Identifying the Mechanisms of Seeing Color with Jeremy Nathans, MD, PhD

Erin Spain, MS [00:00:11] This is Breakthroughs, a podcast from Northwestern University, Feinberg School of Medicine. I'm Erin Spain, host of the show. Today's guest has played a very important role in helping us understand how humans see the world. Dr. Jeremy Nathan's is a celebrated molecular neuroscientist, and his groundbreaking discoveries in the visual system has led Northwestern University to name him the 2022 recipient of the Mechthild Esser Nemmers Prize in Medical Science. The $200,000 Nemmers Prize in Medical Science is awarded every two years to a physician scientist whose research exhibits not only outstanding achievement in medical science, but also lasting significance. Today's guest certainly fits that bill. Dr. Nathans, welcome to the show. We're excited to talk to you today about your research and your path to becoming such a renowned physician scientist. Welcome. 

Jeremy Nathans, MD, PhD [00:01:09] Thank you. It's a pleasure to be here.   

Erin Spain, MS [00:01:11] Well, you spent much of your career as an investigator of the Howard Hughes Medical Institute and a professor at Johns Hopkins University School of Medicine. And in fact, Baltimore is your hometown. So share with me a little bit of your backstory and how you became interested in medical research.   

Jeremy Nathans, MD, PhD [00:01:27] Well, I think my initial interest was sparked in high school. I had some good science and math teachers. I seemed to be reasonably good at it. And so I decided as an undergraduate to study chemistry and biology. So a little bit of physics. And I met inspirational professors. I was an undergraduate at MIT and the teaching was outstanding. I also had a lot of great classmates who were also inspirational, and I should add that my father is also a biomedical, or was a biomedical scientist. In fact, here at Johns Hopkins. And so talking with him and just seeing how much he enjoyed what he was doing was, I think, a positive influence in a big way.  

Erin Spain, MS [00:02:04] I do want to mention that your father, Dr. Daniel Nathans, in 1978, won a Nobel Prize for his role in discovering the first tools for understanding and manipulating DNA. So you come from a sort of a long line here of scientists. Tell me, how did your father influence you?  

Jeremy Nathans, MD, PhD [00:02:22] Well, I think mostly it was seeing how much he enjoyed doing what he was doing. I should say my mother, who's a lawyer, also was enjoying what she was doing. So it gave me the sense that you could have a job that was also gratifying, challenging and gratifying. They weren't very overbearing. I think they were pretty hands off as parents. But, you know, each of their children, their three of us, ended up sort of following his nose and then mine led me to science. The other two did not. They did not end up in science. But they're both historians and they're doing what they want to do.  

Erin Spain, MS [00:02:52] The visual system is your area of expertise, and you've described the eye as not only physically beautiful, but beautiful in an engineering sense as well. Explain that beauty to me and what drew you to study the visual system? 

Jeremy Nathans, MD, PhD [00:03:07] Well, I think we take many of our sensory systems for granted at some level because we're so used to how well they work. That is until in some cases they don't work well. And then we really notice it. But our sense of hearing, for example, our sense of vision, touch. These are all extraordinarily evolved systems. Just as an example, in the visual system, the retina is sufficiently sensitive that it can detect just a handful of photons, say six or seven photons, which is a tiny, tiny amount of light and a tiny amount of energy. So it's exquisitely sensitive. It's also able to assess various attributes in a visual image, like the colors of objects, the motion of objects, the depth of objects, and almost seems completely effortless to us. One way of appreciating how difficult these analyses are, and they start in the retina, but don't, of course, end there. They are also carried out in the brain. But a way of understanding how difficult these analyses are is to see how difficult it's been for the artificial intelligence people to try to reproduce this in computers. It's extremely difficult. Face recognition, for example, although it is happening now in the A.I. world, we do it effortlessly. Each of us knows probably thousands of individual faces. And if you see someone from a different angle, someone you've perhaps never seen from exactly that angle, you can immediately recognize them. It's quite amazing.   

Erin Spain, MS [00:04:32] You started studying the visual system as a graduate student. Is that right? 

