The Bioinformatics CRO Podcast

Transcript of Episode 91: Zameel Cader

Disclaimer: Transcripts are automated and may contain errors.

Grant: Welcome to the Bioinformatics CRO podcast. Today, I’m joined by Professor Zam Cader, a clinician scientist at the University of Oxford. Zam is professor of neuroscience and neurology, a consultant neurologist, and director of the Oxford Headache Center. His work sits at a fascinating intersection: headache and pain disorders, human genetics, induced pluripotent stem cell models, blood-brain barrier biology, and translational drug discovery.

Grant: His group works on building more human relevant systems for understanding neurological disease and for finding better therapeutic targets. What makes Zam’s story especially interesting is the breadth of roles he has taken on: physician, neuroscientist, consortium leader, and entrepreneur. Today, we’ll talk about what he’s working on now, how he got there, and what advice he has for clinicians and scientists who want to build careers that cross disciplinary boundaries.

Grant: Welcome to the show, Zam.

Zameel Cader: Hi, Grant.

Zameel Cader: Great to be here

Grant: For listeners who are meeting you for the first time, how do you describe the scientific and clinical problems you spend most of your time thinking about now?

Zameel Cader: So I think both shape each other a lot. I think one of the fantastic things about being both a clinician and a scientist is that you’ve got a ready motivation to keep you coming in, keep working on the problems that you keep working on. So I’m a neurologist so I see people with brain and nerve problems, one of the commonest things that I see are people with headache and with pain. And it’s such a burden, both on the individual but also on society, on healthcare systems. We do have pain drugs and they can be very effective. talk about things that are effective for a chronic headache, for chronic pain conditions, that’s much tougher, that’s much harder. so given the amount of unmet need that there’s around for these kind of conditions, I think that’s really one of the main motivating factors for why I want to try to get understanding of why it is that people develop these problems.

Zameel Cader: then not just that, but to then see how do I then make that work into something that’s gonna ultimately benefit people who are suffering with, pain, headache and indeed other neurological problems?

Grant: What makes pain and migraine scientifically challenging?

Zameel Cader: I think almost every single person working on their particular thing will say it’s really challenging, and they’re absolutely right. I think the human body is such a fascinating thing so complex, so many different factors systems working together, trying to keep balance, trying to keep us alive and functional for a good number of years. And it’s extraordinary that it does but of course, it’s not then surprising when things don’t work and things do start to break down or in some way or the other. headache and pain is a good example of that, I think, because we need pain. Pain is absolutely essential for our survival. It tells us about the world around us, what’s harmful, what to avoid. It teaches us things. So it’s a really fundamental aspect of being a person. Being a human is experiencing that.

Zameel Cader: And when people develop a pain disorder, then what is perhaps normal, becomes not normal, and there’s lots of different reasons why that might occur. so you ask the question, why is it so challenging?

Zameel Cader: I think firstly, it’s the causes of why someone develops a pain disorder are really varied different factors, coming together. And again, as with many disorders, it’s a combination of the genes that you inherit that may make you vulnerable to certain things, with the environment that you’re exposed to, and the environment in the very broadest sense.

Zameel Cader: So you’ve got these factors playing together interacting with one another. And then secondly, if you think about how we appreciate pain and we sense pain, then you can recognize that the system really quite complex. So there is a pathway from, for example, if we take think about pain experienced by an injury to our skin.

Zameel Cader: Let’s say you get a burn. There’s a pathway that goes from our skin, travels to the spinal cord, and then from the spinal cord, it travels up to our brain. But along that pathway, there are lots of places where there are interactions that take place, modulation of the signal, and that starts probably right at the skin. of different cell types that are present that are determining how a sensation is interpreted. as it– as the signal gets sent into the spinal cord, there are circuits that are present in the spinal cord modify pain traffic. And alongside the nerve circuit, there are other cell types that are important, which again, can modify how the neurons behave. then we get up to the brain.

