Science Friday
Hosted by Ira Flatow
When the Nobel committee called, Fred Ramsdell did not pick up. Plus, searching ancient archaea for solutions to modern antibiotic resistance.
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Science Friday is supported by MathWorks, creator of MATLAB and Simulink software for technical computing and model-based design. MathWorks, accelerating the pace of discovery in engineering and science. Learn more at mathworks.com. Hi, this is Ira Flatow, and you're listening to Science Friday. Today on the show, we'll talk with the winner of this year's Nobel Prize in Physiology or Medicine.
She looks me at this big grin, and she says, "You just won the Nobel Prize." And I said, "No, I didn't." And she looked at me and said, "I have 200 text messages from your friends who said you did."
This week, scientists found out if they won, among the highest honors in science, the Nobel Prize, and not by opening a sealed envelope, but by answering a long-distance phone call. The phone rang for three scientists who now share the prize in Physiology and Medicine: Dr. Shimon Sakaguchi, Dr. Mary E. Brunkow, and Dr. Fred Ramsdell. They discovered a key mechanism that regulates the body's immune system, and together, their discoveries outlined the role of the peripheral immune system, how the immune system knows to attack just the foreign invaders and not its own tissues and organs. They found that regulatory T cells work to keep the immune cells in check, but things
can go awry if someone has cancer or an autoimmune disease. Joining me now to talk more about his work is Nobel winner Dr. Fred Ramsdell, co-founder and scientific advisor at Sonoma Biotherapeutics. He's joining us from his home in Montana. Welcome to Science Friday, and congratulations.
Thank you very much, Ira. A pleasure to be here.
Nice to have you. Now, I know that your phone didn't really ring for you, did it?
It did not, no.
Tell us what happened.
Yeah, so my wife and I tend to take long camping, backpacking trips right after Labor Day, when kids go back to school and everything clears out. And we left our Seattle home and worked our way through Washington and Idaho and through parts of Wyoming and Montana. And so we've been on the road for about 25 days, I would say. And the day of the announcement, which I did not know was the day of the announcement. We were up in the high country at about 8,000 feet with six inches of fresh snow. And my phone was on airplane mode, of course, because there's no service anyway. So we got out, we drove down, we drove through Yellowstone National Park.
We went through some little town and I hear my wife in the car saying, oh my God, oh my God, oh my God. And we're in grizzly country. So I thought.
So you're thinking the worst.
Well, I thought it's not, there's no grizzlies here. And then she gets out of the car. So I know there's no grizzlies at that point. And she comes back and she looks at me with this big grin and she says, you just won the Nobel Prize. And I said, no, I didn't. And she looked at me and says, I have 200 text messages from your friends who said you did. And I thought my friends might play a joke on me, but they're not coordinated enough to play that good a joke on me.
Right.
So I was pretty stunned, but it was, it was an interesting day for sure.
Well, I'll bet. Were you able to celebrate?
Uh, yeah, kind of funny. My wife went down and bought the only bottle of prosecco they had in the hotel. And so we drank that while making phone calls and then we went out and found a little Irish pub in Livingston, Montana and sat at the bar and hung out there.
Um, let's talk a bit about your research. Tell us why your research is so important. And help us better understand how the immune system works and what you were working on.
Yeah. So happy to do so. So we've known for a long time that the main function, as you mentioned, of the immune system is to protect us from pathogens, viruses, bacteria, whatever. And yet we also know that sometimes it goes awry and it attacks our own tissues. And that could be multiple sclerosis, it could be rheumatoid arthritis, Crohn's disease, a number of others. And we may able to characterize that fairly well. But we've never really totally understood the balance between getting rid of a pathogen and attacking your own tissue.
One of the things that when I was at a biotech company called Darwin Molecular, we had a collaboration with Oak Ridge National Labs. And it was a, it was a group that was set up during the Manhattan Project. So go all the way back to World War II, when the US government wanted to understand the effects of radiation on mammalian cells and organs and tissues. And so they set up a genetics unit for mice. And this group had kept alive and still, I think, has mice that go back to the 40s. Some have skeletal formations, some have neurologic characteristics. The one we looked at had what was essentially massive autoimmune disease. It is though its immune system attacked every tissue in its body.
