Jonathan Rothberg: The Scientist-Entrepreneur (Health & Veritas Ep. 48)

On the Health & Veritas podcast, Yale physician-professors Howard Forman and Harlan Krumholz talk about the latest news and ideas in healthcare and seek out the truth amid the noise. In this episode, Howie and Harlan react to President Joe Biden’s declaration that the pandemic is over. Then they’re joined by Jonathan Rothberg, a Yale-trained scientist who has created new methods for sequencing DNA and founded a series of successful biotech companies.

Jonathan Rothberg

Yale School of Medicine

Howard P. Forman
Professor of Radiology and Biomedical Imaging, Economics, Public Health, and Management; Co-founder, Pozen-Commonwealth Fund Fellowship in Health Equity Leadership, MD/MBA Program, and MBA for Executives Program
Harlan M. Krumholz
Harold H. Hines, Jr. Professor of Medicine and Director of the Yale Center for Outcomes Research and Evaluation
Jonathan Rothberg
Founder, 454 Life Sciences, Ion Torrent, CuraGen Corporation, Clarifi, RainDance Technologies, Lam Therapeutics, Quantum-Si, Hyperfine Research, and Butterfly Network; Professor (Adjunct) of Research of Genetics, Yale School of Medicine

September 22, 2022

Listen now:

Disclosure: Harlan Krumholz is a consultant to Tesseract, a portfolio company of 4 Catalyzer, which was founded by Jonathan Rothberg.

Links

“Biden: ‘The pandemic is over’”

Eric Topol: “To boost or not to boost”

“An integrated semiconductor device enabling non-optical genome sequencing”

”Butterfly Network Distributes 500 Butterfly iQ+ Devices to Healthcare Workers in Kenya to Transform Maternal and Fetal Health”

”AI Estimation of Gestational Age from Blind Ultrasound Sweeps in Low-Resource Settings”

Butterfly Network

Protein Evolution

Hyperfine

”Uncovered Medical Bills after Sexual Assault”

Learn more about the MBA for Executives program at Yale SOM.

Email Howie and Harlan comments or questions.

Subscribe to Health & Veritas in Apple Podcasts, Spotify, Google Podcasts, or your favorite podcast player.

TRANSCRIPT

Harlan Krumholz: Welcome to Health & Veritas. I’m Harlan Krumholz.

Howard Forman: And I’m Howie Forman. We are physicians and professors at Yale University. We’re trying to get closer to the truth about health and healthcare. This week, we will be speaking with Dr. Jonathan Rothberg. But first we like to check in on current health news. What’s got your attention this week, Harlan?

Harlan Krumholz: Well, I keep wanting to get away from the pandemic, and then the president goes on 60 Minutes and says that the pandemic is over. I thought, “Well, maybe we should just discuss this a minute and see what we think about it.” I’ll share my views on it. I’m interested in what you think.

First of all, first of all, I mean, I know that that’s the president, but I think we should all know that people are expressing opinions that mean different things. They didn’t come out with a declaration that was signed. It wasn’t a George W. Bush moment where he said, “Mission Accomplished.” I think we’re used to presidents expressing a sense of what’s going on in the nation. So I want to just put aside, I know there’s a lot of criticism and so forth and people taking the words literally. If you go around the country, that’s what the country’s doing right now. I mean, the country is moving on.

Now, whether or not the country will be able to move on, whether the virus will not rear its ugly head in a way that it did early in the pandemic, is an open question, and what we need to do to maintain this over-ness. I mean, I think one of the issues, and I wish the White House may have seized this a little bit more, is that over’s not a single state. It’s a dynamic state. In this moment where, we’ve talked about on the program and the paper that we published, it said we didn’t have excess mortality in the spring and as far as I can see, we really aren’t in an excess mortality moment now in highly vaccinated states for sure. I think it’s okay to say we’re—I prefer the word hiatus. There’s a bit of a hiatus, but this is a dynamic, changing situation.

It’s not one where something’s on or off. It’s something that we’re constantly monitoring and that doesn’t obviate the need for vaccines, it doesn’t obviate the need for preparedness, doesn’t obviate the need for Congress to come up with the money to support the pandemic response. I mean, over’s not a yes/no; it’s a spectrum, and it’s “Where are we today? What is going on today?”

