Speaker 1:

Welcome to AACE Podcasts. Thanks for tuning in as we elevate clinical endocrinology by taking deep dives into trends and topics that can help us improve our patient care and global health. Find the latest episodes on aace.com/podcasts. And now let's meet the endocrine experts who will be talking with us today.

Dr. Melissa Putman:

Hello, and welcome to this AACE podcast, which is our first ever Legends in Endocrinology series. And my name is Melissa Putman. I am an endocrinologist at Massachusetts General Hospital in the Diabetes Center here. And I am so excited to be talking with one of my mentors, one of the true legends in diabetes, Dr. David Nathan. David, you can introduce yourself.

Dr. David Nathan:

Well, firstly, thank you, Melissa, for taking on this chore. I don't really know what to say about being the first legend in endocrinology. It's a rather daunting task. I'm not sure that anything I've ever done deserves that label. But I'll do my best to have a lively discussion with you.

Dr. David Nathan:

So I'm David Nathan. I've been involved in diabetes research for now, a half a century. So I think that's the reason I'm a legend. I've just outlasted everyone. And I've had the good fortune to work with dozens and dozens of outstanding investigators both at the bench as well as in clinical research, incredible research nurses and coordinators in the various trials that we've done. And then of course, had the pleasure of working with so many volunteer participants who really are the engine that makes the big question in clinical trials go forward. So I've just been incredibly fortunate to do that. I've been at the right place at the right time. So if I'm legendary, it's only because I've been around other legendary people.

Dr. Melissa Putman:

Okay, if you insist. I'm not sure that's entirely true. So I have, David, a list of questions that I am supposed to ask you. But I also think that this is a great opportunity to go a little off script, because I know you are always one to tell us your opinion whenever we ask. So I'm going to start off with the easy questions and then we will get progressively harder.

Dr. David Nathan:

All right.

Dr. Melissa Putman:

Are you ready?

Dr. David Nathan:

I'm ready.

Dr. Melissa Putman:

Okay. The first question, tell me about your mentors, what they meant to you, how you met them, all the details.

Dr. David Nathan:

Yeah. Considering that I've been around for as long as I have, I think it's fair to say that I've had lots of people who have taught me and from whom I've learned. The two really major mentors I think in my career that I would want to acknowledge, the first is Joe Avruch. So Joe is a basic scientist with an MD who spent his entire career at MGH, which it appears I have as well, and who was really my mentor early on when I was first at the lab. And then later kind of guided me into doing clinical research and has just been an incredibly sage scholar. He's just one of the smartest people I know, and has always guided me in my career and I'm forever grateful for that.

Dr. David Nathan:

The second one is Oscar Crawford. And my first really, as a kid, because I was quite young at the time, when I joined, I was selected to be one of the principal investigators in the Diabetes Control and Complications trial, the DCCT. Oscar was truly the legendary leader of that study from the time that he was involved in Congressional Diabetes Committee and really helped formulate the study to start with, and then as the leader of that study for the decade it went on for. And I just learned so much from Oscar in terms of how to run large, collaborative studies. He was a wonderful leader, and I've tried to emulate him when I do, when I've done, had the pleasure of taking on that kind of role in other studies.

Dr. Melissa Putman:

Nice. No, I think you definitely have. Okay. And then, tell me what accomplishments are you most proud of during your career?

Dr. David Nathan:

I must say that I don't think about individual. I've had some individual accomplishments, things that I helped work on in the lab that I really... And even there, there were a number of colleagues I had, whether they were junior colleagues or senior colleagues, or whatever, who helped me with some of the early, singular things that I've done. But the things that I think I'm most proud of would be those advances in research that have absolutely benefited people. Doing science is a thrill in and of itself, solving problems, answering questions I find is what has motivated me for my entire career. But when you answer a question, the answer of which benefits people and that you see actually being played out, that's magical. That's just something that doesn't come along very often. And I've been fortunate enough to have it happen with me in my career a number of times.

Dr. David Nathan:

So the Diabetes Control and Complications Trial and its follow-up, EDIC follow-up, observational follow-up, have altered the course of diabetes treatment, type 1 diabetes treatment, I think forever. And that again was a collaborative, huge effort by both clinician investigators, bench scientists, trial coordinators, and of course the participants, many of whom remain in the follow-up now going on 40 years later. So to me, that is really obviously one of the, I think, singular accomplishments, but it was a plurality. There were numerous people involved in that.

Dr. David Nathan:

Similarly, the diabetes prevention program, which established that this, what seemed to be, an ever-increasing epidemic, pandemic of type 2 diabetes, that it could actually be interrupted. This was the first real demonstration that either the medication, metformin, or the lifestyle intervention aimed at modest weight loss and increasing physical activity, either of those interventions reduced the development of diabetes. In terms of public health impact, I think those are two of the greatest things I've been involved with.

