. I’m not just analyzing other people’s data. We can generate our own data in the lab. That was really great. 

Jason: So Luis and I worked on developing human brain tissue. We acquired that. And then we studied multiple aspects of it: how well STEM cells model the actual development of the in vivo brain. And then we also studied how chromatin accessibility changes during neural development and the developing human brain.

Grant: We use those data sets. I feel like everyone does.

Jason: You do use those data sets? Oh, nice. I’m glad. I’m glad to hear that. That’s cool. 

Jason: Luis is great. You should have Luis on. I like Luis’s insights into anything. Anytime I try to do something new, I always ask Luis. I’m like, do you think this is a good idea? If he thinks it’s a good idea, then I do it. If he thinks it’s a bad idea. Then it’s usually a bad idea.

Grant: Cool. So, what’s the wet versus dry lab balance in your lab now? 

Jason: So I’d say it’s pretty 50:50, and leading a little more wet now. So it was leaning a little more dry before. The initial experiments in our lab were growing these hundred different stem cell lines that Luis and I generated in Dan’s lab. And then, I shipped here to UNC and then we ran these QTL studies here and now we have a lot of data.

Jason: So we have a lot of hypotheses because you can get co-localizations between your eQTL and caQTL with GWAS data. Okay. So now we have both the system for discovery and an experimentally modifiable system to see what the effects are and why those effects exist. So now we’re in that stage where we analyzed a whole lot of data, and then we have all these different experimental hypotheses. So now we need to do all the validation for those experimental hypotheses. 

Jason: Yeah. So I’ve been really fortunate to get students who are interested in both sides that were willing to come with me, even though I’m not the best wet lab biologist in the world, but I still have decent resources.

Grant: They don’t know any better. 

Jason: They don’t know any better. That is the definite truth. 

Grant: Yeah. I think back to when I was a student, I mean, I had no clue what I was doing. It was just pure luck. 

Jason: So yeah, I’m definitely taking advantage of that, you know? The main thing is being nice to people. I think if you’re nice to people and you try to be a good mentor, then word gets around that like, “Hey, this guy’s not a jerk. He cares about science.” And so other people hear that from the other grad students and they were like, “Oh, maybe I want to work with this guy who is not a jerk.”

Jason: I think we’re like 60, 40 now. I mean, it’s still pretty heavy for dry lab stuff, but. A lot of, even the bioinformatics students are doing wet lab experiments now to try to validate their hypotheses. 

Grant: Nice. So tell us about getting started. What were your biggest surprises? Obviously you would have been as well prepared as anyone going into it, but what weren’t you expecting?

Jason: Yeah. I mean, I think how long it takes to do anything is like a big surprise and kind of a disappointment. Also how lonely it is at the beginning. First of all, imposter syndrome is overwhelming. When you come in and you have an empty lab that’s a little bit dirty and you have your office space and you have nothing. No people, no experiments going, no data. It’s just you. And it’s like, awful. I think when you just start out that first week.  The process of building the lab, getting equipment, getting people takes a very, very long time, especially because you want to hire the right people. You want to make that lab environment good, so people actually enjoy working there.

Jason: You want to have very competent people who have skill sets that are complementary and not identical to your skill sets. And the major recruitment that you get is graduate students who have a defined schedule of being able to join your lab. So you can only get graduate students on the rotation schedule and then they join your lab.

Jason: So all of that leads to huge delays in the ability to make a functional lab with enough people and enough equipment. And enough, whatever the experiments are to do anything. So you can have all these ideas, but you can’t do anything at the beginning. So that was like a six month process.

Jason: And, you know, the people here were really nice and they also explained this to me. They’re like, “Oh, it took me six months to run my first gel” or something like that. And I was like, “Oh, thank goodness.” That makes you feel much better when you hear that. 

Jason: I mean, that took a while, especially the first project. We had this QTL project, which was my R00 project. It took a long time to get running, but it finished and was running and I had a great technician to help me out with that. Now we have all this data that allowed me to get more grants.

Jason: And now with the students and stuff, I feel like I don’t have to be here. I mean, I still have to be here, but they’re rolling. And they’re smarter than me and they can just do it. You know what I mean? I’m just providing advice. It’s not quite at the point where Dan’s lab is: like a super mature lab where he has like many postdocs who have really, really strong experience. Like I have a very grad-student-heavy lab. People still need to be trained and stuff like that, but it is much more to that point than it was five years ago, which feels good. That feels good. 

Grant: So going back to that, that startup phase, would you ever consider starting a company? 

Jason: You know, I’d consider it, but I don’t know what I have to offer yet, The Grant Belgard. I feel like my end goal would be wanting to make some sort of therapeutic. That would be an ideal for me. And I don’t have that yet. Like my research hasn’t led to that yet. So if I ever do feel like I have something to offer that I can sell that other people would want to buy that I think can help the world. Then yes, I want to do that. But right now I don’t have that. I don’t have that, that thing. 

Grant: Yeah. It’s interesting. These days the virtual biotech model is in Vogue. So. It’s quite common for a very small company. One, two, three, four people to develop an asset and essentially get to the stage where it’s ready for later stage clinical trials and have pretty much all the work for it outsourced. And so really the core team is finding organizations for that, interpreting the data, raising money and so on, as the asset progresses. 

Jason: That’s interesting. 

Grant: And there even organizations today that do that with pretty complex biologics. So, you know, gene therapies and things like this. So it could happen one day, maybe Jason Stein. 

Jason: Yeah. I mean, yeah maybe, I don’t know. That sort of idea is quite different from the way academia works, where you farm out the experiments to other people. So in that case, you’re mainly doing either bioinformatics or just even interpretation of the experimental outcomes? Like how does that work?

Grant: Interpretation, deciding what to do next, there’s a lot of coordination that has to happen and quickly and it’s very interdisciplinary, right? So you’re working, not even primarily with bioinformaticians. You’re working with chemists with biologists, with biostatisticians, with clinicians. You have to draw on a lot of different skill sets. 

Jason: Yeah. That’s cool. For me, first I don’t know anything about business. Like you know a lot about business. I don’t really. I don’t know how to do that, but I feel like the essential thing of a business is that you need to have something that you’re going to sell to other people that they want to buy.

Jason: And so like right now, I feel like I have research. I have research ideas. I have the ability to do research. I have people and the resources to do right now. I hope that that research leads me to something that someone else wants to buy and that would be helpful to the world. But immediately, I don’t see it. I don’t have that right now. 

Grant: You could always spin something out. 

Jason: Yeah, maybe. For example, I talked about the Angelman’s syndrome gene therapy treatment. That’s a thing where it took 10 years. He has something that’s a gene therapy in mouse and human cell lines. I can definitely see that moving towards a company or even farming it out to other people to do experiments because there’s a very clear path. I participated in that, but I’m not like leading. So, for my own research, I don’t really have that yet.  I hope one day to get it. And if I do, it’d be great to either form a company or work with somebody who does. 

Grant: Sweet. So 30 or 40 years from now, what would you like to have done? 

Jason: Like in my career? 

Grant: Yeah or actually more broadly.

Jason: I think about this a decent amount. So I think first it just to be remembered as a decent human to other humans. I feel like, especially now with political situations, that simple kindergarten thing is totally forgotten and is totally the most critical thing for a functioning society. And just the most basic thing is to treat other people with respect. 

Jason: I think in terms of career aspects, if I can, I would like to be a part of developing treatments for psychiatric disorders, which right now don’t have treatments like schizophrenia. I mean, they have treatments, but they’re not good. And a lot of people don’t do well. And there’s nothing really for these people. Like they’re homeless. They’re in state hospitals. It’s a huge burden on society and people are just suffering. But there’s so much good neuroscience that’s happening right now. So much good genetics that I feel optimistic about what could happen for these people. And so if I can help contribute to that, I feel like that would, that would be amazing, like an amazing cherry on top of being a nice person and my career, 

Grant: Very nice. How do you like UNC?

Jason: UNC is a good place. A lot of, a lot of nice people, not a lot of like ego. I mean, there’s still some ego. Science has that for sure. But like people work together really well. Everybody’s been really supportive from a young assistant professor kind of thing, so that’s been great. There’s some administrative things and things that definitely could be corrected or made better, but I don’t really want to be the administrator to do that. And usually the way they have it here and I’m sure in many places is the squeaky wheel gets voluntold to fix the problem. So you’re limited in your squeaks based on how much time you want to spend fixing the problem, which kind of makes sense. 

Grant: Well, you know you’re getting someone who’s passionate about it. 

Jason: Right. Yeah, exactly. Exactly. We only have time to do so much. And if you want to spend your time doing research, then you spend your time during that research and find alternative solutions to problems.

Grant: The ego thing in science is pretty interesting. It’s been pervasive, from even quite early days, back to Newton and Hooke. Ego has always been a bit of a problem. For a lot of people they are quite ego motivated more than anything else, but not everyone. I mean, some people are just nerds and like doing it right. I don’t know. What was your sense of that? I would say probably more people are just nerds in like doing it, but ego thing is pretty common. I don’t know. 

Jason: Yeah. Yeah. It’s hard. I can’t say I’m immune to it. 

Grant: I feel like it’s enriched in academia. No offense. 

Jason: I think you’re absolutely right. There was this paper written–it wasn’t a paper more of a website–where somebody proposed a new model for academia. Basically how it is now, I’m supposed to form my own very small business where I get people to work in my lab. I get grants from the federal government or foundations to support my work. And like I had my own business and Hyejung or whoever’s next door has her own business. Mark Zilkha has his own business. 

Jason: There is not this overarching effort, as is seen in physics, for example, where we all work on the big problem and we all do our individual small part for that. And some organizations, like the Allen Institute, I think have done pretty well. They work on giant problems that cost crazy amounts of money and they have each little person contributing to that.

Grant: And then on the other hand, you have the human brain project. Right? 

Jason: Right. There’s definitely examples where it didn’t work, but the ideal situation for me would be like, I have Luis and we work really well together. If Luis and I could form our own lab where we’re just two people running a lab, that’d be cool. But universities don’t often do that. They don’t recruit two people together. It’s like, why? Why not? We worked so well together.

Grant: Bring middle earth to UNC.

Jason: Yeah. We have to get Selene to want to move to North Carolina. Yeah. I think those things would be really cool, like to try to make something like that or to have very large projects. I know the human brain project didn’t work, but if you have very large projects where you actually have a very clear definable goal and steps that you want to get there. Where everybody says, “I’m not going to try to be the one who discovered it. I’m just going to do my part of the bigger entity.”

Grant: That’s basically, what academics refer to as “industry.”

Jason: Is it? I’m not sure I believe that.

Grant: Yeah, you know, we are in the same boat rowing towards the same goal. At its best. 

Jason: Yeah at its best okay. Because I feel like industry is dominated by the pursuit to make money and increase stockholder wealth right?

Grant: If you don’t make anything that’s useful, then you’re not going to make any money. 

Jason: Right. But that’s the essential problem. With research we don’t necessarily know if we’re going to make anything. You have to figure out what’s wrong first. And then you can make something. With psychiatric illnesses you have to still figure out what’s wrong first. And then you make something. There’s been a lot of drug development where you don’t know what’s wrong. Just throw a lot of stuff at it. And then you, you see minor therapeutic advantages.

Grant: Well, a lot of big drugs have just been discovered through pure serendipity with no known mechanism of action. Right? I mean, a lot of the big discoveries of the fifties and sixties, that in many cases took a very long time to improve on

Jason: Yeah. But clearly improvements are needed and there hasn’t been much in a long, long time. Especially in psychiatry. Yeah. 

Grant: Yeah. A hundred percent. Well, we are at about time and we just need to upload. 

Jason: Okay, cool. 

Grant: Thank you so much for joining us today, Jason. That was very enjoyable. 

Jason: Absolutely. Thanks for having me on the second edition? Is that right?  

Grant: I think this is episode four episode four.

Jason: Well anyways, thanks for having me. I really appreciate it, Grant. Hopefully I didn’t talk your ear off. 

Grant: No, it was great. Thanks, Jason.

 The Bioinformatics CRO Podcast

Episode 3 with Ben Logsdon

In this episode, Grant sits down with Ben Logsdon, director of computational biology at Cajal Neuroscience, to discuss new perspectives in Alzheimer’s Disease research, incentives in academia, teamwork, and societal resiliency.

(Recorded on Oct 1, 2020)

On The Bioinformatics CRO Podcast, we sit down with scientists to discuss interesting topics across biomedical research and to explore what made them who they are today.

You can listen on Spotify, Apple Podcasts, Google Podcasts, and Pandora.

Transcript of Episode 3: Ben Logsdon

Grant: Welcome to The Bioinformatics CRO Podcast. I’m Grant Belgard, and I’m here with Ben Logsdon. Ben, would you like to introduce yourself?

Ben: Hi Grant. Thanks for having me on the show today. I’m a computational biologist. I’ve been in the field of computational biology, professionally, I guess, for about six plus years now.  And before that did the whole, you know, postdoc, couple of postdocs and graduate school in upstate New York.

Grant: Great. Thanks.  So tell us more about your path. What made Ben Ben? Start from the beginning.

Ben: Yeah, definitely. Absolutely. So I was in college in undergrad and I was really into genetics and biochemistry and I ended up getting an undergrad BS in biochemistry, but also minored in mathematics.

Ben: So I’ve always kind of had multiple multidisciplinary interests. I’ve definitely pursued both of those going, throughout my sort of trajectory, both professionally and personally. I then went on to Cornell and got a PhD in computational biology, really focused on building new machine learning and high dimensional statistical methodologies to analyze genome wide association studies and high dimensional gene expression data sets. And really the driving purpose behind all of it was just wanting to understand these complicated systems, you know that in physics, there’s these simple rules. And, you know, humans have spent hundreds of years building better instruments to figure out what those rules are to try to understand them.

Ben: But biology is just this, like it’s the frontier man. Like we still don’t know the rules. I mean, we have ideas about pieces and parts of it, but I’ve always been fascinated by that. And it’s like one of those places where a lot of biology that’s being done right now, or has been done has not really focused on this sort of more quantitative side of things up until I would say relatively recently. You know, and there’s a lot of really good work you can do just at the bench doing Westerns and gels and all that good stuff. Like that’s been really powerful to help us understand and disentangle some of these systems, but I’ve always sort of been of the opinion that to understand these things you need a bigger tool set. 

Ben: So that was kind of the motivation to do more quantitative stuff at Cornell and get better chops on the stats and machine learning side. And then after that, you know, I went to the Fred Hutchinson Cancer Research Center, did a postdoc there with Charles Cooperberg looking more at genetic epidemiology, sort of like a method development for analysis of a whole exome sequencing and rare variant analysis type work. And then decided I wanted to do something with potentially more translational impact and did a second postdoc at University of Washington, focused on applying these sparse model building methods to gene expression, data sets in cancer to try to come up with alternative ways of identifying driver genes that, you know, wasn’t just based on mutations, but trying to use expression signatures or detecting within expression data, signatures of drivers.

Ben: But then I guess the real thing that I’m passionate about now, and I’m really grateful for. You know, I just left this job at Sage Bionetworks and I spent six and a half years there working in the neurodegenerative research space. And that’s just been an amazing experience. And, you know, as a computational biologist, oftentimes you kind of are like a hired gun, right? Like some principal investigator or in CRO-land, especially, some client brings you in and is like, “Hey, I’ve got some data to help me make sense of it.”

Ben: But I do think I’m not just interested in doing data analysis. Like I think in the context of Alzheimer’s disease in particular, like, I really want to understand the biology as well. And really want to help sort of marry all of these different quantitative techniques with the right data sets to inspire the right question that then the folks doing the bench work can go track down, develop new assays, do the right experiments so we can actually like start figuring out these diseases.

