Mice Don’t Menstruate: Reimagining Women’s Health Using Organ Chips with Dr. Donald Ingber
about the episode
In this episode, Sharon is joined by Dr. Donald Ingber, Founding Director at Wyss Institute for Biologically Inspired Engineering at Harvard University.
Dr. Ingber’s commitment to following his passion has led him to countless medical and technological breakthroughs, including organ-chip technology. These incredible chips recreate the structure and function of human organs. Drugs can be administered through organ-chips so that blood impact can be monitored. Once more widely adopted, organ-chip testing will be able to replace animal testing. As Dr. Ingber shares, the results will surpass those of animal testing.
The organ-chip technology already includes women’s health models and holds great promise to revolutionize this under-invested area. Because animals, namely mice, do not have menstrual cycles, their biological environments are already skewed to test any women’s health-related projects. Organ-chips are a great solution to close the data gap. Dr. Ingber shares two projects underway in partnership with the Gates Foundation: to create a cure for bacterial vaginosis and to create a non-hormonal contraceptive.
Dr. Ingber highlights the importance of nurturing the business side of scientific breakthroughs so that innovations can reach patients. Twenty percent of Harvard’s intellectual property comes out of the Wyss Institute, and both funding and mentorship play crucial roles in that success metric.
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“For the last 15 years, I’ve been at meetings with the FDA, the EMA, and with pharmaceutical biotech startups. Everybody agrees that animal models are suboptimal and have real problems. Now that there are alternatives emerging, the question is: Who’s going to take a step forward to take the risk?”
About Dr. Donald Ingber
Dr. Donald Ingber is Founding Director and Core Faculty at Wyss Institute for Biologically Inspired Engineering at Harvard University, Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital, and Hansjörg Wyss Professor of Bioinspired Engineering at Harvard John A. Paulson School of Engineering and Applied Sciences. Dr. Ingber is Scientific Founder, Board Member, and Scientific Advisory Board Chair at Emulate, Inc., the leading manufacturer of organ chip systems.
Dr. Ingber’s Organ Chip technology was named one of the Top 10 Emerging Technologies by the World Economic Forum and Design of the Year by the London Design Museum. It was also acquired by the Museum of Modern Art in New York City for its permanent design collection.
Episode Outline
(00:53) Meet Dr. Donald Inbger
(02:11) Where Art Meets Science: Inside The Brilliant Mind of Dr. Ingber
(07:08) What Is Organ-on-a-Chip Technology?
(13:17) Reimaging Women’s Health with Organ-Chips
(21:11) Think Outside The Box: Bringing Innovation to Life
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Sharon Kedar (00:02):
Behind every pioneering idea, method, and device is a fellow human or humans, a trailblazer who is daring enough to ask the questions that push the boundaries and make the impossible possible. I'm Sharon Kedar, Co-Founder of Northpond Ventures, a multibillion-dollar, science-driven venture capital firm, and the host of Innovate and Elevate. In each episode, we'll have candid, in-depth conversations with top doctors, scientists, and innovators, about leading-edge discoveries and how they impact our lives. Season one focuses on women's health, with the aim of helping women lead our healthiest lives. You'll hear from leading experts, such as Dr. Kathryn Rexrode, Division Chief Women's Health at Harvard's Brigham Hospital. It's time for all of us to Innovate & Elevate.
Sharon Kedar (00:53):
Welcome Dr. Don Ingber to the podcast. Dr. Ingber is the founding director of the Wyss Institute for Biologically Inspired Engineering at Harvard University. The Wyss Institute was founded 15 years ago in 2009. Dr. Ingber is the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital. Dr. Ingber is the Hansjörg Wyss Professor of Bio-Inspired Engineering at the Harvard School of Engineering and Applied Sciences. Dr. Ingber's human Organ-on-a-Chip technology has been honored as one of the Top 10 Emerging Technologies by the World Economic Forum, Design of the Year by the London Design Museum and acquired by the Museum of Modern Art, MoMA, in New York City for its permanent collection. Dr. Ingber is scientific founder, board member and scientific advisory board chair at Emulate, Inc., the leading manufacturer of Organ-Chip systems. Dr. Ingber, welcome to the podcast.