Meanwhile, I just came back from a trip where I attended an Open Science Conference, Chan Zuckerberg Initiative put together all the grantees who were in Open Science. They help fund medRxiv. As a co-founder of medRxiv, I’m grateful for that support. But it was really great. They brought together people who are promoting a different air of science, one that’s more collaborative. I like to express it as moving from “me science” to “we science” and focusing on teams and sharing.

But the point I wanted to make about this was that I hadn’t seen anything like this in a long time. Testing every day. You didn’t get your lanyard for the day with a color for each day until you had tested negative. Masks everywhere, and a pretty conscientious group. I mean, there was a large-scale enforcement of this policy, and yet still there was someone who tested positive on day one. There were about 200 people there. Someone tested positive on day one; two people tested positive on day two. So among people who already tested positive, you couldn’t be at the meeting unless you tested negative on day one. Now two more people on day two. I don’t know what, quite, was happening. I was talking to someone who’s doing a lot of screening in theater and hearing that there are these local outbreaks and that the new variant BA.75 is starting to become more prevalent. We’ll just have to see. I mean, is this again, is it going to be a flu-ish thing or is it going to be more dangerous?

Anyway, going back to the president and when the president says it’s over, I think you’ve got to take not with a grain of salt but rather an assessment of a dynamic and changing situation. He’s reflecting the mood of the nation and what actually is the situation right now. I think “over” is probably too strong a word. That’s why I said I like hiatus. It’s a quieter period than we’ve seen before, but at any moment it can change, and that’s why the preparedness is so important, that’s why the investment from Congress is so important, that’s why the vaccinations continue to be important.

I’m going to just say one last thing about the vaccinations. Lots of people are writing about the vaccines. Topol wrote a really great piece on Substack arguing for people to get the boosters. I don’t disagree with Eric. I also think that we ought to not just talk about the relative reduction; that is, the boosters can reduce risk, especially people 50 and older. But the question is, what is your risk? So, 50% of what? Is it a high risk, a low risk? I think at this moment, if you’ve been previously vaccinated and you’ve been infected within the last couple months, the vaccine is unlikely ... Many, many, many people would have to be vaccinated to produce one person to benefit. It’s definitely not clear that that benefit is even a mortality benefit, it may be a hospitalization benefit.

So people I think are rightly trying to consider their risks and benefits in this. I think ultimately we need to watch and see how dangerous the pandemic is, but people need to make their own personal choices. I think, like you asked me last time, “Are you going to get it?” I should have answered it like this. “Yes. I’m just not sure exactly when. Am I going to get it right now? Am I going to wait a month or two and just see what happens with the pandemic? This is what I’m trying to decide.” But there’s no question, I agree that we should be prepared for changing situations. I don’t know what your thoughts are on this.

Howard Forman: Two quick things in response. One, pandemic is a technical term, and the president really misused it there. It would’ve been much better if he avoided the use of “the pandemic,” and he just said, “The crisis is over” or “We’re going to move on.” I think pandemic means a worldwide outbreak that is ongoing and affects multiple continents at the same time. We’re still in a pandemic from a technical point of view.

But I think his sense of it was correct in the sense that we’re not in the same phase we’ve been on and off for the last two years. Let’s hope that we don’t have a massive outbreak again this winter, but none of us know the answer to that. So I think your term hiatus is a good way to think about that. I will say that since you’re in the air of disclosure, since you said what you said, I am scheduled for my flu shot next week. I’m scheduled for my bivalent booster at the end of October. I can always change those things, but at the moment, that’s what I’m set for. That will get me about four and a half months since my second booster, and it’s the usual time I get my flu shot each year.

Harlan Krumholz: I think I’m going to follow your lead. I like that schedule. Maybe I’ll follow you on that and flu shot too. Good point. Hey, let’s get on to our guest.