Jeremy Nathans, MD, PhD [00:04:36] Yes. I was a M.D., Ph.D. student at Stanford at that time, and I was working in the laboratory of David Hogness, a very eminent molecular biologist. But the project that I was working on was really going nowhere. I was sort of casting about for something else that might be a thesis project. So my mind, in a sense, was prepared to hear something new. And I heard a couple of lectures on vision, one from Lubert Stryer, who's well known as the author of a very excellent biochemistry book, and Denis Baylor, a neurobiologist. And they described their work on the biochemistry and the electrophysiology of vision. So this was in 1980, and I really hadn't thought about vision much until then. But I heard these lectures and that together with the general interest in identifying a new thesis project, propelled me to the library to read more about vision. This was, of course, pre-internet. If you wanted to read, you had to go to the library. In reading about it, it occurred to me that there were various unanswered questions, which with the new recombinant DNA technology, the ability to isolate genes, were now potentially approachable. 

Erin Spain, MS [00:05:39] And so you went on to be known as the first person to isolate and characterize opsin genes contributing to human color vision. That took place because of this work and your thesis. Is that right? 

Jeremy Nathans, MD, PhD [00:05:52] Yes, I would say I was at the right place at the right time, and I also had the right advisors. It was just the dawn of gene isolation technology. The Stanford community was very good at it. I was blessed with very supportive advisors. Lubert Stryer, in addition to my thesis advisor Dave Hogness, was also very supportive. I think it was a problem that was ripe in the sense that the field had defined it as an interesting question and the technology then arrived. So sort of this collision of worlds, the technology from molecular genetics and the insight from the vision research world. And I just happened to be at the place where the collision occurred. 

Erin Spain, MS [00:06:30] Well, you would go on to show that people who are red-green colorblind have variations in their red-green color detecting genes. Tell me about that. 

Jeremy Nathans, MD, PhD [00:06:39] Yes. So that was an idea that had been around for over a century. Many people, many very smart people, people smarter than I am, have worked on color vision over the years, starting with Isaac Newton, who did some of the incisive experiments actually as an undergraduate. He was the first person to pass lead through a glass prism and realized that splitting up light into its component colors was an analytical tool that could be used in a precise way to find the properties of light. But many others: Thomas Young, James Clerk Maxwell, Hermann von Helmholtz, George Wald... The list goes on and on. And by the early part of the 20th century, I think many people in the field realized that the simplest explanation for variation in color vision was that there was some sort of inherited defect in whatever the molecules were that captured light. Of course, in the early part of the 20th century, no one had any idea what those molecules might be, but they understood the genetics and they understood the sort of engineering essentials of the light capturing system, and that's what was needed to make that conclusion. 

Erin Spain, MS [00:07:46] It's been incredible, I'm sure, to watch technology and how things have changed and what you're able to do now when it comes to, for example, you have genetically engineered mice in your lab, so that instead of seeing only two color receptors as mice normally do, they're able to see three color receptors as primates do. Tell me about those mice and the implications of this.  

Jeremy Nathans, MD, PhD [00:08:10] Yes, that was an experiment that we did with Jerry Jacobs, a very distinguished primate neuroscientist. And Jerry had many years earlier figured out the pathway of evolution of tri- chromatic color vision in primates. And he realized that the proto primate, that the primate who perhaps 100 million years ago was the ancestor of all current primates, including us, was an animal with only two kinds of light sensors, a shortwave sensor in the blue region and a longer wave sensor in the region of the red and green sensors that we now have. And Jerry, through both electrophysiology and also through genetics, traced out the duplication of the genes that code for the red and green receptors in one subset of primates. And then the generation of variation in those gene sequences in a different set of primates. Turns out that the African primates like ourselves, have one color detecting system, and the South American and Central American monkeys, the other branch of primates, have a different system. So we were wondering, when I say we, I really mean Jerry and I, because we work together on this, we were wondering whether we could reconstruct the first step in the evolution of primate color vision in a non primate animal. And of course, the mouse was the obvious choice because genetic engineering techniques are very sophisticated in mice. So basically we were able to engineer a mouse to have the same system as the South American primates. And those mice, as it turns out, behaviorally, have trichromatic color vision, just like a South American primate has. So I think the most, to me, fascinating part of this set of experiments was that it strongly suggests that the primate brain is not unique in its ability to analyze color at tri-chromatic level, but that every mammalian brain, even simple ones like a mouse brain, have an inherent plasticity that will allow them to process an additional complexity of color signals if those signals simply arise in the retina and then project to the brain. 

Erin Spain, MS [00:10:09] Yeah. Tell me, what is the focus of your research today and what are some of the areas that you are now studying in your lab? 

