There are no ‘low-hanging fruits’ in science

April 25, 2019 — Noncommunicable diseases (NCDs) are the leading cause of death around the world. And of those NCDs, chronic cardiometabolic conditions—such as heart disease and diabetes—are particularly deadly. For more than two decades, Gökhan Hotamışlıgil, James Stevens Simmons Professor of Genetics and Metabolism and and director of the Sabri Ülker Center for Nutrient, Genetic and Metabolic Research, has been working to understand the root causes of these diseases—what goes wrong at the cellular and molecular level to make us sick. In this week’s episode we share a wide-ranging conversation with Hotamışlıgil, focusing on the burden of cardiometabolic diseases, the importance of basic scientific research in treating and preventing these conditions, and the unique challenges of running a lab like the Sabri Ülker Center.

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Molecular Guardians (Harvard Public Health magazine)

Could a popular food ingredient raise the risk for diabetes and obesity? (Harvard Chan School news)

Full Transcript

NOAH LEAVITT: Coming up on Harvard Chan: This Week in Health…
Understanding the basic biology of some of the world’s most prevalent diseases.

GOKHAN HOTAMISLIGIL: We cannot make sound, preventive or therapeutic strategies or tools without really understanding the basic science, basic mechanisms that give rise to disease.

NOAH LEAVITT: In this week’s episode: An in-depth conversation with the scientist who is deepening our understanding of conditions like diabetes and heart disease—and trying to find ways to treat or prevent them.
Plus—he shares the challenges of running a lab that is trying to understand fundamental things about how our bodies work.

GOKHAN HOTAMISLIGIL: No matter how creative we try to become, our maximum level of creativity is far below the level of complexity of nature.

NOAH LEAVITT: Hello and welcome to Harvard Chan: This Week in Health…I’m Noah Leavitt.

AMIE MONTEMURRO: And I’m Amie Montemurro.

NOAH LEAVITT: Noncommunicable diseases—or NCDs—are the leading cause of death around the world.

And of those NCDs, chronic cardiometabolic conditions—things like heart disease and diabetes—are particularly deadly.

AMIE MONTEMURRO: These diseases are influenced by a variety of factors—our genes, our environment, our diet—but what’s clear is that the burden of these conditions is growing. And while in the past they’ve been viewed as illnesses of affluence, there are rising rates of NCDs in low- and middle-income countries.

NOAH LEAVITT: And in this week’s episode we’re speaking with a scientist who is trying to understand the root causes of these diseases—what goes wrong at the cellular and molecular level to make us sick.

GOKHAN HOTAMISLIGIL:My name is Gökhan Hotamisligil, I’m J.S. Simmons professor of genetics and metabolism at Harvard T.H. Chan School of Public Health.

NOAH LEAVITT: Since 2014, Gökhan Hotamisligil has led the Sabri Ülker Center, which studies the basic mechanisms of a range of noncommunicable diseases.

Their research has helped shed light on the molecular basis of obesity, diabetes, and other cardiometabolic disorders, as well as age-associated conditions like neurodegeneration.

One of their key findings involved uncovering the role of something called the “endoplasmic reticulum” in protecting cells from shortages or surpluses of certain molecules

NOAH LEAVITT: I had the chance to sit down for a wide-ranging conversation with Hotamisligil, where we discussed the burden of cardiometabolic diseases, the importance of basic scientific research in treating and preventing these conditions, and the unique challenges of running a lab like the Sabri Ülker Center.
Take a listen.

NOAH LEAVITT: Your lab focuses a lot of its research on cardiometabolic diseases– things like heart disease, diabetes. Why focus your research energy in those areas?

GOKHAN HOTAMISLIGIL: Well, from an impact perspective, these are the problems that represent the greatest threat to global health, in every part of the world. And so, therefore, if you are really hoping to make an impact, even if you make a small, incremental impact, it is going to have a huge influence on the global scale. So, from a discovery perspective, these are extremely [LAUGH] challenging. There is no single explanation for any one of these diseases.

So, for some, this may actually be [LAUGH] a reason to run away from these diseases, but I see that also as a great place of opportunity. If a problem is very complex and challenging, that means there’s a lot of places that you can make exciting discoveries. So, from both discovery perspective and impact perspective, these are very exciting problems to tackle.

NOAH LEAVITT: And I want to talk a little bit more about the complexity in a few minutes. But when you talk about these being huge, global threats, I mean, what’s the burden of these diseases? And are we seeing changes, over time, in who is being affected by these kinds of conditions?

GOKHAN HOTAMISLIGIL: Chronic noncommunicable diseases, or the way I refer to them is “chronic metabolic diseases,” one important characteristic of these problems is that they don’t come alone. They don’t– usually. I mean, occasionally, they will come alone. But in overwhelming cases, they will come as clusters.

