The Bioinformatics CRO Podcast

Transcript of Episode 26: Jim Ray

Disclaimer: Transcripts may contain errors.

Grant Belgard: [00:00:00] Welcome to The Bioinformatics CRO Podcast. I’m Grant Belgard. And joining me today is Jim Ray. Jim is the executive director of the Neurodegeneration Consortium at MD Anderson. Welcome, Jim.

Jim Ray: [00:00:10] Hi, Grant. Thanks for having me. It’s great to be here.

Grant Belgard: [00:00:13] It’s great to have you. So can you tell us about your work at the Neurodegeneration Consortium?

Jim Ray: [00:00:18] Sure. So I’m at MD Anderson Cancer Center, which is part of the University of Texas system. And it’s the number one cancer hospital in the United States. So it’s a place where patient care is of utmost importance, but it also is a very strong research institute and one of the investments MD Anderson has made is in drug discovery. We have an entire division committed to discovering novel therapeutics, and not surprisingly, most of it is focused on oncology. Being that it’s a cancer center, but my group is actually focused on neurodegenerative diseases. Alzheimer’s is the primary focus of our mission, but in the process of studying the pathways that lead to Alzheimer’s disease, we feel like we can also impact other neurodegenerative conditions like Parkinson’s and multiple sclerosis, ALS, as well as provide therapies hopefully one day for cancer patients receiving therapies that damage the nervous system. I think one interesting opportunity that’s come out of this being at a cancer center as a neuroscientist working on neurodegeneration is understanding how devastating cancer therapy is to the nervous system, whether it’s whole brain radiation or whether it’s chemotherapy. And many of those same pathways that are activated to cause this damage are the ones that are important for Alzheimer’s disease. So that’s the space we live in, is looking at the intersection between neurotoxicity and neurodegenerative processes.

Grant Belgard: [00:01:42] And how long is MD Anderson had a big presence in neuroscience?

Jim Ray: [00:01:45] We have a lot of neuroscientists there that have an oncology angle to brain metastases are a critically important area of research, so there’s a lot of people who are interested in that as well as these neurotoxicities. Cancer causes depression and fatigue. Cancer therapy causes neuropathy and cognitive impairment. So I was actually pleasantly surprised to find a relatively robust neuroscience community here when I came. However, we don’t have much of an emphasis on neurodegenerative disease historically, so for that reason, we actually teamed up with our partners at MIT, where Dr. Li-Huei Tsai is the principal investigator there participating in the NDC and at Mount Sinai School of Medicine, Dr. Alison Goate, who’s the director of the Alzheimer’s Center there and is an Alzheimer’s geneticist, is part of our consortium as well. And then we have a number of academic collaborators at other institutions, and that really beefs up our ability to explore novel areas of biology outside of the walls of MD Anderson.

Grant Belgard: [00:02:46] You went to MD Anderson from Takeda, right?

Jim Ray: [00:02:49] That’s right, yes.

Grant Belgard: [00:02:50] Can you tell us about that move? And I guess also moving from San Diego to Houston?

Jim Ray: [00:02:56] Yeah, well, my career has been entirely in biopharma. I’ve spent 11 years at Merck, and then I left to help start a company called Envoy Therapeutics, which was based in Jupiter, Florida. We were acquired by Takeda, so left from Jupiter, which is an incredibly beautiful place to live, to San Diego, which is an incredibly beautiful place to live. So I could be part of the Takeda experience after the acquisition and it was fantastic, loved it. It’s a great company, but my wife is from Texas. At least half my family’s from Texas, and MD Anderson had this amazing opportunity to do something very different, and there was quite a bit of philanthropy that had been raised to entice MD Anderson to dedicate some of their resources to Alzheimer’s disease. They just needed somebody who knew drug discovery to come in and try to lead it and thought it was an exciting adventure and get a chance to live close to family. And why not? Moving from Jupiter to San Diego to Houston wasn’t sounding so great from a location point of view, but actually, Houston is a very exciting place to live. We have the largest medical center in the world here. There are just thousands of faculty in the area. There’s like 10 million patient visits here a year. So the access to the science is amazing. So I really have enjoyed my time here.

Grant Belgard: [00:04:13] Yeah, I was an undergrad across the street at RICE, so I’m a big Houston fan.