Howard Forman: Today we welcome Dr. Jonathan Rothberg. Jonathan Rothberg is a scientist, serial entrepreneur. He successfully founded and launched over 10 life science companies while holding an adjunct professorship at Yale. 2016 he was awarded the National Medal of Technology and Innovation under the Obama administration for introducing massively parallel or next-gen DNA sequencing technology, increasing the speed and efficiency of genome sequencing and analysis, something that hopefully we’ll come back to a little bit later. Using this technology, Dr. Rothberg sequenced the first individual human genome and started the Neanderthal Genome Project, which aimed to sequence the Neanderthal genome. In 2014, he founded a medical technology incubator named 4Catalyzer. He’s an Ernst & Young Entrepreneur of the Year and received The Wall Street Journal’s first Gold Medal for Innovation along with Nature Method’s first Method of the Year Award.

He received his bachelor of science in chemical engineering at Carnegie Mellon and then received three degrees from Yale, a master’s degree in MPhil and a PhD in biology at Yale. He’s a member of the National Academy of Engineering and is a life trustee of Carnegie Mellon University. He personally holds over 100 patents.

I first met him during his stint as founder and CEO of CuraGen back in 1999 when he spoke to my undergraduate class. Since that time, I’ve been fortunate to have him advise and hire students on multiple occasions. He has spoken many times to my various classes and groups, and I’ve personally been in awe of his ability to innovate in and around the life sciences, more recently attempting and succeeding to democratize parts of healthcare while also making enormous leaps in our uses of technology to diagnose, treat, and manage disease.

Our listeners rarely get to hear from true entrepreneurs and many only see the successes, but it is rare to see someone succeed as many times as Dr. Rothberg has. So, Jonathan, just to start off with, entrepreneurship is very personal to you. Can you tell our listeners about what has and what continues to motivate you about innovating, about commercializing, about democratizing and making it so successful?

Jonathan Rothberg: I’m an entrepreneur because I love a lot of people. Every company I start started specifically to address a problem that may face somebody I love or they’re facing now, whether it’s next-generation sequencing. When my son was born, I was worrying about him. Or ultrasound on a chip and portable ultrasound because I wanted to know what was happening with my daughter’s kidneys. So I’m an entrepreneur because I see problems that people I love face, and I want to make sure I have no regrets.

Howard Forman: Can you tell us a little about the evolution of the Genome Project, let’s say, from the beginning of your career to right now because you’ve been touching on the human genome for longer than almost anybody.

Jonathan Rothberg: I started to become interested in sequencing in the 1980s when I was sequencing viruses as an undergraduate. When I was at graduate school, the Human Genome Project took off and started to accelerate, and the goal was to sequence a canonical human genome that would be a map for all of us.

I started my first life science company not to sequence a human genome but to leverage that information for complex diseases. In the late 1990s, early 2000s, I realized what was more important was the genome of individuals as opposed to a map that told us what we had in common. In 1999 when my son was born, I realized that I wanted to understand his individual genome. I wanted to know why he was in the newborn intensive care unit having difficulty breathing. While the human genome had been mapped and there was a canonical reference for all of us, that didn’t help me explain why my son, Noah, was having an issue. So I started what became the first next-generation or fast genome sequencing technology. It led to the development, leveraging Moore’s law, of fast DNA sequencing and the ability to sequence individuals. Instead of spending $3 billion to have a map of all of us, you could spend less than $1,000 dollars to map an individual.

Howard Forman: How has that evolved to today? Because I understand even now you’re continuing to think about how do you innovate? How do you democratize genomic sequencing?

Jonathan Rothberg: There was about a 10-year gap between the first DNA sequencer that we released to the market at 454 [454 Life Sciences] and the FDA approving DNA sequencing for diagnostics. During that 10 years, though, institutions like Yale used DNA sequencing in core facilities under their own institutional review boards to help patients. Since then, almost all DNA sequencing has been in core facilities under experts, whether that’s for medical reasons or even things like ancestry or hobby genomics, if you will. There are services where you can send your genome out and get it sequenced. But they all have a fundamental issue, and that is you no longer control your information. It’s somewhere else.

So while DNA sequencing has come down in price, while it’s expanded in its use from cancer to complex diseases to following residual disease to understanding and tracing COVID, it’s always been in a core facility and centralized. My first two DNA sequencing companies helped those kinds of things, whether it was at 454 or at Ion Torrent, where we first put DNA sequencing on a semiconductor chip.