And it was fatal to the mouse in three weeks. Whatever is going on in these mice is completely fundamental to that regulatory process. And so Mary Bronco and her colleagues worked tirelessly to actually identify and clone the gene responsible for that. And that gene later became known as Fox P3. And it was back in the day, it was the mid 90s. So sequencing was still, I won't say an art form, but it wasn't what it is today. You couldn't do it like, like you can do today. And so it took a long time. We found this gene. Myself and people in my group realized that it was, the gene was only expressed, was only active in a very small subset of T lymphocytes
or T cells in the blood. And somewhere between 1 and 10% in, in people. And it's the only place it was found. And it correlated with a cell type that Shimon Sakaguchi had been studying for five to 10 years at that point, which he could show could have some of these regulatory properties. But he didn't have the tool. To really characterize those cells well and understand the molecular basis for how they worked, which is what now we could do. And so, back in the year 2000, we said, all right, now we know that this tiny population of cells is responsible for maintaining, as you described quite accurately, peripheral tolerance.
It keeps the immune system from attacking itself. And this is also true in humans, it's not just a mouse phenomenon. So, even back in 2000, we said, all right, if we could use these cells, we could treat people. And so, for the next 20 years, people piled on and tried to figure out, how do they work? What are their properties? You know, how can we exploit that? And then, fast forward, fast forward, I'm sure that's the right term, slow forward to today, people are now, my company, Sonoma, but there's other companies doing the same thing, are trying to use these cells in people, in patients, in early clinical trials to treat various autoimmune diseases. And, you know, it's early days.
Such as?
So, rheumatoid arthritis is one. People are also looking at type 1 diabetes. People are looking at graft rejection and transplant tolerance.
So, how soon could we see some results?
So, soon. I think within the next year, maybe 18 months, we're going to see very early data. Now, again, remember, this is version 1.0 of an incredibly complicated drug. But, you know, there's still a lot of variables, and we have a lot of ways we know that we can make these drugs better, longer lasting, et cetera. We just don't know how well they're going to perform in their first iteration. But, but we're hopeful. You know, I'm certainly optimistic.
Well, we wish you great luck, and we congratulate you again, and hope you'll get a decent bottle of champagne that you can celebrate.
I will find one somewhere, don't worry about it.
Congratulations, once again, to you and your colleagues, and to all the winners of the...
Thanks very much, Iris. Lovely talking to you. Appreciate the time.
You're welcome. Dr. Fred Ramsdell, co-founder and scientific advisor at Sonoma Biotherapeutics. He was joining us from his home in Montana.
After the break, using ancient organisms to develop new antibiotics.
Archaea, this incredibly interesting domain of life, has never really been systematically explored as a source of new, potentially therapeutic molecules.
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Roughly 36 million people have died over the past three decades as a result of antibiotic-resistant infections. That's according to one global estimate. With no signs of slowing down unless we can take action to address the growing threat. Our next guest is looking to solve the antibiotic resistance crisis in unexpected places. He's identified promising antibiotic candidates lurking in ancient archaea, small organisms classified as the third domain of life that can survive some of the most extreme conditions in the world. Joining me now is Dr. Cesar De La Fuente,
associate professor of bioengineering, University of Pennsylvania, based in Philadelphia. Welcome to Science Friday.
Thank you. It's a pleasure to be here.
Let's get right into this. I want to start with a quick refresher for those who aren't familiar with archaea. What are they?
So archaea are these really esoteric organisms that, for the longest time, scientists, they didn't really know what to make of them. They actually, for many, many years, they thought that these were bacteria. But with a lot of pioneering work by Carl Woos and other scientists, sequencing their genetic material, they figured out that they actually belong to their own branch of the tree of life. So if you think really broadly about the tree of life, it has three primary branches. It has eukaryotes, where we belong, humans. And then it has bacteria, and it has these archaea, which are these incredible organisms that can withstand conditions that would kill us humans within minutes.
So I think we can learn a lot from them, and perhaps we can try to find interesting functional molecules that are produced by these really ancient microbes.
So Dr. De La Fuente, why did you decide to see if archaea would make for good antibiotics?
Well, if you think about the history of antibiotic discovery, we've really exploited fungi and bacteria as a source of new molecules. But Archaea have existed since the very beginning of life on Earth. And so we thought that perhaps they, over time, had to develop strategies to counter surrounding competitors, right? Like bacteria, for example. And so in order to do that, they perhaps had to develop antimicrobial compounds. That's one aspect. Another way of thinking about it is some of these peptides might be simply be used as part of the host defense mechanisms of Archaea.