Dr. Donald Ingber (02:09):
Thank you.
Sharon Kedar (02:15):
Don, it's been such a pleasure to know you. I think it's been five years knowing each other both as fellow board directors on Emulate, Inc. and through our unique partnership with Northpond Labs and the Wyss Institute, I wondered if we could have the viewer and listener get to know you a little bit better. You have appointments through surgery and engineering. You founded the most innovative institute at Harvard and your inventions are in art museums. You could have chosen many paths as a scientist and engineer. Can you take us back to your younger self and just tell us a little bit about how you got here?
Dr. Donald Ingber (02:55):
I grew up on Long Island in New York, middle class. My parents didn't go to college. I went to public school. I was lucky enough to get into Yale as an undergrad. I was strong in science and math, but when I got to Yale, it was this incredible liberal arts institution and I kind of held back a little on the science and took courses in everything I possibly could and got really in love with all just learning and I started research there when I was, I guess, a junior, but it was also the same time that I took an art class in sculpture because it was called Three-Dimensional Design and I was doing work in molecular biology where everything was, at the molecular level, three-dimensional design, and in this art course, I learned about a way to build things called tensegrity that comes out of the Buckminster Fuller world of architecture, sticks and strings that don’t touch that hold themselves open.
Dr. Donald Ingber (03:52):
I learned about that the same day I was culturing cells in a cancer lab where cells were changing shape and the professor in this course had used one of these models and it changed shape the same way, and I basically realized that cells must be built this way and that sort of took me on a path towards pursuing this idea, which I just thought was obvious. But then I got into medical school and graduate school at Yale and I started pursuing this even further because I could see you could explain things I couldn't. And so that got me on a path to sort of thinking about structure in biology and mechanics in biology, and I got involved with cancer research and that eventually brought me to Harvard because I did a postdoc with Judah Folkman, who at that point, had the idea that you could treat cancer not by killing cancer cells, but by starving the tumor of blood vessels, inhibiting capillary blood vessel growth known as angiogenesis, and that was very physical in nature.
Dr. Donald Ingber (04:52):
He also had found that the shape of the cell controls its growth. I won't go into everything in my path, but the point was I just followed the path of least resistance, like where my passions lied and where I thought I could see things other people couldn't see and finding the right place to be able to pursue them. That brought me to Harvard. Long story short, it brought me into discovering that one of the first drugs to go to the clinical trials to treat cancer by inhibiting angiogenesis, it brought me to collaborate work with other faculty like Bob Langer who pioneered so many entrepreneurship in science basically. And I got involved in startups and tissue engineering. I wanted to pursue my ideas that physical forces, mechanical forces can be as important as chemicals and genes which came out of this sculpture class and tensegrity sculptures. And so I collaborated with engineers and had to learn engineering in the process and all of that kind of took me on the path of where I am today. If you just follow your passions, you'll end up where you want to be and that's what I've done.
Sharon Kedar (05:56):
When you were in college, what sparked taking this art class that has really transformed your journey? Was it interest, random, both?
Dr. Donald Ingber (06:07):
Well, one thing I'll say is that when I was a kid, my hero was actually Thomas Edison and not Einstein. So the inventing part of this and physical building things is always part of it for me. But I took that art class because I saw kids walking around the campus where they were holding things that visually to me looked like biology. They looked like the structure of a virus, so they looked like the structure of the molecule, but they were beautiful. And to me, that meant that they were doing something that had the essence of how nature builds. And when I asked them what's the name of the course, they said Three-Dimensional Design, which as I said, is kind of how we were learning about molecular biology in those days. The shape of the DNA, the helix, is what stores information. You could make it out of other chemicals, and if they match that way, they do the same thing. So it's really the shape and lock and key and enzyme substrates that they bind together like a lock. It's the shapes. And so that's what brought me to that.
Sharon Kedar (07:12):
May I ask you to just explain to all of the viewers and listeners what is Organ-on-a-Chip technology? What's your big idea and vision for its impact on the world?