Jim Ray: [00:04:17] Oh, is that right? I didn’t know that.

Grant Belgard: [00:04:19] So how do you think all your time in BioPharma has impacted the decisions you’ve made as head of the consortium? And do you think there are maybe ways that you approach decision making and so on in a different way than maybe you would if you had come up through the professorial path?

Jim Ray: [00:04:38] Oh, it’s tremendously impactful. Like I said, I started at Merck and spent over a decade there. So at the time I joined, Merck was the largest pharmaceutical company in the world, then later acquired Schering-Plough make it even bigger. So I got to be trained by the best. These were some legendary figures in medicinal chemistry and drug metabolism. And the power of a large organization like Merck or GSK or Pfizer is unbelievable. It was fantastic education in terms of learning drug discovery, but not only drug discovery, but how to think strategically about the entire process of making therapeutics. And it’s so much more to it than the science. It has to be commercially viable. It has to have a strong patent position. It has to have a clinical path. You have to be able to distribute it. You have to be able to educate physicians on how to deliver it. That entire chain of events exist in large pharma. So it’s I think everyone who’s interested in drug discovery should experience it to get the entire picture. Then going from there to a small startup, I think was employee number six.

Grant Belgard: [00:05:41] You need everyone to be a generalist to some extent, right?

Jim Ray: [00:05:44] Yes, exactly. Now you learn everything yourself. It’s you can’t call somebody and ask them what to do. And that was also a great experience to tap into that entrepreneurial spirit and that innovation that pharma relies on to feed their pipelines, it was great. And then Takeda was a mid-size pharma, so sampling all three of those environments was extremely helpful in terms of building up the skill set to actually do drug discovery from end to end.

Grant Belgard: [00:06:12] And so how do you accomplish that through the neurodegeneration consortium, I mean, it sounds like you work with a bunch of academic groups, you work with some companies. How does that look?

Jim Ray: [00:06:20] Although we’re located within a research hospital, we’re actually very similar to a biotech company. We are not faculty. We’re administrative staff hired by the institution to produce therapeutics, and we work in project teams across disciplines. We have medicinal chemists, we have antibody specialists, cell therapy specialists, manufacturing for cell therapy. We have drug metabolism. All the disciplines that you see in a mid-sized biotech company are available to us either internally or through our contract research network. So it’s partially a hybrid model, but it basically we have all the capabilities necessary to take drugs from idea stage all the way into phase one. On the oncology side, you could continue in clinical trials at MD Anderson, but for the Alzheimer’s and neurodegeneration side, we would partner with people who have those capabilities. We don’t have a clinical operation to do those studies, but we can take drugs from one of our collaborators has an idea. We can screen for inhibitors or activators of the pathway and then optimize compounds and prepare them for clinical trials.

Grant Belgard: [00:07:24] And what impacts have you seen from COVID and how do you think those impacts might be different with the model you have versus a fully integrated pharmaceutical company versus a biotech startup?

Jim Ray: [00:07:35] Being in a cancer hospital where we have immunocompromised patients, extraordinary caution had to be taken. We actually shut down the labs for an extended period of time. And during that time, we have a relatively small team, full time dedicated on the neuro side. We didn’t have a lab to go to, so we spent 3 or 4 months just thinking about the disease. And that was really exciting, actually, a period that I was really worried about that people would lose engagement or not know how to contribute if they were primarily working at the bench. But it turns out that everyone really contributed to thinking about new pathways and disease mechanisms, and we came out of that period invigorated and ready to get back in the lab and try some of these ideas. So it was an extremely disruptive not only for us, our partners in other countries, in Italy and the UK and Germany and so forth were being shut down as well. But I think at the end of the day, learning to work remotely, learning to tap into talents that we didn’t know were there, these have all been benefits of having to rethink the model in which we work.

Grant Belgard: [00:08:43] And if you can talk about it, what mechanisms are you most excited about?