Zameel Cader: And then in the brain, hugely complex organ, of course, and lots of different regions in the brain that can then work together be able to, provide context to the pain, for example, an emotional aspect to the pain. And it goes beyond that purely physical phenomena of some kind of stimulus turning into electrical signal, which is then detected into something that’s much more layered with meaning and emotion and so on.

Zameel Cader: And so that’s part of the reason why trying to first understand pain and then to develop treatments against pain

Zameel Cader: can be quite tough.

Grant: When you see patients and then return to the lab, what kinds of questions really stick with you?

Zameel Cader: This is really important. I think for a long time in research knew best or doctors knew best and would pick on things that were, perhaps of academic interest, and a lot of the time that may have coincided with things that were also important for making a difference to patients. But what I’ve been really heartened to see over sort of years is the importance of the patient voice and the carer’s voice in saying, what are the things that are important for us to study? again, as a doctor, what I want to do is to make a difference to the people that I see, to reduce the burden of the pain that they have and other symptoms associated with that, that may vary from one person to the other. And for some people, that might be a particular intensity or type of pain that they experience. For someone else, it may be the unpredictability of their pain.

Zameel Cader: Or for another person, it may be because they get severe nausea or light sensitivity with, let’s say, their headache attack. And understanding what the priorities are for the patients now I think has become increasingly something that I really take into account when I’m then trying to what area of research I should be really trying to work hard on. of course, the thing that drew me into this field in the first place is because I really like trying to understand how things work. What are the fundamental building blocks? So yes, my priorities will be set by patients, and they can often bring incredible insights into how we should run the research. I’ll als- always try to link that back into how do I break it down? How do I think about the that might be working together to then induce that pain state?

Zameel Cader: And then from there, we can then think about how we might develop drugs or other treatments that might help

Zameel Cader: solve that problem.

Grant: So turning that around what do researchers often understand about headache or pain disorders that patients rarely get told clearly?

Zameel Cader: There’s often a gap between, what’s being carried out in the lab and what’s, there in terms of what patients and the people that I see are understanding. But I think often, it’s not so much the concept because I think people with lived experience of pain or people who look after those with pain really very much grasp the kind of scientific concepts are. And in fact, they’re thirsty to be able to understand it. So I think it’s more maybe a difference in perspective and urgency, and I think as a researcher, you realize that things take quite a lot of time. And the process of scientific discovery is often uncertain, and that can be quite difficult to convey, the uncertainty, and that even when a study comes out and it looks as if that is an answer, it’s not really an answer.

Zameel Cader: It’s a current position, which in the future, may be reinforced with further studies or may be dispelled, and that’s an important part of the process. So that uncertainty, I think, is probably something that researchers appreciate and may be a bit more difficult for people who are suffering with these con– conditions to grasp in the same way.

Zameel Cader: So I think it’s probably one important area.

Grant: As a researcher, how do you deconvolve the subjective experience of pain from measurable biology without losing what matters clinically?

Zameel Cader: That is a really tough question, Grant, and I’m not sure that anyone has really worked it out yet. Because one thing is really true in the pain field, which is that we really suck at making drugs work for pain come through our research studies. when we do work in the lab it works beautifully very often. And yet when we get through to the clinic, in the clinical trial or actually being given to patients, there’s a really big between what we see in the lab and what’s there clinically. And I think at least part of it is because of that subjective experience that is such an essential component of pain.

Zameel Cader: And, some of the other things that we’ve just talked, talked about previously, which is pain isn’t just a one-dimensional thing. There’s lots of other factors, and for different people, different things matter. So unless your drug is hitting the things that matter, then a person may not necessarily respond in a clinical trial in the way that you might expect them to respond. So I think there are some things that are possible to be able to take into account of, and there are some things that are really challenging to be able to take into account of. I’m a scientist that tends to work with cell models And trying to encapsulate subjective experience in a cell model is not gonna happen. So often the aspects that I’m working with is simpler

Zameel Cader: aspects

Zameel Cader: in some ways of the biology where we can more strongly the things that we are seeing in the lab with more definitive markers that might be present in patients. And this is a goal, again across not just the pain field, but much of drug discovery, is to try to pick out features that patients with a condition have that can a objective robustness to them, because then I think we’re much more likely to be successful in our efforts to be able to translate from lab to clinic. And we call those kind of things endophenotypes, for example, where there may be a particular feature that a patient exhibits that shows more consistency, or it may be a biomarker that again serves that kind of purpose.

