Scientist Stories: Sangeeta Bhatia, When Miniaturization Meets Medicine

Welcome, welcome to Director's Dialogue, our virtual conversations with visionary leaders of science, education, and the biotech industry. These dialogues offer an inside perspective on the emerging opportunities, challenges, and trends in biomedical science and biotechnology. Our guests share their most meaningful experiences and observations, tell us what excites and concerns them about the present and future of bioscience, and describe innovations that could dramatically affect the future of human health. You can participate as well by submitting questions to the question and answer box at the bottom of the screen. Uh, send your questions at any time during the discussion, and we'll answer as many as we can at the end. In our last dialogue, we talked about big things: the planet, its warming atmosphere, and how we can mitigate the impact of global climate change. Tonight we go small, talking about nanoscale biotechnologies that are spurring a revolution in diagnosing and treating disease. Our guide for this fascinating journey is Dr. Sangeeta Bhatia. She's a scientist, an inventor, an entrepreneur, a teacher, and a mentor and advocate for the more diverse, inclusive science and engineering enterprise. Sangeeta earned her bachelor's in engineering from Brown, a master's in mechanical engineering, and a PhD in biomedical engineering from MIT, and an MD from Harvard Medical School. Today at MIT, she is the John J. and Dorothy Wilson Professor, Director of the Laboratory for Multiscale Regenerative Technologies, and Director of the Marble Center for Cancer Nanomedicine. She's also an investigator of the Howard Hughes Medical Institute. Sangeeta is globally respected for her pioneering research at the intersection of nanoengineering and foundational biology.

Respectable—

respected is actually quite an understatement. She is one of just 25 people ever to be elected to all three U.S. National Academies: the Academy of Sciences, Engineering, and Medicine. An innovator and entrepreneur from the outset of her career, she filed her first patent application before even completing her PhD. Just a few years later, she was named one of MIT Technology Review's top 100 innovators in the world under the age of 35. She has launched 5 startups and is a founding advisor for an array of companies created by her students. She also serves on Vertex Pharmaceuticals' board of directors, Brown University's board of trustees, and the scientific advisory board of both the National Cancer Institute and the Chan Zuckerberg Biohub. Welcome, Sangeeta, and thank you so much for joining us.

Hi, it's lovely to be here.

Tonight I'd like to talk to you about 3 topics. Um, first, the exciting things you're learning and creating at the intersection where nanoscale engineering, basic biology, and medicine converge. Second, your experience as an entrepreneur translating your research discoveries into practical advances in diagnosing and treating disease. And thirdly, the challenges that women, and especially women of color, still face as scientists and entrepreneurs. Let's start with the science. You create unbelievably small biological devices. What opportunities arise when you work at this nanoscale? Could you give us an example of a nanoscale diagnostic you've developed?

Sure. Well, I think that the power of the nanoscale is both in the power of what happens to the physics at small length scales and also the biology. And if you'll permit me, maybe I can show you a picture.

Absolutely. Share the screen.

All right. Can you see?

Yes, I can. Hopefully everyone can.

Great. So I, you know, so I think nanotechnology sounds like, um, you know, a science fiction kind of word, but it's actually in our everyday life. It's inside these computer chips that are in our daily existence, and this shrinkage of these integrated circuits to the nanoscale has allowed us to fit sort of one transistor now to a billion on the same footprint. So there's been this enormous power and push-up for miniaturization that's come out of the computer science world. And the sort of way that plays out from a nanotech for bio perspective is just shown here. If we see a human hair is 100 microns, we're talking about materials that are 1,000 times smaller. And what's fascinating about them is here you see some on the right. They have all kinds of interesting properties. So if I just take gold, for example, the optical properties of gold change from a brick of gold to this nanoparticle of gold actually being optically red. And some of these other materials have size-dependent fluorescence and electronics and magnetics. So that's been very interesting for the, for the physics and material science community. And what I've been really interested in is whether we could use also their size-dependent biology to help with diagnostics. And what I mean by that is that depending on how big we make these materials, they will traffic differently in the body. So I'll show you a little movie. So this is an image of a blood vessel, and around the blood vessel is a tumor. And what we're doing is injecting nanomaterials into the blood vessels that are about 50 nanometers in size. When they get into the—

The big red things there are your red blood cells?