Jim Ray: [00:08:47] Well, I think we’re in an extremely exciting moment for Alzheimer’s research right now. When I was a postdoc, it was the first big breakthrough in the field, and that’s when two genes, the amyloid precursor protein and presenilins, presenilin 1 and 2 had been found to be causative in familial Alzheimer’s disease. And they were linked together mechanistically, as it turns out for those of you who know the story, the villains are actually enzymes that cleave APP to release the a-beta fragment which forms the plaques and Alzheimer’s disease. I think we’re at that same type of moment again, and that’s due to the power of human genetics studies that have been published over the last 5 to 7 years. We now have at last count, I think, around 75 genetic risk factors for Alzheimer’s disease, many of which map to the myeloid cells of the brain, which are the microglia. The most powerful known risk factors for Alzheimer’s are microglial expressed genes. They’re not expressed in the neurons at high levels, and that caused the entire field to pause and rethink the disease mechanism. So we’re very interested in finding pathways in microglia that can be modulated by small molecule therapies. So that we can promote a disease protective phenotype in these cells or to prevent them from aggravating the disease because they seem to be the gatekeepers in terms of whether you progress to a disease state or simply accumulate a little amyloid with age as most people do.

Grant Belgard: [00:10:15] Do you care to comment on the amyloid hypothesis and biogen’s drug?

Jim Ray: [00:10:20] Sure. I think the amyloid hypothesis has been extremely important for the field, and you have to think back to where Alzheimer’s was before the amyloid hypothesis. Most people who weren’t scientists in the field thought of senility as something that happens to some people as you age. Maybe it’s inevitable. You just kind of get that point. And it was the amyloid hypothesis that gave a molecular underpinning to a disease process that actually could be stopped and the field changed dramatically. As a result, people started making a-beta in the lab and aggregating it and giving it to neurons and seeing what happens. And the clinical trials, of course, have been disappointing. We as a field been able to remove amyloid from the brain or inhibit the production with BACE inhibitors and seen no real clinical benefit, with the exception now of a couple of antibodies, one from Biogen, the Aducanumab, and then Lilly’s antibody have both shown some hints of, I think most people would describe as modest activity. So a lot of people would like to say that the amyloid hypothesis has been disproven or I think that’s a little harsh. It may be that you need to intervene way earlier in the process, that once you get accumulated amyloid, a second phase of the disease has been triggered and it’s no longer relevant to remove the amyloid. If you get early enough, you can see some hints of activity. But regardless, we’re learning a tremendous amount from this experience. I mean, you don’t know until you do the experiment what the answer is. We did the experiment and we’re starting to learn the answer. I think the current hypothesis around tau spreading like a prion and microglia contributing to this process may be where the new wave of therapeutics are going to come from, and those may wind up being more effective in people with the disease.

Grant Belgard: [00:12:09] And what do you think about these reported associations between gum disease and Alzheimer’s and Gingivalis antibodies and so on?

Jim Ray: [00:12:17] It’s really interesting. And you can expand that to herpes infections and other forms of viral infection or fungal infection or spirochaetes. There’s actually a fungal infection. There’s a long list of systemic infections that people have linked to Alzheimer’s with varying degrees of validation of the data. I think actually the dental health angle with the gingivalis infection is a strong link. The Cortexyme is going after that aggressively with their phase two trial. I think it makes sense that if you’re chronically inflamed due to some low level infection, that it could influence the priming of your microglia, which in turn could change the way in which they are addressing other age related problems in the brain. So I think it’s an interesting hypothesis that deserves some investigation. Absolutely.

Grant Belgard: [00:13:12] It’s quite interesting, isn’t it right, that the genetics for Alzheimer’s is pretty convincingly pointing towards towards microglia, but that’s certainly not the case for a number of other neurodegenerative disorders. What’s your working model of how different neurodegenerative conditions are related to one another? Like if you were to cluster them into a few buckets, which ones would be put together and why?

Jim Ray: [00:13:34] A interesting question. So the way I personally look at it is that all of these diseases are ultimately driven by protein misfolding and not the most novel thought I’ve ever offered. But a lot of people think of it the same way and then how exactly it manifests differs by disease. So the genetics of Parkinson’s are quite different than Alzheimer’s, but ultimately you do have alpha synuclein aggregation. Just like in Alzheimer’s, you have tau and amyloid, same with TDP-43 or 12 and tauopathies, etcetera, or even in Huntington’s disease. So these protein misfolding accumulation seems to be central, but seems also to be caused by a number of different upstream factors and the genetic forms of the disease, it can be overproduction of the protein or a mutation in the protein that makes it more likely to aggregate. But in the sporadic, much more common forms of the disease, I think that’s an open question why age related neurodegenerative diseases manifest in one person as ALS and in another person as FTD, frontotemporal dementia. And that’s the best example because in many cases, the risk factors for those two very different clinical diseases are the same.

