It has been two and a half years since I’ve stood at this podium. Thank you all for coming. It’s so good to see people in person in the Salk Auditorium and thank you to everybody who’s joining online. We’ve had some incredible outreach over the past couple of years during the pandemic. I know today we’ve got people joining us from as far field as Hawaii and Germany. So welcome to everybody and a special welcome to President Gage and his lovely wife, thank you for joining us. And I’m Cheryl Dean. I’ve forgotten how to do this. I’m a little rusty. I’m the planned giving council here at Salk. I work with people who have included Salk in their estate plans or have questions. Sometimes they want to give something that’s more complicated than just writing a check or sending cash or stock.
So if you have any of those types of interests, please get in touch with me, happy to help you out. And let’s see, let me run through some general things. For those of you online, we have closed caption instructions for whom that would be helpful. And please take advantage of that. Webinar participation, so this is a hybrid event we will be taking questions from everybody. Some have already been submitted. If you have a question, please hit the Q & A and after Greg’s talk, we will be alternating questions from people here in the auditorium and those of you online. And yes, today is our first in-person Power of Science. We used to call these sessions back to basics, but now it’s broader so we need a bigger name. So we’ve got Power of Science. And the title of the talk today is 21st century Salk building a more resilient world.
And our speaker today is the illustrious Dr. Greg Lemke. Let me tell you a little bit about him. You’ll never guess this, but he was born and raised in a rural farming town in West Central Ohio. And from his humble beginnings he became a national merit scholar at MIT. He did his graduate work at Caltech and a postdoc fellowship at Columbia University with Nobel laureate Richard Axel. We at Salk are very fortunate that Greg came to Salk back in 1985 and he has spent his entire career here.
He’s the Françoise Gilot-Salk professor and is a Fellow of the American Association for the Advancement of Science. And I’ll mention just a few awards, because he told me to keep this short, but you’ll get a glimpse as to how many areas he excels in. He’s received UCSD’s outstanding Teaching Award multiple years, the Javits Investigative Merit Award from the NIH and he is an advisor to numerous biotech firms. So on top of that, when Greg isn’t in the lab, he enjoys classical music and a little known fact before he began his lab, he was a professional singer. He’s got an amazing voice. So with that, please help me welcome Dr. Greg Lemke.
Thank you very much, Cheryl. So the talk today is really in two parts. As Cheryl mentioned, I’ve been at the Salk Institute for my entire career as an independent investigator since late 1985. And so the first half of the talk or so talk will be about 35 or 40 minutes. I’m going to give a couple of examples from my own work about how science has evolved and has advanced from the time that I came to the Salk to the present day. So I’m going to give you two examples of that. And then in the second half of the talk, I’ll speak about what this means in the context of the campaign that the institute recently launched. So to get started, this is the title of the paper that I published from my postdoctoral work with Richard Axel that Cheryl mentioned. The paper was published in 1985.
The project I was working on addressed a protein that’s in a structure called myelin, which is the insulation that surrounds all of your rapidly conducting nerve fibers in your body. So without myelin your nervous system basically doesn’t work. This is the structure that’s attacked in several autoimmune diseases, including Guillain-Barre and multiple sclerosis. So my project was to try to isolate the gene that included the major protein of peripheral myelin. That’s what I actually did in Richard’s lab. And that’s what this paper described. A big part of the paper was determining the structure of the protein, which you inferred from the structure of the gene. So I had to isolate the gene. That was a big project and then I had to sequence that DNA. And I did this project as the paper says in 1985. At that time I was in one of the top molecular biology laboratories in the world and I was using fairly state of the art methods to determine this structure.
And that’s, what’s shown on the right there. That is the nucleotide sequence on the top, those letters, A, C, T and G and underneath that is the inferred amino acid sequence of the protein. So I did this in 1985. This was for me a discovery moment. Every scientist has discovery moments. They’re one of the things that make it special about being a scientist. I can remember being in my apartment in New York, going through this sequence and getting these amino acids. And I could visualize what this protein looked like, how it was arranged in the myelin sheath, how it might be working, what its overall structure was.
When scientists have that moment, as I said, it’s a special moment because if you think about it until you tell somebody else what you know, you’re only human being on the planet who knows this biological truth. Of the billions of people on earth you’re the only one who knows what structure of that protein is. And every scientist who’s made the discovery has had that moment. It’s one of the special things about being a scientist. But in order to make that discovery, I had to sequence this DNA. And as I said, I was using cutting edge techniques and in 1985, that sequencing effort I did this all manually myself, took me approximately four months.
If you were to sequence that same length of DNA today, not in 1985, but in 2022, using the fastest slickest automated DNA sequencing machines like the ones we have here at the Salk Institute, how long do you think it would take you to sequence that DNA? It wouldn’t take four months. It would take you approximately 35 milliseconds.