Ben: It’s also been fascinating in the Alzheimer’s disease space, how the field has been very married to a very small set of hypotheses about like, what is driving this disease. And, you know, just looking at some of the data analysis of the new, the omic data coming out of Alzheimer’s, it’s not as simple. Like amyloid and Tau, you know, the signatures are there and there’s really interesting results or insights to be gleaned from that, but there’s so much other biology that’s going on and it’s very complicated.

Grant: You’re looking under the streetlights, right?

Ben: Yeah. I mean, the streetlamp effect is real. And, you know, you can talk a lot about misalignment of incentives in academia and industry, and why that leads to lack of diverse portfolios in terms of risk as well as the technology needed to generate data, to be able to even articulate some of the new hypotheses. Right? Like you think about for a long period of time, it’s just people looking at tissue slides under a microscope and saying “okay, well, we see these amyloid plaques and these neurofibrillary tangles, what’s going on there?” And then omics just opens up a whole new frontier of possibilities in terms of the biology and the molecular causes of the disease. And you can’t see it right under a microscope necessarily, unless you know what gene you want to look at.

Ben:  And really, I think a lot of it is like knowing what the players on the chess board really are and what the rules of engagement for those players are and how it relates to what we already know. 

Ben: The thing with Alzheimer’s disease that makes it very different from cancer, for example, is that Alzheimer’s, you can’t profile the tissue during the course of the disease, right? Like you can’t get antemortem tissue samples. And so all you see is what’s happened at the post-mortem. And so it really is like a Sherlock Holmes mystery, in some sense: you know what happened after the fact, but then you’re trying to like put the pieces together as to what the sequence of events that led to that is?

Ben: I think that makes it a very different type of problem than in cancer. And some sense it’s a lot harder because you’re having to do a lot more inference and we don’t have good model systems. There’s plenty of mouse models where you can just crank the amyloid to 11 and yeah, like things change, but that doesn’t mean if you cure Alzheimer’s in a 5XFAD mouse, that whatever that drug is, is going to work in phase three human trials. 

Ben: So, yeah. So I think, I guess to wrap up the answer to your question about my arc, I think it’s really been one of been really sort of generally curious and expansive in my interests, like wanting to understand biology and the quantitative mathematics/statistical side, but really sort of gaining a passion for their application to neurodegenerative disease in the last six years. 

Ben: And at Sage I’ve been working in these amazing National-Institute-of-Aging-funded consortia: the Accelerating Medicines Partnership in Alzheimer’s Disease (AMP-AD), the Model AD consortium, and most recently I was in the TREAT-AD consortium. And these are like multimillion dollar, multi-institutional, open-science consortia that are trying to pull back the curtain on other causes of the disease through new data generation and analysis of that data. So like AMP-AD was focused on generating data to do systems biology analysis like: WGCNA, or causal network analysis, those sort of things on gene expression from post-mortem brain to prioritize new targets and disease; model AD, building 50 new mouse models of late onset Alzheimer’s disease; and treat AD sort of like the open drug discoveries idea, where we actually would have medicinal chemist, structural biologists, people who had experience in developing high throughput, screens, and assays, and then marry that to everything upstream. 

Ben: Right. So it’s just been an amazing experience working with so many different types of people. I think that’s not something you would generally get to experience as much in academia, Like as a bioinformatics expert, you generally have the PI who has some biological question, and you’re asked to analyze some data. And in this case, there were a lot of different perspectives and language, how people talk about things.

Ben: And so it’s been great, it was a really amazing experience and definitely opened my eyes to like, you know, how complicated all these processes are. Like from a philosophy of science side of things, like all of this is open science. So like everything was being put out in the open through the AD knowledge portal that’s hosted at Sage. And I think that’s also something that the young guard is recognizing: how important it is as we go forward. That the actual value of any individual data set is usually–unless you’re talking like clinical trial data, obviously, but like preclinical/basic research– like the value of any of those datasets is actually pretty minimal on their own. And it’s only when you can start combining them and layering things up that you can really realize their potential. 

Ben: But a lot of people, in terms of incentives, are like “I’m going to like generate this data and then, you know, sit in my lab and have some postdoc crank on it for two years until they can hopefully find some gold and get a Nature, Science, or Cell paper right.

Grant: So following on the misalignments of incentives, what do you think are the strongest misalignments and what do you think might be some reasonable reforms that should be considered to mitigate them? 

Ben: I mean, I think a lot of it has to do with academic promotion, right. That basically people who are looking to get tenure, they’re being judged on two highly-related criteria. Actually really one criteria, which is how much indirect they bring into their institution, which is a function of how many successful R-level grants they are applying for and getting. And that’s all predicated then on how many publications they’re putting out because publications are kind of the raw material to demonstrate leadership in a particular field or domain.

Ben: I do think that, you know, in terms of the misalignment of incentives, I mean, the problem with that is that it sort of leads to a model where people are all trying to be an expert in one narrow thing and some of these problems, the scale of the problem, it’s not something that you can do if you just have one hat.

Ben: And so then it makes it much more difficult for the traditional R kind of awards, where you have the academic who has a lab that’s like cranking away, cranking out postdocs and graduate students who are all working on that one tiny little bubble on the edge of human knowledge that they’re trying to expand.  I’m less familiar with physics, like in actual experience with how it works in the world of particle physics. But in that case, there are papers with 10,000 authors on them and the instruments are just so big and expensive that in some sense, they have to work together with lots of people with different expertise in a lot more coordinated fashion, just because the scale of the problem is so big and complicated. 

Ben: But in biomedical research, it’s still a little bit of the wild West for academic research labs. It’s kind of like having your own little company, where you’re trying to put in competitive bids to the federal government on research proposals and you’re trying to demonstrate that you can be out in front and push the boundary of human knowledge in a very specific way. But I think those incentives lead more towards putting out lots of papers and being able to secure a lot of indirect dollars to your parent institution and that doesn’t necessarily mean you’re going to be taking risks, right. You’re going to want to continue to keep your lab funded. 

Ben: I think one of the challenges is for some of these areas of biology, where we don’t really understand what’s going on and we have a lot of the streetlamp effect, as a community, we need to take more risks and we need to spread that risk around to a much broader pool of people working on these problems. We need a leaderboard of hypotheses and have people work cranking away on all of them. And then as a society, we’re investing proportionally across them. 

Ben: You can’t ask an early stage academic investigator to be like, “Oh, you should go after this target that nobody knows anything about. There’s 10 papers in PubMed on it.” They’re going to be like, “no, I’m going to go after the one where we have a lot of prior evidence and we can write a sweet R01, right? Yeah. 

Ben: So I think that’s one big misalignment of incentives where for people who want to get tenure, both in terms of the review process for grants, but also in terms of how they’re being assessed. There’s a general sort of necessary conservatism. Maybe that’s fine in academia. It can just be how it works, but then there does need to be some other outfits that can contribute to our collective knowledge and take some of those risks and push the boundaries a little bit more.

Ben: And a lot of that has to do with how academic organizations organize themselves. They’ve decided that they have this concept of tenure and that’s the big carrot they have for all these early stage investigators. 

Ben: It’s interesting. Cause I think once you get to someone who’s a later stage investigator who has already made their name and they have less to lose. They’re actually more likely to take some of these risks and go after like projects and ideas that are a little bit more on the frontier, a little bit more on the boundary, but 

Grant: Well, they certainly afford to do so. They typically have larger labs. They may have HMI funding or something like this, and the failures don’t really count against you. And the productivity per dollar I don’t think counts against you that much if you’re still publishing high-profile interesting papers. What I’ve seen from a lot of labs  is they’ll put postdocs and graduate students on fairly risky high risk, high reward projects, which are great when they work out.  And that kind of stuff is pretty important to move science forward, but it doesn’t necessarily always serve the postdocs well, who may have been put on an unsuccessful project given the rest of, of the system that’s currently in place. 

Grant: So if Francis Collins is–who knows why– listening to this podcast, driving into Bethesda what would be your message for him?

Ben: Oh, Oh man. Put it on the hot seat. Yeah. I mean, I think the way in which the labor market works in academia should be completely rethought. I think that postdocs are incredibly, on average, under compensated given their level of training and that you look at fields where there are good industry opportunities–I’d say more in this sort of machine learning area or EE or CS–you see this just brain drain from academia. And I think that’s a problem. I think for me personally, it’s super frustrating that on the biggest problems of our time, like curing Alzheimer’s disease or cancer or all these huge biomedical research problems, you have a huge brain drain of folks with quantitative skills. They’re all going out to Amazon or Facebook or Google or whatever because the financial compensation is just, it’s just not comparable, right? Why would you do a postdoc when you could get a six figure salary?

Ben: I think that’s one thing I’d say. And then in general, like postdocs, you can end up having folks be taken advantage of, because the actual academic job market is so absurdly expensive or absurdly competitive, and people just get stuck in a permanent postdoc, where they’re just in a lab. It’s comfortable, but there aren’t a lot of good opportunities to progress professionally. And so people will stay in postdocs for seven to eight years. 

Ben: So I think, you know, if I was talking to Francis, I’d say like, “Hey, there needs to be a complete rethinking of the training model to address the problems that we have. The old model doesn’t work. Like you don’t have this model where you can just have people come in as grad students, get their PhD, go do a postdoc with the one expert in the field and then have their own ideas and get that first R01 or do a K award or whatever, and then go off and start their own lab.

Ben: I just don’t think it’s going to work like that going forward. If we’re actually going to make progress on some of these problems, you need to be able to assemble teams of people with complementary expertise who can work together well as a team. And that’s just not something you’re trained for in the academic model necessarily. Like you have to figure out where you’re going to have the insight. You know, the lone genius in the tower, who’s going to figure it all out.

Ben:  Really thinking how to restructure the training model comes, at the end of the day, it comes down to the funders. Because the PIs are the ones that are applying for grants and those grants are being used to pay the postdoc or grad students salary. Yeah. Maybe that’s a little too radical of a take, but I do think it’s true.

Grant: Yeah. There definitely are some bad habits. We sometimes have to train people out of, when they come from academia. When you’re going to assemble teams with complementary expertise because I think there’s a lot more general teamwork in biotech. The incentives are set up in a very different way. Charlie Munger said, “you show me the incentives and I’ll tell you the outcome.”

Grant: So channeling Peter Thiel here, what’s something you believe is true, but where most people would disagree with you? 

Ben: I think we don’t talk or think enough about the long view in biomedical research. I’m not sure people would disagree with me on this necessarily. I think that they just haven’t really thought about it. Have you ever read the foundation novels by Isaac Asimov? 

Grant: Yeah. 

Ben: So just for people listening, in those novels you have this galactic empire, that’s hitting the end of its tenure, basically, and about to descend into some like 10,000 year dark ages or something. And this guy, Harry Selden’s like, “well, that sounds terrible. Let’s do something about it.” He creates this organization called the foundation. The long and short of it is that the foundation’s purpose is to marry changes in policy and technology and like all of the things that make a society work and come up with probabilistic models associated with those and make subtle changes. Putting off, pushing on all the levers so that humanity doesn’t go through another 10,000 year dark age. 

Ben: Basically, from my perspective, we think a lot about the short game–like going back to incentives in the private corporation world or public corporations. But in the private sector there’s a lot of focus on shareholder value, maximizing profits and like, those are fine. I think that having good incentives, having people be productive and produce goods and services that are valuable to the community are great. For a lot of areas in human society there’s problems that are very amenable to that solution. In my mind, it’s like those market forces are really good at finding local Maxima. But I think for the longer view problems, you need a little bit more than that.

Ben: The only thing we have now–for biomedical research to be specific–is the academic model where you’re funding people to satisfy their academic curiosity about little pieces of this bigger puzzle of say neurodegeneration or evolution, or biology, development, whatever. And I don’t think it’s as intentional as it could be. I think that there could be grand projects or grand plans. Not so much like the war on cancer. That always kind of felt like it was more of a PR stunt to raise lots of money and awareness. These bigger projects where you’re saying here are the things we need to understand to be able to actually move the needle on this and here’s how we’re going to fund this in a very intentional way over, not three years, but like, 20-30 plus years. 

Ben: So you’re expecting failure and you’re building all of those things in and as a society, we just don’t talk and think like that. Half of society struggles to accept climate change is real. So it’s definitely an uphill battle, but like

Grant: Well, the NIH funding is a roller coaster.

Ben: Yeah

Grant: It’s hard to make a 20 year plan when you have no idea what will be happening with the overall budget. I do think that is a pretty controversial take, right? Certainly projects like ENCODE and the Human Brain Project and things like that have gotten a lot of criticism from scientists saying the money would be better spent on R01 or, internationally, R01-like grants. But it’s interesting, the kind of long view and squaring that with our system of funding is a challenge.

Ben: Yeah, definitely. I think the biggest challenge really is the human side of things and figuring out how to design these systems or articulate these plans in a way that works, given the sort of vagaries in personal human interest. I’ve worked in multiple consortia and with lots of different scientists in my time and it’s pretty amazing the variety of ways in which things can go wrong when you’re talking about collaborative exercises. I can’t remember who I was reading on Twitter or somewhere about, but there’s a scientist who was talking about how “I can’t trust anyone else’s data but my own. Cause at least with my own data I know exactly how it was collected. I know it was done right.” But I think at some point we have to, cause we just can’t get far enough having individual investigators.

Ben: The amount of people who are suffering so badly because of some of these diseases and the fact that we just work together. Like that just seems like it shouldn’t be the reason why we don’t move the needle. So I think that there’s some aspects here of the science of science that probably needs to be brought in. Like there was an interesting paper that came out–I think it was in nature last year–talking about how small teams could be more disruptive, that they can coalesce a new idea and move it forward very quickly. So they’re like the explorers who are going out and discovering some completely new, you know, asteroid or something.

Ben: But then it takes the whole community to vet that thing and move everyone forward. So in terms of how we work together as scientists, I think you need some hybrid model where you’ve got small teams that are taking big risks and then maybe finding some crazy new biology or whatever, but then you have to bring the whole community along.

Ben: The danger of some of the high profile publications is there’s such an incentive for people to be the one who discovers that asteroid. There was a paper that came out recently on somatic recombinants in APP, [Amyloid Precursor Protein] and they thought that some of them were more pathological and that they were getting reintroduced into the genome and all this crazy stuff. And that was a paper that came out of Nature a couple of years ago. And there was paper that came out recently basically saying how that was probably just an artifact. That’s like an example of where the community is doing its work, but it’s on such a slow, long timeframe. 

Ben: I don’t think it’s a problem that we make mistakes as a scientific community. Like that’s kind of the point, right? You’re on the boundary of human knowledge. It’s an inherently risky enterprise. Your ideas are probably going to be wrong more than they are right. But that doesn’t mean we shouldn’t have good mechanisms for vetting that. And, but also for encouraging that exploration in a productive way.

Grant: Absolutely. I mean, in my experience, it can be more difficult to get a rebuttal published. You can be in review for much longer and the standards in some cases can be even higher than for the original paper. And I think part of the reason for that is there’s not enough tolerance for people being wrong.

Grant: And I don’t mean things like fraud. I mean, that’s a totally different matter, but when people get a paper retracted or something, it can be seen as the kiss of death for the first author and a stain on the senior author and so on. And as long as it’s an honest mistake.

Grant: The consequences can be so severe that people will defend bad work that’s wrong long after they should, just engage their critics and recognize, “Oh yeah, this is, this is wrong.” And retract the paper with a relevant statement and move on. 