Grant Belgard: [00:14:45] It’s wild.

Jim Ray: [00:14:46] Yeah, it is. It is. There’s a lesson in there somewhere. I’m not sure we totally understand why those pathways differ in people to drive them in one direction versus the other.

Grant Belgard: [00:14:59] Most of these diseases we’re talking about, the biggest risk factor is age. How do you think about aging?

Jim Ray: [00:15:05] Absolutely. So our brain is a unique organ. It’s protected behind the blood brain barrier that presents, of course, a necessary element to its function. And protection against infection, which I’m sure evolutionarily speaking, was very, very important. But it also presents some challenges. You don’t have access to the same level of clearance mechanisms you would in, let’s say, your liver or other organs. So you have to have special clearance mechanisms, the ones that appear to be really important in the brain include autophagy, the Glymphatic system and microglial mediated phagocytosis and clearance of debris and so forth. All three of these are compromised during aging. So whether your, for example, the Glymphatic system is triggered by sleep in part. So as your age, your sleep gets disrupted, deep sleep particularly in which you might expect the clearance of misfolded proteins and other toxins to be at its peak is reduced with age. The ability of mitochondria to supply energy to highly energy demanding processes like autophagy or like phagocytosis is diminished. And so I think aging is particularly impactful to the brain environment because of its unique physiology and because of its protected behind the blood brain barrier. Those elements conspire to make the brain a place where proteins can aggregate and then eventually trigger inflammation in the disease.

Grant Belgard: [00:16:34] So speaking of the Glymphatic system, I mean, this may be a bit of a detour, but do you think there will be any other huge anatomical surprises like that to be found?

Jim Ray: [00:16:44] Wow, yeah. That the Glymphatic system is one of those that as soon as it was discovered, you had this V8 moment, if you remember those commercials where you’re like, Oh yeah, that of course that’s there, right? I should have known that, should have predicted that which is how something’s a great discovery when it’s obvious the minute you hear about it. So I think there’s still a lot to learn. I’ve been a little bit interested, for example, in these little tiny connections between neurons. People have seen these tunneling nanotubes.

Grant Belgard: [00:17:13] Yeah, there was just a report out about exchanging mitochondria, right?

Jim Ray: [00:17:17] Yeah, exactly. The idea that these cells in the brain are exchanging subcellular compartments through exosomes or shuttling mitochondria between each other through tunneling. I think that cell interaction part, we’re just scratching the surface.

Grant Belgard: [00:17:34] Yeah. I really wonder about what would drive that in case of neurons have these single post-mitotic cells that need to survive for decades. And of course, their mitochondria may not make it. I don’t know if they’re like sharing mitochondria to maybe replenish that pool. Like I don’t know.

Jim Ray: [00:17:51] I think the reason why you would want this exchange is unknown as far as I know. There’s probably some good ideas, but certainly I haven’t seen an explanation myself. Of course there’s other ways to the cells are exchanging all kinds of material and then just the complexity of the synapse itself as a protein machine is beginning to be understood. I’ve seen some really cool papers where people have done reconstruction of the synapse from proteomics studies and ultra high resolution microscopy. So that element of the brain, I think we’re starting to really understand at a deep level. But all these other connections between brain cells are going to be needing the same level of attention.

Grant Belgard: [00:18:33] And how do you think about sleep? Like what’s always amazed me is the huge variation person to person in certainly how much sleep they need to feel rested. I don’t really know how well that corresponds to neurodegeneration risk, right? Like if you’re just naturally a short sleeper and you feel fine, is your risk not elevated even though you’re sleeping six hours a night?