Dr. Donald Ingber (07:25):
Yeah, so that little device that Sharon held up, Organ-on-a-Chip, it's a device, as you can see, it's about the size of a computer memory stick. It's made out of optically clear rubber-like material. We used computer microchip manufacturing methods to create it originally. And what we do is we create two hollow channels that are parallel to one another. You can think of like two tunnels that you drive through, and the wall in between has holes in it, so things can pass back and forth, small things. And we use that to recreate the structure and function of, believe it or not, human organs. So for example, for the lung, for the air sac of the lung, we have the lining cells that line your air sac on one wall of that channel. And on the other side of the porous membrane we have the capillary blood vessel cells.
Dr. Donald Ingber (08:14):
But what's cool is we also, it's made out of a flexible material and we have little chambers that we can apply suction to that can stretch and relax. So we can mimic breathing motions and we could put air in the top channel over the air sac cells like in your body, and we could put flowing fluids like a blood substitute through the blood vessel channel. And when we do that, we actually recreate the structure and function. We line it with living human cells of an organ, and the same little device can be used to model the intestine by using cells of the intestine lining and blood vessels and giving peristaltic-like motions, or of the skin or of the kidney or of the bone marrow.
Dr. Donald Ingber (08:57):
And so we are able to actually recapitulate the structure and function of living organs this way. And the goal is really to replace animal testing, to be able to have personalized models so that you could have your Lung-on-a-Chip and test the drug or your Lung-Cancer-on-a-Chip and test the drug, will it work against the cancer? But which one produces less toxicity in your liver and kidney? And really be able to shortcut, accelerate the drug development process faster, cheaper, more effective, safer. Because right now, animal models take a lot of time, a lot of money, and more often than not, do not predict what happens when you get to a human clinical trial. And that was really what triggered the development of that.
Sharon Kedar (09:46):
I read an article with you commenting about how an Organ-Chip is much better than an animal. For instance, if you're taking a drug three times a day versus once a day, if you're testing on an animal, the animal likely doesn't have the disease that you're testing for. So can you talk about some of the facets that you think are better in Organ-Chips than animals?
Dr. Donald Ingber (10:11):
Oh, absolutely. That is absolutely true. First of all, animals are often inbred, they have very similar genetic makeup so that you get very similar results, which makes it easier to interpret, but that's not the way humans are. Humans are incredibly diverse. And so the other thing is that we have the cells come from patients. So we could say test Chips on Caucasians versus Afro-American versus Hispanic. We've done this with Vagina Chips for example, where drugs are going to be tested with women in Africa versus the United States. You can do it with adult versus child, man versus woman. There's real problems in clinical trials that women are never as well represented as men. With these Chips you could do 50/50 sorts of testing. So there's lots of things you could do in these Chips that are better than animals.
Sharon Kedar (11:01):
The technology is truly incredible. What do you think the biggest barrier is to adoption?
Dr. Donald Ingber (11:07):
I think it's overcoming the natural human adversity to risk taking in the workplace because one of the places where Emulate, Inc. has shown that Chips are incredibly effective, is at modeling liver toxicity, the injury to the liver by drugs, which is a very common place for drugs to fail in the clinic or after they're approved to have problems in the clinic. These sorts of Chips can be used to inform when you get conflicting results, which the pharmaceutical industry often gets during the development process when they use different animal models. I think it's really the risk. They're used to dealing with animal models. Everyone else deals with animal models. So you as an individual in the trenches, if you're a toxicologist, have to be willing to take the risks to say, "I'm putting my bet in this new technology." And that's true with any new technology when it's taken in, it's very hard to get those first users to make that jump.
Sharon Kedar (12:02):
When I think about innovation, I do agree with you. I think it usually takes a catalyst and you almost need someone to step forward so that others basically must follow suit or come across a bit more archaic. But that vicious cycle of lack of innovation turning to innovation and adoption, it's a fascinating journey and it'll be interesting to see what catalyzes the adoption.