Dr. David Nathan:

I also was fortunate to be near the beginning of the implementation, development and implementation of the hemoglobin A1C assay, and I contributed to that. That obviously became an incredibly important tool in terms of research and diabetes management. I was fortunate enough to be down the hallway from Joel Habener, who's really the father of the GLPs, which you can't have anything in medicine for more than five minutes without talking about GLPs, either dancing or singing or doing something. So I was fortunate enough to be down the hallway from Joel and actually I did some of the very first clinical experiments giving GLP to people with diabetes to normal volunteers. And that was something that I must say that when I need a good dose of modesty, I look at the conclusion of my first paper, which said something to the effect of, "Whether this will ever prove to be an important medication remains to be seen." Something like that. So clearly, I must say, I couldn't have possibly foreseen I think where that medication went.

Dr. David Nathan:

But so I've done things individually and lots of them with fellows and with junior faculty that I'm very proud of and that they should be appropriately very proud of. But the big items were really the big science questions, the kind of things that only the NIH sponsors and supports. One of my concerns, maybe we'll talk about it, is whether that kind of support is under threat. But anyway, those big studies are the ones that really transformed public health.

Dr. Melissa Putman:

Yeah, absolutely. So thinking about the questions that you have answered, what do you think now are the most pressing questions that we still need to answer in the field of diabetes?

Dr. David Nathan:

Yeah, so many questions, so little time it seems. Yeah. So I think that the major, I think, frontiers out there are clearly, I mean several different ones. One is of course in type 1 diabetes, is there really a cure? Firstly, are there treatments that will have less of a burden on the patient than the ones we have now? We've now established, I think, how to treat people and how to prevent them or decrease to a great extent the burden of having type 1 diabetes over a lifetime, that is reducing the complications that they have. The methods that we have, really because of the message from the DCCT, have evolved enormously, including closed-loop and semi closed-loop pumps and continuing improvements in transplantation. But I think one of the major things there is in terms of once you develop the disease, whether you can reverse it, obviously, immune modulation of islet cells to make them less immunogenic and maybe allow transplantation of modified islets so they can survive. I think those are major questions in type 1 diabetes.

Dr. David Nathan:

In type 2 diabetes, which is the pandemic with 38 million in this country and hundreds of millions around the world with really the most common chronic disease that we have, it really is, I think, facing firstly, how to get better care to populations that are under resourced, the LMIC, the low and middle income countries, LMICs, and how to make sure that all of this fancy treatment we have, which is demonstrably, I think, improving people's lives and their outcomes, how we can actually get that to those kinds of populations efficiently and cost effectively. Beyond that, it's that we treat type 2 diabetes like it's all the same thing. And we've known about MODY and monogenic diabetes of various sources for a long time, but it turns out that within type 2 diabetes writ large, there are of course dozens of types based on different genotypes, based on different pathophysiology within them.

Dr. David Nathan:

And I think that one of the major challenges we have is to start trying to improve the individualization, the personalization of treating type 2 diabetes. And that is a huge public health issue. If you could do a simple panel in your office and determine what would be the most effective medication to control glycemia that has been shown to have long-term benefits in an individual, that would be great, instead of just treating everyone as if they have the same disease.

Dr. Melissa Putman:

Yeah, that's fantastic. Now, your legend's review was titled, Goodbye to All of That. Tell me more about your concerns about us moving into this future, what you're most worried about for future generations.

Dr. David Nathan:

Yeah. So the, Goodbye to All That, for listeners who may not know, was a famous book after the First World War written by Robert Graves, just a wonderful British writer. And he was basically, not bemoaning, was bemoaning and grieving what had changed in the wake of the First World War. A goodbye to the life as it had been known in Europe and the UK after the First World War. I stole that, unabashedly stole that from him, because as I see what's happening in public health and in research these days, I'm concerned that what we've gotten used to in this country, and that is extraordinary support, long-term, consistent, unwavering support from the NIH based on merit. It's not like there was cheating going on. It's not as if people got in line and just said, "Oh, give me the money," and they gave them the money.

Dr. David Nathan:

I don't think that the public recognizes as much how much competition there is and how difficult it is to get a grant, and that they award grants in the top 5%. And that in addition, the NIH was making some of these awards, especially some of the big ones, the ones that I've been involved with, the multicenter clinical trials, for example, on the basis of perceived public health needs, which were generally right on target. And now, unfortunately, I think that that era may be coming to an end. The studies in which the ones I noted earlier on that I was most proud of because they actually changed the lives of people, those never would have been supported by the other major sponsor of medical research and that's the pharmaceutical industry, which does important work, granted, but most of it is based on trying to develop their drug or their application or their technology, because they have stockholders to answer to and they need to make a buck.