Yeah.

That's the correct size?

No, the red blood cells are much bigger. Good eye. So then these 50-nanometer particles can enter into the tumor microenvironment. And these ones are designed to sense enzymes in the tumor microenvironment, like proteases. So these proteases are what help remodel the extracellular matrix in tumors as they invade and spread. And so these sensors, they get activated. And what happens when they get activated by this cleavage event is they liberate this even smaller little blue ball that you saw. And that is a 5-nanometer molecule. It's a string of D-amino acids. And what happens is when they get back into the bloodstream, this is where the size dependence takes over. The kidney is a filter for a 5-nanometer particle. So what happens is the parent particle keeps circulating, but that little fragment gets into the urine and it gets concentrated. So altogether, what's happening is we've given this nanomaterial into the blood, it gets activated in the tumor microenvironment very sensitively, and it liberates a reporter that gets concentrated in the urine after 1 hour. And so this is sort of a super sensitive nanoparticle urine test. And what we've done is actually create cocktails of these so that they could sense different proteases. Proteases are a family of 550 enzymes in the human genome. And so here, what you see is—

So I assume cancers have different proteases? Is that the worry?

Exactly. So the one that I showed you, that little yellow one, was to represent MMP-9, matrix metalloproteinase 9, which chews up a particular protein called type IV collagen. But there are many other ones. And so in order to detect a cancer accurately, you need to sort of detect many different proteases as an ensemble. And so that's why we need a cocktail. And so a typical cocktail would have sort of 10 to 20 of these. And so here what we've done is basically inject a cocktail. And then if you're going to inject a cocktail, then you also need a barcoding scheme. And so here the barcoding is color. And you can see they end up in the urine in different colors. But in reality, what we do is we make them different masses. So we do mass spectrometry on the urine. So it's basically a nanoparticle urine test and it's very sensitive because of the amplification. And it's also specific because of that multiplexing.

So, but proteases exist in other tissues and normal tissues in the body too. So how do you distinguish the proteases in the normal tissue and the proteases in a cancer?

Yes, such a good question. So you can do it two ways. One is by profiling the diseased tissues and finding proteases that are disease-associated, and then the other is by sending the nanoparticles to specific tissues and enriching them and concentrating them. So these nanoparticles were designed to concentrate in the liver, for example, where they naturally go, and so you enrich for a liver signal. And the startup is actually making a liver diagnostic test for a disease called NASH, which is a liver disease. And so that's one of the tricks that we use.

How do you send the particles to the liver?

Yeah, so it turns out that the liver is a natural concentrator. Its job is to filter. And so if you do nothing fancy to your nanoparticle, it goes to the liver. Yeah, so that's an example of a diagnostic that we, that we made using nanotechnology, and it takes advantage of that size dependence.

And is that diagnostic already used?

So it's in clinical trials, so they finished their phase 1 clinical trial right before the pandemic.

Because you obviously have to figure out that it's not harmful.

Exactly, yeah, you have to pick the parts— we picked the parts of the material so that they could be they had already been FDA approved in other systems. When we first invented it, though, we actually had magnetic particles in the center of it because we were trying to make a smart MRI contrast agent. And what the students noticed was that the bladder was lighting up whenever there was cancer. And then we realized that we had invented a urine diagnostic, and then we took the magnet out.

Serendipity of science.

Exactly.

And, and so, um, the concentration obviously matters, right, at the end, sort of to use it as a diagnostic. So, so you would, you know, take this before you go to the doctor, and the doctor can read out the concentration. The concentration would somehow depend on the size of a tumor or the the mere existence of the tumor?

Yeah, this is another great question. So, you know, so when engineers, we sort of like invent something and then we find the use case. So what we realized is if you look at sort of the landscape of cancer, there's the early detection problem, right? So you would, just as you say, you would go to the doctor maybe every year, you would get a shot and then you would give a urine sample. And there would be a classifier that had been classified to call cancer of a certain size and type. So that would be early detection. We also are working on one that is a drug response monitoring version of the technology, and this actually responds when the immune system is activated in immunotherapy. And in, in that setting, as you know, the proteases involved with T-cell killing are things like granzyme, and so we have granzyme sensors in there. And you can see very rapidly that there are tumor responses using this urine test, at least in mice, before you could see sort of imaging changes. And so we are sort of actually discovering new use cases all the time, but those are sort of two of our favorites at the moment.