Dr. Donald Ingber (12:36):
For the last 15 years I've been at meetings with the FDA, with European equivalent agencies, with pharmaceutical biotech, everybody agrees that animal models are suboptimal and have real problems. Everybody agrees that there need to be alternatives. And now that there are alternatives emerging, the question is who's going to take that step forward to take the risk? I think the first company that starts getting drugs through faster at a lower cost, when that happens, everybody will shift, but you need that one first company to go through, get drug approval and be open that it's used this process.
Sharon Kedar (13:19):
Can we talk about an area that you've been a trailblazer? So women's health is an area that the Wyss Institute has focused on. Thank you for inviting me a year ago to do a panel on the topic. I think the White House did their first ever initiative a couple months ago, women's health initiative, Renee Wegrzyn from ARPA-H invited me to the launch of that and I was struck by the massive underinvestment in women's health. Dr. Kathryn Rexrode sort of opened my eyes to a lot of that. I know she's a Visiting Scholar at the Wyss. You already have organ models for, I think it's the vagina, the cervix, and the fallopian tube. So can you talk about how those models might transform women's health and just your broader perspective on Organ-Chips and women's health?
Dr. Donald Ingber (14:09):
Sure. Gates Foundation came to us, they've been funding work. We were doing an intestine with malnutrition in low-resource nations, which is going really well. And they are trying to develop a therapeutic that would be low cost, that could be broadly available for bacterial vaginosis in women. Now, bacterial vaginosis happens all over, not thought to be that serious in the United States, for example, but it's a major cause of preterm labor, loss of the fetus and increased infection rates, all kinds of problems, particularly in these low-resource nations. And so they were looking for effectively a probiotic therapeutic they call live biotherapeutic product, LBPs now, which are living microbes from the microbiome of the normal vagina that came out of research from a number of labs in the field that suggests that there's a healthy microbiome and an unhealthy microbiome and that if you could flip it from unhealthy to healthy by delivering the good microbes that you may be able to prevent this condition.
Dr. Donald Ingber (15:20):
But you can't test this in animals because animals have different microbiome than human, mice don't have a menstrual cycle. And so they asked us could we build Chips that would model the vagina and cervix? If so, could we culture microbiome on it? Because we had a culture microbiome in the intestine. And if so, could we test these products? With the idea that they're going to a clinical trial, but if we did this in parallel, if this really predicts, then we could optimize, develop better and better versions of it. And so very simply, we developed a Vagina and Cervix Chip. We can grow microbiome on it. If we put the bad microbiome on it, we see injury, inflammation, all the things you see in vivo. If you put the good microbiome on it, it looks healthy, they're in balance. And you could flip it in terms of suppressing the inflammatory response if you add the good microbiome to the bad microbiome.
Dr. Donald Ingber (16:18):
And now we're working with them with this live biotherapeutic product that's going to clinical trials in Africa and at Mass General in Boston. And we are basically trying to use that to optimize, improve the formulation. So that's how it started. We literally put human sperm in these Chips and you could see sperm motility. You could see how bacterial vaginosis affects that. We just got another Gates grant to study non-hormonal contraceptives using these much more natural environments. Part of that we're developing a Fallopian-Tube-Chip, we're just beginning, that looks interesting. They allow one to study processes that are incredibly hard to study in vivo, incredibly complex. For example, the obstetrician-gynecologists that collaborate with us, it's like they have all these questions like, what's the role of the microbiome? What's the role of pH? What's the role of oxygen? You can't control these parameters in a human independently. You could never study a human without a microbiome. And so we can study which one of these contributes.
Sharon Kedar (17:27):
As you're talking, I think about the data gap and where Organ-Chips can help solve it. Just the reality that women were not required to be part of clinical trials until 1993, which is 70 years I think after women were given the right to vote. It's just sort of mind-boggling when you think about it. And then when you talk about things that I was not aware of, like mice not having a menstrual cycle, how do you even catch up with the data gap? And it seems like Organ-Chips could be a huge part of the answer.