Zameel Cader: And so although I can’t capture subjectivity in the models that I use what I do certainly try to do is to try to build correlations the cell models and what the patient experiences, and that’s, I think, a key goal of the work in my lab. And I apply that across a lot of the work that I do, is to try and establish those types of

Zameel Cader: correlations.

Grant: What makes a headache disorder a good window into broader questions in neuroscience?

Zameel Cader: It’s a fantastic disorder to be thinking about the brain in general because it is something that clearly is affecting multiple brain systems and, the brain hugely fascinating, intricately complicated system. And when someone develops a headache, and I’m gonna particularly stick to migraine, when I’m talking about headache.

Zameel Cader: And the reason I say I’m sticking to migraine is because a lot of the changes that are occurring in the brain a migraine episode have been characterized. We may not understand of the changes that occurs in a migraine, but through various approaches and techniques, we’ve at least been able to get a window into what’s changing. And migraine is a very common headache disorder and perhaps it’s the commonest type of headache disorder that clinicians see. So the commonest headache that people get is tension type headache, but most people put up with that, take a simple painkiller, and it goes away. But if a headache keeps coming back and is debilitating, it’s almost certainly a migraine. And people with migraine a third of them get something called an aura, are transient neurological problems that affect them maybe for about fifteen to thirty minutes, and then it completely resolves.

Zameel Cader: And the commonest type of aura that people experience is a visual aura where they may experience flashing lights, zigzag lines, colors and so on. And so one of the earliest discoveries in the migraine field around what’s occurring in the brain when you’re experiencing an aura. And there is this phenomena called cortical spreading depression, which is a wave of activity that slowly spreads across a brain region.

Grant: What do you think neuroscience drug discovery has historically gotten wrong?

Zameel Cader: So again, as we’ve talked about already the brain is complex. Neurological disorders are complicated and relying upon models that are in some ways simplistic and give easy answers may not be the right approach. Because whilst they can allow us to get through the very earlier stages of drug discovery all of our milestones and success criteria, what’s very clear is that when you meet patients for the first time with your candidate drug, very often it fails. And I think more time spent in what’s called the pre-clinical phase could well increase the chances of success.

Zameel Cader: And two examples of how more careful consideration in the early phases can improve success. The first is the understanding that the incorporation of human genetics significantly increases the likelihood that your drug is gonna be successful, and that’s been shown now, I think, very clearly by the recent successes that if you’ve got a genetic association with your drug target, then that’s much more likely to succeed.

Zameel Cader: So in other words, making the effort to do human genetic studies is worthwhile. The second is that we should be using human cells in order to be able to test compounds, to be able to test whether the targets are relevant. For the longest time, the neuroscience drug discovery community have utilized animal models, and they are very useful because they provide a whole system in order to be able to test your mechanistic hypotheses, for you to be able to test your drug candidates.

Zameel Cader: But the big problem, of course is that they’re not humans. And with the advent of modern molecular studies, single-cell transcriptomics, for example It’s becoming more and more clear just how different at the molecular level the human system is from the mouse, which is one of the commonest animal systems that’s used. That’s true at the molecular level, it’s true at the functional level, and of course, if you take a mouse brain and a human brain, you can see huge, literally, differences between the two, both in terms of the size, but also in terms of the complexity of the of the structure of the brains. And so in many ways, it’s surprising that things that were developed using animal models were successful at all. But I think as, with the low-hanging fruit now taken, we need to fully embrace that we really need much better validation with human tissue.

Zameel Cader: And that’s the field that I work in, which is in human stem cell models.