That is less than a third of a 10th of a second. Less than the time that it takes me to snap my fingers. So that’s an example of how science and technology has moved in these few decades from the time I came here to the present day. Since I cloned this gene, since we identified this structure, there’s been enormous amounts of work on this protein done. There’s been a crystal structure solved. There are inherited diseases in human beings in which this gene is mutated. So on the right, there is a diagram of what we think the protein looks like in the myelin sheath and every circle, there is a different amino acid and every amino acid that has a color associated with it is mutated in patients who have peripheral nerve diseases. These diseases have been around for over a century.
They’re all named as is illustrated at the top line here after 19th century neurologist, two French neurologists and an English neurologist, Charcot-Marie-Tooth. So a lot of people walking around with these diseases and this particular protein that I quoted in 1984 is mutated in many, many, many of them. We now know based on those mutations and when these things occur how severe the patient’s disease is going to be and what potential treatments are available to them. So that again is an example of things that have changed from 1985 to 2022. So that’s the first example I wanted to give you. The second is after I came to the Salk Institute, before I worked on the myelin protein structure, it’s a protein called protein zero. I had worked on the cells that make that structure. Those cells are called Schwann cells.
I had purified a growth factor, which is important for the development of those cells. And it was learned after I’d done that work, that the molecules that are controlling the activity of that growth factor are a set of molecules that my colleague, Tony Hunter discovered here at the Salk Institute. So Tony is one of our most distinguished scientists. He is best known in the scientific world for discovering a modification of proteins called tyrosine phosphorylation. This is where you have a particular amino acid called tyrosine in which a phosphate group, a small chemical is placed onto that tyrosine residue in proteins. And in general, this is an important signaling event. In most cases, this strongly activates the activity of these proteins. That tyrosine phosphorylation and the enzymes that do the phosphorylation called tyrosine kinase were discovered by Tony here at the Salk Institute. He’s been very widely recognized for that work.
This is a photo of him receiving the inaugural Sjöberg Prize for Cancer Research from the king of Sweden in 2017. Tony’s work has had incredible impact in the world. You can’t read this slide, but what it is, it says on the right, these are FDA approved, small-molecule drugs that target Tony’s enzymes, the tyrosine kinases as therapies for cancer and other diseases. And the reason you can’t read the slide is because there are so many of these drugs. These are not drugs in development. These are FDA approved drugs that are used to being treated patients. And these are only the small molecules. There’s also a whole big set of antibodies that target these same enzymes, these tyrosine kinases. So a few years after I came to the Salk I was inspired by Tony’s work. And we were interested in a subset of these enzymes, these tyrosine kinases that are not soluble enzymes inside the cell, but they’re the same enzyme that’s linked to a receptor protein that goes through the membrane and sits on the surface of cells to detect extracellular signals.
And the way those proteins work, those are called receptor tyrosine kinases. When the signal binds to the extracellular part of the receptor, it activates these kinases and it does all kinds of important things in the cell. I don’t have time to tell you what these are, but they’re extremely, extremely important proteins. So when I came to the institute, this was before any sequencing of any genome was done. We didn’t know how many of these receptor tyrosine kinases there were. So in this project, which was carried outed by a postdoc in my lab, Carrie Lie you see this paper is published in 1991. So shortly after I came to the institute. Carrie set out to determine, to try to figure out how many kinases receptor tyrosine kindnesses there were in the nervous system.
And this paper that he published here again, at this time used another cutting edge technique for the time something called the polymerase chain reaction or PCR. This is the thing that’s used nowadays to detect the coronavirus genome tissues. But at the time in 1991, this thing had just been invented. And so we used it and Carrie identified a whole more amino acid sequences, a whole slew of kinases. So it turns out, we now know you have 58 receptor tyrosine kinases in your genome. And in this one paper Carrie cloned 11 of them identified, 11 of them. And over the years my lab has worked on many, many, many of these proteins. But for the example, I want to focus on this family that’s highlighted in red here, which at the time we called the Tyro 3 family. So there were three receptors that we identified in this family, we called them Tyro-3, Tyro-7, and Tyro-12.
They were at the time, what were called orphan receptors in that they didn’t look like the RTKs that we already knew about. So we didn’t know what their were. We didn’t know what they did biologically, et cetera. So we had to work over this for many years and we eventually discovered all that stuff. So the receptors are now called the TAM receptors. Tyro-7 has been renamed AXL, Tyro-12 has been renamed MER. So the first letter of this family, Tyro-3, AXL and MER gives the name of the family. These are the TAM receptors. My lab studies these intensively now. We eventually identified the proteins that activated them, that bind to them and activated them. There are two proteins called Gas6 and protein S. And then we made another discovery about this system the whole system only works if the very end, the blue end of those end proteins also bind to a lipid called phosphate serum.