Dr. Donald Ingber (18:03):
Yeah, I mean, absolutely. We model hormonal cycling during the menstrual cycle on the Chips, and we see changes in the Cervical-Chip that looks just like in vivo. We take little samples like a clinician does to look where you are in the cycle. We get the same sorts of readings. We've looked at how hormones, as well as bacterial infection, affect the cervix and the structure of the cervix, which could be involved in preterm birth and what leads to preterm labor. You could see breakdown of the wall of these Chips just like you see breakdown in the cervix that loosens and causes preterm birth. We see cervical plug formation, mucus production. And yes, you can get cells from premenopausal, postmenopausal women, explore what's different. You could look for non-hormonal ways to modulate it so women are not taking these incredibly potent hormones that have other potential deleterious side effects.
Dr. Donald Ingber (19:00):
So yeah, it opens up this whole palette to paint with in terms of both discovery and therapeutic intervention, as well as diagnostic, being able to diagnose. And it can be personalized, potentially. It's cost, but I think of personalized two ways. You could think of it like your Lung-on-a-Chip or whatever, but it also could be Chips that represent a genetic subpopulation or a very similar group of people in terms of background, age, sex, ethnicity, et cetera. And that's important because most drugs now, drug companies spend a huge amount of money, tens of millions or more to get to the clinic, then they do an expensive clinical trial. And they almost always fail.
Dr. Donald Ingber (19:47):
And what they then do is basically do statistical analysis to say, "Is there a subgroup that responded a little better?" And if they find it, a couple of years later, they'll do a targeted study, and if they're lucky, they'll get approved for a very narrow application, this age group, sex, this disease manifestation, these symptoms, whatever. If you could start in the beginning by developing drugs for identify 50 Hispanic women who have the same condition, let's say chronic obstructive pulmonary disease, and they're ultra sensitive to the smog, and you get those 50 women and you develop a drug that works with all those women and you can get their other Organ-Chips to look for minimizing toxicity, then you use those women for the clinical trial, and that would be faster and cheaper and more likely to succeed in my view.
Sharon Kedar (20:41):
I know that you often take a problem and approach it from how do we solve a disease or a problem. And so there's so many ideas running through my head, but you take something like menopause where women are basically lab experiments today and you use this Chip instead, that's probably preferable.
Dr. Donald Ingber (21:05):
There's no better model than human. I mean, in the end, that's what we really need.
Sharon Kedar (21:15):
You're willing to be creative, you're willing to take risks, you're willing to try. And it feels like with the topic of today, women's health, we just have to try and it feels like there's just so much low-hanging fruit for a brilliant scientist such as yourself. Why do you think it's an under-invested area?
Dr. Donald Ingber (21:37):
I don't know the answer to that, but I think some of it is historical in the sense that people tend to work on what they've worked on before and what they were trained to do. And funding agencies will only fund you if you've already done most of the work. So it's very hard to totally change directions and take on something you've never done before. And we're lucky at the Wyss Institute that we got a big philanthropic gift that gave us this incredible freedom, and the gift was actually explicitly not to do standard government-funded iteratives, incremental stuff, but to take on risks and do high-risk, high-impact. So that allowed us to really shift directions and take on lots of different opportunities. The other place that does it is when people are trying to solve a particular problem. Certainly, I think the ARPA-H initiative is a great way to do that because they're explicitly putting funding out that are carrots to scientists to change direction, and they don't have to have worked in that before.
Dr. Donald Ingber (22:36):
But if you were just to look like, the system tends to work in very incremental changes and you're doing what you did before. So if the history was that it was mostly male-oriented focus, it's going to take a long time to change that unless you start having additional funding out there that recognizes you don't have to have worked in this before, because by definition, if you did, you're limited to a very small number of people. Plus, those people are probably going to do what they did before. So you're not going to do breakthrough, new innovative stuff.
Sharon Kedar (23:07):
You could take any organ and virtually any problem and start to come at it with an Organ-Chip. I mean, is that too broad or is that right?