And so that was part of the hypothesis. And also, more broadly, one of the goals that we have in my lab was to mine all of biology as a source of new antimicrobial molecules digitally by using AI systems. And we had already explored eukaryotes and bacteria. And so to really achieve our mission of searching across the whole tree of life, we hadn't looked at Archaea. And it was the remaining domain of life that, you know, remained to be explored. So that was another sort of impetus for doing this work.
Well, give us some good news. Did you find anything there that's useful?
Yeah, well, one of the advantages of looking at biology and the code of life digitally, in this case, we looked at proteomic data from Archaea, is that we can do it really quickly on the computer. We can do it at digital speed. So instead of having to wait for years to come up with new candidates, you know, the computer operates very rapidly. So what our AI system did is it mined through over 200 Archaeal proteomes that are available. And the AI system, which is called Apex, it identified over 12,000 potential molecules that might have antimicrobial properties, right?
Wow.
That's all done on the computer. And then what we do is we actually make a lot of these molecules. So in my lab, we have an AI lab, but we also have a chemistry lab. So we have robots that can That can actually manufacture some of these small peptides. So through chemistry, we synthesized eighty of these molecules that we call archaeasins. So we had to come up with a new name for for this class of compounds. And once we do the synthesis, we actually do validation, ground truth, experimental validation, where we we grow bacteria in test tubes and we expose them to to these archaeasins. And what we saw was quite incredible in the sense that ninety three percent out of
those eighty molecules that we synthesized were effective against clinically relevant pathogens. So that was really part of the aha moment.
Wow, you must have been surprised by that, I would imagine.
Yeah, I mean, it was a it was a really high hit rate. And, you know, they were able to kill things like E. coli and Sido monasauruginosa and Staphylococcus aureus. So some of the the greatest, the most dangerous pathogens in our society that that kill the most people. So that was that was kind of incredible.
Well, and being successful, what kind of, I guess, secret sauce did these archaea have to target these bacteria that our normal antibiotics can't? What were they doing differently?
Well, they were able to make this polypeptide chain, so chains of amino acids. You can think of them as sort of like a collar of pearls, each pearl being an amino acid, a building block. And they were able to make this polypeptide chains in ways that are quite different from what we've seen before, and in ways that enable them to to target the membrane of bacteria. And the membrane of bacteria, if you think about it, is the wall that allows bacteria to protect themselves from the outside world. And so by attacking that wall, you can actually you can actually compromise bacteria and you can kill them quite rapidly. So that's what these molecules from from archaea are
capable of doing.
How long before I might be prescribed an archaea antibiotic? How far off is this? I imagine it's it's a long time away.
Yeah, I think it's still we're far from that. And in this particular paper, we showed preclinical efficacy in mouse models of infection.
But in order to take this to humans, we still have to go through what are called IND enabling studies. IND stands for investigational new drug studies and then take it all the way through clinical trials.
Is it possible to patent these new microbes?
We're actually, we're in conversations with the university. It's a really interesting question because natural molecules are not patentable, right? Because, well, there was this legal case back in the day where it was determined that things that come from nature, you can't really patent them because nature produced them and they belong to everyone. But if you, in this case, if you develop an AI model that can identify things that have been, you know, that are typically hidden to science for a long time, right? And for the very first time, we're identifying some of these molecules. Well, in that case, that might be considered a non-obvious discovery because we're using new tools that we've
developed and that allow us to unveil noble molecules that are sort of hidden at plain sight. And so in that case, they might be, but it's an ongoing conversation. It's an interesting one.
Because a lot of times, you know, in order to get something produced en masse, you have to be able to make money on it. And that means a patent, right?
Yeah, exactly. You need a patent in order to be able to, you know, if you wanted to develop this further, either by creating a company or by licensing the technology, the IP, intellectual property. Of course, my primary objective is not to do this for money. I've never really been moved by that. And one of the greatest examples of that is that I work on antimicrobial resistance, where there is really not a lot of funding. And it's becoming increasingly difficult to actually do work on antibiotic discovery.
Well, I wish you good luck and thank you for your work. And we'll look forward to watching how this plays out, Dr. De La Fuente.
Great. Thank you so much for having me. It's been, it's been a pleasure and see you next time.
Dr. Cesar De La Fuente, Associate Professor of Bioengineering at the University of Pennsylvania, of course, that's based in Philadelphia.
Hey, thanks for listening. If you have a comment or question or a story idea, our listener line, it's always open. Call 8774-CY-FRY, 877-the-number-4-CY-FRY. This episode was produced by Soshana Buxbaum. I'm Ira Flatow. Thanks for listening.
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