And over the years, we’ve done tons of experiments, published lots of papers. We’ve shown that these receptors play important role in the development and the growth in metastasis of many cancers. They play important roles in the infection of target cells, by envelope viruses including the coronavirus. They’re important endothelial cells in all of the blood vessels in the body. They’re very important in regulating their mature function.
They’re extremely important in immune regulation. And I’ll talk about this just a second and in tissue homeostasis. So this is the regulation of the properties, the balance like properties of many of your tissues. So one of the features of homeostasis that’s particularly important is in the renewal of many of your tissues in your body every day. And this turns out to be a very fundamental and very basic thing. So as you’re listening to me now, something like two to three million cells in your body are dying and being renewed every second.
So on the order an excess of a hundred billion cells in your body die every day, you have lots of tissues that have to be renewed. And so one of the things these TAM receptors do is they’re critical for the ability of immune cells in the body called macrophages to recognize these dead cells and then to eat them. So you can’t have all these dead cells piling up in your body, you have to clear them out. You have to recycle all their materials, you have to make new cells. And this is a picture of one of these immune cells called a macrophage that’s been caught in the act. The macrophage is the blue cell. It’s been caught in the act of eating this orange dead cell. This cell expresses a TAM receptor. It turns out that the TAM receptors are critical for this function all over the body.
If you don’t have the TAM receptors and you don’t do this, you have all kinds of problems. One of the diseases that we have been looking at in the context of this activity of the TAM receptors is Alzheimer’s disease. So there’s a population of those blue cells in your brain, macrophages in your brain that are called microglia. And those microglia they’re the brain’s macrophages, they eat dead cells that are generated in the brain routinely. So our President Rusty Gage is very well known for his analysis of a phenomenon called adult neurogenesis. Where you generate new neurons, especially when you’re young in a couple of centers in your brain. But in those centers, when you generate these new cells, most of them don’t become neurons. They don’t go all the way to differentiation. They die and they have to be cleared. And the cells that do that in the brain are these microglial cells.
Now for a number of reasons, microglia have been implicated in Alzheimer’s disease. And so we decided to study this in mouse models of Alzheimer’s disease. And for this work, we again relied on a cutting edge technique. So this is a cutting edge technique that’s now less than two decades old. It’s about 15 years old. And we relied on my colleague, Axel Nimmerjahn who works in this building and who pioneered this technique. And this is the ability to visualize the activity of cells in the brain in live animals. So you look in the brain while the mouse or other animal is alive, and you look to see what the cell is doing. So I’m going to show you an example from this work, which we actually just published last year. So I’m going to play this movie in just a sec, there are two profiles here. This is in the cortex of a mouse.
So to make this mouse, we’ve had to use a lot of cutting edge techniques. So in this particular mouse, we have used genetics to label these brain macrophages, the microglia. And in these images they are white. Now they’re also white in a mouse model of Alzheimer’s disease which is called APP/PS1. And then in these mice, we’ve also either have them just the disease or have the disease without our two TAM receptors, AXL and MER in the microglia. And then we’ve labeled the famous a beta plaques of Alzheimer’s disease in these mice with a dye called MX04 which is red. So that’s what you’re seeing here. On the left are normal microglia and on the right are microglia that don’t have AXL and MER. Okay? So before I play the movie, you just look at, you can see these two sides are quite different.
On the left all the microglia seem to have been condensed, and they’re all glommed onto the surface of the plaques. It’s actually hard to see the plaques because most of them are covered by microglia. On the right it’s easy to see the plaques because most of them are completely unattended by microglia. And if you look carefully at these cells, they have these long processes that are all radiated out. One of the things that’s remarkable at the microglia that Axel Nimmerjahn actually discovered by looking in the videos is that their processes are incredibly active.
So I’ll play the video for you now. And I want you to look at this carefully, the video loops over about 90 minutes, it’s really sped up. So you’re seeing what’s happening in these cells over 90 minutes. And what I want you to really notice is basically the cells on the right, which lack the TAM receptors are behaving as if there aren’t any plaques in the brain. It’s like they don’t even know the plaques are there.
They’re not attached to the surface of the plaques. Their processes are extended way out like they would be normally. They’re not like the angry microglia that my graduate student at the time, Youtong Huang, characterized these cells on. So this analysis shows basically that these microbial cells are not even responding. So this is a really cutting edge technique now. And since the microglia are one color, they’re white, and the plaque is red we can ask, how active the microglia are at this eating process that I showed you for the dead cell? They do the same thing. And it turns out they don’t do this at all. You don’t really have to pay attention to this or know what’s going on this slide, just look at the height of the red bar versus the height of the gray bar. So the gray bar is just the disease allele.