Jim Ray: [00:19:00] Oh, that’s a good question. I suspect there’s research on that question that I’m not aware of. But definitely we know that disrupted sleep is coincident with Alzheimer’s. And if you interrupt sleep intentionally, you get all kinds of bad things that happen to you from a biomarker standpoint, including for Alzheimer’s biomarkers. It seems very likely to me that sleep is an important active process. And when disrupted, as David Holtzman and others have shown, you accumulate toxic proteins in the brain. So it seems like it probably is on the pathway there. But whether someone who needs four hours sleep only needs four hours sleep because they’re have a super souped-up clearance mechanism in their brain and everything’s clear in four hours and that’s all they needed. Or they’re actually feel okay, but they’re not. They’re actually sleep deprived in some ways, even though they feel fine. I think that’s a great question, Grant. I don’t know the answer.

Grant Belgard: [00:19:55] So let’s talk about your own path. When did you decide you wanted to be a scientist?

Jim Ray: [00:20:00] Oh, well, I wanted to be a neurosurgeon from the time I was 5 or 6 years old. I thought that was the coolest thing I’d ever heard, that you could actually operate on the brain. And I spent my entire life working towards the day I become a neurosurgeon, working in hospitals, worked in the OR, worked in the ICU for my summer jobs and premed path. And then one day I walked into this class called Molecular Mechanisms of Development which was an intro to molecular biology and the very first lecture I was blown away, changed my mind. I’m going to be a molecular biologist. I loved it ever since. I just couldn’t believe that you could clone genes. And it seems so obvious now.

Grant Belgard: [00:20:44] It is pretty cool. Right?

Jim Ray: [00:20:45] Right. This was 1988, 89. It was a long time ago. So now this stuff gets taught in high schools. But for me, biology had been memorizing anatomy, doing comparative evolution, learning the Krebs cycle, that kind of stuff. And but here, you could actually snip out a gene and study it in isolation and figure out what it does. And back then we thought we had 100,000 genes. I was like, Well, I just discovered one of those, that would be awesome. And I was particularly interested in differential gene expression. How come some genes are expressed in one cell type or in one situation, but not in others? How does that happen? How does that work?

Grant Belgard: [00:21:30] Well, it’s interesting that that’s still a huge question, right? Like you look at any kind of cell type marker patterning or something and you come up with different ribosomal protein subunits in different cell types and so on. You have this enormous specificity of genes that people often think of as more or less interchangeable, but it seems like they’re probably not.

Jim Ray: [00:21:51] Yeah, it’s amazing, isn’t it? I mean, going back to the discussion we were having a moment ago when people were isolating microglia from the mouse models for Alzheimer’s disease and sequencing them for the first time. The number of gene expression differences in those disease associated microglia is amazing. There’s thousands. It’s almost like a completely different cell type. If you were blinded to the experiment and someone just showed you the gene expression differences and you’re used to looking at gene expression data, you may think that someone was showing you two different cells, like a liver versus intestine cell or something. And the idea that those cells can switch their molecular phenotype so vigorously in response to an insult is amazing. And I don’t believe we understand that mechanism yet.

Grant Belgard: [00:22:40] How conserved do you expect those Microglial states to be among mammals?

Jim Ray: [00:22:47] Probably have a minority view on this one. I think ultimately we’ll find out they’re well conserved. I think that the original few publications that really concern the field oh my gosh, maybe the mice are responding so differently. It’s irrelevant to the human. May have had some technical challenges to those data and may have made the situation look more dire than it actually is. And one reason I think that is because one of the risk factors for Alzheimer’s is TREM-2 and the TREM-2 knockout mouse phenocopies in terms of microglial response to plaques, the human loss of function. So I think that the responding to, in this case amyloid plaques in a similar way, there will be significant species differences. But ultimately whether the exact genes are exactly the same repertoire, unlikely, but probably the net direction of the functional changes is going to wind up being similar.

Grant Belgard: [00:23:44] How do you think about definitions of cell type versus cell state? Like every single cell conference, people are always arguing about this.

Jim Ray: [00:23:52] Yeah, right. Well, I mean they’re useful. It’s useful to have markers for cells to be able to generate hypotheses, to be able to measure response to an intervention or a genetic manipulation. And to quantify your data. It’s all important to be able to do that. But I think during development, that’s an important concept because you can have irretrievable differentiation from one lineage to the X, and the cells then become very, very clearly different. But when you’re talking about the difference between a monocyte and a macrophage, it’s probably a gradient. There’s probably hundreds of variants of those two extremes.