So, if you have diabetes, you have more, much more risk for cardiovascular disease. If you have cardiovascular disease, even some components of cardiovascular disease, you’ll have much higher risk for dementia, stroke. And if you have insulin resistance, you’ll have higher likelihood of fatty liver disease, certain cancers, neural degeneration, bone disease.
So, in a way, these clusters actually is very reminiscent of aging. So, whatever happens during aging, all of these problems actually happen in the course of metabolic disease, except in a shorter period of time. It’s almost an accelerated form of aging.

And, for this reason, of course, both as part of aging process itself, which is now one of the most important drivers of global health problems– changing demographics, changing the age distribution– and the cluster actually exposes people to multiple diseases, so that also increases the burden tremendously.

So if you want to really understand, actually, even beyond the importance of metabolic disease in isolation, to also tackle the issues related to aging, healthy aging, really understanding these problems is fundamental. So in terms of burden– I mean, I can give you some numbers. I mean, you can give many numbers, but– diabetes, for example, 1 out of every 10 individual has diabetes. Right now, close to half a billion people on Earth have diabetes. Another half billion have prediabetes. So that means that, within the next 25 years, it is possible– actually, more than possible– that the diabetes numbers can double. And the majority of this, of course, comes from low- and middle-income countries.

I mean, diabetes kills close to 5 million people every year. This burden, just of diabetes, is more than tuberculosis, malaria, HIV, infectious diarrhea, pneumonia, combined– and multiplied. Cardiovascular disease is the number one cause of death, globally. It kills 20 million people, every year. One out of every four individuals on earth, one out of every four individuals on earth, has fatty liver disease. And so, really, we’re approaching [LAUGH] a really, statistically, so alarming place that the overwhelming majority of the people living on earth will be suffering from one or multiple combinations of these problems.

NOAH LEAVITT: This is maybe just kind of a big existential question, but you were just talking about the scale of these conditions and the tie-in to aging. I mean, are we investing enough in these conditions? I mean, are we doing enough to invest in studying these diseases?

GOKHAN HOTAMISLIGIL: It’s hard to say that, as the burden of disease increase and spread, so it’s not just really a problem of higher-income countries anymore. Even, for example, in the past decade, diabetes incidence doubled in sub-Saharan Africa. In sub-Saharan Africa, there were countries with 0% diabetes. Now, it’s approaching 7 and 1/2%, 8% of the population with diabetes. So far, it’s pretty clear– in the majority of these diseases, what we have used for preventive measures or to curb the pandemic is not very successful. Because we cannot really stop the increase in disease, except for very few examples. For example, in stroke we have been successful in reducing. But what really comes as a very big surprise is now it’s started appearing in the young age. So, if you reduce the stroke in the classical age bracket, but now it’s started popping up at much higher rates in the younger generation. So we really have to fundamentally change the approach. But the unfortunate reality is, government-based funding for these problems is not really increasing in proportion to the increasing challenge, or the scale of the challenge. In some cases, it is even decreasing. And this is especially true for the United States and Europe. In some areas of the world– for example, in China, Singapore, Korea– there is, of course, huge investments into science. But there is an another alarm, for the governments to really realize. Because, with respect to the total expenditure of economic scale like America, resource expenditure’s nothing, really. It’s a very small drop in the bucket. And it’s very critical. But, I mean, life goes on, so we cannot really wait to pursue research and then wait for the governments to be enlightened and then put their actions together. The good thing is, there’s always a very nice balance. And so, when the governments don’t do the right thing, corporations do the right thing, individuals do the right thing, foundations do the right thing. So there’s always a balance somewhat established in this equilibrium.

And also, we wouldn’t be able to do what we are doing if it was only indexed to government funding. We wouldn’t be able to do 10% of what we are doing right now. And we are able to enjoy this long-term and deep analysis of these big problems, because of [INAUDIBLE] care center, which became a reality because of the generosity of a family.

NOAH LEAVITT: And you talked a little about the work you’re doing, this kind of really deep analysis. So what are some of the big questions that you’re trying to answer? You said a moment ago, this kind of need to change the fundamental approach in how we look at the diseases. So what are some of the big questions are you and your lab are trying to answer about these conditions?