Dr. Donald Ingber (23:16):
Pretty much. I mean, we haven't found one we couldn't do yet when asked to do it. So that's all I can say. The other thing I didn't say is that we actually have linked many of these together by the blood vessel channel so that we transfer fluid from one to the other to create what we call the Human-Body-on-Chips. And so we did I think eight organs, we've done up to ten organs together, and you could add a drug, watch it be metabolized by the liver, which releases an active metabolite and see how that acts on things. And you could see how different organs work together.
Sharon Kedar (23:51):
So when you think about five years from now, do you think we'll have married Organ-on-a-Chip with some areas of women's health where viewers and listeners see the direct benefit in their lives, or is it more longer term?
Dr. Donald Ingber (24:08):
If this clinical trial works and we end up confirming that we could kind of replicate patient responses on these Chips and then lead to better and better versions, that's something that could have impact in the next five years because those trials are starting soon. We have other drugs that are in clinical trials for viral infections and things like that. This last month, there was news around the world that the first kidneys from pigs that were engineered so they don't have viral infection were successfully transplanted into humans. And the humans left the hospital and are doing well.
Dr. Donald Ingber (24:43):
The people that get the credit were the surgeons who implanted the organ, but the technology was actually developed at Harvard and the Wyss Institute, and it went out as a company. Neither the company nor Harvard or the Wyss were mentioned. But it's also true about science in general. The public doesn't realize that the economy is driven by industry, which is driven by new technologies, which is driven by science. I mean, we wouldn't have microchips, optical fibers, drugs without the science, and that's where the big money makers are, and AI. But they don't see that as connected to scientific research.
Sharon Kedar (25:22):
What's fascinating is when you talk as the inaugural director of the Wyss Institute with the largest gift ever given to Harvard in 2009 to start the Wyss Institute by Hansjörg Wyss, $125 million, you are uniquely positioned to, and you have, thank you for all that you've done, make major transformations when it comes to science. I think it's so hard. So many people think that the idea or the science is the key to bringing that translationally to humanity, but creating a business around a brilliant piece of science is probably 90% of it. And I think that it's incredibly admirable, your focus on translation and realizing that there is that gap and helping to serve as a model for the world in terms of what translation could look like. I think that's what you and the Wyss Institute are doing.
Dr. Donald Ingber (26:18):
Not enough scientists realize this. I mean, I learned it early on because I got involved with things moving to the clinic and startups, but there are scientists who are ashamed to put in a patent, and I try to explain to them it will never reach a patient, it will never help anyone if you don't patent it because no one is going to put the investment you need to bring it all the way to patients. And as you said, the hardest part of the process is actually commercializing these things. And that's why we set up a major focus of the institute is developing a whole funnel and pipeline and mentorship and innovative process to accelerate that. And it's worked really well. As you said, we've had something almost 60 startups. It's really incredible.
Sharon Kedar (27:06):
Well, congratulations on all this success. Thank you for being on the podcast. Thank you for everything you're doing in the world. I really enjoyed spending time getting to know you and just appreciate you and appreciate your time today.
Dr. Donald Ingber (27:20):
It's always a pleasure talking, Sharon, thank you so much.
Sharon Kedar (27:22):
Thanks. Thank you for tuning in. Please connect with me, Sharon Kedar, on LinkedIn for additional innovative content. If you enjoyed this episode, please take a moment to like it, and don't forget to subscribe to the channel by clicking the button below this video. The views and opinions of the hosts and podcast guests are their own professional opinions and may not represent the views of Northpond Ventures.
About Your Host
Sharon Kedar, CFA, is Co-Founder of Northpond Ventures. Northpond is a multi-billion-dollar science-driven venture capital firm with a portfolio of 60+ companies, along with key academic partnerships at Harvard’s Wyss Institute, MIT’s School of Engineering, and Stanford School of Medicine. Prior to Northpond, Sharon spent 15 years at Sands Capital, where she became their first Chief Financial Officer. Assets under management grew from $1.5 billion to $50 billion over her tenure, achieving more than 30x growth. Sharon is the co-author of two personal finance books for women. Sharon has an MBA from Harvard Business School, a B.A. in Economics from Rice University, and is a CFA charterholder. She lives in the Washington, DC area with her husband, Greg, and their three kids.
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