So are the proteases— if you have metastasis, could you kind of use this to figure out where they originated?

Yeah, that's a great question. So we, we haven't done so much on tumor of origin, although that's a good idea. And certainly some of the new cell-free DNA assays are looking at that just by using DNA in the blood. What we've done recently, we're about to publish, is actually use the same material and put on the material a PET probe so you could do an imaging study. And so the idea for this use case is imagine you're monitoring a patient, let's say after ovarian cancer surgery, and you're monitoring them for recurrence and the urine signal lights up. The next thing that the physician would want to know is where the tumors had spread or are located. And so you could take that very same parent material, load it with a PET dye, in this case copper-64, that had been kind of FDA approved and then visualize the tumor. And so you wouldn't do a PET scan every time, but you would only use it when the urine test was positive.

This is fascinating. It's like, and it feels like it's not science fiction.

Yeah, I think, I mean, that's, you know, we're going to talk about entrepreneurship later. And I think what's, you know, exciting is that, you know, first it was a paper publication and a patent, and then with the startup you could scale it up and do toxicity studies and talk to the regulators and physicians, and now we're getting into patients finally.

That's exciting. That's really exciting, also coming from probably very basic studies you initially did, and then you really kind of thought of this practical application, right? And that's really where the turn comes from, going from, you know, the discovery to using that discovery for translation. And so what are some of the other fundamental questions in biology that your lab is currently interested in? So what's kind of in the pipeline that we can— in a couple of years you will have translated it? Sure, something optical.

Yeah, it turns out that this— I think these nanomaterials are also good for lots of other things. So the one that I think will be in the public's mind's eye is packaging RNA. So RNA is packaged in a lipid nanoparticle.

That's the vaccines many of us have taken. Yeah, yeah.

And so we are looking at— we've developed a nanoparticle strategy for delivering immunostimulatory nucleic acids that penetrate deep into tumors using an active trafficking pathway. So I think nanoparticles are really going to be the solution for a lot of these genetic therapies, whether they're RNAs or CRISPRs or base editors. They all need carriers, which are nanomedicines. The other thing that we're really interested in is actually the nanomedicine field as a field. You mentioned I run a center, so there's a whole bunch of us at MIT across the street in the Koch Institute working on these technologies. We've learned a lot about how particles traffic, as I mentioned. So if you do nothing, they go to the liver. If you change the size and shape, they go somewhere else. And it turns out that circulating DNA that I mentioned, cell-free DNA, it actually circulates as an— as a particle, as a biological particle, as part of the nucleosome, the nucleosome core particle. And so one of the things that I've been doing recently with the Broad Institute, with Victor Edelstein's group, is looking at the similarities between synthetic nanoparticles and nucleosome core particles and seeing whether we could use some of the strategies from one to the other.

So this is really using, making use of the endogenous biology in a way.

Exactly.

Are they similar in size? So they're very similar in size?

They're very similar. So they're bigger than 5 nanometers, so they stay retained and they don't get out of the kidney, and they get taken up by Kupffer cells, which are the clearing cells of the liver, and the pathways have some similarities and some differences, and so we can, we can learn a lot by comparing them both.

That's very, very interesting.

So yeah, and I guess maybe just to say, the other thing that I'm really interested in is all these proteases that you just mentioned. There's— now we have a way actually to monitor protease activity.

Oops.

We have a way to monitor protease activity, just as a question, which is it's been hard to measure and monitor the activity of proteases. Kind of in situ in tissues in the presence of other inhibitors. And so we're at the moment really interested in that in the development of lung cancer, which is driven by inflammation early on through the activation of a family of cytokines, most notably one called IL-1 beta. And IL-1 beta is produced as a proform and activated by proteases locally to drive inflammation. And so we're now trying to use these same techniques just to understand how is the immune system involved with early lung cancer development. So again, very fundamental questions that kind of just emerge from the tools. Yeah.