Grant: And to a lesser extent that I think that happens very frequently. There are a lot of papers out there where essentially the core conclusions of the paper are wrong. And everyone in that subfield knows that, but if you aren’t in that field–you’re entering from an adjacent field and things like this–unless you really talk with people or have a postdoc spend a year or two trying to replicate the results you don’t know, and we don’t currently have a good mechanism for communicating that because again, in many cases, people fight the retraction so it doesn’t happen.

Ben: That’s partially due to the incentives, right? It’s like your stock options or something, man. Like once you have a couple of those Nature papers, you could just keep exercising your scientific credit options for a long, long period of time. 

Ben: I think it’s a human behavioral thing. Like there’s a network effect: the rich get richer, that sort of thing. You’ve established yourself as a leader in the field, so it’s going to be so much easier for you to get that R01 or whatever other federal funding opportunity. When people are wrong, they’re going to fight tooth and nail because it has a very direct effect on their ability to continue to professionally be a scientist in the current model.

Grant: And the other thing I’ve observed–I’d love to hear your thoughts on this–is sometimes the criticism is wrong and the results are solid, the methods are solid, but in many cases, other bystanders rush to conclusions. They see a criticism or a rebuttal of a paper and without really reading it and judging it for themselves and assessing it on the merits, they take a shortcut that “this is crap.” Sometimes that’s right. I think sometimes it’s not. Sometimes these rebuttals are–let’s see, podcasts appropriate language– incorrect. 

Grant: And I think right now everything is very stilted. So, there is good conversation at conferences in person, but that’s not recorded that doesn’t get disseminated. There’s sometimes very polarized conversation on Twitter that doesn’t really get us towards the truth. How do you think we could set things up and take advantage of the internet and everything to get us closer to that in a way that is better recorded and more easily disseminated across both that sub-field but also the broader community.

Ben: Yeah, that’s a great question. I know that journals will often let the authors post their own rebuttal to the rebuttal. I was trying to think of a really good example of that. I think it was–oh, what’s his face?–David Reich at Harvard. If you read his rebuttal to the criticism, it was like a masterclass in how you defend yourself. But at some level, it almost feels like it’s a little bit more like science is becoming some sort of legal enterprise where you’re trying to make a case and it becomes less and less about a holistic synthesis of all of the evidence and more about debating your opponent and winning points on them in some way.

Ben: I think to answer your question, if there are ways in which it’s easier to share primary data, share all of the methods that are used and have almost like an audit type process. Where someone who doesn’t have any skin in the game, who’s an objective outside observer as much as possible, can go in and do an assessment. That would be one way.

Ben: The technological side of that is you have to be able to share data and methods. But I think until we get to that point, you’re always going to have this back and forth, these grudges that come up between various research groups. I think that’s all a lot of noise. 

Ben: Like you said, Twitter. I really like it– science Twitter–for seeing new science hot off the presses. Like that’s Twitter at its best, but for actual meaningful dialogue about these things, it’s just too easy for it to devolve into everywhere else in the internet. And then at that point, you’re just like, “okay, this is a waste of my time. I’m not getting a lot out of this.”

Grant: I mean, I’ve seen a lot of people essentially go quiet in the last few years or just leave their accounts together. I don’t know what your impression is of that, but my sense is maybe four or five years ago, there was a bit more of the back and forth. And now it’s gotten so polarized that you do see certainly some combative figures that are always jumping in and fighting with each other. But a lot of people just kind of lurk. And that’s mostly what I do. I just look for interesting papers.

Ben: It’s just too easy to say the wrong thing. I was just reading this article in the New Yorker. I’m going to be totally typecast now to your listeners: this guy loves the New Yorker. But it was in the one recently where they’re talking about the COVID-19 crisis and people getting shamed on social media. And how we still don’t quite understand the effect of social media. Public shaming has been how society enforces certain behaviors, but we’ve now created a technology that puts it on steroids. And what’s the effect of that? And just sort of fascinating.

Ben: And I think it can stifle open and frank conversation because people don’t want to login and get all this hurtful feedback from hundreds of thousands of people. That’s just a bummer man. 

Grant: I mean, it seems like the challenge is the monkey mind, and maybe tech can’t save us. Maybe it kind of amplifies it. And although–the thing is–some of the same people who are just total jerks on Twitter, are perfectly nice seemingly reasonable people in person. I think there is a psychological element to being face to face with someone versus typing on your phone.

Ben: Yeah. The anonymization piece of it. I think you could talk about that in the context of peer review too, if we’re just hitting all the related topics. I think the anonymization, there are good reasons for it in peer review. There’s also probably some pretty good reasons against it.

Grant: Do you sign your reviews?

Ben: I haven’t been. I might start now, especially when I’m going to a startup. I might start signing them because I’ll be in industry. Because your incentives are less linked to the whole academic system, there’s less chances for things being held against you later.

Grant: Right? It’s crazy. Some of these grudges you see they date from 25 years back. But it’s such a small world that it does have a substantial, negative impact.

Ben: It’s a very small world. Like the number of people in Study Section is not that many. And it’s basically like the last person standing, who gets to the point where they get invited to the study section. 

Grant:  Especially where a single person can essentially sync an application. I think that’s kind of a problem maybe and how the aggregate scores are competed.

Ben: Yeah. You know, I think most people are acting in good faith in Study Section. And in most reviews I’ve received as an author, there’s obviously exceptions where people are just kind of nasty and that’s just unnecessary. We should all as a community, make a strong stand like, “don’t be nasty in any of your reviews.” I don’t know why that’s a cultural thing in science where people can be just straight up mean, just give your thoughts and give it to them straight. But there’s no reason to tear people down.

Grant: Well, some people are just mean. For some people, the anonymous factor plays a role, but there’s some scientists out there writing under their own name that are very openly mean well beyond just making their scientific point. I mean, it’s kind of funny because you know, I’m pretty sure, like most of us, they were probably bullied as kids and things. Somehow some people become the bully.

Ben: Yeah they probably internalize it and they probably aren’t even consciously aware of what they’re doing is the sad part. It’s just how they’re reacting to that situation, given their personal history. Right. 

Grant: Yeah. Do you have anything else you’d like to add?

Ben: Yeah. I mean, a question I have for you, maybe I turn the Peter Thiel question back on you. I’m just curious what your take is on that. Like, what’s an opinion that you hold that other people would find controversial? 

Grant: That’s a good question because it’s not actually something I’ve thought about. Even though I asked you right? 

Grant: I think the chances of an existential calamity to modern society are higher than most people think. I mean, there’s a lot of fragility. We are extraordinarily dependent on the internet for so many things. And in many ways, if a lot of the backbone infrastructure of our civilization were suddenly severely disrupted–you know, if you’ve got a very strong solar storm or something like this–I think it would be difficult for us to reorganize quickly.

Grant: I mean even this COVID stuff. This is like an IFR 0.5% respiratory virus. Throughout the 19th century, we had infectious disease epidemics that were far more deadly on a regular basis, every several years. We’d have something like this.

Grant: And of course we’ve tamed that through modern medicine and with vaccination, good clean water, and things like this. But something like this that no one would’ve really batted an eye at in the 19th century has done a lot of damage around the world. Not enough to end civilization as we know it or anything like this. But I do think it reflects a greater level of fragility because a lot of the ways we used to do things, we don’t don’t have anymore. So a lot of even workplaces now increasingly are getting rid of landlines. It’s just so many things that were backup systems, we’ve gotten rid of for the sake of efficiency that we can no longer fall back on. 

Grant: And I don’t know specifically what that shot could be. It could be any number of relatively low probability things, but if you take a lot of low-ish probability things and integrate over time, the chances of something happening are more than negligible. 

Ben: I was just gonna say, I totally agree with that. So I don’t fall into the camp that doesn’t, but

Grant: So maybe it’s not as controversial as I thought. 

Ben: I don’t know if I’m a typical person. But I think that a lot of that has to do with incentives. Like you said: efficiency. Markets are always looking for unrealized short term efficiencies, but these big scale risks, these black-swan events. The local risk model where your tails are very thin and you’re like, “Oh yeah, no, that’s like a 15 Sigma event. That’s not going to happen until the heat death of the universe.” Well, no, the distributions for those sort of events don’t follow that for a while. 

Ben: I think a lot of the incentives are linked to short term thinking. Coming back to what I was saying earlier, if you think more long term, then you start to think “Oh yeah, no, we’ve got to design our systems to be less fragile. We have to build in redundancy” And that there’s that concept of antifragility, where you actually have things that, in the presence of perturbations, become stronger. Those sorts of conversations, it’s rare to hear them. It’s not like what we’re taught. It’s not like this crazy political season that’s what you’re hearing on the debates.

Grant: Right. Well, and that’s another thing, maybe my other answer to that would be–although I think this has become a lot less controversial in the last few years–is just that the modern democratic-neoliberal order is much more fragile than most people recognize and we take it for granted in a lot of Western countries, in English-speaking countries, and things. We assume it will be like this indefinitely. But there are already cracks, right?

Ben: Yeah. Not just in the US either. It’s like everywhere.

Grant: Right. And the relative freedom and prosperity and things that we’ve enjoyed for a number of generations here, in the long view of history, is very short. Hopefully we can keep that going for as long as possible. But I think it’s far from guaranteed. You know, we could see things break apart in our lifetimes. I don’t know. Hopefully not.

Ben: Gosh, I hope not. And that has become a lot less controversial in the last few years, but yeah. I think climate change, that’s the real X factor. I mean, even the defense department was putting out a report on how climate change is going to cause all this geopolitical instability.

Grant: I mean, I think climate change is a part of it. I think it’s a lot bigger than climate change though. Climate change certainly contributes to and accelerates a lot of the habitat loss and things that were already occurring and have been for a very long time, but at the end of the day. Actually in our last last episode Chris was here, we actually talked a bit about ecological disaster. 

Grant: I think something like that is more than just a possibility, depending on how you define it. If you talk about mass extinction events, that’s a certitude. It’s already happening in a lot of the insects and things like this, on which ultimately the charismatic megafauna depends, are already on their way out.

Grant: You know, it’s kind of a nervous laughter kind of situation. But yeah. People are pretty adaptable. It’s not–I don’t think–going to be the end of, certainly not the end of life on earth. And I don’t think the end of humanity on earth or anything like that, but it certainly will make things different. And there will probably be a lot of people wishing that their ancestors had made different decisions.

Ben: Yeah, I totally agree with that. It’s all kind of unnerving. I’d really like times to be a little less interesting for a bit. They just seem to be getting more interesting.

Grant: Yeah. Boring isn’t bad. Yeah. 

Grant: So what are you doing in between Sage and the startup? I know you’re not hiking the continental divide or something, but obviously your options are limited at this time.

Ben: I know. I’ve had a week off and I’m in Bend, Oregon right now taking a little bit of a break. Though it wasn’t much of a break cause I was working the last two and a half days on finalizing the editorial changes on my last paper from when I was at Sage. So I feel like I was kind of trolling myself. Like “I’m going to have this week off to relax.” And then I’m like, “Oh no, I need to get this edit. Cause it’s going to be a pain to do that once the job starts.” 

Grant: Oh yeah you’re going to be busy.

Ben: But that’s done now. Thankfully I got those in yesterday. So I don’t know. You know, I’m an aspiring ultra runner. So, I do a lot of running. I’ve got a big race coming up in February next year. Hopefully it’ll happen. Obviously who knows with COVID. It’s the Black Canyon 100 K down in Arizona. So I’m just trying to put all the work in so that hopefully that’ll go well.

Grant: Well if the official race doesn’t happen, you can always go to Arizona and run by yourself. 

Ben: Go run for like 11 hours.

Grant: Make yourself a shirt, right?

Ben: That’s right: 11 hours just in the desert.

Grant: Thanks for joining us today, Ben. I appreciate it. 

Ben: Thank you, Grant really appreciate being here today. It was a lot of fun chatting with you.

Grant: Awesome.

The Bioinformatics CRO Podcast

Episode 2 with Chris Ponting

In this episode, Grant sits down with Chris Ponting, chair of medical bioinformatics at the University of Edinburgh. They talk about myalgic encephalomyelitis (ME) and potential parallels to COVID-19 “long-haulers”, CRISPR, and ecological disaster. (Recorded on Sept 25, 2020)

On The Bioinformatics CRO Podcast, we sit down with scientists to discuss interesting topics across biomedical research and to explore what made them who they are today.

You can listen on Spotify, Apple Podcasts, Google Podcasts, and Pandora.

Transcript of Episode 2: Chris Ponting

Grant: So welcome to The Bioinformatics CRO podcast. I’m Grant Belgard, and joining us today is Chris Ponting. Chris, would you like to introduce yourself? 

Chris: Hi Grant. Yes, my name is Chris Ponting. I’m from the University of Edinburgh. I’m the chair of medical bioinformatics here. 

Grant: Lovely. And Chris was also my PhD supervisor many years ago. And then my supervisor for a second time, a couple of years after that. 

Chris: Well, you’ve gone on to greater things than I have, so well done. 

Grant: Oh, I don’t know about that. So, yeah, I just wanted to talk about some of the things that you’ve gotten into in recent years, especially your move to ME and CSF. I’d love to hear about that and what your thoughts are on the comparisons that are being drawn to post-COVID syndrome. 

Chris: That’s really interesting and a story that really goes back many years. So I was at university with a guy called Simon McGrath and some years later he got ME, myalgic encephalomyelitis. And it destroyed his life or at least his expectations and hope for the future. I felt for many years that I could do nothing about this as a scientist. And then recently I was just thinking that perhaps the techniques of population genetics might be interesting and useful. So I dipped my toe in it, and eventually after some years, some discussions, and bringing together many people from across the United Kingdom, we were awarded just this year over 3 million pounds to start a genetic study of myalgic encephalomyelitis, ME. 

Chris: In the middle of that, of course, COVID comes along. It was apparent to many beforehand and certainly more now that there are some interesting overlaps between post-COVID syndrome or long COVID or whatever you want to call it.

Chris: And after all, many people with ME report a viral infection before they come down with their syndrome. And this is exactly what’s happening now with long COVID. Now I don’t wish to say that long COVID is ME, it isn’t, but some people may resolve from long COVID into ME, which in this country as an adult, you need to have symptoms for over four months.

Chris: But watch this space! Basically, I know some people are doing some, or the beginnings of some genetic studies of long COVID. And it’s going to be fascinating to compare the genetic signals for ME, with the genetic signals for long COVID. Are they different? Are they the same or do they overlap, but not completely, et cetera.

Grant: Have there been any genetic studies of ME that have been broken out by the kind of proximal cause. So if it were a viral infection, have there been genetic studies broken out by the subtype of virus and so on?

Chris: So you would have thought that there would be plenty of genetic studies and well-powered ones involving many people. And you would think so because in this country, in the United Kingdom, around a quarter of a million people suffer from ME. But there are not. There aren’t any well-powered genetic studies anywhere in the world. So we know, nothing about the genetics of ME. We know that there is evidence that it is inherited, which gives us some support for our case that we should do this genetic study. But we know almost nothing about what will eventually be seen, obviously, as being a whole set of different conditions, which have different contributions made by the environment and from different parts of our chromosomes. It will be one of these complex disorders and teasing everything apart will take time. But given that there’s no effective treatment for people with ME, we really have to start with the genetics because we know almost nothing as researchers in ME.

Grant: And why do you think it’s been so neglected? 

Chris: It’s been neglected essentially because of this lack of information. The ignorance that we, as researchers, have towards it. We know almost nothing. It’s multisystem, which is difficult.