And that indicates how much of this labeled material is taken up inside the cells, which we can see in these movies. And when we have AXL or MER gone, that’s what the minuses mean. This is a mouse that is mutant, it doesn’t have any AXL or MER. This phagocytosis is dropped way, way, way down. So these microbial cells can’t eat this a beta material, which is presumably causing the disease in the mice. And until we did these experiments, it was widely assumed that this eating process was controlling the growth of the plaques in these mice and so the prediction from you don’t have any eating, you don’t have any of this phagocytosis has really dropped like tenfold. The mice should have many, many, many more of these plaques, which are called dense score plaques. But when we actually measured it the mice have fewer phage plaques.
They don’t have 10 times as many plaques. In the red curve they have about 40% less, exactly the opposite of what we expected. So I don’t have time to go into all the science on this, but I’ll just give you the basic conclusion here. So here’s that structure of the TAM that I told you about before. These plaques, we discovered have this key phospholipid called phosphatidyl serine that you need for the system to get activated. And what’s happening in the middle panel here is this system in this phagocytic cup of a microglial cell is eating this loose A beta stuff and it’s taking it inside the cell. So it’s internalizing it into that yellow ball at the bottom, which is called an endosome. And what happens inside cells is that endosome then moves to another compartment, which is called a lysosome, which is illustrated on the right that transition.
And in the lysosome the pH drops and proteins become concentrated. Those are the two things that favor the aggregation of a beta into this fibrillar material that gets deposited into the center of dense core plaques. So our conclusion from this paper is that microglia do not constrain the growth of dense core plaques in Alzheimer’s disease. Exactly to the contrary, microglia phagocytosis creates those plaques and a follow on conclusion from that is that dense core plaques may be analogous to other situations in the body where your immune system has some threat that it can’t defeat. So if you’re a minor and you breathe in silica or metals, you breathe in silica, you can develop a situation in your lungs called silicosis where the macrophages of the lungs eat these silica crystals and then form what’s called a granuloma around them.
The most famous case of a granuloma is in tuberculosis. You have tuberculosis bacteria in your lungs, it’s not all over your lungs. It’s been eaten up by macrophages and they formed this very elaborate structure that’s shown in the middle called the TB granuloma. And this is a mechanism of walling off and sequestering this material so that’s not all over the lung. Well, we’re hypothesizing that the dense core plaque of Alzheimer’s disease is exactly the same thing. The brain is overproducing a beta it can’t get rid of it and so what your brain’s macrophages, your microglia do, is they concentrate in the dense core plaques. So if that’s the case, how do you approach this in the context of a therapy? This is the last thing I’ll say about science. So you may know last year, the very first drug that addresses the underlying biology of Alzheimer’s disease was approved by the FDA.
That drug is an antibody called aducanumab it’s sold as Aduhelm by the company that makes it, and this drug was approved in a very controversial decision. Even though the FDA advisory panel voted overwhelmingly against approval. The drug has two features. One of the things that it does very, very well in patients is if you give it to patients over a period of months and you image how much of a beta plaque burden they have in their brain using PET imaging it very dramatically lowers this burden. However, if you ask what’s the effect for the patients over the course of 6-18 months? Basically the drug doesn’t work.
And so there was a big hoo-ha surrounding this. And so our model is the patient’s cognitively better after 18 months. Well, their amyloid burden, their PET burden is much lower, but they’re not better. So our suggestion is that if the dense core plaques are granulomas and if the only thing you do is bust them up and put a beta all over the brain, you don’t do something to get the a beta out of the brain, then those drugs are unlikely to work. So this is very cutting edge. This decision just went down at the end of last year. The office of Medicaid funding says they’re not going to pay for the drug. So it’s a very controversial thing right now. And I think this work that we really started on the receptor tyrosine kinase is like three decades ago and have now brought forward to the TAM receptors in Alzheimer’s disease.
It really illustrates the power of basic science to move the needle. So, those are two examples from my work. I see some of my colleagues in the audience they could give you equivalent examples from their own work. This is really the power of science, is really the power of basic science to understand things we really, really care about. And so for the last part of the talk, I’m going to really say a few things about what I think this means in the context of the new campaign that the Institute has launched. So I’m going to introduce this with a little video. I hope Mike, this is not too loud. We have a little video that says a few things about what the goals of this campaign are and what we hope to achieve. So this is two minutes long.
So that’s where we are now. Hope you recognize at the end of that video, two people I’ll talk about again, but one of the persons shaking hands was Tony Hunter the scientist, I mentioned who motivated our work on receptor tyrocine kinase. So, the campaign in the present day really has its origins from stuff that our founder Jonas Salk talked about many, many decades ago, that in this slide is listed as The Salk Vision. And it’s really the features of the institute that are special. Most important is discovery through collaboration, which is actually set up in the structure of the building. So our original buildings really were a partnership between Salk and Kahn. A lot of people don’t know that the original plans for the building by Louis Kahn are completely different from the building we have now.