That's— Let's turn to Sangeeta Bhatia, the entrepreneur. So you've told us everything from Phase I to— what you're just really discovering in the lab. So what excites you most about the process of translating lab science into tangible products? And I'm sure some of us in the audience may probably say, so how did you get started on seeing that that's a possibility?

Yeah, that's a great question. I think, so I'm the daughter of immigrants and You know, in some ways I think entrepreneurship is a little bit like the immigrant journey, which is that you embark on a journey and you don't know what awaits you, but the kind of the important thing is to begin. And a big part of your journey is who is by your side and who you kind of collect. And that's a really, you know, a big part of the story of entrepreneurship. And I'm the daughter of Indian immigrants, and my dad was a serial entrepreneur, so he was very specifically interested in me being an entrepreneur. When I became a professor, he actually said to me, well, okay, but when will you start your first company? So not just like the— not just a company, but the first company. So I, I think it was really seeded in me pretty early on that, um, this was sort of— I think his expectation of a way to make impact. And of course it's not the only way to make impact, but I think that was, that was in a way that kind of how I was raised. And I certainly have seen that my startups have helped to take my technologies to the next level in kind of in every case. So in the case we just talked about, I couldn't have gone into the clinic, you know, from my lab, right? And so we needed the startup and to do the toxicity to go to the FDA and design the trials. I invented a while ago with a student a liver on a chip, like a little human micro liver, and we needed the startup to sort of manufacture those at scale and put them in 96-well plates and make them available for pharmaceutical drug discovery. So I think for me, the startup is just a vehicle for impact at scale and The surprise has been that it's informed my science, and which is something I didn't expect, but you, you learn about new questions and we're natural problem solvers, and so you get out there and you think like, oh, that's it, everything works.

Yeah, not everything works, and then exactly, maybe I have to go back to the drawing board. Exactly. So what are one or two of the most important things you've learned in the course of launching all those startups, 5 startups, and advising on many others. So it sounds to me a little bit like a student's project, and now you need like 50 people working on this, and so that's what you do.

Yeah, and I think, um, so yes, the lessons are, I think that at least for me, that I didn't really understand the problem that I thought I did, you know. So I'll give you an example. In, um, in the Human Micro Liver Project We thought that we had invented a little human liver and that would be good for predicting drug toxicity that had a species specificity, so it couldn't be seen in mice or rats and it was only showing up in humans, and there were great examples of this in the literature and we could show that that was true. When we got out into the, into the world, we built our tool, we miniaturized it, and we started talking to to people who were really discovering drugs, they said, you know, toxicity testing is a problem, but what you're describing is what we call idiosyncratic drug toxicity. So it happens at kind of like 1 in 1,000, 1 in 10,000, and you're just making one person's liver in your little well. And we don't think that's the best use of the tool, but we have a really hard time predicting drug metabolism. And the reason is we are making drugs that last longer and longer for sort of 1-day testing or 1-week testing, and the assays that we have only last an hour or 2. And so it turns out if you have a liver that lasts for 3 weeks, it's a really great tool for metabolism. And so we just didn't understand that at all because we weren't in that world and we hadn't seen that until we got out there.

That's really neat. So you, you talked about your father, but have there been other role models and mentors from whom you've been able to learn about biotech entrepreneurship?

Yeah, there are. I think, I mean, like you, probably like you, so many people help you along the way. My dad was the first. The next big one was my graduate advisor, so his name was Mehmet Toner, and is Mehmet Toner. I was one of his first students, and I, um, the night of my PhD defense, he realized and taught me that we probably had invented something over the course of my PhD, which was the stabilization of liver cells in culture, and that the, the public thesis defense would have been public disclosure of invention. I didn't know anything about patents or patents.

You would have just talked, right?