Chris: If it was affecting only one system, then we would know what to do, but, for some people it manifests mostly in muscles, others in the brain, others it may be perceived as an immune response problem, for many people it’s all three or more. So that’s a problem, but also there’s been a problem with its diagnosis. It’s a diagnosis by exclusion, meaning that it’s not particularly easy to diagnose. And that means that often people are not diagnosed. Indeed in the United Kingdom, the time taken on average to be diagnosed is about eight years. It’s neglected because we know very little. So “Let’s start finding out” is my view. 

Grant: And are there any countries that have been ahead of others on looking into this or has it been very well neglected across the board?

Chris: So it’s neglected a disease across the world. There are many countries where it’s not recognized at all by health professionals. And there are many health professionals across the world who think of people with it, with ME, as malingerers or who make up their disorder for whatever reason. It is the most devastating of diseases. In terms of quality of life, it’s so much worse than almost everything, including many cancers and multiple sclerosis, et cetera. Why anyone anywhere would make up such a disorder. I just don’t know.  It’s almost Victorian in our approach to this disease in the sense that when we look back on this, maybe in 10 to 50 years time, we will understand what it was. And think “why on earth did we overlook it and disbelieve all of these people for so many years.”

Grant: So I guess this feeds into another question, which is what do you think we need to do differently in biomedical science? And there are probably many answers to this, but. 

Chris: So one thing is we need to listen. If we’re studying a disease, then the person with the disease is often the expert on it. They have lived the experience of the disease. If they say that it fluctuates in different symptoms, that’s what it is. So listening and acting upon the experiences of people. And it’s not just their lived experience, but also they’ve become experts in the literature. They often, in my experience coming in from the outside has been, many people with ME, despite the fact that they are fatigued and they have post exertional malaise, and often can’t do things even things like brushing their teeth, but they do get involved and read the literature and are experts in it. And so I’ve often gone to my friend or others of people with ME and asked their advice as to what we should do scientifically.

Chris: And we should also pay attention to the fact that there are many scientists who have ME, many people who, in multiple different professions who have long COVID. I see nowadays that such experience can be thought of as being negative, that somehow subjectifying their experience, because it is they who are suffering, actually is not valuable. We need to be dispassionate in our observation of disease. And actually, I don’t think that’s right. 

Grant: That’s really interesting. So if I were to push you a little bit out on a limb and ask you to speculate, what do you think we might learn about the disease, if you had to give your best guess about ME CSF and it’s overlap with long COVID and so on? You don’t have to answer this.

Chris: I don’t mind answering questions, which are all speculative. I think as scientists, this is what we do. We do speculate, but in the knowledge that many things that we speculate about, we have no evidence for.  We put forward hypotheses, which is a part of speculation, and often we try and work out whether those are false. So one answer to your question is that I would not be at all surprised if it were to turn out that there was a mitochondria component. So, as you know, the mitochondria is the energy of the cell, so the battery of the cell. And if something were to go wrong with that, it would affect many different systems. It would affect the immune system. It would affect the nervous system. It would affect muscle, et cetera. And, and that would make complete sense to me if that was going wrong. 

Chris: But I actually think it will be many things. There have been people with ME, who’ve been diagnosed with ME, who have surgical operations on their neck and have had many fewer symptoms since then–not a large number, a smaller number. And I need to say that it is a procedure that is fraught with risks, so anyone thinking about it should go to their GP, their practitioner. But it is highly likely that there will be many different contributions made. And this is not easily understood because the medical model is that if you have a set of symptoms, it will be one thing.  But from genetics, we know that many different things can break and manifest in the same way in a person.  And there are many different ways in which the clinician can be hoodwinked by symptoms into thinking that symptoms are one thing and they’re many. So I am willing to speculate on the basis of evidence and thus far, we have none. So from our genetics, we will have some, I hope. And from there we will draw up the hypotheses and hope that many of the experts in those different fields will take on the challenge of seeing whether those are false or indeed real. 

Grant: And can you talk a bit more about your genetic study, and, you know, the design and when you might expect the results?

Chris: I think the results will come in about two and a half years from now.  What we will have done by then is to look at the DNA differences in 20,000 people with ME in the United Kingdom: differences with respect to the general population. We’re lucky in this country because we have something called the UK Biobank where half a million people have had their DNA changes read out. And so all of that’s been done. We don’t need to look at those, who we would call controls. We only need to look at the 20,000 cases of ME. Now we had no idea how long it would take us to get to 20,000 and we haven’t yet formally launched, but we have a registration page on the Decode ME webpage, and 20,000 people with ME in the United Kingdom have registered for this study, which is outstanding.

Chris: And the work that’s been put in by charities and digital marketing companies, et cetera, to get us to that point, even before we launch is fabulous, which gives me confidence that we really will be able to go quite fast in the early stages. What we’ll find, I don’t know. Maybe we find nothing–possibly–but we should look.

Grant: That’s outstanding. What are your thoughts on how communication from scientists has been handled with COVID-19? With, you know, many preprints going out, there have been a number of preprints that have influenced the discussion among the general public that wouldn’t pass muster on review and so on.  On the other hand, certainly science has moved much, much more rapidly with this than I think anything we’ve ever seen before in a positive way as well. What are your thoughts on that and on how politicians have kind of adopted, in many cases, scientists to agree with whatever they want to push? In the state of Florida, for example, our governor recently had a series of conference calls with some scientists who had somewhat fringe views on the pandemic and what should be done about it. But what are your thoughts on all that? 

Chris: Well, I think it’s really interesting because previously I think the public thought of scientists has been quite a homogenous bunch with the same views. Um, and that’s not true at all. People think of things in very different ways. And those kinds of controversies and conflicts in ideas really have not been exposed to the general population before. But now that they are because we’re seeing people on the same day writing letters to the same place to say, I believe in X and others saying, I believe in not X and that is causing confusion, but it actually reflects the reality.

Chris: I think the more it is understood that there are differing points of view and the more that you air them, the more people can weigh in and give their views, the better. And that is happening. Although you implied that peer review, which takes preprints into the publication domain, isn’t perfect. And just because it gets published, doesn’t mean that it is correct. And in fact, it’s the goal of scientists to demonstrate that what was known previously was either imperfect or incomplete. And also I don’t think the general public understood. 

Chris: Now your question also makes me say that the politicians who are considering the scientist views really are not qualified to understand the science, which is a shame. Why is it that scientists don’t become politicians? If we had a cohort of scientists who were members of different legislatures.

Grant: I guess Germany does, right? 

Chris: It does. They’ve had a very coherent response to COVID, but our country in the United Kingdom–and I think in the United States, it’s the same–there are almost no scientists. And I think that’s a huge deficit because the greater expertise, and the breadth of expertise that there is in parliament here, I think the better laws will be made and the better decisions would be taken. At the moment, we have the situation where people who have taken arts degrees–which are great–are making essentially scientific decisions. And I’m not sure that that has led to good outcomes here in the UK. 

Grant: So if you’d be willing to speculate again, the UK seems to be undergoing a second wave now, right? How do you expect that to play out? I mean, obviously there are a lot of decisions every day that you have to make about how you and your own family will respond to this.

Chris: I think it’s incredibly hard for every single person to judge what they should and what they shouldn’t do, and it’s leading to a huge amount of anxiety. We went to a restaurant as a family last night for the first time in a huge while. But of course we were worried about that. Should we have done that? Are we infectious? Are others infectious? Should we wear a mask? We did. Unfortunately, I think this is going to be the situation for others. 

Chris: Someone asked me yesterday, “how long is this going to last?” I mean, how do I know? I’m not an expert. I’m not a virologist or an epidemiologist, but I answered. I said, “I think we have another two years of this. I don’t think we are going to be saved early by a vaccine or several. We don’t know whether a vaccine like that is going to have great efficacy across the whole population.” So the best thing to do is to try not to infect people. And people are finding this hard because they lose their freedoms. They are used to traveling the world. They are used to doing X, Y, and Z and hate the idea that they’re being told that they can’t do it anymore. But a better idea is to protect other people. And I’m an optimist that feeling of protection others will eventually prevail. 

Grant: I do think there’s been a bit of a move in that direction even here. I would say a few months ago was probably the height of people screaming at each other because they didn’t want to wear a mask or whatever. But I think over time, people are realizing that the virus is real. You know, certainly if you go out when sick and so on you’re kind of in A-hole.

Chris: We needed to be tested because one of the household had symptoms. And so we went to a drive-in testing facility locally. And that was a sobering experience: watching the line of cars, watching the expense that the state has put into testing so many people, getting your results back within 15 hours was amazing.

Grant: That’s fantastic. That’s unheard of here. 

Chris: It’s not half an hour as it is in airports in Germany, et cetera, I mean, in Italy, but that was a sobering experience. I think, for us all. And it brought it home to us how widespread this is. That yes, maybe one in a thousand people are infected at any one point, but that is a huge number. 

Grant: What are your thoughts on–I don’t know if you’ve looked into this. You don’t have to answer if you haven’t. But, what are your thoughts on the prevalence of long COVID, and the longer term consequences? I mean, it seems, there are a lot of contradictory numbers about, you know, exactly how different studies are conducting surveys and differences in definition and so on.

Chris: This is a great example of where science doesn’t know. It doesn’t know how to define “recovered” for people with COVID. And if we don’t know how to define people who are recovered, then we don’t know how many people are ill still after, however many months. So we have to set down our structures, our frameworks, our concepts, and that’s beginning to happen. And upon those, are new studies that are going to be determining the proportion of people who are unwell still. Now there will be people who’ve been in hospital and intensive care who will still be ill. Um, and they are often going to have other conditions and they will be very poorly for a long period of time. And then there are people who are going to be unwell essentially for the rest of their lives, just as people then me off and. 

Chris: Your question is really how, what is the proportion of people who have been infected will be affected with ME like symptoms for the rest of their lives? It could be small. It could be of the order of 1%, which is the mortality rate as well. 1% of everyone is a large number. So if it’s 10%, it’s 10 times that large number. And we would have in that scenario a whole stratum of our society who would be unable to work, unable to look after themselves in many cases. A quarter of people with EM are bedbound or housebound. And if that’s the case with some people with long COVID eventually, then that would be the case. 

Chris: It’s a horrifying thought that that might be the case. But people with ME look upon that as something that might be an opportunity for ME to be understood, but more importantly, with a huge amount of empathy and a fellow feeling that they’ve always been left alone by society. And through no fault of anyone, they might be joined by a large number of others, which will mean that society will have to pay attention, which they haven’t for so long. But I haven’t answered your question. Your question was, what’s going to be the health burden in the future? And the margins of error of an estimate are too large to know at the moment. I don’t know.

Grant: Yes. Speaking of COVID, have you attended any virtual conferences? 

Chris: I was a co-organizer of a conference over the last two days. I think most people are Zoomed-out, being on Zoom or whatever calls, throughout the day. People, including myself, by the end of the day were just exhausted.

Chris: That conference actually, however, had some energy to it. We made use of breakout rooms and that was sort of randomly done. We allowed, you know, people to interact in ways which were less formal, and we paced it I think quite well. At least the feedback said so, but conferences are going to change quite clearly. 

Chris: I go back to the ecological case that conferences actually have not been very good for our environment for many years and I’ve contributed to that. So we will continue to communicate in that way virtually at conferences. And I think that’s a good thing. We will miss one another. We will miss, you know, looking one another in the eye and having a beer or whatever, but that’s a small price to pay really for everything else that’s going on at this moment. and what’s already happened over the last few decades.

Grant: Why do you think zoom is so fatiguing? And everyone has the same experience. You know, you can be at a conference all day and it’s fine, but if you’re on back-to-back zoom calls for three or four hours, you’re exhausted.

Chris: I think in a conference you can zone out. You can kind of do what aquatic mammals do and switch your brain off and sleep. Well not sleep, you know we don’t sleep in conferences, but you can at least zone out for short periods of time and then come back in and focus. If you’ve got a bank of 20 people staring at you, you shouldn’t really do that.

Chris: And so you don’t and you fix on what’s going on, and I think that’s very tiring. So at the beginning of lockdown, when we have back-to-back Zooms throughout the day: eight or whatever per day. I had to change that. I had to move to being more spread out. And as winter comes here, we’re going to have to organize ourselves so that we can go out in the middle of the day and actually see some sunlight and get some exercise. So we’re going to have to plan our days differently. 

Grant: So I guess on a completely different note do you want to talk about your novel or will that be more of a surprise?

Chris: I’ve forgotten that I told you about a novel. I basically finished a novel. I’ve not sent it to anyone. The first version was read by my wife and she was rather scathing, probably quite correctly. So there is now the second version, which is probably a bit more thoughtful and explanatory. And it’s a dystopian novel. It does derive from a genetic story, but it takes a whole bunch of quite broad subjects from the ongoing ecological disaster that we’re in. And it has a theme that I thought was not particularly topical at the time, which was viruses. But now that it’s done, it’s complete, viruses of course now de rigueur. And so people might think that, I took inspiration from the COVID pandemic, but actually this wasn’t the case. 

Chris: The idea is that it is the human race on the earth that is the virus that is infecting our biosphere and so many species are being driven to the wall by our infection on the planet. It’s not a particularly nice idea. It’s not a particularly new idea. I go on to say that there’s more to it than that. It is that the men of the human race that are culpable. So there is a character–giving some of the plot away cause it’ll never be published obviously. 

Grant: You could always self-publish. You can get anything out these days. 

Chris: I could self publish. Yes. There’s a character, a woman who basically realizes that one way of putting a handbrake on the ecological disaster is this essentially to try and hobble males of the human race. So she introduces a virus to do so, which targets the men only and in so doing it does two things: it hobbles the males, and reduces the ecological disaster. But unfortunately viruses will do what viruses do well, which is evolve. And so, the virus then begins to jump to other animals and to women.

Chris: And causes a devastating effect on the whole of the human race, which has only countered–I’m telling you the whole story now–it’s only countered by the introduction into the germline of a mitochondria-like entity, which targets the factors that have led the males to be hobbled. And basically immunizes some people but these are only women to the effects of this virus. And so we have basically a matriarchy, whereas previously we had a patriarchy. 

Grant: That sounds really interesting. I would love to read it. 

Chris: I’ll give you a copy. I’m going through it one last time at the moment. 

Grant: That’s great. So maybe that feeds into one question I like to ask, which is: what would you do if you weren’t a scientist? Would you be a novelist or something else? 

Chris: Absolutely. I’ve already started thinking about my next one–if I’m going to write a next one. I’ve actually enjoyed writing a lot because it is freeing. As a scientist, I have to write facts, the facts as I understand them. As a novelist, you can write anything, and that freedom to venture anywhere in your mind is wonderful. You’re not constrained by the evidence that’s out there. So I’ve really enjoyed doing that, but it also takes quite a lot of rigor to do and to plot out all of the different characters and the themes, et cetera. So this is what I’m doing now for what might become a second, which is on the theme of clonality.

Chris: The idea is that–I haven’t written a word of this–that a male clones himself, thinking that he will gain immortality. But actually all that he does is introduce another male into the world. Who’s much younger than him. And he finds it to be quite a challenge to his sense of superiority.

Grant: Interesting. And I’m guessing it’s not in the same world as the first novel. It’s a totally separate world.

Chris: Yes, both of which are empty of COVID-19. 

Grant: And what’s your process like for that? I mean, do you dream up all the characters and the plot and so on before you start writing or is it very iterative between the writing process and kind of picturing the world?