Now, I think the world is changing. Everybody goes to Google to understand their own health. I think it’s time to bring DNA sequencing into the home so you can have that same information. Do I have a disease recurrence? Do I have an infectious disease? Or even what my ancestry is. But I want to keep that information on my own cell phone and not in a cloud, not in a network, not available to, whether it’s insurance companies or law enforcement.

Harlan Krumholz: The question I have for you is, and I have a couple, but one is, what is your creative process? I mean, one thing is you seem to be a never-ending font of ideas, and I’m going to tell you what I’m going to bookend it with after you finish that. It’s one thing to have ideas, but then you execute. The issue is you can start to have ideas and try to figure things out but unless you’re highly disciplined in the execution, that won’t see the light of day for benefit for people and be scaled out. You’re able to do both. But I want to start with the creative part first. What’s your process? I mean, how do these ideas come to you? When you’re sleeping, when you’re eating, when you’re exercising? When do they come to you?

Jonathan Rothberg: I want to take both questions together because they’re related. First of all, all of them come from need. They don’t come from an idea. I had a need with my daughter. I had a need because she was driving up to Boston to have ultrasound exams. I had known from my work at Ion Torrent that if you can leverage Moore’s law ... And Moore’s law just says, “When you put things on a semiconductor, every year becomes half as expensive and twice as powerful.” So now we all walk around with a supercomputer in our pocket. I said, “Look, why not put ultrasound on a chip?” This comes to the second part. You have to match the idea with a team that can execute on it and bring it to completion because for over two decades, people had wanted to potentially to use Moore’s law, micro machines, semiconductors in ultrasound.

But when I wanted to do it, when I wanted to put transducers on a semiconductor so we would have ultrasound on a chip, just like people had put computing on a chip, just like people had put imaging on a chip with your camera and your cell phone, like we had done it with DNA, I needed to match it with somebody that could finish that project. I literally went to Max Tegmark, who is a professor at MIT, and said, “Look, I want to put ultrasound on a chip. It’s not easy. But if you give me the best student from MIT, then that’s something that’s doable.” Max said, “That’s easy. He’s in my lab. It’s Nevada Sanchez.” I met Nevada, and I scaled the problem to the person, and Nevada was somebody that could take on a project like that.

So you’re right. You have a need first, you have an approach to it, and then you have to make sure it gets finished. To get it finished you really have to find somebody with the technical skills, and literally they can’t “know better.” Nevada didn’t know that for 20 years people had failed at this.

Howard Forman: Can you tell us a little about your forays into environmentalism and how you’re looking to improve the environment?

Jonathan Rothberg: Right now we’ve taken all the tools that we’ve developed in protein engineering and artificial intelligence. Two fresh Yale graduates, Connor Lynn and Scott Stankey. I was introduced to them by my son, Noah, and they wanted to do something with this technology. They literally systematically looked through opportunities for protein evolution, for protein engineering, for artificial intelligence on proteins. They found an incredible opportunity, taking plastic and turning it back into the material that would come from oil. So instead of having recycled plastic, which people don’t want, it would literally make fresh plastic—infinite recycling. It’s in New Haven. I visited last weekend. They have 100-liter reactors taking plastic waste and turning it into the original monomers. Right now, 10% of the world’s oil goes into plastic. Instead, we literally have an infinite recycling loop.

Harlan Krumholz: So it’s turned out in the history of medicine that’s sometimes something that’s innovative, effective, efficient, would be good for everyone, fails to get adopted because the incentive models are stacked against changing the status quo. There’s so many people that have a vested nature in the status quo. You come up with a great idea, you execute, you’ve got these remarkable tools. What kind of headwinds are you encountering in terms of culture in medicine, and what are your strategies to get people to look beyond their own maybe short-term interests to what really is going to be the arc of history within how medicine’s going to evolve?

Jonathan Rothberg: Wow. I love the question, and I don’t have a magic wand. But I’ve lived it over and over, and sometimes you luck out. What I mean by that is we introduced a low-cost and the world’s first portable MRI at Hyperfine. I was terrified that the established players would not want us in their institutions, but something paradoxical happened. Anytime a Hyperfine MRI was put into an institution, the large magnets, whether they’re Siemens or GEs or Phillips, were used more because now you could schedule those inpatients in the intensive care and they’re getting more utilization.