Zameel Cader: And the reason I work in that area is because getting access to human tissue isn’t always easy or straightforward, particularly nerve tissue or brain tissue. human stem cells provides us a way to be able to get access to that and to be able to experiment on those types of systems.

Grant: So what does a more human-centered model of drug discovery look like in practice? What does that stack look like?

Zameel Cader: I think it’s fair to say that you won’t find a drug discovery pipeline now that doesn’t have human as part of its workflow because limitations of the older um, paradigms are just too apparent. And different companies whether they be pharma or whether they be biotech working in the drug discovery space use different ways of getting access to human-centric approaches. Some companies will have embedded within them, groups for example, develop human stem cell models, and that’s part of their own internal pipeline. But many companies also use external collaborations, and there’s good justification for going to external. One is that working with human cells is non-trivial. It’s technically very demanding Requires quite a lot of time and effort, as well as cost.

Zameel Cader: And so it would be beneficial for many companies to go to someone with an established credibility with working with human cells in a particular area. And there are several options, I think, for these kind of human systems to be incorporated into drug discovery workflows. So you can work with academic groups. And from an academic perspective, I’ve engaged with lots of biotechs and pharma and those have been some of the best research programs that I’ve run. For example, I ran a consortium called StemBANCC, established

Zameel Cader: for

Zameel Cader: drug discovery

Zameel Cader: of the earlier stages of induced pluripotent stem cell, development. And that was fantastic because we worked with companies like Roche, with Johnson & Johnson, Pfizer

Zameel Cader: and

Zameel Cader: so on, to be able to develop these human cellular models for that specific purpose of drug discovery and to make it available for both academic and industry researchers. And such public-private partnerships are ongoing because very often, the material needed to make stem cells is present in hospitals and in academic groups, so one has access to, to that kind of resource, as well as leading-edge expertise in a particular disease. Then on the other end of the spectrum academic groups, there are also contract research organizations can provide cells, human cells or can provide assay services. And, one of the things that I felt a number of years ago was that there was a lack of that kind of expertise and provision for the community.

Zameel Cader: that’s what led to founding a contract research organization called Oxford StemTech which has now been running for four or five years and provides, I think, a much needed expertise in the field for neuroscience human cell assays.

Grant: How do you decide when a human stem cell model is telling you something biologically meaningful rather than just technically impressive?

Zameel Cader: Again, another of challenging question one that the field is constantly wrestling with. There are lots of different types of signals that you can get from human cell models, and the challenge for the researcher is trying to decide whether the signal that they’re getting, is it an artifact? Is it consequence of the platform that one is using? Is there real biology being demonstrated? then is there real biology that’s being demonstrated that’s relevant to the patient condition? So there’s lots of different layers, different levels of findings, phenotypes that you might observe in human cell models. And one of the jobs of the researcher is to try to work out what’s what. And there are different ways of doing that. And of course perhaps one of the important things is to reduce the likelihood that what you’re observing is just technical noise.

Zameel Cader: And you do that by ensuring that you’ve got sufficient replication in your studies, your study is well-designed, and that the statistics that you undertake are appropriate. And again, the research and the analysis is designed in a way that you’re gonna be able to get meaningful and robust answers. And that’s non-trivial, and I think that’s a field that’s continually evolving. And that’s one aspect. The second aspect is, again, thinking about relevance, things that are biologically meaningful and patient-relevant. Again, perhaps coming back to an earlier question that you had, you know, what is it that I think drug discovery companies and those in that field are doing wrong? One of the things that I think we are not embracing enough is diversity of patients and of people when we’re doing our research studies in the lab.

Zameel Cader: And again, this comes down to resources and the challenges of being able to do studies at scale. very often when we do a stem cell study, we might take a stem cell line from perhaps three, four with a particular condition and three, four donors who don’t have a condition. But that’s just a very small group, subgroup of the population that you might be interested in studying.