Dr. David Nathan:

The NIH, without that goal in mind, has actually saved a lot of bucks. If you look at the savings because of the delay, decrease in complications of diabetes, both type 1 and type 2, we're talking about multi-billion dollar savings. If you think about the prevention of or the delay, if not prevention of type 2 diabetes, which was demonstrated by the Diabetes Prevention Program, we're talking about countless dollars that can be saved. So it's not as if there isn't a financial interest there, but it's not to make a profit for the United States of America. It's to do good science with public health in mind. And my fear is that with ideology inserting itself into the process, that kind of science may no longer be done. Moreover, the uncertainty of funding is just catastrophic for young investigators.

Dr. David Nathan:

So I've had the privilege of traveling around the country recently giving lectures to different universities, including a number of them in very red states. And whenever I go to be this visiting professor, give a lecture, whatever, the chair of the department asked me to meet with the trainees and junior faculty and whatever. It is extraordinary how shaken everyone is. "Did I go into the right field? I could have gone into business with my brother-in-law. Why didn't I go into business with my brother-in-law? I wouldn't have to be worrying about not only competing, but now competing for a smaller pool of dollars or dollars that may not be given because somehow I mentioned diversity in my grant." So my fear, this Goodbye to All That, is that the scientifically objectively judged science that was rewarded may no longer be the case, that entire areas of research will be cut out because of ideology.

Dr. David Nathan:

And the other issue is that I grew up in an age where science kind of meant competence, that you had to master something and understand it. And now, I think to some extent, the people who are calling the shots are not suited to what they're doing. They have no scientific background. They don't know what science is, and they are acting it according to some ideology. And science and ideology, and I won't be naive, it's not that science and ideology are always totally separate, clearly. But making ideology such a powerful engine driving what science we do is really dangerous, I think.

Dr. Melissa Putman:

I know you've never been one to shy away from expressing your opinion. What advice would you give younger faculty investigators starting out right now? Because I agree, it's a scary place, and I'm worried that we're going to be losing a lot of talent because of these changes that are happening. How do we keep them? What advice would you give to this next generation coming up right now?

Dr. David Nathan:

It's hard. So this is the question that I've been asked when I visit different universities around the country and say, "What do we..." As if I have an answer to this.

Dr. David Nathan:

And the only answer that I have to young people is that, "If you choose to do something that you love, even when the going is really tough, it's worth doing. Because at the end of the day, you're doing something that is just so appealing to you that doing anything else seems like it would be a waste of time." So that's out of a soap opera of some sort when it comes down to...

Dr. David Nathan:

And so I tell people, "Keep your head down, do the work you do, work with your mentors, try to figure out what is the," as we've always done, "what is the best path to get funding to sustain your career?" Because frankly, without support, science doesn't happen. You can't do... Especially the kind of human research that I've been doing the last 40 years or so, that takes huge investments.

Dr. David Nathan:

I'm aware, of course, that Congress has approved the NIH budget most recently, and that has been true of Republican, of Democrat led Congresses, because frankly, I think, firstly, they're all aging. They all have aging relatives. And if you can find some medical bioscience, biomedical science that will extend their lives, the lives of their families, they go, "Yeah, how can we be against that?"

Dr. David Nathan:

On the other hand, the process I think has got to look as if it's objective and fair. And in fact, although this current administration seems to be saying that there's something wrong with it, they're, if anything, tilting it away from objective, scientifically credible kinds of reviews. And so, I fear for that. I fear for the disintegration at some level of the NIH and the wonderful people of... Working at the NIH, these are incredibly talented scientists who've dedicated their lives to working for less than they would get in the private sector to do what is sometimes a thankless job, giving out small amounts of money to many, many hungry mouths out there to be fed, and they don't have enough to feed everyone. And that they are being undermined, that they're living in more uncertainty than we are even, I think makes it very difficult to keep this huge enterprise and it is a huge enterprise functioning as well as it should.

Dr. David Nathan:

So in terms of what I tell people, I say, "As long as you're doing what you love to do, then it'll never be the wrong thing. Keep your head down, do the best work you possibly can."

Dr. David Nathan:

It is more important than ever, I think, for people in research to really dedicate their lives to research. People say, "Well, I'm a clinician. I'll be seeing patients 80% of the time, and I'll do some research 20% of the time."

Dr. David Nathan:

In these competitive times, that is a recipe for disaster. They will not be competitive. As smart and as talented as they may be, there's somebody else out there as smart and as talented who is doing this 100% of the time, and they're just not going to be able to compete. So we need to make sure that people, including MD investigators, PhDs obviously, but MD and MD PhD investigators need to spend as much time, focused time as they can. They need to be given the opportunity to spend most of their time doing their research. In the absence of fellowships and the absence of funding, that becomes a much more difficult thing to recommend.