Chris: So those are the two processes I’ve adopted. The first was organic: organic growth that just percolates up in your brain and that leads to all sorts of conflict in your mind and inconsistencies in the plotline. So I had to go through the plot again and again and again, to try and make it consistent. That took a long, long time. So what I’m now doing is trying to ensure that the plot is cogent, well-thought-out, the characters are three dimensional, and their interactions with one another are well-described even before the first word is written. So let’s see, the first way of working led to a full draft. The second way of working hasn’t yet generated a single word. So let’s wait to see. 

Grant: That’s great. So what do you think is the most interesting thing happening in biomedical research today? You don’t have to pick one, you can pick a few.

Chris: I think the most interesting thing that’s happening in research is how it’s becoming much more immediate in its effects on the population because of COVID-19. There are researchers now who have generated findings last week, who put them up as preprints this week will know that through the media they will become known by millions of people tomorrow. That immediacy of effect is changing the way that researchers are considered by the population, by governments. But it’s also changing the way that scientists themselves are thinking how they can do that science and what effect and impact they have on others. 

Chris: A lot of science is done without thinking about “what is the impact? What is the benefit, the immediate benefit?” These are blue sky science, and that’s a good thing. So I think hopefully once COVID blows itself out, there might be a long lasting impact on the idea that scientists should engage more with the population, work out what are the issues that vex them most, and also work on things that are more impactful. So that to me is interesting, more sociological than anything. 

Chris: What was interesting before that, of course, was the advent of CRISPR: this idea that as scientists of model organisms from flies to mice, to human cells, we can go in and edit and cut and paste and change DNA. And in that intervention ask, “what does this letter do out of our 3 billion? What does that letter do?” And really, we hadn’t had that ability before. And that really was game changing almost within months everything changed in genetics. 

Grant: And where do you think that’s headed? What do you think will be the most impactful thing that comes out of CRISPR and related technologies?

Chris: I think. All of those technologies are now giving insights into the world of molecules that we had never had before. What do I mean? I mean that we’ve been able to observe. We’ve been looking at cells and molecules and watching them go by and prodding them and seeing what their response was. But never really have we been able to intervene directly in a very targeted manner and have alongside the edited cells, the other cells, the wild type cells, and then compare them one to another and actually see what is going on.

Chris: That may not seem to be a big deal, but absolutely it is. And it’s taking biology, I think, one step closer to other types of interventional science, for example in physics and chemistry, where previously biology was much more observational. 

Grant: Do you think we’ll still be eating meat as widely as we do today in a generation?

Chris: No, we won’t be eating meat, if we’re still around a generation from now. I don’t believe so. There will be a proportion of our population–as ever–that will take up a large slice of our resources of the world, but most people I don’t think will be eating meat in a generation. At least my vegan daughter would hope that we don’t see as much meat then as now.

Grant: And do you think CRISPR and related technologies might play a role there?

Chris: I have to be careful here: I have colleagues who work in this area. Is CRISPR going to have a long lasting effect on livestock? It is going to have an effect and absolutely is being used currently to improve–as some would call it–on livestock traits. Is it going to last for more than a generation? I don’t think so. But whatever prediction I make, of course, doesn’t matter because I’m just one person. And once another generation has turned, I will have shuffled off my own mortal coil. So I can say whatever I want now. 

Grant: And have you seen what Meatable and similar companies are working on now? It’s a little bit of genetic engineering, but…

Chris: Yeah, I don’t know much about this. 

Grant: Moving to lab-grown meats to get away from animal-derived. 

Chris: My, my question would be what are the resources that are required to generate those lab grown meats? It may be that there are issues there that would need to be, considered quite carefully. The best thing is simply not to eat meat or drink milk. I’m not a vegan, right. I’m just saying that’s the best thing for our world going forward. If everyone were to make that same decision, the whole world would be such a better place. 

Grant: Certainly. In, I guess, probably even still the very early stages of a very great extinction event. Yeah. And practically speaking, do you think that there’s much chance of avoiding that or are we so far along at this point?  

Chris: As a human race, we’re not avoiding ecological disasters at all. We’re observing them and not learning from what has happened over the last few decades. It’s a train crash that we’re observing year on year. And I’m constantly reminded by people in my family who say “Yes, COVID is a huge thing, but the biggest thing, the greater thing than that, is the ongoing ecological disaster.” And I played my part in that. I think everyone in my generation needs to stand up and retell exactly what we’ve done and then ask ourselves what we need to do in the future.

Grant: This is depressing, but true, right? Um, so what do you think is your most controversial opinion in science? 

Chris: So we have evidence that we’ve published that 90% of the human genome does not alter who we are and what we do. And that if there were to be any changes in that 90%, it wouldn’t affect us at all.

Chris: Many people I’ve talked to who are scientists, or who are not scientists, are absolutely outraged by this idea. The scientist cannot believe that the molecules that we have in all of cells, or parts of molecules would not generally do anything. But that’s what the data says. I have to look at the data and come to a conclusion. We’ve looked at the data in a particular way that no one else has. And absolutely. It makes sense.  It comes to that conclusion, and others, using different approaches, come up with something similar.

Chris: So interestingly. We as humans would like to be sort of perfect objects, where you know, the genetic codes in our chromosomes are, in some way, perfect machines. It’s not true at all. In fact, you know, that there is an evolutionary argument, which is well-established, that as a population we’re pretty poor at getting rid of bad mutations. So we carry them in our population and pass them down through the generations often, more often than other species. So we’re certainly not the epitome of all animals now in that respect. So I think that’s a really interesting view of the human genome. And not one that, as I said, every single scientist and every single member of the general public would agree with. 

Grant: That’s interesting. You’ve certainly ended up in a very different place than where you grew up as a child, moving to England and then Scotland and so on from Uganda. Where do you think you’ll retire? 

Chris: That’s a great question. Where I’m allowed to retire by my family. Where would I like to retire? I spent two years on the West coast of Canada. And the countryside there, the variety of countryside from rainforest to arid desert in just a hundred miles or so, is outstanding and outstanding beauty. Great people: the Canadians. And I quite like that. I won’t be allowed of course. We’ll have many more family ties inside the United Kingdom. But I can always think of that as a dream and wonder whether that’s going to happen or not. 

Chris: Um, England? Unfortunately I’m less fond of England than I was. So I’m not going to retire there. Politically I think it’s not a place that I recognize as the one that I grew up in. 

Grant: Do you expect that by the time you retire, Scotland will even still be part of the UK? 

Chris: Well, this is a big question as to what’s going to happen with Scotland. The current opinion polls are that if there were to be a referendum now, Scotland would go independent. The separation of Scotland from the rest of the United Kingdom would take a very long time, just as the separation of the United Kingdom from the European Union, which I regret hugely, will take far longer than anyone has ever thought. And that will happen with Scotland. 

Chris: We share a border, which is, you know, you can not see the border, you just pass through it. It’s just like a state line in the US and that would just have to change, particularly if Scotland were to become again part of the European Union, which most people in Scotland would wish. 

Grant: Just logistically it seems like it would be difficult for them not to. It’s such a small, well, it would be such a small country. 

Chris: It is a small country. It’s, you know, 5 million or so, but that’s sort of similar size to other members of the European Union. And such countries have benefited hugely from being part of that Union. And I think sometimes we focus too much on large versus small equating them to important to not. And Scotland’s always been at the edges of the United Kingdom and made much of that. I think it might do so again. 

Grant: Great. Is there anything else you want to say before we wrap up? 

Chris: Not really Grant. It’s a pleasure talking to you. And I wish that I could ask you as many questions as you’ve asked me today. So we should catch up separately. 

Grant: Yeah. Definitely. 

Chris: And I wish you well, you and your family well, obviously. I don’t think so. I’ve covered quite a lot of ground and probably some ground that I’m happy to stay in, but I’ve not covered before politics, et cetera. 

Grant: Thank you for joining us, everyone. Hope it was a nice conversation.

Chris: I’ve enjoyed it a lot Grant. 

The Bioinformatics CRO Podcast

Our Inaugural Episode with Razib Khan

On The Bioinformatics CRO Podcast, we sit down with scientists to discuss interesting topics across biomedical research and to explore what made them who they are today.

You can listen onSpotify, Apple Podcasts, and Google Podcasts, with Pandora coming soon.

In the first episode of The Bioinformatics CRO Podcast (Recorded August 24, 2020), our founder and CEO Grant Belgard talks with Razib Khan, geneticist, science communicator and director of science at the Insitome Institute, about consumer genomics, SARS-CoV-2, and academia. 

Transcript of Episode 1: Razib Khan

Grant: Welcome to the inaugural episode of The Bioinformatics CRO podcast. I’m your host Grant Belgard and joining me today is Razib Khan. Razib would you like to introduce yourself? 

Razib: Yeah sure Grant. I am the director of science at the Insitome Institute. I run a few blogs. I do a lot of random things. I run a blog called Gene Expression I run a blog called Brown Pundits.  I run a podcast for the Insitome Institute called The Insight so just check on Stitcher, iTunes, whatever. And I also run a podcast called Brown Pundits and that’s just like a fun project on the side. I have a Twitter, Razib Khan. That’s basically it. I do some other things. I do some consulting. You know, Grant and I have a conflict of interest, maybe we should just disclose: I did some work for Grant in the past. And yeah so I have my fingers in a lot of different things. 

Grant: Yeah I love your blogs. I highly recommend your blogs. I’ve kept up with them for a long time and a lot of other people have as well. So, what made Razib Razib? 

Razib: So yeah, a combination of genes and environment. If I want to think like a behavior geneticist. I do have a pedigree, I have three siblings. And I can tell you that there’s much more concordance between my youngest brother and myself. We didn’t really grow up together because I’m way older than him so that does suggest that there’s a strong heritable component of some of my tendencies. But in terms of growing up, I grew up in Eastern Oregon. So I think that gives me a very different perspective than a lot of people that I’ve met in academia who grew up in, say, upper middle-class suburbs. 

Razib: I grew up in “cowboy country”. There were literal cowboys at my high school in terms of that’s what they did after school as their job. So I have kind of a different cultural perspective. I consider myself a northwesterner, but I’ve lived in urban areas in my adult life. So, you know, I’ve seen the start-up scene in the Bay Area, I’ve lived in Austin. So what made me me is kind of like having this life background, I think, where I lived in rural areas, my dad was a college professor, and I lived in urban areas and I saw the global economy and I see the global economy. My family’s from Bangladesh but obviously I’m an American. 

Razib: In terms of my intellectual interests, I started biochemistry as an undergraduate because my family’s Asian American and if you’re going to do biology it has to be biochemistry or biomed but they don’t really understand it. But I was always attracted to genetics. I actually did a fair amount of molecular genetics as electives for the biochemistry which as you know biochemistry was in the chemistry department; it wasn’t in the biology department. 

Grant: A respectable degree.

Razib: Basically what we always say is we had to take physical chemistry, which is like. You know, at my university physical chemistry was a very difficult course so it was like we took physical chemistry. We are legit chemists okay? 

Razib: So that’s where I started but eventually, I faded back towards genetics and genomics. I’m not really good with my hands in terms of pipetting and stuff like that, so benchwork was never my thing. I worked in IT for a while and then eventually I went to grad school at UC Davis. I did not finish. I am still everything but a dissertation. And I worked in evolutionary genomics mostly with mammals and I do a lot of work with humans. I’ve worked for personal genomics companies. 

Razib: I have a lot of interest in history that gives me a unique skill set in being able to do the data science, you know, doing some algorithm writing as well as knowing basically what outputs or intelligible to the end-user, which can be kind of difficult if you’re a technical science person. Anyone who has ever seen an error output on a computer understands that that can be a problem with the technical person because error output does not tell a normal person anything except it scares them. So that is a skill being able to figure out what the consumer needs definitely that I think I bring to the table.

Grant: And where do you think you’re heading in the future? I mean obviously you have very broad-based interests and you found your way to science communication platforms and is that something you’re planning on doubling down on?

Razib: Yeah I don’t know, I mean it depends on, and I’m using a start up word here, what your bandwidth is. Right? I still do write for various publications when I get the chance. I don’t do it really for the money. There’s not that much money in it but who else is going to speak about what I speak about? If there is another Razib Khan I’ll give them my notes and I’ll just move on, because you know I’ve got three kids. I’m a busy guy–you know what I’m saying? 

Razib: I do it partly because you know who else is going to do that? But the Insitome Institute purview is to do science communication. And that’s what Spencer Wells and I do, my boss who is the director, we do the Insitome podcast. And so yeah there’s still a lot of science communication to be done and that I do expect to be doing, but I also do work in consumer genomics as you know. I do a fair amount of contracting and consulting with people and I do have some experience in that space that I would like to provide. I am trying to actually finish some papers, which I don’t know if I should talk about, but I’ll just put it out there. I am trying to finish some papers on some topics that nobody else seems to be really interested in and get that out there. So I’m trying to do a bunch of different things, so I’m not in a situation where I  have a straightforward “what am I going to do with my next 20 years”. The past 20 years have been pretty surprising to me. I mean who knew what genomics-based data science was 20 years ago? It wasn’t a thing. So what’s going to be a thing 20 years from now? And I think a lot of people feel this way. So my goal is to be nimble and you know just go with the punches and try to survive in this world because it’s pretty tough right now. 

Grant: You’ll find your way. So speaking of consumer genomics companies, what’s your take on what’s been happening in that space in the last couple of years, and where do you think things are heading?

Razib: I did a podcast with Libby Copland, Lost Families, and we talked a little about the Insitome in April, if listeners want to look that up type Libby Copeland, she has a book out, Lost Families. She asked me that and we had a discussion a little back-and-forth because she’s done all of this research in consumer genomics. 

Razib: I have friends who work in 23 and Me, friends who work in industry, my boss founded the Genographic Project. I actually have consulted for Linda Avey, the founder of 23 and Me. I consider her a friend. She is a really good person by the way. I’m just gonna put that out there. I have nothing bad to say about her. So, I’ve had a lot of discussions. 

Razib: It seems like there’s a leveling off of growth in that field. And some people say oh it’s because of privacy concerns. Other people say it’s kind of market-saturated for the initial wave of consumers. I suspect it’s both.  I do think the privacy concerns are starting to spook a lot of people. But who they are speaking is the next marginal consumer. So the initial consumers that were going to get it, they were going to get it no matter what. You could say, “oh we are going to use your DNA and we are actually going to release it out to the cloud in a tarball and everyone can access it.” And there’s just a core group of people that don’t care. They are still going to do it. So those people are insensitive to that. As you get further and further out through word-of-mouth because these are Christmas gifts, you know things people talk about over Thanksgiving in terms of their results a lot of awkward results sometimes.

Grant: I will just interject here that Grace, who is helping us out with this podcast, got as a Christmas gift from me: an Insitome ancestry kit. 

Razib:  Okay okay, so you know eat your own dog food. I’ve been on all of the platforms. So there’s ups and downs to all of them and it’s an interpretation service so they are all interpretation services. The killer app of the last decade that just went by was Genealogy and Ancestry to a great extent. 

Razib: The medical aspect has not really become unlocked yet. I do think it will be. So right now we have about 10% of Americans on these platforms okay? 30 million people. Probably a little bit more than 30 now. But it’s really leveled off so that’s about 10% of Americans. I don’t believe by 2030 we are going to be any lower than 75%. Okay? I think a lot of kids will be genotyped, you know low coverage and various coverage sequencing. Grant you work in the medical genetics phase, medical genomics, you know the gain that can be had by detecting novel variants, you know variants of unknown significance in young children if they have an idiopathic condition. And these are not most children but there’s enough with them that a lot of hospitals are already doing this with “mystery conditions” for newborns because newborns cannot give you any feedback about what’s going on with them. So these are the niche cases. They’re little segments but the segments keep on expanding. 