Zameel Cader: So you’re really not able to model the diversity that’s present for that condition. So I’m really a firm believer of trying to increase the numbers of donor lines that we interrogate when we do our research studies. And I liken it to how we used to do genetic studies or genomic studies 15, 20 years ago. resources and cost limitations meant that we often did candidate gene studies rather than approaching in an agnostic way, and we would, you know, take maybe a gene, take a few handful of individuals with a condition or without a condition, and test for association of that gene. And that might produce an association, but almost inevitably, when the large scale studies came along, they, they turned out to be false associations. I worry that we’re in a similar phase with cell studies, that we do small scale cell studies at the moment.

Zameel Cader: We find these associations, but when we get around to doing the larger scale stuff, which we will do, much of those are gonna really stand the test of time? I’m worried that many won’t.

Grant: Major concern. So what is the right way to think about the gap between a cell model, a patient, and the treatment?

Zameel Cader: I don’t think there is one right way. I think there are multiple different approaches. So, Again, if I stick to my field of human stem cell models, one of the most amazing things about working with human induced pluripotent stem cells is that they’re capturing the genetics of the individual. Because what you do is you take a blood cell, for example, from an adult with a condition, and from the blood cells, and specifically a common starting cell is an is a precursor to a red blood cell, which still has its nucleus and still has its DNA, and that’s turned into a stem cell. So the DNA that was present in that person is now in your stem cell. So all of the genetics and the risk factors that have predisposed that individual to a condition that they may develop or have are present in your model. So that already brings a gap closer between your model the person.

Zameel Cader: Now what’s missing is the environmental exposure And that is something that we can reintroduce. And I think that’s often something that people appreciate with the cell models. V-very often it’s all about the genetics, it’s all about the fact that they capture the genetic susceptibility. with our cell models, we also have an opportunity to be able to modify environment that that cell experiences over quite prolonged periods of time. So for example, we did that when we studied neurodevelopmental processes for people with a type of epilepsy And what we found was that cells that were carrying a mutation in a fundamental gene that controlled cell growth controlled the balance, the energy balance. so it’s a gene that’s really important for almost every cell, a mutation you’d imagine would be absolutely disabling and deleterious.

Zameel Cader: And what we found was that by modifying the amount of glucose that was present and being delivered to those cells, either completely rescued any abnormalities that were there magnified the abnormalities. And so, that just for me really reinforces the importance of gene environment interactions. And when we look at our cell models, just be thinking of the genes.

Zameel Cader: We need to be thinking about what the environment that these cells should be being exposed to that might then allow the disease to manifest. Now, coming back to pain, the question is: are the challenges that a cell might need to be exposed to to be able to induce a pain-like state? And we don’t know. But we’ve got some good candidates. So that might, for example, include adding inflammatory factors, cytokines, and interleukins to our pain nerves might then lead the pain nerves to enter a kind of sensitized state. So this is one of the things that we’re gonna be working on over the coming years, is to try to understand that gene-environment interaction to then be able to bring the patient the cell models closer together. Then your other question was around treatment, and then how do we get to treatment?

Zameel Cader: So our approach is, again, to go back to the patient and to select patients that we’re going to model based upon how they responded to treatments in life. So you might imagine someone with migraine, and what we have are individuals who’ve responded to one of the new migraine drugs. Called the gepants. And so patients who have responded, we can make their cell models, and the patients who haven’t responded, we can make their cell models. And it’s a question that we haven’t yet answered, but we’re hoping to answer is, do their cell models from the people who respond to a treatment, are they different to the ones who don’t respond to a treatment?

Zameel Cader: So that’s how you might then be able to bridge across two treatments.

Grant: What are the hardest parts of building human models of the blood-brain barrier?

Zameel Cader: So the blood-brain barrier is a really interesting structure. It’s made of brain endothelial cells, and these are specialized cells specific to the brain because they have what are called tight junctions between them. That means most substances can’t cross from the blood vessel side into the brain. They also, these endothelial cells, have very dampened transport mechanisms. And what that means is that when a substance might enter an endothelial cell itself, in other tissues, normally that substance might then get ferried across the endothelial cells and then cross the membrane on the other side to get into the tissue. But in the brain, that is dampened down. That’s a process called transcytosis. That’s dampened down. So we have that. That’s, that’s the core of the blood-brain barrier.