Yeah, I would have just And actually, it turned out the law at the time was you had until midnight the day of your defense, um, and it was pre-cell phone. So the night of my PhD celebration dinner, I was at the, at the cell, at the wall phone in the restaurant where my parents were, you know, were celebrating my PhD, talking to the patent attorneys so that we could get the patent filed by midnight. And that patent actually became the foundational case for the company that I just described, which which was called Hepragen that made the microliters for pharma. And I wouldn't have known that at all. Like I needed somebody to show me, to show me that and to teach me that. So he was the second one. And then the third one was Bob Langer, who of course is such a prolific entrepreneur. And he's really, he continues to help me. He's on the board of some of my companies. And he's somebody that I can go to and ask questions about like, has anybody tried this? Is this a good idea? Please introduce me to an investor, you know, like very, really granular company building advice.

Yeah, because that— I'm sure that advice is really important for being successful, because you could also get burned, I guess, in that process, right?

Yeah, I think it's, it's, it's really important to— I mean, I was talking about people earlier, um, just— and I think your investors are just as important people just like who you pick a graduate student or a collaborator, right? Those investors are going to be part of your world, and so getting the right introduction and making the right choices is really important. For Glimpse, the nanoparticle company, Bob actually introduced me to the venture capitalist who ended up investing. We were at a football game with our families, and he knew I was working on this project, and at halftime he said, like, why don't you tell him about— that's what you need is somebody who's always ready, right? Yeah, like a sponsor, not just a mentor, you know.

Yeah, yeah. Oh, that's great. That's, that's a great segue to our third topic. So in a recent study by the Boston Biotech Working Group that you, Nancy Hopkins, and Susan Hockfield organized, you found that women at MIT rarely start companies. Or sit on boards, very different from what we've just been talking about with you. Indeed, you estimate in this study that just looking at 9 MIT departments, women could have started roughly 40 additional companies. And MIT is just one example, so this is not, you know, particular. And you mentioned in this editorial that was published May 7th and science that a number of initiatives, including Equality Can't Wait, founded by philanthropist Melinda Gates and Mackenzie Scott, aim to expand the influence of women very specifically now. And you point to a possibly even larger barrier for women of color in biotech and as entrepreneurs. How would you describe the particular challenges facing women and women of color in biomedical and biotech startups?

Yeah, it's a—

Wendy, I was listening to you. It sounded very easy, but I'm sure—

You know, well, I think, first of all, there are barriers. And I think they are— I mean, like all unconscious bias, I think they are invisible to many of us. And it's really the reason that Nancy, Susan, and I did the study which you just cited, was to actually quantify a perception and to give, to really put numbers and to put data in front of people. Because I think, I mean, you may find it surprising, but up until even just last year, I was having a conversation with many of our colleagues who say, look at the biology pipeline. 70% of our undergraduates in some institutions are women. And And it's been over 50% for probably over a decade, maybe even more. So it's really, it's just a matter of time. And, you know, the pipeline is full. And if we're just patient, you know, we're going to find them here just as faculty entrepreneurs. And if you study the data as we did, it teaches you that that's not right. It's not a matter of time that women are not, the numbers are not improving. Improving.

The pipeline idea is actually totally wrong. Yeah, totally wrong.

So, so that's very sobering. I think, um, you know, so then you start to hypothesize, and what we're trying to do is sort of do, I'll say, experiments based on hypotheses while we study the problem, because we have to do both at once. Um, and some of the hypotheses we can learn from other sectors, um, are that, that women have been left out of what Susan calls network effects. And the biggest way that that shows up is access to venture capital. So in the piece that you cited, others have looked at how— what fraction of US venture capital dollars go to women-founded companies, and it's 2.7%. Yes. And for people of color, it's less than 1%. So huge barrier. So how do you get access to capital? And then you back up and you think like, well, how do you get access to capital? You have to, you have to know people, you have to have the introduction, you have to know what to say, you have to know that you have an invention even to shape into a project. So how would you get benchmarked about what an invention was? Well, one of the ways is to be in the ecosystem, to be a scientific advisory board member or to be in the boardroom as a boardroom director. And even if it's not your company, you're witnessing the scale of projects, what happens when an invention happens in an academic lab, the way it gets resourced. And then you can say to yourself, like, oh, I have an invention like that. I probably have a startup to do. But if you're completely disconnected from the whole ecosystem, like, you don't even know what you don't know. Or you—

yeah, you don't even think it's a possibility, right?

Right.

Yeah, no, and it's, it's interesting because we're so good in training on the various steps of becoming a scientist, but this part's completely left out, right?