And that’s because almost at the last minute, Jonas intervened and directed how the building should be constructed and that this principle of collaboration should be emphasized. As always the motivation was, as it says, here is designed to empower the brightest minds to pursue scientific answers to the most pressing health issues that we have. These are the ones that I hope I touched on in the science part of my talk. And Jonas felt that the pursuit of science and he knew this, I think intrinsically over time in ways that I illustrated in my own science had to change and grow and evolve. It had to advance.
You had to go from taking four months to sequence a kilo base of DNA to being able to do it in a fraction of a second. So in the current campaign, we have overall these goals that are mediated on understanding basic biology that will allow us to achieve some of the things that are listed here, that is mitigation of climate change, advancing healthy aging, stopping cancer, preventing and treating neurodegenerative diseases and fighting infectious diseases.
The goal of the campaign is to do that in really essentially three legs. And we are going to have overall what’s indicated here a holistic scientific approach. So the theme of the campaign is building a more resilient world. That’s really what we’re trying to achieve and understanding all of the biology that we do at the Salk Institute. We have six scientific centers that are emphasized in this campaign. These are cancer, computational biology and engineering, immunology and infectious diseases, aging, neuroscience, and plant biology. So the campaign overall is a 500 million campaign and it has three basic legs that this campaign will fund. Those are people, technology and space. So of those legs, I would say people are probably the most important component. They always have been. Advances and discoveries are made by scientists. That was true when the institute was founded.
And it is true today. Some of the folks on the top are among the founding fellows of the Institute. There’s Jonas forth from the right there. The short guy, almost all the way on the right, some of you who are older or at least as old as me might remember this name, his name was Jacob Bronowski. And when I was a kid, I remember he had a series on television, on PBS, called The Ascent of Man, that even as a kid I found fascinating. Bronowski was one of the founding fellows of the Institute. He was a polymath and a Renaissance man. He wasn’t a conventional scientist. But it was that quality of person who was here originally and it’s that quality of person that we need to continue to attract to the Institute.
So the scientists who work here are at all levels. And these scientists all have to be supported. They include our professors, assistant professors and associate professors who are members of our faculty, the Salk fellows, who are folks who have just gotten their PhD and have done something spectacular where we think they can start up their lab without even doing a postdoc. All of our postdoctoral fellow who are at the bottom of the list here, they’re probably the main engine that’s driving the science. I was a postdoc when I sequenced P0 in Richard Axel’s lab. And we need to fund these things. So one of the mechanisms we have used previously and we want to do as part of the campaign is to endow these positions. So when I first came to the institute in 1985, essentially all the faculty had to raise all of their own salaries. So we weren’t paid by the institute. There was no money to pay us. We had to get that money off of brands and other things. Over the years, as a result of initiatives like this, that we want to reinforce going forward, we’ve been able to endow nearly all the senior faculty here at the institute, and many of the junior faculty. We would like to move that concept into all levels of the scientific enterprise here and including the postdocs. So people are a critical thing. The other is technology. I hope you got at least a feel for the scientific examples I gave you about how technology has moved dramatically from 1985 and how it continues to move forward. There was no way that we could have thought that we could look at the behavior of live cells in a live animal with a microscope in 1985.
It would’ve been a fantasy, but now that’s routinely done. We’ve sequenced the genomes of most of God’s creatures now. And as I told you, we can do this really, really, really fast. People who have diseases want to know whether they have genetic diseases, they can get that information in a matter of days. So technology has moved very rapidly. We need to be able as a part of an institution going forth, not only to keep up with the technology, that’s evolving in the community, but to make new technology for ourselves here. There’s some examples here about what this technology vision is, is employing computational mathematical methods to analyze huge biological data sets. Just think about that. Your genome is billions of nucleotides. It’s not a thousand. So these data sets have to be, first of all generated, they have to be stored, but more importantly they have to be compared and manipulated and understood.
And so that technology has continued to evolve. We’re framing more and more biological problems as computational problems to provide insights into both the biology and to the diseases that may evolve out of that biology. We’ve got machine learning algorithms that can be used for problems ranging from classifying genetic sequences and from analyzing images like those images I showed you in that microscopy of the moving cells, there’s a huge amount of data. So technology is a big component of this. For the campaign as I said, we’re going to have six centers of excellence. We are talking about a new building, which I will mention in just a second, which we also have some models up here. These centers of excellence are in plant science, cancer, computational biology and engineering, healthy aging, the NOMIS center, which is immunobiology, and the center for neurobiology.
Four of those new centers will have very important representations in the new building. And two of them will be built out and expanded in our existing buildings. So as part of the campaign, a very important thing to mention were the two people who were at the end of the video shaking hands with, or one of the persons at the end of the video shaking hands with Tony Hunter and that’s Joan and Irwin Jacobs. So the Jacobs have been great supporters of the institute for many, many years. Irwin was the chair of our board of trustees for a number of years and they have made a hundred million dollar matching gift to the Institute. The terms of that match are that for every $2 that are contributed to the institute, Joan and Irwin will contribute an additional dollar up to 100 million. It’s quite a remarkable gift.