Dr. David Nathan:

So I'm not sure what... I come back... They ask me, "Well, how are you going to recommend... What are you going to say to young investigators who are coming along?"

Dr. David Nathan:

And the answer is, I give them a pat on the back. I say, "Keep doing the great work you're doing. As long as you love doing what you're doing, how can it be bad?" But at the end of the day, if the money disappears, we're in for a very rough ride.

Dr. Melissa Putman:

Yeah, it's a really rough ride. The other, I think, issue too is that as the NIH is pulling back, it's requiring institutions to step forward more to support the research enterprise. But it's harder to do that because Medicaid's getting cut and all these other different funding avenues are going away. So it really is challenging.

Dr. David Nathan:

So we need to look for new sources of revenue and institutions that are old and have endowments such as mine, such as Harvard and the Mass General Hospital and whatever, are of course reluctant to dip into those piggy banks. I think that the federal government would love them to use those dollars, whatever. I wonder why we can't tap into pharma. Right? Pharma is doing quite well. They're selling drugs. The GLPs alone, as you know, kind of floated Denmark. It represented 11% I think of Denmark's economy a couple of years ago. So the GLPs alone...

Dr. David Nathan:

So, a modest tax, a modest tax on what the pharmaceutical industry earns, this would be... They'd say, "Well, how would... We have stockholders we owe money, we can't do that."

Dr. David Nathan:

But a modest tax of some sort that could be applied to the pharmaceutical industry's revenues, that could be then used to support independent investigators, not their investigators, independent investigators, I think would be a great idea. Easy for me to say. Whether pharma would ever buy into this kind of thing... They'd say, "Well, we already spend a lot of money on research and development." It turns out when I last looked into this a number of years ago that the budgets for most big pharma for advertising was larger than for research and development.

Dr. Melissa Putman:

Really?

Dr. David Nathan:

Yeah. And in fact, many, if not most of the ideas that get developed into drugs started in NIH sponsored laboratories, and then they become biotech companies.

Dr. Melissa Putman:

Like GLPs.

Dr. David Nathan:

But it's really NIH investigators that have initiated many of these great ideas that become important pharmaceutical agents. And again, what pharma does is important, no question. They develop the drugs, they test them, they get them, they do the trials that are required by the FDA, including for diabetes drugs, cardiovascular safety testing. But that said, they should give more. We should find a way for them. And I think that would be a wonderful thing.

Dr. Melissa Putman:

Yeah. No, we need to get creative. No, I think that makes good sense. Okay. We are going to wrap this up with two last questions. The first one, is there anything else that we didn't talk about today that you want people to know about you, your work, anything that we haven't talked about?

Dr. David Nathan:

I have a wonderful and supportive family. That's my major accomplishment in my life, my wife Ellen and my two boys, and my two new grandchildren. Actually, that makes everything else... As bad as things are in the world, just thinking about them lights up my day. So that's something I guess. But other than that, no, no. I don't think I want anyone to know anything more about me than I've already.

Dr. Melissa Putman:

Okay.

Dr. David Nathan:

The more I talk, the more trouble I'll get in.

Dr. Melissa Putman:

That's probably true. That's probably true. Okay. So to end, do you have any quotes, any philosophy, anything to leave us with that have played an important role in your life? Any advice, final quotes, David Nathan quotes, that we can come away with?

Dr. David Nathan:

So I've been quoted before as when people want to celebrate some of my, again, collegial accomplishments, make good colleagues, treat them well. When you have young mentees, junior faculty, make sure that you do everything you can for them and just try to remember how sometimes difficult it was for you coming up. I must say that my... I was just in the right place at the right time, and I had the right people to work with. It really was. I mean, much of the happenstance of my career was that when I started off, nobody did clinical research. We all were expected to go to the bench and do bench research. So clinical research was somewhat new as a career path, at least at Harvard and Mass General.

Dr. David Nathan:

I was fortunate enough to have mentors who left me alone. I mean, they let me kind of do my thing. I didn't have too many missteps, and there was such a large world of discovery out there that everywhere you looked, you could find something interesting and important to do. And again, I've had the pleasure of a wonderful company along the way. So I would just say, celebrate your colleagues, be nice to people, create an environment that's good to work in and you'll have a successful career.

Dr. Melissa Putman:

I love it. Those really are words to live by. I love it.

Dr. Melissa Putman:

And that's it. Thanks so much for listening to this AACE podcast and our first ever Legends of Endocrinology with Dr. David Nathan.

Speaker 1:

Thanks for listening to another great AACE podcast. Join us for another episode at aace.com/podcasts and help us in our mission to elevate clinical endocrinology. Together we are AACE.