Yeah. Well, and I think that's a great point. And what I, what I actually believe is that it's, it's just another— it's no scarier than just another in other fields, like you and I have learned. Like when you write your first NIH grant, it's somebody teaches you, you write 3 specific aims, this is how you do it. And, and, and, or you submit a publication and the reviewers, reviewer number 3 will give you a hard time and then you have to rebut them. You know, it's just our, it's just our craft. This is our profession. And entrepreneurship is the same thing. It's, there's a pitch deck, there's a There's a valuation. There's just a whole bunch of different words, but there's nothing mysterious about it. You just have to learn the lexicon and someone has to teach you.

But you have to have access, right? Because what you're talking about, that's sort of gender, race neutral, right? That's just a trait. But so how do we break down hurdles and barriers?

Yeah, so I think— so if this is— I mean, it's still a hypothesis, but let's, let's say that we're going with it. Then I think you— there's some very specific interventions that it suggests, right? So one of them is to increase representation of our women faculty on— in the boardroom and as scientific advisory board members, even when they're not starting companies. And so the Boston Biotech Working Group, the venture capitalists in that group pledged to do that, to increase their boardroom diversity. So that would be one thing. The other is something that we're calling the sabbatical program, where women, tenured women, can get a sabbatical to spend time as sort of entrepreneurs in residence in a VC firm, just to understand what it's like just to be resident and watch pitches and be on that, meet the other venture capital lists and have those relationships. So all of, I think, the interventions are sort of aimed at this kind of network connectivity as a very first step.

Does that seem like they need a little extra help and that's maybe not what you want to— it's already denigrating in a way?

I know. Yeah, it's interesting. You know, my theory on that is the truth of the matter is that women have mostly been left out for 40 years while this industry grew up, and so we kind of have to hack into a system. And so, you know, I— my sort of philosophy is if we need to take a different approach or a special approach, or it— it— I'm just impatient for change, and I think we should just do it because I—

you're sick and tired of it.

Well, I think of the The slope of the line is so shallow. So Melinda Gates, who you cited, her group Women in Tech did a study of when would there be parity in patent filings. Again, very quantifiable thing. The current slope of the line, 2092. 2092. I mean, not even in their life. So it just has to be faster.

And I think this is so helpful, just like the original study in the '90s about just equality and with space of professors at MIT, right, where the, the important part was it was measures, right? It wasn't anything that— if you can measure it, so you can also just as well measure success, which is good, right?

And hopefully, exactly, we can measure the change.

Yeah, we can. Yeah, hopefully. Can, can you maybe describe more, like, one one or two initiatives that you have helped launch and give young women role models and mentors in science, how one could actually really approach this? Sure.

Yeah, so I think—

Younger people, so not the tenured women faculty who are going on sabbatical.

Yeah, so I think to your point, I mean, it's a whole pipeline. And it starts— I mean, women in STEM, as you know, the data are that young girls around the age of 11 to 13 start to drop out of the pipeline, and then it progresses at various stages. So when I was an MIT graduate student in the '90s, together with some fellow students, we started something called Keys to Empowering Youth, which is to bring middle school girls to MIT campus into labs where they do interactive projects. And the idea is that they get access and exposure to world-class laboratories and equipment and young college students. It's run by the Society of Women Engineers, so they meet, you know, 20 young women who are going to be engineers in a day, and then they also see each other, so there's sort of a cohort effect of the excitement of science. So that was started in the '90s. They've seen about 2,500 girls to date on MIT campus. It's spread to other campuses. Campuses. And I have two girls who I mentioned, so they've both been through Keys, which is nice. Now my older one is about to go off to college to be a STEM gal next year. So that's one thing.

Are you telling her the same as your father, sort of, when are you starting your company?

Well, I've learned it's tricky parenting because my husband is actually also a biotech person, so he's in the same space. And so it's— we try to sort of gently encourage, but if we push too hard, she might, you know, she has to make her own choices. So parenting is probably the hardest thing of everything we've talked about tonight.