Grant Belgard: [00:24:32] And it’s interesting. Even in the same organ, it seems like different cell types can be either discrete or fuzzy in different ways. So for neurons, oftentimes you see large differences relative to say astrocytes, where it often seems you have several axes of variation that are real and reproducible and so on, but that are more continuous than having discrete attractor states.

Jim Ray: [00:24:53] I agree with that. When I was at Envoy, the purpose of our company was to study cell type specificity in the brain, and this was using Nat Hines’s technology back trap, a ribo trap. What we learned is there are clearly distinct cell type states among neurons, but there’s also a tremendous amount of overlap and gradation between states. And I think the single cell sequencing data is going to eventually show that not every GABAergic positive neuron in the hippocampus is the same, that they’re probably intentionally somewhat different from each other. And we need to learn what those differences are and understand why they’re important.

Grant Belgard: [00:25:32] Yeah. Even in one of the early large scale single cell papers from the Allen Institute, they were showing these cells in these cross-over states.

Jim Ray: [00:25:42] Is that right, yeah.

Grant Belgard: [00:25:43] Cool. So can you talk maybe a little bit about the acquisition of Envoy and how things changed? And did you immediately move out to San Diego or did you stay in Jupiter for a while and then your role changed? How does the medium sized pharma acquisition of a small biotech look?

Jim Ray: [00:26:00] I think there was a huge lesson in that. I left the conference security of Merck where even though it’s not true in Big Pharma, you feel like that you could retire from there. Now there’s a lot of churn in the industry, a lot of turnover, but in terms of the spectrum of stability in our field, Big Pharma is on the more stable end. To leave that and go to a tiny little startup is a bit scary. So what you do is think about should I buy a house and should I make friends? What if we go bankrupt? What if we run out of money? What are we going to do? What if we don’t succeed? And Big Pharma if you don’t hit your objective for your I&D that year, you may take a hit at bonus time, but you don’t get fired. Usually in a small company, if you don’t hit that, you may not get your next tranche, you may not get any investors to step up. And so it could be disconcerting in terms of planning. And that’s fun because now you get to control your own destiny. It’s not up to someone else whether or not your drug is developed, it’s up to you. What I didn’t expect was that it could actually succeed. I was worried about what if it fails? What if this doesn’t work out? I never prepared for the possibility that we could have tremendous success and that be recognized by pharma and we be acquired that’s quickly.

[00:27:19] So that was a shock. And for anyone else who’s thinking about taking the plunge and going into a startup, I would suggest that you plan for success as well as failure, because obviously both can happen. Going back to Big pharma or mid-sized pharma after being in a small company, took a period of adjustment because you’re so used to being able to do whatever makes sense. So if we wanted to do a high throughput screen on a target that came out of one of our experiments, we could talk about it at lunch and then call a CRO that afternoon and get a PO generated before we went home that day. In pharma you have to go to the high throughput screening people, talk to them, then you got to go to the Target evaluation committee, talk to them. Then you got to write up the target CV and have that approved by another committee. And then you got to present to your department. It’s like completely different. So going back from this incredibly agile environment to a structured environment, it wasn’t bad. It was just a big difference in a period of readjustment.

Grant Belgard: [00:28:23] I guess in your case, you’re going back though, somewhat to something you were familiar with as opposed to I don’t know if there were others in the company where they had only been in small companies before.

Jim Ray: [00:28:33] Yeah, there were. And I think it was a shock for them. It was a shock to have governance, that it was a shock to have a bunch of meetings, to have to worry about your outlook calendar. So much in a startup, you just grab people and talk. In pharma, you need to schedule a meeting. It’s like two weeks from now we’ll get together for 30 minutes, just walking, sticking your head in the the CEO’s door to ask a question is something that doesn’t happen in a big company, but it can happen in a biotech company no matter who you are. There’s only 20 of you, maybe.

Grant Belgard: [00:29:09] And what advice would you have for people looking at drug discovery that maybe you see frequently violated?