So first of all, sometimes you’re afraid for no reason. When you understand it better, it turns out you’re complementary. That said, the second part of your question is why you need massive capital into startups because it takes years to change clinical practice. Whether it’s Butterfly with a portable ultrasound or MRI, it takes years to get people to say, “You know what? Sorry, Howie, but we don’t need the radiologist today. Our intern can scan just fine and get the answer.” That takes time, that takes education, that takes collaboration with nonprofits, with radiologists to publish, and it takes capital.

So startups for health tech have to be well capitalized well beyond what you would need for a software startup because it can take one, two, or three years to get those clinical practices changed. Sometimes you need laws changed. There are laws, like certificates of uses for MRIs, that were written for multimillion-dollar machines. When we go to sell an MRI, the certificate of use can take more lawyer dollars than the cost of our machine. So there are headwinds. The only way I know how to get by headwinds is to outlast them, and you can only outlast them with access to capital. So you do need patient investors because while ultrasound in the chip will be ubiquitous five years from now, while portable MRI will be ubiquitous, while DNA sequencing in the home or in the clinic will be ubiquitous, it takes time: the regulatory time, the institutional time, the educational time. I have no magic wand. Need lots of help. Write lots of papers on this, Harlan and Howie, and help us turn it into a tailwind.

Harlan Krumholz: So everybody looks at Jonathan Rothberg now, but at the time you were getting your degree, you got your PhD, it did take some courage to go on a different and new path. Can you just take us back to that for a second? Just that decision that you made, where you said, “I’m going to go out and try to do something different.” I mean, was it scary or did you not even think about it? Because you were on a track to be a remarkable academic and then you take a different turn. What was that like? What did that feel like at that point of making that decision?

Jonathan Rothberg: Wow. I remember it quite vividly because I just spent some time this summer with my academic advisor from Yale, Spyros Tsakonas, Artavanis-Tsakonas—we just call him “Spyros.” I remember going into Spiros’s office telling him I wanted to start a biotech company, and he immediately told me, “That is a half-baked idea.” So I responded, “No, sir. It’s fully baked.” You’re 100% right. At the time, with the exception of probably going to work for Genentech, it was frowned upon to walk out of an academic position to go to a company. It was really Genentech with their ability to do great business, great medicine and great science that kind of paved the way.

I’d say over the last two decades, it’s become a norm, especially because of the success of those software-only businesses. I’m hopeful it will become more of the norm, and George Church has been a pioneer here, for students to walk out of laboratories and start companies. There’s still a big gap between healthcare companies, which are so domain knowledge–required and software companies. Huge difference in the amount of capital you need, huge difference in the amount of expertise or domain knowledge you need, but at least it’s not frowned upon, and you won’t have your advisor tell you it’s “half-baked.”

Harlan Krumholz: Well, you really set the pace on that. But yeah, at that time I thought that really did take some gumption to make that choice. Well again, I think we’re all happy you did by the way.

Jonathan Rothberg: I don’t know. Spiros still hits me sometimes. My mom would always ask me the same question though, and that is, “Are you doing good science?” My answer had to be yes, whether I was in an academic lab or at a company. I’m pretty proud that our companies have had the cover of Nature and Science. We’re able to do real publications in real science. So I think you still have to answer the question my mom asked, “No matter where you are, are you doing good science?” If you are, it’s okay.

Howard Forman: One last quick question. Harlan started off by saying how grounded you are, and it’s true. You’re an incredibly humble person. Can you tell us how you stay grounded? What grounds you?

Jonathan Rothberg: Well, I have five children, and everything I do is for them. I do want to say one other thing, though. You said I was charitable. I actually think everything we do should be aligned. So the charity work I do is just higher-risk entrepreneurship. I sponsor people where I don’t have my own solution. I care about epilepsy; I care about some childhood diseases. I do sponsorship with people that are better able to answer the question than I can, where I can’t match a team to the question. But there’s no difference in what I sponsor through charity and what I put my money in. All of it is to save the life of somebody I love, and I just want the best path for it, so it’s pretty aligned. In terms of being grounded, that’s trivial when you have five kids. My older ones tell me I’m a permissive parent and give me guidance on how to raise the younger ones. I think anybody that’s a parent is grounded.