Zameel Cader: But in addition to the blood-brain barrier, we also have other cell types that are really essential for barrier function, and one of those other cell types is called pericytes. And we know that they’re important because if you remove pericytes experimentally, the blood-brain barrier becomes leaky. So we know that they have a very important role. Then another really important cell type are astrocytes, and astrocytes are on the brain side, they contact the vascular cells, the endothelial cells, and the pericytes. And again, they’re also really important for regulating barrier function. And we also think that other immune cells like microglia probably have an important role as well. So there is the anatomy of the blood-brain barrier. There’s a polarization. You’ve got certain features on one side and other features on the other.

Zameel Cader: Then you’ve got a cellular complexity, and you also have a functional coupling between the different cells. And so trying to reproduce that in vitro quite challenging. And there are models that have been reported, but I think there is still more work to be done to really to be able to establish a bonafide blood-brain barrier model.

Grant: How has human genetics changed the way you think about neurological disease?

Zameel Cader: I started off in my sort of research journey studying human genetics. After I qualified for medical school and did the early training, I then started a PhD. And my PhD was trying to identify a gene causing a Mendelian disorder where patients would suffer episodes of imbalance and that condition’s called episodic ataxia. by Mendelian disorder, what I mean by that is, is that a mutation in a single gene is sufficient to cause the condition. And we were gene hunting essentially at that time for rare conditions that were being caused by and abnormalities in single genes. And this was 25 years ago, perhaps. and since then, the field of human genetics and genomics has really changed, transformed into something that certainly would’ve been unrecognizable to me when I was doing genetics back in my PhD.

Zameel Cader: And we’ve moved from the study of these rare single gene mutations to now complex disease, where it’s a combination of both genes and the environment that cause disease, and where the genes are no longer single genes, but small changes, variants in the genome very slightly increase your risk on their own and collectively perhaps increase your susceptibility to a condition. And this whole field of human genetics and genomics has been transformative, I think, across all of medical science because taught us it’s shown us many of the processes and mechanisms that might underlie the common diseases that humans suffer. It’s also illuminated mechanisms that might be targeted for drugs. So it’s part of the research that I do. It’s a fundamental part of the research that I do. You can’t ignore genetics because it’s such a strong factor in why we develop disease.

Zameel Cader: And as we’ve talked about already, this, it comes back to the basis of our cell models and how we drive drug discovery. I think that there is still a lot to be done in this space. Although there are now many genetic studies genome-wide association studies where we’ve been able to identify variants associated with a condition, it is still very much the case that for many of these variants, we really don’t know what they do. is it that you go from a variant? How does that variant increase your risk of disease? How do variants in one gene or one part of your genome interact with others? I would hope that some of the cell models that we generate some of the research that we do can help, better understand kind of mechanisms.

Grant: How did your path from medicine into genetics and neuroscience unfold?

Zameel Cader: I was an unusual person perhaps in that I always knew, even when I started medical school, that I wanted to pursue medical research. And I had a first proper exposure to research at the University of Birmingham and they do an intercalated medical degree. And that’s done in the third year of our medicine program. And so I did a degree in pharmacology, and I was in a department which was working on long-term potentiation, which is a form of cellular memory. And it was also around the time that a molecule called G proteins the diversity of G proteins were just being discovered. And it was just absolutely fascinating. I said I knew I wanted to do research, but that absolutely affirmed that, that, that was the career that I absolutely wanted, and reinforced just how, incredible neuroscience is. And that cemented my ambitions.

Zameel Cader: So I then finished my medical degree, came to Oxford shortly afterwards very quickly entered my PhD going into genetics and genomics. Once I’d finished my PhD and then my medical training I then was successful in getting a, what’s called a Medical Research Council Clinician Scientist Fellowship, which allowed me to establish my own independent research career. And then from then on, it’s really been trying to continue research in the way that I’ve described.