Jeremy Nathans, MD, PhD [00:10:17] Yes, that was sort of the beginning of my research in the retina. It's branched out to some extent since that time. The origin of our current research really goes back to my arrival at Johns Hopkins. We got interested in inherited defects in the visual system that are of clinical significance. I would say that color vision defects, most color vision defects are not really that clinically significant. If you are so-called colorblind, which we use that phrase, but it doesn't really mean a complete absence of color vision. It means just a reduction from three down to two channels. But if you're if your color vision has been reduced to two channels, that's a mild handicap, especially in certain professions, like if you're going to be an electrician. But it's not really a significant effect on quality of life. But there are many other disorders, especially those involving degenerative diseases of the retina, which are of great clinical significance. And so that was where my interest started to turn after I set up my own lab. And we've studied a number of disorders. Retinitis pigmentosa is a major one that we studied for many years, macular degeneration as well. But most recently we've been focused on vascular diseases of the retina. So there are a number of disorders either acquired or inherited, in which the blood vessels are aberrant. In some cases they're leaky, in other cases they grow in aberrant ways. And so we studied in particular a series of monogenic disorders in which the vascular development was incomplete, insufficient within the retina. And the retina, like the brain, is very uncompromising in its requirement for a blood supply and very intolerant of an insufficient blood supply. So individuals with these diseases really have serious retinal function problems. And we discovered that one major source of the retinal vascular disease of this kind, these inherited developmental diseases, is mutations in genes that encode a signaling pathway in which the glial cells send a signal. It turns out it's an unconventional Wnt signal. So Wnt, a large family of signaling proteins, it's an unconventional Wnt signal sent from the glial cells to the blood vessels. The blood vessels have the receptors, the glial cells make the ligand. And if that system is defective, there's insufficient vascular growth. 

Erin Spain, MS [00:12:33] Now, you are a physician scientist. The Nemmers award is awarded only to a physician scientist. Tell me about taking these discoveries in your lab and how you bring them back to the bedside.  

Jeremy Nathans, MD, PhD [00:12:45] That's a complex ecosystem, and we occupy only a part of it. I think that connection is being made now. There are a number of companies that are interested in the Wnt signaling system as a target for therapy and eye disease. So there are novel molecules now, engineered antibodies, in essence, which can selectively activate Wnt signaling and which at least in animal models look potentially promising. I think we're a long way from human therapy. We're still some years away from clinical trials. It's a reasonable path to pursue. I'm cautiously optimistic that something useful will come of it. 

Erin Spain, MS [00:13:24] I want to talk a little bit about your work as a professor at Johns Hopkins. You teach a class called "Great Experiments in Biology," and it's one of the most popular classes on campus. Tell me about your philosophy as a professor. 

Jeremy Nathans, MD, PhD [00:13:38] Well, I think part of what a professor should do, what any teacher and mentors should do, is inspire the next generation of scientists. It is, to some extent, a young person's game. And I think the older folks should have a parental role in that. They should provide what the young folks want and need, and then to some extent get out of the way and let them do what their imaginations allow them to do. And so part of my teaching, the connection of my teaching to that philosophy is that I don't want to just teach the facts. I don't want to just teach the experiments that led us to those facts. I'd like to teach how people thought of the experiments. What were the questions? What were the challenges, what were the blind alleys? All the interesting twists and turns. You know, if you look at a textbook, for example, you very often don't get that in its full glory, a textbook or the web equivalent has limited space and time. And so you're generally presented with the successful final result, but that misses a lot of the fun. And I think the human part of the story is both inspiring and fascinating. 

Erin Spain, MS [00:14:45] You talk about fostering the careers of young physician scientists and that this is very important to you. And in fact, in 2017, your family sold your father's Nobel Prize award, and the proceeds from that sale went to an endowment that supports the research of young biomedical scientists at Johns Hopkins Medical Center. Explain that decision. That's not something that you hear of very often, the selling of a Nobel Prize. Why did you sell your father's medal to fund this award? 