Razib: So those of us who remember the Internet in the 1990s, which Grace probably does not remember, but it was super exciting for a lot of us. And we had no idea what people were going to do with it. We had fantasies. I will tell you Grant, I think I’m a little older than you. I remember getting a gopher, which is like a pre-web thing, and it was a text interface. I remember reading about Ethiopia on the CIA gopher page for Ethiopia. And I was super excited because I could read about Ethiopia without opening an encyclopedia or going to the library. That’s what I thought the Internet was. That’s what the Internet was in 1993. And now the Internet is a lot different. The Internet is podcasts, Twitter, a lot of stuff that is good and also considerably bad stuff, but different than I was expecting. But this is you know 25 years since I got on the Internet and I couldn’t have guessed what we see around. Like some things I could’ve guessed but like a lot of it is super surprising to me. 

Razib: So think in genomics 2010 is the same as 1995. Like that’s when 23 and Me really came out with a big marketing push and people started talking about personal genomics. It was pretty low boil I think for the first five years. And then it really jumped up right before 2019. A lot of this is marketing spend. If you look at Ancestry‘s marketing spend, as it increased there was a linear response with purchasing. I know through the grapevine that the former CEO of ancestry–he kind of admitted this–basically they did not expect that there was going to be a linear response to their marketing spend. I think it was a little bit more than linear because word-of-mouth triggered and kicked in at some point. And so it just became one of those gifts like $100 price point $99 $79.

Grant: Black Friday sales.

Razib: Yeah and so it just became a thing and like YouTube unboxings of Ancestry kits became a thing. So it’s become part of our culture but it hasn’t become ubiquitous. And so I think that’s the next step. I think medical is going to help make it ubiquitous. The problem with medical and consumer is you don’t want to buy a kit that tells your mom that she’s going to develop breast cancer by the time she’s 60. Telling people that they have a health risk is not a feel good gift. So they need to figure that out. I’m not a marketing person. It’s not my job. I think probably some sort of distribution deals with hospitals is the way to go. I think that’s the future. 

Razib: And also I wouldn’t be surprised if some European country with socialist or semi socialist medicine it’s just like “You know instead of building our own genomics service for our citizens and let’s just contract with Ancestry or 23 and Me and have them build something for us”, turn the key, and then maybe the data is stored in those countries with some bureaucrat somewhere. I know for example Estonia is trying to do things to provide genetic kits and services to its people just as part of its national health. Because I know a scientist who is on the Government board and at a conference he came up to me and started asking questions about it. Because they’re like “We are serious. We are a small country and we can scale it.” And they have really really good distribution and fluency with information technology. That is what it is. Genomics is information technology.

Grant: So speaking of data protection and distribution where do you think those Genomes will be housed? I know there are ideas about this and many of them are in conflict with one another. 

Razib: Yeah. Well I think it depends on the country. In China they’re going to be housed where the government wants them to be housed and the government is going to know everything about your genome. Like they’re already sampling males because they want to get genetic profiles of potential criminals because 90% of violent crimes are committed by men. So that’s why they’re targeting males. So in China it’s going to be like that. 

Razib: In Europe they have the GDPR, which is like the data protection law. That’s what genetic data is under. And different countries have ways of enforcing this. Like in France genetic testing of the sort that we do in the United States for consumers is banned. Like they have to ship it to Belgium, drive to Belgium, and pick it up if they’re a French genealogy fanatic. There are some. Germans have a fraught relationship with genetic science, So if it’s anything relating to human genetics, they are really terrified of it. So that’s not really a good market. Other European countries like Scandinavia are much more open and much more enthusiastic. 

Razib: So how do they deal with privacy? One idea that Spencer and I have been kicking around is some sort of encryption key where you’re the only one that can unlock it, which is the kind of thing that is relatively common. And now with block chain and all of these crypto companies we could just cryptify your genome. So you are the only one who is able to unlock it that way. Of course the problem is if you lose the key, it’s gone. But then sequencing is pretty cheap too. So you could just do it again, so that’s one solution. 

Razib: The issue with genomics is, aside from somatic mutations, your sequence does not change. Your germ line mostly doesn’t change, there’s a few mutations over time whatever. Anyways so if someone has it, it’s there, they have it forever. So my genotype and a GCF Of my whole genome sequence is actually publicly searchable, if anyone wants to search Razib Khan genotype, you can find them. I’m not scared personally because I’m not an important enough person, where someone would design a bio weapon to come after me. I mean it would be way cheaper to hire a hitman.

Grant: Did you already buy life insurance?

Razib: I do have life insurance. So you know but if I was the head of state somewhere there would be a concern. Maybe. Maybe. Bioweapons are expensive and not very effective. I’m not super worried about that. There will be a point where sequencing is so cheap and so many people have done it in so many different places, that I do wonder if privacy concerns will just disappear. You know we share a lot on social media about ourselves and nobody seems super stressed about it even though if you had talked to people like a couple of decades ago they would be like “that’s creepy.” I wonder if people will be more chill about it in the future. One of the weak points is hospitals. They are not very good about data protection. Like there have been traditionally problems with a lot of hospitals. And they usually just pay a fine and they’re like whatever. The issue is if you do your genome and they release it by mistake…

Grant: Once and done. 

Razib: Yeah it’s out there. It’s out in the wild. And so I don’t really know the long-term prospects for privacy. I think in the short term privacy is feasible if you care. I don’t care, but if you care, there are services you can go to that are very bespoke, where you can be sure and trust that they are deleting your data and stuff like that, but that’s not going to be the thousand dollars genome or $300 genome. That’s going to be people that will charge you a premium because they are going to validate everything in a way that you know that they are deleting everything. They are sending you a physical copy. There are things you can do like that. I think in the short term, we don’t know for sure, but I strongly suspect that a lot of consumers are going to be okay with a lot less privacy than you would think.

Grant: Yeah it seems to be. I am on 23 and Me under a pseudonym. I paid cash for a prepaid card. I had the kit shipped to another state and address that was completely unconnected to me and through a series of coordinated happenings, I got the kit in my own hands, but of course these things can be triangulated through family members and what not, so it’s not foolproof. 

Razib: Yeah I think if you are a white American, it is highly likely that you are easy to identify. Like it’s 95% likely now just because there’s enough people in there. Like if you’re adopted and you don’t want to know who your relatives are, do not do this because you’ll automatically get a match. And maybe you’ll delete it from your mind, but that’s going to give you information automatically. So when you have 10% penetration that’s penetration for almost all the pedigrees for Americans. There’s still some gaps for black Americans although that’s closing and other groups. But really the way the statistics of this works is you don’t really need to sample that much to get all the pedigrees.

Grant: Right. Interesting. So based on the mumbling so you hear what things do you expect to transpire in the coming years that you think relatively few people are expecting.

Razib: I don’t know. It’s difficult because I don’t talk to normal people about genetics so anyone I know, they know everything because I talk about it like yeah this is going to happen. So for example I talked to my friend Rob Henderson and he’s a prominent person. He’s a writer he happens to be from kind of a lower class background and he went to Yale. He didn’t know who his biological father was. He’s getting his PhD in social psychology I think at Oxford. He’s a smart guy. He was shocked when I told him “don’t do a DNA test if you don’t want to know who your dad’s family is because you’ll automatically know.” And he was like “really?” And I was like “yeah if your dad is a generic white American it’s in there. You’ll automatically know.” If you’re ambivalent, which he was, you shouldn’t do that. 

Razib: I think I told Grant the story I don’t know if I did, it’s a really weird story. One of my friends had heard that his dad had had an affair and he had a half-sister. And he was like “Should I use one of these tests to find his half siblings. What are the chances?” And I was like “You’re going to find something, not necessarily the half sibling but you could figure things out of who’s related to who and all the stuff.” He did get a match of someone who looked like a half sibling, but it turned out it wasn’t a half sibling it was his stepdad sister. So he found out that his stepdad is his biological dad. He said he’s not gonna tell his mom, and he’s not gonna tell his stepdad, who he hates. And so these are the things that are going to come out. And I don’t even know that his stepdad knows because I think his mom probably, you know. His mom might not even know about his parentage. But my friend’s problem is he saw the match with his stuff and so she probably saw the match with him. So don’t open some things that you don’t know how to deal with. It’s like a Jack-in-the-Box coming at you. Don’t be surprised. 

Razib: And sometimes it’s funny and silly works like I had a friend and she’s like classic southern California blonde and her husband who is 100% Irish American but she’s like “I think he’s part black because of his features“ OK I was like “well you know you guys should just do the test” because you know they wanted to have kids. It turns out they both were hemachromatosis carriers or something, but it’s not a big deal. It’s whatever. But here’s the funny thing: he turned out to be 100% Irish, and she was 2% African. And so we figured out that there is a blank spot and her mom’s genealogy from the early 19th century. This is not a shocking thing. It’s just a big laugh, that she was looking for black ancestry and her husband, and it turned out that she herself had had an ancestor who passed from black to white in the early 19th century, which is not super over the top. And so that’s silly. That doesn’t affect a lot of people. 

Razib: But with the genealogy thing you might think it’s silly, but for a lot of people it shakes them in weird ways. I didn’t find anything super shocking. I found some surprising things, but nothing that was super shocking, so I can’t relate to that personally. And honestly who really cares who your ancestors were. That’s just my personal opinion about me, but to a lot of people it’s a much deeper thing. And there’s all these stories that go along with it. 

Razib: I consult on Skip Gates’ show. I didn’t mention that at the beginning, but I consult on his DNA show on PBS. And so George RR Martin he has a thing where his paternal grandfather is Italian and he’s from Jersey and he’s got this Italian background, but actually it turns out that his paternal grandfather was not his biological paternal grandfather. His paternal grandmother was a secretary for a Jewish guy and that’s his biological grandfather. So when he found that out through the genetic testing, that he’s 25% Jewish not 25% Italian. Now I’m only bringing this up because— I didn’t watch the episode and I don’t know how he reacted but— he always had this schtick that he would talk about how he was like Martino or something and he’s Italian and he’s from Jersey. And he can kind of keep the story because that’s how you’re raised but his understanding of being Italian… I don’t know if he wants to bring up the fact that “Well I’m also part Jewish” you know, there’s a lot of things like that that change family stories and that’s not super significant. 

Razib: The disease stuff can be super significant. I’ve had to talk to friends about stuff they found that was surprising, which was sobering because the disease stuff is never “it turns out I am superman and I have super powers.” There’s no gain of function mutations that give you a secret invisibility power that you didn’t know about. So it’s never positive really. I mean for some people it’s positive where they didn’t have the risk for something that was autosomal dominant but really mostly it’s a bad thing. 

Grant: And of course something like that wouldn’t be shocking right? You kind of just do a punnett square or something and you know.

Razib: Yeah, so for other people I have found out things that a lot of people don’t connect you into so I’m not always aware of things that are or aren’t genetic. So I’ll give you a concrete example of this. A friend of mine is at high risk for cataracts. Very high risk to go blind early in the probably have to do surgery and hopefully they’ll have a correction. But his family is from India And one of his parents went blind, but that’s just very common in India because of my infections and stuff. And so that’s what he assumed it was. Because that parent had an eye infection of some sort and so the doctor said “oh it’s probably because you have the eye infection and that’s causing the blindness” and all the stuff. And so that’s when my friend knew. And I mean he’s a college educated person he has a science degree and so he just assumed that that was what it was, but they got his parents tested. And they both have some sort of autosomal dominant trait where you have a 50% chance of getting cataracts by the time you’re 50. And he’s 37 now. So you know, it’s just something that’s on his mind. He has a 90% chance of getting cataracts by the time he’s 65. And I haven’t kept up with the surgeries that he might have to do to not go totally blind. But that was an awkward conversation because when he got the testing I was like “oh there’s only a small probability that there’s going to be anything that’s going to be a problem”, which is true. Your prior is that you’re not going to discover anything new, but there’s going to be a minority of people who are going to discover the new thing. And it’s not going to be a little new thing. 

Razib: If it’s a disease thing, it’s going to be a big thing if it’s going to add value. Because knowing you have a 1.5 greater odds of developing type 2 diabetes is not that big a deal. That’s not really actionable, and that’s not gonna change you very much. But knowing that you have 25 times the odds of getting cataracts by the time you’re 20 or by the time you’re 50 is a big deal. And I felt kind of crappy because I told him honestly “Don’t worry bro you’re not going to find anything. You don’t know anything from your family background“. That’s literally what I said. But there are things like this that happen. And I think this sort of stuff is going to affect our lives in the next decade. And how that’s going to affect consumer purchasing decisions, I don’t know. That’s just an awkward sell. But the kits and the tests are going to get from the people that are deploying them to the people that are going to use them, and that’s going to go back to the doctors. It’s got to go back to the healthcare system. That needs to happen so that people can make better decisions with their lives. Now I kind of sound like an infomercial here, but that’s what it is. It needs to be informational to people about why you want to do this. Some people want to put it off as long as possible, and that’s a choice. 

Razib: In some countries they’re not going to give you the choice. I’m 90% sure that in Britain they’re not going to give you the choice. Because the healthcare system is soup to nuts. They take care of you top to bottom so they are invested in you. They can make the decision for you. And they’re going to nudge you. And they’re already nudging people. And they really want to nudge you hard. So if they find out that you have certain risks or dispositions, they don’t want you to make life decisions that get you really ill because then they’re on the hook for it. 

Grant: And certain HMOs might be the same way.

Razib: Yeah. The issue with HMOs in the United States is they are very sensitive and vulnerable to bad public relations. When you have a government monopoly, they are much less sensitive to bad public relations. As long as the government doesn’t cut their funding, they are fine. That’s the downside of a monopoly. That’s the downside of socialized medicine run by the government. There is no way you have leverage against it aside from through the government itself. The upside is that they can make some unilateral decisions. I do think a lot of innovation might actually happen in Europe because it’s a monopoly and people are scared in the United States. People are scared across the whole world of genetic science partly because of GATACA and the Nazis and all that stuff. Now, use correctly it can make your life better. 

Razib: And so how do you get people over the hump? Well in a system where the government has socialized the cost we as the individual don’t have the final choice on everything. And I think that might allow certain innovation to happen and then it eventually will come back to the United States as people see “oh they’re not using it to round up the genetically unfit“. And if they are using it to round up the genetically unfit then we’re not going to do that. So I’m just saying that we are going to see some experimentation across the whole world with this sort of science and with this sort of technology and we’re going to see what works and what doesn’t and how things work differently.

Grant: Yeah it’ll be interesting to see what happens in China in this space.

Razib: That’s a word for it. Interesting yeah.

Grant: So where do you think science is going and the ways that we do science will change over the next 1 to 2 decades? Tech and all the knock on social effects of tech are kind of revolutionizing everything. What do think this impact and the broader political impact will be in science and in the context of science? 

Razib: I mean it’s weird. Science has had multiple phases. Science and technology have had multiple phases of enthusiasm. Sputnik era: enthusiasm. 1970s: Environmentalist movement etc. etc. and then I think like in the 80s and then into the early Internet era–I mean not to be the old guy but I remembered 1995 to 2000–oh my god we were so optimistic about the Internet. We didn’t realize at the time. 

Grant: Democratize the world right?

Razib: Yeah it’s like “oh I can talk to somebody in Ecuador.” I specifically remember having a chat with someone in Ecuador, and I told my friends the next day “I talked to somebody in Ecuador” it was so amazing. And now it turns out that I didn’t anticipate how toxic Twitter would be, how social media would be used to destroy people. All of these things you can go back and read about it, people did not anticipate that. We didn’t understand the human capacity for depravity. And I’m using that in a very broad broad sense. Like Facebook has been used to coordinate ethnic cleansing in some countries. Like we didn’t anticipate that. We thought it would bring people together, and today I think that a lot of people when they’re not on the web. When they’re not on the Internet, they are happier. Like being disconnected is a thing when I get an email it’s a “now what?” sort of situation. Whereas 25 years ago or even 20 years ago I was like “who emailed me!?”