Howard Forman: Well, we appreciate it, Jonathan. Appreciate you joining us and everything that you do. You’re a local, and you really are supportive of the community as well, so thank you.

Harlan Krumholz: Thank you so much. So great to have you on.

Jonathan Rothberg: Yep. Thank you. That was fun, guys. Thanks.

Harlan Krumholz: All right. So, Howie, that was a terrific interview, and so nice to have Jonathan on. Let’s go to our next section here. I want to know what’s on your mind lately. What’s keeping you up at night or getting your attention?

Howard Forman: Yeah. So there was a letter to the editor, of all things, not even a full paper, in The New England Journal of Medicine last week that raised a surprising/not surprising point that victims of sexual assault, of which 38% were below the age of 18—12% were male, which to me were surprising, but then I did a little research, and I realize that it’s actually quite common—who were treated in an emergency room, that among those a large percent are responsible for substantial costs of their care despite the Violence Against Women Act of 1994, which mandates that persons seeking care after sexual assault should not be charged for the evidence-gathering portion of their care. The authors point out that billing for evidence gathering still frequently occurs because the act allows healthcare facilities to bill for diagnostic testing, laceration repair, counseling, prevention of sexually transmitted diseases, HIV infection, emergency contraception. Abortion bans in some states make this even more complicated, as they point out.

I want to capture just a few quick points here. One, the unfunded mandates that a bill like this creates create challenges. By that I mean it’s easier said than done for legislators and government to mandate something when they’re not actually paying for it. Who is expected to bear these costs?

Two, asking people to have evidence collected in an emergency room or another healthcare setting but then to not be responsible for the large bills that are part of this is inhumane. So we’re further victimizing these individuals. In the category of glass half full, only 16% of these patients were expected to pay out of pocket for care. But in the category of glass half empty, the authors raise the concern that people are actually avoiding care because they fear a bill. So we’re seeing a biased sample here. Some might also wish to avoid the stigma of even seeing a bill associated with their sexual assault.

The authors end with this statement, which I’ll read in quotes, “Broadening the provisions of the act to cover therapeutic services, not just evidence collection, would help some survivors avoid financial hardships. More extensive reforms, including universal health coverage, are needed to ensure that costs are not a barrier to essential medical care and forensic evaluation in cases of sexual assault.” I can’t agree more. It just raises the issue again about how fragmented our system is and how even in the area of forensics and sexual assault, how we fund healthcare matters a lot.

Harlan Krumholz: It just feels inhumane. I mean, it’s sort of like we’re taking care of people without regard to thinking about them, their circumstance, their situation and context. I mean, the stuff just gets rolled into administrative billing, and it just seems cruel and toxic, financially toxic for sure, to so many people. So I’m glad you brought this up.

I hope we can uncover more and more of these things. But yeah, I mean, it’s disheartening to know that our healthcare system can be so indifferent to this. Again, I don’t think it’s a person who’s being indifferent. It’s just the way the system is set up that it ends up inflicting this harm, and no one’s really noticed that this happened. Even like we’ve got to talk about this in 2022, write a letter to the editor. I mean, it’s just crazy. So anyway, like I said, Howie, thanks so much. You’ve been listening to Health & Veritas with Harlan Krumholz and Howie Forman.

Howard Forman: How did we do? To give us your feedback or to keep the conversation going, you can find us on Twitter.

Harlan Krumholz: I’m @hmkyale. That’s @hmkyale.

Howard Forman: I’m @thehowie. That’s @T-H-E H-O-W-I-E. You can also email us at health.veritas@yale.edu. Aside from Twitter and our podcast, I’m fortunate to be the faculty director of the healthcare track and founder of the MBA for Executives program at the Yale School of Management. Feel free to reach out via email for more information on our innovative programs, or you can check out our website at som.yale.edu/emba.

Harlan Krumholz: Health & Veritas is produced with the Yale School of Management. Thanks to our researcher, Jenny Tan, and to our producer, Miranda Shafer, two amazing people that make this podcast what it is. Talk to you soon, Howie.

Howard Forman: Thanks very much, Harlan. Talk to you soon.

Department: Faculty Viewpoints

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