Grant: What have you learned from leading large collaborations that you could not have learned running a single lab?

Zameel Cader: They’re very different beasts running large collaborations and running labs. running large collaborations requires, really, it needs a passion working with others to solve problems, communicating and try to find the best path with the talent that you’ve got available.

Zameel Cader: Because, it’s joyous and it’s incredible to be working with people at the forefront of their particular research area, being able to pull people together on a problem to solve. And you get access

Zameel Cader: to

Zameel Cader: expertise and resources,

Zameel Cader: which

Zameel Cader: isn’t so easy when you’re running your own individual lab. Now, of course, when you’re running your own individual lab, you’re often looking to establish collaborations, and you work hard to do that. But the mindset and the approach and the sort of immediacy of running multi-group research experiments is very different when you’re running a consortium.

Grant: What surprised you the most about building a company?

Zameel Cader: So building a company has its rewards and its challenges, and it’s really tough, and gives back a lot. It’s just so many different emotions that you go through when you’re running a company. I was very fortunate to have two exceptional co-founders for Oxford StemTech who were previously researchers in my lab then left to start the company up. So we started off on a shoestring and have slowly been building the company over the last several years. and it’s a fantastic team. And I was not sure… I started off in academia. I was never sure whether I would get the same rewards, stimulation and output that I had in academia from a company. And I’ve really been pleasantly surprised just how fantastic the team at Oxford StemTech are.

Zameel Cader: They have been able to establish workflows, experiments, run internal R&D at pace, and to be able to deliver robust, reliable results, generating actually some amazing new insights into mechanisms along the way.

Zameel Cader: Even though our priorities are quite different, an academic lab versus a company, nevertheless, some of the things that we’ve been finding in a company have just been extraordinary. and one of the things that I think perhaps benefits the company from having an academic co-founder is that I’m still keen to publish, whether it’s a company or whether it’s in academia. So I hope some of the things that we’ve been finding in sort of recent years in Oxford StemTech will be published soon. And I would certainly say that you have intellectual drive fascinating outputs, whether you’re in an academic lab or whether you’re in a company

Grant: What advice would you give to early career scientists who want to work on translational problems without losing scientific depth?

Zameel Cader: The main factor for a successful career in translational science is motivation, passion, and those come from understanding that there is unmet need. People are suffering with conditions that if we get our science right, we can make a real difference to. And if you start from that position, you’re driven by your patients, you’re driven by the need that’s out there, then you will want to ensure that the science that you do is robust and is meaningful. And that necessarily means that it has to have scientific depth because doing things half-baked to get a quick win, to get a quick result without showing reproducibility isn’t going to help your patients. It’s just gonna generate more uncertainty, might undermine other work that’s going on.

Zameel Cader: it’s really important that you maintain integrity, that you train yourself in, scientific thinking, and certainly with people that come through my lab or through the company, think that ability to think critically, to think deeply, really focus on the question that you’re trying to answer and not to be, led by sparkly new science but really to get back to the core of the problem.

Zameel Cader: That’s really what you want to drive you. That’s what I try to impart now, I think, to people that come through that I, have the privilege of being mentor to or supervising or line managing and to develop those skills because, whether you learn this technique or that technique or whether you get this paper or that paper, that’s not what’s gonna make you successful.

Zameel Cader: What’s gonna make you successful is that… those core skills that we’ve discussed.

Grant: And what do you realistically hope the field will be able to do for patients 10 years from now that it can’t do today?

Zameel Cader: So coming back to the translational sort of science, I think we are lacking meaningful treatments for chronic pain conditions. The treatment landscape for headache is much, much better. It’s been transformed by the recent therapies that are available, and I think chronic pain could follow. So I would hope in 10 years we would have treatments like we have for migraine and headache, and I think that’s achievable.

Grant: Zam, thank you so much. It’s been a great conversation.

Zameel Cader: Great. Thanks so much, Grant.