Grant: “You’ve got mail”

Razib: Yeah it was exciting. Like “oh my girlfriends emailing me”. Like I remember that was a big thing “oh well she emailed me today”. Even though we saw each other every day. So that was like an exciting thing and now today I just don’t want to be bothered. I get a lot of requests because I am a “public person” and so I get a lot of direct messages and sometimes I try to respond. I can’t respond. All these questions and I just can’t deal with it. And it’s made the whole world accessible to me but now I’m accessible to the whole world. And that’s a downside of information technology that we couldn’t anticipate. 

Razib: So what about genetics? I don’t think that we know all of the consequences of knowing all of your relatives. We’ve talked for decades and genetic science about how this is going to affect dating. So I have never done anything like Internet dating. I’ve been non-single since the year 2003. So this is all abstract for me, but I could see there being a situation, where it’s like in the Jewish community where everyone know is a Tay Sachs carrier. You don’t wanna marry somebody with that. Well it’s just like automatically with your dating profiles you might do an intersection with carriers so that you know. A lot of people if you’re just on Tinder you’re not thinking that far into the future but if you’re a match.com you might be. So depending on your level of seriousness you might want to exchange the information ahead of time. 

Grant: It’s more efficient unless you want to go through IVF. 

Razib: Yeah you just could get it out of the way. Some people don’t care but if you want to anticipate having to do a pre-implantation diagnosis which some people might have to do. Maybe just get that out-of-the-way. I don’t have it be a surprise. And they’re all sorts of weird things like some people have bad credit I mean do you ask people immediately? Probably not. The questions about people that you don’t ask immediately and there’s other things that you do. I don’t know if the genetic thing is going to be one that you were asking mediately. 

Razib: The issue with genetics that I tell people is genetics is also something that you see on someone’s face. So you see me and you automatically know kind of where my ancestors are from. My risk of being a cystic fibrosis carrier is is quite well. You just know that as a prior. It’s not like genetics is a total mystery to people. It’s like you kind of know how much money someone makes by the car they drive the way they’re dressed. There’s always information you can get from people and it’s how much you want to put out there. 

Razib: The thing with genetics though is you could fake a sequence, but your genes are your genes. I’m just being honest about it and at some point we’re probably going to have to do some validation services, where you provide the SSL of the sequence. Because what if someone sends you a fake sequence? Because they don’t want to tell you that they have some autosomal dominant trait. It’s common and dating services. What if you carry the dominant for Huntington’s. Even if people are interested in a serious relationship they just don’t want to deal with it. Because that’s kind of heavy. 

Razib: I know people–well I don’t know them personally–but I know a woman whose sister has Huntington’s. And her nephew won’t get tested because he has a 50% chance of being a carrier. You know, she tells him that he should be super serious about protection then. Because she basically said he’s not the most responsible kid. Well, what if that’s on dating profiles? What if you can check it? It’s just like when you, when you blackball people for employment because their credit rating is bad. That’s kind of unfair in a way.

Razib: So is it unfair to not want to date somebody seriously that has Huntington’s? Cause they’re going to develop Huntington’s if they carry the autosomal dominant. Right? So, I mean, these are social questions that we don’t have to confront today because most people haven’t gotten sequenced. And Huntington’s as, as you guys know, it’s a repeat. And so I’m not sure if it’s going to be on a genotype array, like you’d have to do some sort of tagging. So it’s not even trivial to just have it with your 23 and Me. Even if they could provide it, it has to be like whole genome sequencing. So the technology is a little bit in the future, but it’s going to be something we confront.

Razib: Like if you are a person that has an autosomal dominant disease, that’s going to present later in life. That’s pretty, that’s pretty heavy. That’s pretty heavy. And this is why a DNA test for Huntington’s disease is not a feel-good consumer product. Like this is a problem. 

Grant: Yeah. So where do you think academic science is headed?

Razib: So basically COVID-19 has accelerated certain things and the financial crisis in academia that was going to happen because of demographics because Zoomers are a much smaller generation than millennials. What was going to happen is happening now.  

Razib: There are some departments that are laying off. Mostly not in science. STEM is not predominantly dependent on tuition money or liberal arts colleges are when universities get NIH and NSF.  So academic science is special in certain ways where there are certain types of innovation, certain creativity that occurs there that is really difficult to happen, or really does not happen in industry because industry is more siloed.  Just the way sociology works, right? You don’t get the cross-fertilization in the seminars just doesn’t happen. So there’s a reason academic science is there. 

Razib: I do think academic science is getting too politicized.  What’s the next consequence?  One consequence is when people are looking for what to allocate resources to. The national science foundation, NSF funds, non practical things. That’s its goal.  It will have practical implications, a lot of the time, way down the line, but NSF is where you go if you’re an ecology lab and you’re not going to get funded by the NIH, which you’re not. I mean, there’s different ways, you know? So I think that will be cut. 

Razib: I think, I think trust in academia and faith in academia is declining. That means public academia, public academics will have problems because if you’re in a red state, when they go to allocate budgets, they’re going to cut.

Razib: Now. I know universities get a lot of funding from various sources. I don’t really know how comfortable a lot of academic scientists are going to be with public private partnerships, but that’s probably going to be a thing just to survive. There’s some universities, agricultural universities, where I went to UC Davis. They were actually very happy with that. And that’s part of the tradition. Monsanto, or whatever the company is called now, has a lot of projects there. But a lot of academic scientists and universities are not happy with this.

Grant: Hopefully Nassim Taleb is not listening to this podcast. 

Razib: Well, if he is, he’ll say we’re morons and idiots. But Berkeley for example is very, very anti Monsanto. Anti-public private. I’ve had friends, who were discouraged from ever looking into that because it would be seen badly kinda by their department, but I think they need to look at that because the funding is going to be an issue. There’s also overproduction of scientists.  They’re not all going to land in academic spots. There’s going to be a reduction in R2 universities, research 2 universities, liberal arts colleges that absorb some people. That means everyone’s going to be competing for the same few spots. They’re already having, you know, a thousand applicants for one job, so it kind of seems a bit like a hellscape.

Razib: A lot of people are going to be really stressed and anxious. You know, in a way academics are actually quite privileged.  When I was a grad student at UC Davis, I got the best health insurance I ever had by the way, because the UC system is part of Cal, the California buying system. And so they buy gold plated insurance for everybody, at least for graduate students and above. And so, there’s a lot of good perks that come with it, even though people complain, and that’s not a law of the universe. It’s the way our American society works today to give people the leisure to study things that they love and that they’re passionate about. 

Razib: Like I talked to some people on the Senate staff who were prominent Republicans, I’m not gonna name who, but you’d recognize the name. And they were like, “yeah, we can’t defund the universities cause they would say that we were like primitive barbarians, but the first chance we really get without the media saying that, we will do it.”  

Grant: Well, I mean, it’s been quite interesting, as you mentioned, the broad based support has fallen apart in relatively recent times and in just recent years. And this politicization is nothing new in the humanities and so on. It is newer in terms of the kind of openness of the contempt and things like this in the sciences.

Razib:  The whole atmosphere is very, very hot-housed and hot houses, uh, they eventually burn out and so it will. You know, what cannot be sustained won’t be. And I feel like that’s going to be the issue in academia, which might be good for industry.  More people with abilities and skills and talent will go into the private sector, but we’re going to be losing something. We’re going to be losing some really curious creative people who might’ve gone in some impractical directions that would give us some real innovation. 

Grant: Do you think there’ll be a decoupling between traditional universities and funded research? 

Razib: I think there will be more, there’ll be more or diversity of think tank research institutes. And also I think we seriously need to consider the European technical university. Technical universities exist to further technical knowledge. Period. Right? And that’s fine. People would fund that. I mean, you can be a communist who cares. If you’re working in solid state physics, and you’re building a better microchip, nobody cares. That’s your business what your politics are. 

Grant: So I want to make sure we have some, some time to talk about the elephant in the room before we wrap up: COVID.  What the hell happened? How did we end up here? And where do you think things are going? 

Razib: Yeah. I wrote an article in City Journal in April where I simply said it was elite. So people can Google “Razib Khan City Journal.” But basically I said the elite systematic failure. I should have probably emphasized Trump more if I was going to be totally honest, but I didn’t probably because everything when it becomes about Trump, it goes crazy.  So I didn’t say much about Trump in the piece. So my thesis is the American society as a whole is obsessed with symbolic, you know, like, postmodernist stuff where it’s about the word you use and the representation and the symbol. And that is actually what Trump is good at. He’s good at these nicknames, but what will we really need to lead us right now as an engineer? Like some of them I can do the cost versus benefit that can do the math. That’s not our political elite right now. In fact, our political elite right now is mostly lawyers. They’re mostly talkers. 

Razib: So as listeners know, you can’t debate COVID away. You can’t beat them by out-arguing them, by redefining them. Trump has kind of tried to do that a couple of times. Even into the middle of February, you were crazy. Like all the cool kids, all the blue checks on Twitter said you were crazy. If you expressed worry–and I’m not talking about Q Anon and Maga Twitter, I’m talking about Vox and you know, like, Huffington post people–and they were saying like, “Oh, these Silicon Valley guys are just weird, and it’s only like anti-Chinese racism.”

Razib: And so they were more preoccupied about whether we were racist against Chinese people, than whether there was a pandemic happening. Right? COVID doesn’t care about our categorizations. It doesn’t care about our borders. It’s just a force of nature.  It’s like a typhoon, it’s like a tornado. It’s like an earthquake. 

Razib: We shouldn’t be fighting COVID because it’s impacting poor people or people of color. We should be fighting COVID because people are dying. Period. Right? It doesn’t matter–like in my opinion–it doesn’t matter what their race or what their class, what country they’re in, how old they are. One of the elephants in the room of COVID is it really affects old people in nursing homes.

Razib: Um, No offense to Americans or Europeans because there was an article about Belgium.  It’s kind of shocking to me when I think about it, what we do with old people, by packing them into nursing homes and visiting them every now and then. 

Grant: Out of sight, out of mind.

Razib: The mortality rates in some of these nursing nursing homes in New Jersey or in Europe is terrifying. Like large numbers of people are dying. They’re dying miserably. They’re dying horribly. This is why some of us were alarmists. And the fact that we’re not talking more about this says a lot about us as a society and our values. Yeah. It seems to me there’s been very, very little mourning in Paris. They just pushed it out of sight. Out of mind. 

Razib: One of the complaints that I have about the media is they emphasize young attractive… like I believe that every single young, attractive white woman who has died from COVID has been profiled in the media. Okay? I think that the media wants you to think that it could be anybody and it could be, especially these precious people.

Grant: Well, what I found really interesting about the coverage too, is the age range that they look at for that. Right?  I mean, certainly the mortality rate is through the roof if you’re 80 years old and so on. And, in our County, for example, every day, when you have new deaths in that age range, they just list the ages and that’s it. But what’s fascinating to me is that’s also the case for the 55 year-olds, the 60 year-olds, you know, the, the 40 year-olds will get a writeup in the paper. The 20 something year old, certainly will get to write it up. But even the 55 year-olds will get a write up. 

Razib: Yeah. If you’re an old gen X, no. You’ve got to be a young gen X. Now you have to be a millennial. Actually, you just have to be a millennial. If you’re a millennial, you’ll get a write up. It’s generational discrimination. If you’re generation X, no.  If you’re a boomer, no. If you’re silent. Hell no. 

Razib: The thing with the nursing homes is I’ve only read a couple of things because it’s painful to read. We have a sociological problem that I knew intellectually in an abstract way, where the way we in “developed societies” treat our old people is that we rationalize them, just like we rationalize everything in the economy. And so you take your parents, you put them in a nursing home, and they’re taken care of by people who get paid money. What could go wrong? So in normal day to day, that’s fine. You know, even though there are abuses, we all know about it. I’m just saying like, they will take care of them for money, but now there’s a pandemic that they can catch as well from these old people who are miserable, who need extra care and attention.

Razib: What I read sounds like, hell. This is not the way that you would treat your own. Cause you want these people to treat your parents like they would treat their own parents, but they’re never going to. They’re not blood. That’s not how it is. It’s like, we’ve rationalized it. We don’t want to think about it.

Razib: And so the things that I read in the nursing homes, I’m like, “Oh, this makes sense, in a way, because these are people who are probably being paid minimum wage to take care of old people.  and you know, a lot of it’s been really uncomfortable. There’s some gross things and now they’re really sick and they can be contagious to you.”

Grant: You know, what’s been fascinating to me too, is these, these horrific cases, where several bodies were found days after death and it had never been reported and so on, aren’t just happening in, you know, nursing homes in New Jersey, but even in places like Spain, in cultures where that’s not…

Razib: Traditional yeah, but it’s becoming more traditional. And old people, a lot of them, want their freedom. They want to live alone. Sometimes it’s difficult to get them to give up their houses. And I know this personally through my extended family. And that can be a problem. So we have freedom and we have this great economy that provides services to give us this freedom, but I think the problem is we also see the flip side of freedom, where, when push comes to shove, when nature red in tooth and claw comes at us, all of a sudden, you understand why people live in these extended family units, where people can distribute labor and, and things like that. Where it’s not just about the money, but it’s about just the community. And it’s about helping your, you know, relative helping your friend, these sorts of things. I feel like we’ve lost a lot of that. Not everybody. Not every community and not every person, but I know a lot of people who are very alone right now. 

Razib: Quarantine has not been that difficult for me because I’m with my wife and I’m with my kids. I am with my family really as we understand it in the United States, but there are friends that I have who are single, whose lives were socializing with their crew. Sometimes they have to create pods, but it’s whatever. I’m just saying. Those people underwent. Are undergoing or underwent something very different in quarantine than I did. And that’s because of the way we live and arrange our society where people can live alone and have all their conveniences and not be bumped by their parents or roommates or their siblings and all these other things. But the flip side of that is when the water recedes, just you. That’s it. 

Razib: So, I don’t know. I honestly don’t know what to say because I didn’t think we were this society. I didn’t think Europe was that society. Like I read the article in the New York Times about Belgium. The government was quite clearly giving the, go ahead, not explicitly, but through some channels for emergency, that paramedics should not pick up COVID-positive people that were dying in nursing homes in Belgium for a while. Because they wanted to keep the hospitals free for people or more valuable actuarially. They were making the calculation.

Razib: I think that it’s been a good opportunity in some ways for genetic scientists. Some companies have gotten on board with COVID testing and sequencing and doing all sorts of things and there’s been some good research that’s come out of it, but it’s been a horrible indictment about the sociology and political science of this country. Not the science, the science has been okay. I think science has done what it can do. And the primary problem is we had a state capacity issue where–I think, you know, Grant–most people “in-the-know” were starting to get seriously terrified by the middle of February. And then when Iran hit around 20th, I remember screaming at what Donald Trump was doing, going to India right now, when he needed to just like start really turning the ship around February 20th. As it is, it was closer to March 15th. Those three weeks were when New York became what it became. That’s when New York was seated. I think we could have dodged New York. I think we got to dodged that, that horrible thing that happened in New York, New Jersey and to some extent, in Connecticut, if Trump had started on February 20th. I think if he had started on February 1st, I think,  honestly we are society is, I think the resistance would have said he was being insane.