It’s one, obviously that’s going to make a huge difference to the campaign going forward, but it’s part and parcel I would say with the way the Jacobs have lived their philanthropic life in San Diego over the last 20 or 30 years. So part of that thing is going to be this new Jacob Science and Technology Center it’s that new building. It’s the thing you saw lots of things on in the video that I showed you. The budget for this is approximately $300 million. We think it’s going to be a state of the art center and it’s going to provide an additional a hundred thousand square feet of lab and research space for the institute. It’s going to be a re-imagining of this campus. That building is going to basically occupy what is now the parking lot out there.
The design of this building is going to be in keeping with the original design of the institute. So one of the things that makes the institute special, one of the things that historically has always been important here is that the main floors of that institute are all open space. So none of the interior walls in each floor of the institute supports any weight, it’s all drywall, and you can take it all down at once. It means you can reconfigure laboratories as science evolves and advances and changes. This flexible and functional and interactive design is going to be a very important component of the new science and technology center.
The goal is to put this in place, not for people like me or Tony Hunter, who’ve been here for decades, but for the youngsters among our faculty, who’ve only been here for a few years. So I put up this montage, this is a bunch of them. This is really the next generation of science at the Salk. They’re working in all of these centers of excellence areas that I talked about and they are the people for which this campaign is really designed. So with that, I will thank you for your attention. And thank you for listening to me and I’d be happy to take any questions that anyone has.
Thank you very much, Greg. Thank you everybody for coming again. As I’ve mentioned, we have folks who are joining us online if you have questions, please type them into the Q&A part of your screen. And we will alternate. And I’m actually going to start today’s questions with somebody who submitted online when they registered. Dr. Tom Wrighton had asked, have the plans for the Joan and Jacob Science and Technology Center considered including outdoor areas for study and an arena for lecturing? He goes on to say, the weather in San Diego allows us to work outside often and outdoors increases serotonin and happiness and happy scientists are productive scientists. So that question is from Dr. Tom Wrighton.
Okay, Tom. Yeah, I mean, there are outdoor spaces, outdoors is a great thing. You may have got the impression from the videos and you can also probably see from the model up front, a lot of this space and especially the central space can actually be opened up. And so it’s effectively outdoors as well. For lecturing spaces this was always a big issue for the institute. So before this current building was built and before we had this lecture space this was a basic need at the institute. We had our seminars in the middle of lab space in the original buildings. And so that was one of the big, big things here. So there’s some very nice outdoor space both will be on that side of the building and on the space between the new building and this building that allow people to get together to meet in small groups. I don’t know about having lectures there, but I suppose we can think about that.
Any questions? Okay.
Thank you. Can you comment a little bit about technology that’s currently here and a little bit about where you think that might go in the future technology portion?
Sure. A lot of new biology is actually driven by technology. So, for example, those cells I showed you in the brain macrophages in other parts of the body they move around, they can move through the blood, they can move through tissues. These macrophages, until somebody actually looked at them using this microscope, it’s what’s called a multiphoton microscope. And this technology was invented in the 21st century. Until you had that technology, you didn’t actually know what those cells were doing. Their cell bodies are sitting in one place, but they have these fingers that radiate out from them that survey basically all of the brain parenchyma every few hours. So the cell does this. So that’s an example of what technology is doing. Technologies come very, very fast. So one of the technologies that we used in my lab in that Alzheimer’s paper that I mentioned to you is something called single cell RNA sequencing.
This is a technology where you can purify individual cells and in every single cell inventory, how much of all the mRNAs that are expressed from the genome are expressed in that cell. That technology was invented about six years ago. And initially it was only done in a few labs around the world. Now it’s done everywhere. Everybody has to do this technique, has to be part of paper. So these technologies can come very, very, very quickly. The other thing that we’ve tried to do with the Salk and other areas is to actually invent some of this technology. So particularly in imaging and in microscopy, we have the Waitt Advanced Biophotonics Center. We’re doing lots of imaging of cells and tissues and organisms of animals here that isn’t being done any place else. So that’s why this technology component is one of the three components of the campaign. The technology is really going to push a lot of the biology forward without that you’re not going to have the advances that I was talking about.
Well, our laptop just walked out back. So let me grab one more question from-
I can’t remember what I can do here to see if there’s any questions I want to ask.
Well, Greg, thank you for a great talk. I got a million questions, but I’ll keep it to just the new building. And the question I have is number one, I don’t have a sense of perspective. What’s a hundred thousand square feet compared to the first building that Louis Kahn designed? And in that building, because we’ve been on several architecture tours, the unique part about it was separate layers of laboratory space and utility space. I can’t tell from your picture, whether that’s going to be happening in the new building or not. And finally in one of the walks around the campus, they said where the parking lot was, was going to be underground parking. So how do you handle parking when this new building is here? So that’s three related question.