Jeremy Nathans, MD, PhD [00:15:13] Well, a few years earlier, it occurred to me that Hamilton Smith, who shared the Nobel Prize with my father and who's a wonderful man, he's still living, was under-recognized. I should say this was partly by choice. He's a very modest person. He, I think, doesn't like the limelight. He enjoys just doing his science. I thought that we needed to name something for him at Johns Hopkins, and nothing was at that point named for him. And so I started this fund for junior faculty members. So it's an endowed fund. And each year we choose one person from among the junior faculty in the basic science departments and the money that they get, the earnings from the endowment, go to their labs so they can try some research projects perhaps that they didn't have money for. We were kind of casting about for ways to raise money. Of course, the general approach is to call everyone you've ever known, and that turns out to be rather inefficient. This whole process has given me renewed respect for the development officers of all the universities out there. But it occurred to me and my mother, I should say, that the family had this gold medal sitting in a safe deposit box, been there for 40 plus years, and we weren't really doing anything with it so we could auction it. And a number of Nobel laureates have auctioned their medals. And so we contacted Christie's and Christie's was happy to auction it for us. It sold for $300,000 and that money went to the Hamilton Smith Fund for Innovative Research. 

Erin Spain, MS [00:16:42] So where is it today? Do you know? 

Jeremy Nathans, MD, PhD [00:16:44] We don't know for sure. It was purchased by someone in the United States, but it was an anonymous purchase. I'm grateful to them. That was the really big start of the endowment. The endowment, I should say now, is over $1 million and growing. 

Erin Spain, MS [00:16:56] You yourself have received many awards. The Helen Keller Prize for Vision Research in 2019 was one of the latest awards. And now you will be the Nemmers Prize winner here at Northwestern University, Feinberg School of Medicine. How is the Nemmers Prize different, or what is it about this award that you feel really is a good match for you? 

Jeremy Nathans, MD, PhD [00:17:16] One thing that's special is its association with Northwestern and the opportunity to connect with colleagues there. I'm going to visit. I'm very much looking forward to that. I have a number of friends at Northwestern and I hope to make some more friends at Northwestern. I think that bridge with a particular institution is wonderful. I think the more we connect with each other, especially in this era of COVID and less connecting, the better. 

Erin Spain, MS [00:17:42] And tell me about your upcoming trip to campus. What do you plan on doing? 

Jeremy Nathans, MD, PhD [00:17:46] Well, I plan on talking to and listening to a lot of people. It's all about people. And I'm very much looking forward to hearing what my colleagues at Northwestern are doing and what they're excited about. 

Erin Spain, MS [00:17:57] And tell us about the lecture you will be giving. What's it called? 

Jeremy Nathans, MD, PhD [00:18:00] I'm going to talk about vascular biology and in particular, central nervous system vascular biology. The system that I described earlier that controls the development of the vasculature is particular to the central nervous system. It works in the eye and in the spinal cord and in the brain. But amazingly, the same system is used later in life to control the development and then the maintenance of the blood brain barrier and the blood retinal barrier. The retinal version of the blood brain barrier. And that turns out to be a very big deal clinically because decrements in the function of that barrier, this is basically a specialization of capillaries that keeps toxic compounds out of the brain and out of the retina. Defects in that barrier are of critical importance in a wide variety of neurologic disorders: head trauma, multiple sclerosis, infections, degenerative diseases like Alzheimer's and Parkinson's. But the list goes on and on. And so understanding how it's controlled and how it can be repaired is something we're very excited to study. 

Erin Spain, MS [00:19:03] So tell me, what's next for you? What's next for your lab? What can we expect in the future?   

Jeremy Nathans, MD, PhD [00:19:08] Well, I think vascular biology is where we're going, at least for the next several years, five years. We're fascinated by both the beauty of the vascular system and also its medical importance. It's everywhere in the body. It's like the immune system in that sense. It impinges on every tissue in the body, and disorders of vascular function are of central importance to every organ system. I think there's a lot to be learned here that could be useful.   

Erin Spain, MS [00:19:33] Well, Dr. Jeremy Nathans, thank you so much for coming on the show today and talking a little bit about your career and what we can expect at the lecture that you'll be giving at Northwestern this fall. Thank you so much for joining me. 

Jeremy Nathans, MD, PhD [00:19:46] Erin, thank you very much. I really appreciate having the opportunity to talk with you. 

Erin Spain, MS [00:20:00] Thanks for listening and be sure to subscribe to this show on Apple Podcasts or wherever you listen to podcasts and rate and reviews. Also for medical professionals, this episode of Breakthrough is available for CME Credit. Go to our website: Feinberg.Northwestern.edu and search CME.