Razib: They would have eventually come around. But I think for a long time that he would have been attacked because he shut down the economy and did this and this, and you know, it’s only some dumb Silicon Valley bros and paranoid people and a couple of epidemiologists. So I think that would be too early.

Razib: Ideally he would have started that early, but it wouldn’t be feasible. But I think by February 14th, I think enough people were sure that he could have done something and he didn’t. But you know what? Cuomo didn’t do anything either, did he? DeBlasio didn’t either. So it’s not just a Republican thing. This is not a left-right thing.

Razib: Actually, there’s a lot of blood on a lot of people’s hands in our society, in our elites. And, I don’t think that they will be held accountable. They weren’t held accountable in 2008.  when the financial crisis happened, when a lot of people made a lot of money and the government as a whole bailed out the system, you know?

Grant: And people are upset and, honestly, it seems like a lot of the anger is directed at the measures as opposed to people mourning the deaths from the virus or people being upset with the incompetence, with which it’s often been handled. 

Razib: Yeah I mean, so I think part of the issue is there’s been weird enforcement and weird fixations, and some of it is ideological. So like Florida people on beaches: bad.  Black lives matter protesters: Good.  That was pretty obvious.  Also remember that party of the Ozarks, that was the first big thing that the media caught, and it’s obviously like, let’s just come out and say it: like rednecks and the Ozarks, these are bad people. They’re doing something bad. Well, it turned out there wasn’t that much transmission at all, from what I know because it was outside. If it’s outside, it’s probably not that bad. BLM, those protests, are probably not that bad.  So the outside stuff: not bad.  Inside stuff: bad.

Razib: Right. So when I hear Biden saying, “we should have masks outside”, I’m like, “eh, you know, mandatory mass outside is probably overkill.” I mean, you don’t want to do so much that people don’t believe you. I think that there is a problem with some credibility there, that people need to be more measured. They also need to talk about the fact that we’re working with the best science we have, and that might change. And we apologize if we lead you wrong. Cause they did. They have, and we will.  

Razib: There needs to be more humility, less screaming.  Also some people are just using it to kind of be self-righteous pricks, you know? That’s not getting us anywhere. Like you need to, you need to persuade people with the facts and also, like, show empathy. You’re trying to persuade someone. Not because you want to be right, but because you want them to live. Sometimes I hear some people talking or I see things written and I feel like you’re kind of just showing off about how you’re right and they’re wrong, instead of actually writing in a way that indicates to me that you actually care that these people survive.

Razib: And some of the stuff that I’ve heard people just in my social circle or the media say about people dying in red States, they’re almost, like, happy that these people are being insane. And I’m like a lot of them are economically the same type of people that are like Latino field workers and Riverside. I mean, they’re working in agriculture or in rural areas. And, this seems really inappropriate to me. Like you’re missing the forest for the trees and what’s important. We have a pandemic in this country. It’s about people dying and it’s not about who’s dying.

Razib: You know on the other side, like I have heard things about when it was happening in New York and New Jersey where people were just like, “wow, it’s a blue state problem.” And the fact that we are hearing things like this, that people even say this out loud shows you the problem we’re in, in this country. Like if you’re saying it’s a blue state problem, it’s a red state problem. You know what Obama would have said in 2004 is “There is no red America or blue America,” but I guess that’s very 2004. Like it’s done. That’s all. 

Razib: Or I don’t know, I’m being very pessimistic here, but I don’t,  I don’t see a unifying vision right now.  I don’t see a society that can stitch itself back together.  Sometimes these sorts of external shocks can bring people together, and I feel people were brought together for kind of like a month or two. And then it just all kind of unwound in May. And a lot of it was just economic pressure, which a lot of people have been under. And that’s difficult. I mean, there’s just a lot of difficult conversations that I feel like people are not having compassionately. And I think that’s been the ultimate problem.  When people are acting out in a crazy way, sometimes there’s a reason, you know? 

Razib: I have friends who are academics. And I’m like, “you have like a tenured job at an R1 university. Your salary is going to keep getting paid indefinitely.” I mean, yeah, the university could lay you off, but that’s very unlikely with the type of job you have. Okay. You can do social distancing. You can stay inside.  There’s a lot of people who are living paycheck to paycheck and they’re not in that situation. And this is why they’re not being as rational as you, not just because they’re stupid. I mean, they’re probably not as intelligent, whatever, but really they have no options. They’re desperate. 

Razib: There’s that survey that showed that like 30% of young adults have thought about suicide in the last six months. And obviously it increased. I think some of it is hysteria and scaremongering because young adults are not at risk of dying of COVID, but some of it is also like they don’t have a job. Where are they going to get a job? What is the future of this country? There’s a lot of hopelessness, you know, and instead of us stepping up or at least stepping up to COVID-19, we’ve kind of fallen down on the job.

Razib: That’s how I’m feeling right now at the end of the summer of 2020. Maybe something will change and turn around and I’ll be smiling and I’ll be happy. But I stopped–you know Grant, we’ve talked about this–I stopped paying close attention to coverage in June, just because. It didn’t seem like we had what it took to really attack it. And so I will continue doing my quarantine as best as I can. And that’s it. I’m not, like, there’s only so many people I can talk to, only so many people I can convince. We convinced our family and friends that we could go to quarantine early. That took a lot of work in March. That’s done. And as far as the rest of society. I’m not one of those people that’s like, “Oh, you don’t wear a mask. You should die.” Okay. I want to convince people that aren’t doing it, why they should. Okay. But I’m also going to express my alarm. I mean, I have friends who are just like, you shouldn’t be alarmed like this isn’t that bad. And you know, it’s just like, when I read about the way people die, it’s bad.  

Razib: The only hope is–this is the positive spin I will put on it. I just actually had another podcast today that I recorded with someone about COVID-19– I do think that herd immunity is probably a little lower than 50% for various reasons. So it will end even if we don’t get a vaccine, and we’ll pick up the pieces and figure out what this means for us. Because I think after it ends, I feel like people can take a breath and kind of take stock. And I don’t know if they’re going to be happy with what they conclude about our society. I don’t think that we’ve fully processed it because it’s not over, we’re still in it. You know, we’re still like waking up every day, checking the news, checking in with our family and our friends. More and more, more and more of my friends have gotten COVID-19. Not that many, but some of them have tested positive and they have the symptoms, and it’s going through my network right now. But,  I don’t know. I’m just kind of on a pause right now. And I feel like our society is on a pause, but COVID-19 is not on a pause. It looks like it’s slowly winding through and we might be incompetent enough that herd immunity is what protects us. So yeah, on a down note, that’s my COVID talk.

Razib: [laughing] I don’t know. I shouldn’t laugh. I mean, it’s just like, what do I do? This is a nervous laugh. 

Grant: Yeah. If I were forced to prognosticate about it…

Razib: Dark times, man.

Grant: I think there’s a good chance. We’re going to hit some kind of a, I don’t know about a real herd immunity, but at least an effective herd immunity, transient herd immunity, under conditions of social distancing before we get to a vaccine.

Razib: Well, so I don’t know. I think this will change. I think coronavirus will change some things.  I don’t know if I’m ever going to shake hands again. It was always one of those things where I kind of did it because of social pressure. I just didn’t really want to touch someone’s hand. I don’t know where they are, what they’ve been doing. And also like in business, when you shake someone’s hand, I’m always thinking, “okay, how many hands has this person shook today? I’m not just shaking your hand, dude.”  I mean, I’m gen X, I went through the HIV training and that took. Okay? I extrapolated. So I’m not going to shake hands. There was some stuff out today about how teens are not having sex and not like interested in it. You know, I think this is going to affect a lot of people with personal contact until we have a vaccine.

Razib: But even after a vaccine, like this is the first big infectious disease that we’ve had, that has hit our public consciousness this way and had this impact since the 1918 flu. I know the 1957 flu was as bad as this in terms of mortality, but our culture was not impacted in the same way.  

Grant: No one talked about it and it’s very strange.

Razib: There are some newspaper reports about it. People died, but the economy did not get hit that badly. 

Grant: It didn’t imprint on people’s consciousness. Right? Sure. It was in the papers and people working in hospitals obviously noticed. People knew some folks who died and so on, but it wasn’t super new. It wasn’t really remarkable at the time. 

Razib: The world is different. And our economy, the downswing was as big as the great depression in some ways. I mean, it’s obviously structurally different, but you know, I mean, okay, like this is worse than 2008. It is worse than anything since World War II, you know? Great leap forward was really bad. There are bad things that happened after WWII locally. But this is I think the biggest global event since WWII.

Razib: So how can it not affect us psychologically? How could it not change us in terms of how we see. Like when I, when I see movies or TV shows where people are in bars, I get the heebie-jeebies.  I think that will eventually fade, but it’s gonna take a long time. And I think there’s going to be a lot of people on the margin who are already germophobic. We’re just going to say, “you know what? I lived through 2020. I don’t want to take the risk. I don’t want to take the risk. I will drink at home.” Or if you’re going to invite me to drink, it’s got to be a patio place.  

Grant: Well and the virus probably isn’t going to disappear. Right?

Razib: It could be endemic.

Grant: We may get control of it, but it’ll still probably crop up here and there.

Razib: It’ll be endemic. Yeah. So that’s what we’re talking about. I mean, that’s what we’re seeing in places like New Zealand that controlled it. Like it just creeps back in. So until it evolves and gets us really.  I think it’s going to be here to stay. Now that does mean work demand for services of biological scientists. So, you know, undertakers did really well during the black death. I’m assuming. I mean there’s work for people even in a time of COVID-19. In a way I feel like the economic and even the mortality impact is going to be dwarfed by the cultural, social, social impact. 

Razib: We have small children, Grant, and they just kind of accept coronavirus. My three-year-old will yell coronavirus at people if they walk too close to him when he’s in the front yard.  My three year old is also really morbid. He thinks all old people die of coronavirus. Someone recently died that we know, and he’s like, “did he die of coronavirus?” And we’re just like, “dude, there’s other diseases” But he doesn’t know any other diseases. All he knows is about coronavirus, people talking about coronavirus. And I don’t know how my kids get the news. My son has kind of Browner skin and he’s scared of the police, you know? Not even joking. He’s just telling me he should be scared of the police. I’m like, don’t worry about it.

Razib: It’s just like, you don’t know how kids find out these sorts of things. As adults, we’re trying to pay the bills and not get sick. And you got these little kids running around, all these little kids and like, what are they thinking? You know?  It’s just really weird for them because I have a sister who has a newborn or infant.  We don’t know if she’s scared of strangers or he’s scared of strangers. He’s never seen a stranger! So he’s seen doctors, seen parents and seen grandparents. That’s it. Those are the only people that that three month old child has ever seen up close. Right. So, I think we need to think of the social impacts. It is the big thing about COVID-19. Cause I think we know what CFR is, you know, 1%, I don’t know, something like that.

Grant: And actually, so, you know, you mentioned one positive thing about the herd immunity threshold, possibly being lower than anticipated. I’m not sure, but we’ll see and time will tell, but, the CFR does seem to be going down. So the mortality in hospitals, the unadjusted apparent mortality is down dramatically. 

Razib: And also the people who are getting it are the less. Unfortunately, the more vulnerable people probably got hit first.

Grant: Even adjusting for the various risk demographics and so on, mortality in the hospital is still down substantially from the beginning of the pandemic and it looks like it’s down about 40%. Treatments like Remdesivir and all these things, right? I mean, seem to be making a difference and maybe people are getting initial viral loads that are a bit lower. Cause they’re  keeping better distance, wearing masks.  You know, if you were sitting right next to someone at a bar in New York City before they really realized what was happening, you probably would’ve gotten a higher initial exposure. 

Razib: So I think, you know, my discussion on COVID-19 has been very pessimistic. I think from the purely biomedical perspective, I’m cautiously optimistic. I do think we, as in the world, are putting a lot of resources into vaccine work, and I understand vaccines are difficult to develop. They’re not trivial. They’re often not very effective. So I don’t want to oversell this, but everyone’s focusing on this. I would not be surprised if we have a good vaccine in two years, perhaps a year. I have heard that China and Russia are already vaccinating people in government and their army. So, We’ll know how those trials work, you know what I’m saying? They can take a few risks that we couldn’t in the United States. So I think treatment’s going to get better.  So I think the mortality will drop. So from a purely biomedical perspective, we will make it through this, just like we did with the ’57 flu or the milder ’67 flu or the ’68 flu. 

Razib: So that’s doable. I think what COVID-19 though has shown is, what is the measure of a society? If I had to bet if we had like Mitt Romney, I think we would be doing considerably better. Okay. I just like slopping out another Republican. I think Trump to be Frank is. Tactical genius, but he has zero strategic division. And so he’s been going from thing to thing. So yeah, like, I mean, I think that’s a problem, but I think we still would have had a problem with compliance with localities doing their own thing. And so, I think that it’s a little disturbing because.

Grant:  It’s like there would have been a lot of impatience. 

Razib: Yeah. Yes, yes, yes. And in China, they’re not going to have impatience because the government will just like put you in prison. So there are issues like that. I do think the positive lesson would be like South Korea. Okay. I mean, South Korea, they say, “Oh, there’s been an outbreak.” But  if you look at the numbers compared to the United States, even adjusting for population, it’s nothing. If we had South Korea’s problems, we would be so happy. They have a test and trace capability in part because of previous scares. 

Razib: So, you know, we are in this biotech space and I do wonder.  Just things get more efficient as the demand increases, the prices go down, it gets better and better. We have great information technology. Why can’t we have spit kits? For everybody in the world, literally for everybody in the world. Yeah, it would be an expense that we have to take every year or so to produce new spit kits and all these things. But, it’ll prevent what we have just gone through as a world. This massive loss of GDP productivity, psychological trauma. Frankly, I don’t know if I should say the word trauma, but I think a lot of people have been traumatized. There have been suicides in third world countries. I mean, Americans are broke, but we’re not broke, broke ever. Even when we’re broke, you know… There’ve been suicides in India. People have starved in India. Okay. So, the outcomes can be quite deleterious. 

Razib: And so if we just invest more in the technology to do what we need to do. What we need to do is test, trace and contain. That seems to be the magic quote solution. If we ever deal with something that’s very similar. Whereas something like SARS, it’s R0 was lower, I think. And the issue with SARS is it wasn’t as asymptomatic. You got it, you got it. You go to the hospital, you didn’t spread it to other people. The problem with COVID is it hit this sweet spot of 50% asymptomatic spreading it. And these are the people that are spreading it all over the place. And they don’t know. So if you had good testing. So if there’s a local outbreak, just tell everyone to test. Mail everyone a kit, just have it there.  

Razib: Why can’t we do it? You know, we have all of these like other things. We have cruise liners. We have these huge industries that are just for consumption. Why can’t we have this one thing to protect us against this tail risk, which is inevitable. There’s going to be another infectious disease outbreak in the next generation or two. So have the facility. Obviously it is going to have to be a different test, but a lot of the other things can be put in place. Look at South Korea. They didn’t have a test for COVID-19. They had to create one, but they have the whole framework set up. And so, if we’re still going to have a World Health Organization, I think that is really marching orders. 

Grant: Are you optimistic? The U S will do that?

Razib: If you can’t say anything. Nice. Don’t say anything at all. Look, I want to be optimistic. I’m optimistic about being optimistic someday. I don’t know. 

Grant: Good stuff. Alright. 

Razib: I think we’re good.  So I guess I would say though, even if I have a lot of pessimism and concern about what’s happening in this country. I am still excited about the world and excited about science and excited about discoveries. Yeah. 

Grant: Yeah. Thanks. Thank you so much for joining us. It’s been a really fun conversation.