That's not— let's— we— I think we need a whole other hour for that. Thank you. Thank you so much. I think there are quite a few questions from the— from from the audience, and so I really want to take advantage for you to— and I think we're going to go all the way back there, a lot of questions to what you were initially discussing. So you said the urine diagnostic was in phase 1. For which disease or diseases?

Yes, this is a great question. So I mentioned that the particles naturally accumulate in the liver. And so for the first indication, we chose a disease called NASH, which is fatty liver disease, nonalcoholic steatohepatitis. And this is a disease that has inflammation, so inflammation-associated proteases and fibrosis. Fibrosis also has proteases associated with it.

And here's an interesting— we haven't even talked about viruses. Many viruses have viral-specific proteases, have you considered developing this technology to more specifically target virally infected cells?

Yeah, this is a great idea. And so just to add to the question, actually bacteria also have their own unique proteases, so it's fascinating to think about the other protease spaces. The project that we have going on in the lab right now, which is funded by Gates is a project of a student named Melody Amatar. And she's looking at pneumonia. So in the setting of pneumonia, whether it's bacterial or viral. So patient comes in with shortness of breath and a chest X-ray, can you use the protease signature, both the host response to the infection and pathogen-specific proteases to develop signatures of what that infection is non-invasively. And in mice, she's done 7 different mouse models, like of 3 bacterial and 4 viral. It classifies them perfectly. We're working with Deb Hong now to try and advance that further, to think about how to take it to patients. It's a great idea.

Yeah, yeah. And Susna asks, can this technology be used in non-tumor cancers like leukemias? Also, are there any differences in how this should be used in children versus adults?

Hmm, also good questions. So I think we have looked in a number of conditions that are not oncology. And what we always try to think about is what are the diseases where proteases are really driving the most important part of the pathology. So fibrosis is one that I mentioned, there are a bunch of fibrotic diseases that are not oncology. Another beautiful class of diseases, if I can say that, is blood clotting. So blood clots by thrombin. Thrombin is a gorgeous protease with a very specific cleavage pattern. And actually, one of our earliest use cases was a blood clot detector. So right now we've done about a dozen different diseases, half of them are cancer and then some of the others.

And with children?

Oh, and with children, so the regulators like you to, just like we saw with the COVID vaccine, so you start in adults, you show it's safe, and then you can walk back into pediatrics. So that's what we would do here too.

Joan Kleimer is asking, can you tell us about therapeutic uses of nanoparticles and their mechanisms of action?

Sure, so there are many. The one, the one that I was talking about, which was the nucleic acid delivery vehicle, is— we call it a tumor-penetrating nanoparticle. So it packages silencing RNA, or RNAi, to silence an oncogene, so a cancer-driving gene, and then it's decorated with peptides that traffic through the tumor in basically a nutrient transport pathway. It's an mTOR-dependent pathway. So what happens is they get injected and they bind to the tumor and they activate this pathway and then they transcytose, so they go through all the cells of the tumor and then they dump their silencing cargo in the cells of interest and they turn off the cancer oncogenes. So we've done that in ovarian cancer. And we have a different startup that's looking at doing that now in pancreatic cancer with genes like with KRAS, for example. Sorry, I don't know the level of the audience. I'm trying to—

No, I don't know either. But I think they are—

They seem to be, yeah.

Very well—

Pretty scientific.

Scientific, yeah. So here are some other interesting questions. How involved are you in your company? How do you balance the entrepreneurship with academic pursuit, right? And, you know, and family life. So it's all—

Yeah, that's a great question. So the companies are— I mentioned I have two little girls. I think of them like kind of like babies, each one. So like when they're infants, they need a lot of attention to kind of grow up to a certain stage. And so I'm working on a new one now, which is a cell therapy company. And it's taken a lot of my time, but once you get to sort of a critical mass of a team and a certain amount of investment, then it's kind of, it can grow up on its own and you can give advice and come to board meetings and be a scientific advisor. And kind of a sounding board. And pull back more. Yeah. So that tends to be how I've done it. It's really been— MIT is an amazing place because you can go around and talk to people, not just like Bob, who has a certain way of starting companies, but people like Phil Sharp or Harvey Lodish. And you see there are different actual different models for mixing your academic work and your entrepreneurship balance, some people do this time-staggered way that I just described. Some people start companies only with their students, and then the students really do the heavy lifting. So, you know, there's a whole bunch of different models for ways to do this, but that's my way, is I can like kind of only focus on one at a time.