Jim Ray: [00:29:18] Right. You have to be willing to take risk. Drug discovery is not for the faint of heart. I like to say this to people who are thinking about going into drug discovery. Let’s say there’s 50 science nature papers published a week and there may be 20 drugs approved all year, and about 15 of those are probably for oncology. There hasn’t been an Alzheimer’s drug approved since Namenda back in 2003. This is a field in which you are expected to fail at a very high rate. And if you play it safe and don’t take risk, it’s unlikely you’ll ever break out of that. It’s important that you’re comfortable taking risk and people who aren’t comfortable with that probably are going to have a hard time enjoying drug discovery. Another piece of advice is just based on my own experience. I would see drug discovery from a number of different angles. If that’s your field, if you’re an academic who’s done, who’s doing drug discovery and you’ve never been in pharma, I think you would learn a lot from it and vice versa. I think industry scientists tend to think that they know best, which I certainly felt that way when I was at Merck, because Merck was great and we felt we knew drug discovery better than anyone else. And in many ways that was true. But it turned out there was a lot to learn from going to a small company or going into an academic environment where the rules are different. Your risk tolerance is different, your decision-making is different. What’s exciting is different. Commercial considerations are different. And just to see the world in a different way is, I think, very helpful.

Grant Belgard: [00:30:53] What do you think from all your own experiences, from your own academic training, from your time at Merck, from your time at Envoy, Takeda, from each of those buckets of experience, what do you think is the most useful thing you learned from each of them?

Jim Ray: [00:31:09] One of the most useful things I learned at Merck was the art of being a manager. I think big companies do a great job of training scientists to be managers, and being a great scientist has no relationship to being a good manager. In fact, it may be somewhat anti-correlated.

Grant Belgard: [00:31:25] Very true.

Jim Ray: [00:31:26] Right. So learning how to lead a professional scientific staff is a skill set that postdocs just don’t have yet, generally speaking, and learning to do that really well and get the most out of people is a lifelong journey. Everyone can get better, but it’s just a great place to learn those skills. Going to a small company is where you learn the whole process because you’re everything from changing the toner and the printer to meeting with the search and evaluation director of neuroscience from a major company could be on your agenda that morning. Then getting back in the lab and doing experiments yourself and then writing a presentation for the board of directors. I mean everything, you see everything. So that’s a great learning experience. Being back in a more academic environment after being in biopharma for a number of years was also tremendously valuable and educational. I forgot where science comes from. I forgot about the trainees, the people who actually generate the figures and the papers you read, what their motivations are, what they’re like, what they care about, what kind of techniques they think are new and exciting. What motivates your typical professor? We all know this, but it’s recognition, it’s grants, it’s publication. That’s what their careers depend on. And after more than a decade discovering drugs, you forget at an emotional level what they’re going through. And just to be reconnected with the font of all of our knowledge, the scientists themselves in the academic institutions has been a tremendous experience.

Grant Belgard: [00:33:11] What do you think is the worst common advice you hear in this industry?

Jim Ray: [00:33:20] The worst advice, one piece of advice that I think is not particularly great is when bright young scientists are urged to go into industry too soon. If you’re interested in drug discovery and you’re getting your PhD, I would recommend in most cases, doing your postdoc before you go into industry. Establish yourself as a scientist. Get some papers on your CV. You’ll go in at a higher level with more influence. You will be given more opportunity. Generally speaking, there are exceptions, but I hate to see people who were maybe 2 or 3 years of coming in at a more senior scientist level with more opportunities and influence come in more like the guy who runs the binding assay because they pulled the trigger too soon on making the transition. Thus you hear less of this now. But people like this used to like to say that it’s very difficult to go from drug discovery to academics, and once you go there, you’ll never come back. Maybe others have heard that, too. I think that’s less true now than it’s ever been. You see a lot of people moving back from industry into academic environment and doing very, very well. So I think people shouldn’t think that if they decide to spend some time doing therapeutic discovery, that it’s the end of their academic career. It may actually be a boost to it.

Grant Belgard: [00:34:44] That’s interesting. Certainly do hear that a lot. But then I think there are a lot of cases examples of people like you. You’re in an academic institution after spending years in companies of all sizes. Great. Well, thank you so much for joining us today, Jim. It was really nice.

Jim Ray: [00:34:59] I really enjoyed our time together Grant and thank you for the opportunity. It was a great discussion.