Okay. So in terms of size, Rusty correct me if I get this wrong, I think each of the main floors is 16,000 square feet?
So the original floors-
Original building would be 66,000. [inaudible 00:48:56].
But again, so I’ll emphasize that feature again as well. I’ve been here 37 years. There was at one point where our cancer biology labs, which were some of the original labs at the institute were entirely remodeled. So there was a period of time where everybody moved out and everything was taken out and that entire floor was an empty glass box. You could walk around the outside and you could see the floor was intact there was nothing there. So this business about flexibility, about being able to re-engineer space, that’s going to be engineered into the new building as well. The construction of what are called in the famous original buildings, the interstitial spaces, which are partial height that is in 2022 is prohibitively expensive to do. But what Kahn did in thinking about the architecture of scientific buildings, he built a precursor to the Salk Institute called the Richards building at the University of Pennsylvania.
It’s a laboratory building as well. And in that building, what he did was move what he called the servant spaces, which would be equivalent to our interstitial floors, into a separate tower and a wing. And actually Rusty just pointed this out to me in the new building there are features of that here on the outside, these kinds of things are the servant spaces. So we’re not going to have interstitial floors above, but the concept is going to be the same. So that a lot of this space in the new building can be this flexible open space as well. Did I answer all your questions?
Where is the parking?
The parking is going to be underneath. So the parking is going to be underneath this structure.
And I’ve been reassured … Sorry, Cheryl, all the way in the back, that there will be plenty of parking more than we have right now. So I’m thrilled about that. Because just like you, it can be challenging sometimes,
Rusty tells me the cars are actually going to be double decked, triple decked.
That makes me a little nervous. Okay. So we have a question from our online audience. What is an area of weakness at Salk that you would like to see strengthened as the campaign moves forward?
Well, that’s a very, very good question. We’re recruiting for new faculty in the immunology program here immunobiology microbial path, the NOMIS Center. I’ll turn that around, try to play it to a strength of the institute. So one of the key strengths of the institute is its small size. We have 50 some odd faculty. Even with this expansion of the space, we’re not talking about a dramatic expansion of the faculty because we’re really cramped for space right now. So we will have maybe 60 some faculty, low sixties faculty in the reconfigured institute. But those faculty span basically all of biological science. The faculty span people from working in plant biology, to people working in computational neuroscience, to people working in cancer, to people working in neuroscience. And one of the advantages of the small faculty that I think is particularly important is we can assemble the whole faculty together as we do at our retreats.
And all of those people have to communicate with one another. So one of the weaknesses I would like to see corrected is mechanisms for more regularized interaction within the faculty. We have some of that in neuroscience. So neuroscience is also a very diverse area. It goes from developmental neurobiology, all the way up to computational neuroscience and theoretical neuroscience. Those people all get together once a week at a giant lab meeting. I think that’s a weakness I would like to see more of. The campaign can maybe foster that if there were some funds for actually these regularized meetings, because that is one of the key things that makes the Salk Institute powerful. There are many universities and medical schools where a department of, I don’t know, cardiology might have a faculty that’s the size of the Salk Institute faculty. We have, I think what is probably the smallest plant biology group, probably in the world. It’s also the most highly rated plant biology group in the world in terms of the impact of its papers. So it’s small but powerful. That’s something I think we should foster going forward.
Yeah. Just a question in terms of what you spoke about the collegiality and action, I noticed in your slide earlier, you spoke about AI as being a component. My understanding is not sophisticated about this, but my understanding is the artificial intelligence can be incredibly successful and helpful. The problem with it is it comes up with the correct solution. But for us to understand how it came to that conclusion isn’t understandable. So how do you integrate something like artificial intelligence into the discovery of new things, with an understanding beyond just the machine learning and [inaudible 00:54:23]?
And Greg, could you please paraphrase that? Because I was not able to get the mic there quickly enough for everybody listening on the line.
The basic question is applying artificial intelligence to problems. Artificial intelligence, depending on the setting, can come up with a solution to the problem. But it can’t really explain what the basis of that solution is. So I think it depends on what your goals are. So if your goals are to understand a biological phenomenon and to predict how you might want to address that phenomenon in the context of disease, you don’t care. If the phenomenon is correctly predicted you really don’t care. If you want to go back to the mechanism that’s something you have to… It really relies on in the end experiments because you make predictions about how a system works. You say, I think it works this way. Therefore if I do X, Y will happen, that’s an experiment. And biologists still have to do those experiments.
There are many examples of this in biology now. So one of the things I showed you at the beginning of my science talk, what was a crystal structure of the extra cellular domain of that protein P0 that I cloned back in the 1980s. Well, that structure was determined by old-fashioned x-ray crystalography. There are AI based methods now that if you have the right internet link, you can click on and you can enter the name of your protein and an AI method called the AlphaFold will give you a predicted structure of that protein.