Coming back to the last part, have you personally faced sexism when dealing with the VC world?

Yeah, this is a good question. I mean, I think that I have— yes. But I think that the most public story I can tell is one where I had just a wonderful VC mentor. He's quite senior now. And he said to me when I was pitching my last company that he thought I should take my male graduate a male graduate student with me because it would make the audience more comfortable. And, you know, I think he meant it very genuinely that, you know, venture investment is about feeling comfortable, and they thought— he thought he would feel more comfortable if I had a male graduate student by my side. And actually, since I've started telling that story, I've heard that from a lot of my female colleagues at other institutions, that they're advised to bring a junior male colleague along. So I mean, that's just, that's just one example. I think what this— the data actually shows that women and people of color are more often asked in a pitch setting about risk, whereas other groups that are not disadvantaged historically are asked about vision.

Wow.

And so I kind of know that, and armed with that information, when I get asked about risk, I pivot to vision. But you kind of, you have to know the data to see it happening.

That is very interesting because also when you're asked about risk, you are feeling immediately insecure to some extent because of course you know about all the risks and you're worried. Or when you're asked about vision, you feel immediately elated to some extent. Exactly. —right? So that totally changes your response and your feeling to— this is, this is very, very important. There's one question from Regina: It is great that you have a program that exposes students to STEM and getting them interested in the topic. They say the earlier you can expose children to STEM, this increases the number of options for children in choosing what they want to be when they grow up. Are you planning to develop a program for children? Oh, there's something else for you to do.

Well, I am not, but I will say— so Angie Belcher, who is my close friend and colleague at MIT, is super involved in programs for young children all the way down to the preschool level. And so— and there are many great programs being developed at MIT along those lines. They're collected through the public service center. Yeah, but I do think exposing— I think that— I think exposing children to science early on is really important. And I think for even as you train, it's important to remember that sort of like childlike curiosity and wonder for science. I mean, one of the things that we do in my lab is we give the students, the graduate students, 20% of their time to what we call tinker. We call it tinkering time, and it's totally their own time. And the idea is to, is honestly to play and to be creative and to remember like why you love it and why you chose it, because science is full of failure and pressure and it's really hard and you're doing something important, but it might not, you know, work out for 15 years. And so on a day-to-day basis, like, I really want them to remember why they're here.

How do you do that practically?

How do you help students? So I tell them 20% of the time you can do anything in the lab as long as it's safe and I don't have to know about it. The students call them submarine projects. And some of them are like silly and frivolous. Like one year I got like 3D printed earrings from one of them. I mean, you know, just whatever, just something fun.

That's great. Yeah. I think that's a— I like that, but it's still connected, it's still happening in your lab, so that's the good part. Exactly. Thank you so much.

And I think some great projects have come out of the team.

Good, yeah, yeah, yeah. I call them sometimes the Saturday afternoon experiments.

Ah, that's a good way.

But I think it would be more appreciated if I said it's the the 25%, the 20% experiment. So I will change that from Saturday afternoon to 20%. Thank you so much for joining me tonight and making this a memorable addition to the Director's Dialogue series. I really greatly enjoyed the conversation. I'm sure our guests did so as well. And to all of you, thanks for joining us. This actually concludes our our inaugural series of 4 interviews. In our previous discussions, we spoke initially with Susan Hockfield, who was also part of the study we just discussed. We talked to Nubar Afyan and with 3 Whitehead researchers about how their research could help mitigate the effects of climate change. If you missed any of our discussions or want to watch again, you can find links to stream them on our YouTube page. You know, Whitehead Institute is an extraordinary place, and I hope that you will take some time to learn a bit more about our work and what we're doing and the discoveries that we're making at the Institute. Please go to our website to learn more about our research, sign up for Pulse, our monthly newsletter, and please consider making making a gift to Whitehead Institute. Stay tuned for our announcement for this fall series of Director's Dialogues, and by then, perhaps we can also start having this series in person. Stay safe, get your vaccine if you haven't yet, and be well. Good evening. Mm-hmm.