Now, if you actually look at this, it’s very powerful in a lot of ways. But if you actually look in detail about what AI is actually predicting from many of these protein, it’s mostly stuff we already know. And many of the reasons we don’t know the full structures of proteins is because those structures are dependent upon interactions with other proteins. And AI may be able to solve that problem as well, but it hasn’t had yet. So the final analysis answer to your question is I think biologists have to do experiments.
Greg, another question from online, if you could go back in time, what piece of advice would you give your younger self back in 1985?
My younger self in 1985? I’d probably tell him to find a better apartment in New York City. I lived in a very dangerous neighborhood. No seriously. I mean, I think in general I have made decisions in terms of what I wanted to study that I don’t think I would necessarily change. If you type my name, there’s a thing if you’re a scientist you can search all papers that have ever been published on a database that’s run by the National Institutes of Health called PubMed. And so you can type somebody’s name in and you can see all the papers they’ve published.
And so if you do that for me, you’ll see that I have published in lots and lots and lots and lots of different areas because I’ve had to reinvent myself as a scientist. And I think all scientists and all scientific institutions like the Salk Institute have to continually reinvent themselves in order to be relevant. That’s one of the overarching goals I think of this campaign. So in terms of what I would’ve done differently, I don’t know. I have opinions for what I would do now. If I was a young man starting out now I know some of the science I would work on, but I don’t think I would necessarily change anything.
Any other questions from the audience? And I think we’ll make this the last one.
Yeah, with the microphone now. Just for clarification purposes, in terms of your talk about Alzheimer’s, if my understanding is correct and it’s a very simple understanding is that the Alzheimer is basically a defect in the effective elimination of amyloid from the brain. Is that what it basically is?
That would be my conclusion, but you got to be very careful with your words here. So amyloid again is misused a lot in the language. Amyloid is generally used [inaudible 00:58:53] Is that you?
To this highly aggregated form of what’s called amyloid beta. So the way amyloid is generated is you have a normal protein in your body called the amyloid precursor protein or APP that protein, the very, very end of that protein can be clipped off, the last 40 or 42 amino acid that protein can be clipped off and that becomes a soluble protein that floats around. That happens normally in all of us. As we age, it happens more frequently. The problem is if you make too much of that protein and the brain can’t get rid of it. The brain can’t get rid of it, it starts to aggregate and it forms polymers. It links up, it makes bigger, bigger, bigger, bigger structures. And then those things float around and those are very toxic to your brain. So our model is what these brain macrophages, the microglia are doing is taking that loose stuff.
They’re gathering it all up, they’re taking it inside and they’re compacting it and they’re putting it in these dense cores. We’re not saying the dense core plaques are good things. It’s certainly not a good thing to have dense core plaques all over your brain. What we’re saying is it’s your brain’s attempt to make the best of a bad situation, which is the overproduction of a beta. So what you really want to do is reduce that by some mechanism. Think about how you’re going to do that or get the A beta out of the brain. So your brain is actually pretty good at doing this normally. It fluxes most of the stuff across blood vessels, into the circulation and gets it out of the brain. It’s just that when you can’t do that well enough, A beta builds up.
So these dense core plaques, which are the things you see in the PET imaging, we’re saying they’re not the worst of the problem. The worst of the problem is the production of A beta in the first place. There’s a lot of controversy about this because all these drugs fail. What’s called the amyloid hypothesis is wrong. We’re actually not saying that the production of A beta is a bad thing. These A beta peptides. If you have mutations in that APP protein that increase the rate at which A beta is produced, the probability that you will develop Alzheimer’s disease as an adult is a hundred percent.
So we know that overproducing A beta is a problem. It’s just that our dense core plaques is the real problem. A lot of people who die and after death, they’ve been cognitively healthy they’re old people and for some unrelated reasons, they may have their brains looked at and they have lots of dense core plaques in them, but they were cognitively healthy people when they died. So that’s the over overall conclusion from our paper.
Well, we’ve come to the end of our time, Dr. Lemke covered a million topics and there are quite a few questions that we weren’t able to get to, but I will see what we can do to corral him over the next week or so to get answers to all of you who have questions that we weren’t able to get to. And in the meantime, please know how much we very much appreciate your support and continued interest in the Salk Institute. We haven’t been able to come together like this in well over two years.
So thanks to everybody who’s both here in person and here in spirit online. I don’t know exactly when our next event will be, but you will all be notified. And in case you didn’t catch everything that Dr. Lemke said today, because there was an awful a lot presented, this will be online and we will be sending out a link in case you’d like to rewatch it or send it to your friends. Thank you. You’re the first audience to hear about our new campaign. We’re very excited about the building and everything else that comes with it. So thank you for your anticipated support of that as well. And for those of you who are here, you’re welcome to join us outside upstairs for a small reception. Thank you again.