GOKHAN HOTAMISLIGIL: Yeah, so we are a basic science laboratory. And in our laboratory our big goal is really to uncover the underlying mechanisms– so, why a disease emerges, why does it emerge so frequently? If half of the humans living on earth are suffering one form of this disease, does that then relate to our biological infrastructure? Are there vulnerabilities in our biological infrastructure that is not in good match with the current chapter of human history? Because it’s very recent. I mean, compared to our biological infrastructure, our lifestyle and current chapter of human history is very young. And it has happened very rapidly. So, when any structure is exposed to a dramatic and rapid change, there are cracks in the system. And so one possibility is that, if we really examine our biological infrastructure and how we respond to things that are presenting risk, then we will be able to pinpoint where those vulnerabilities are and how really we can aim our interventions or preventive strategies to tackle those precise molecular mechanisms. Because, in general, what I firmly believe is, we cannot make sound, preventive or therapeutic strategies or tools without really understanding the basic science, basic mechanisms that give rise to disease.

NOAH LEAVITT: You spoke about the importance of understanding the underlying mechanisms causing a disease. But on the flip side, are you also looking at, when it comes to aging, for example, the mechanisms that maybe kind of promote helpful aging? So is that also part of the balance, here, of kind of understanding what is going right, biologically, in our bodies, when we age in a helpful way?

GOKHAN HOTAMISLIGIL: Yes. So the program that we are trying to build and execute, here, actually has two pillars. One big one is to understand the natural defenses that are built in human body. Because human body is very resilient, and many of the things, we believe, are the stresses that set the stage for some of the diseases that we mentioned, like diabetes, cardiovascular disease, fatty liver disease– are also the stresses, when we are exposed to them in a limited manner, we have wonderful defenses, so that we can protect ourselves.

Let me give you an example. For example, eating. Eating is a very stressful experience. In a very limited period of time, you consume large amount of nutrients and energy.

So this actually engages a lot of systems to respond, so that they can be properly metabolized, disposed to the proper places if they are going to be stored, stored in order, in a harmless manner. And the byproducts need to be neutralized. So how dramatic is this?

For example, your pancreas need to produce liters, liters, of enzymes, to deal with just your regular eating. Let’s say you’re a good, cautious kind of eaters. You eat three times a day, and in limited quantities. Just to deal with that, your organs need to remove huge amounts of sugar and lipids from your bloodstream. To digest this, your pancreas need to produce enormous amounts of active proteins and then go back to normal.

So this is extremely challenging. But we can deal with this. I mean, if you were a snake, for example, a python, you have a much, much stronger version of this. You can sit down and eat 10 times your body weight. I mean, imagine eating 600 pounds of food in one sitting, in half an hour.
But there is a creature who can do it and still live. But this can only happen once in three months. And it happened every day, the python will get sick and die.

Very similar analogy could be constructed for humans. So, if you eat 10 times the calories that you’re supposed to consume, in much more frequent intervals, you don’t exercise and burn energy, the existing defense system is not going to be enough. But it is there.

So one really big area is, if we find these things, define them molecularly, then maybe we can tickle them a little bit so that they defend the system better. So, if we can scale this up a little bit, then we can increase the health span. And this will have, of course, great implications for age-related diseases.

And so, personally, I’m much more interested in living the same amount of time, but in a healthy manner, than much longer with the diseases. So, if I was asked, I would say, OK, I’ll take x amount of years healthy, rather than 2x amount of years unhealthy. So it is a big part of what we are doing.

NOAH LEAVITT: Well, it’s interesting you say that, because I think what people, a lot of people, hear of treatment or therapy, they think, OK, it’s a drug or a pill. But it seems like– I mean, it sounds like what you are saying, in a sense, is, if we can learn how the body naturally defends itself, we can kind of take lessons from that. Is that what you’re saying? Like, learn what the body is already doing, and see if we can just maybe tweak that to find ways to combat something like heart disease?

GOKHAN HOTAMISLIGIL: Yeah, I am saying that, except there’s a very important difference– that, in a very mechanistic and scientific manner. So that could give us actual results– so, not conjecture or correlation or observational recommendations or interventions, but really things targeting specific molecular mechanisms involved in these responses. So, yes, if we can tickle these mechanisms upward a little bit, we know that we can defend the organs and the systems better.

And that upscaling can come from many angles. Perhaps some can come in the form of traditional medicines. So we find the molecule, we find a switch, and we use a molecule to turn the switch on.

So there are examples of that. It is possible that it’s not exactly an on-off switch but it’s a dimmer, so that that dimmer can be turned a little bit more gradually upwards or downwards, by multiple things, including things that are found in our diet or things that we do as part of our daily lives. But only when we tie these together at the molecular level, with definitive evidence, then we can make an effective recommendation. Otherwise, we make conjectural recommendations which do not in the long term be effective.

NOAH LEAVITT: You need to invest time in understanding the mechanism– which may take a long time, but in the end that pays off in potentially a better treatment or intervention.

GOKHAN HOTAMISLIGIL: So, better understanding– I have a very firm belief that will result in much more effective strategies, to prevent or to treat or to reverse disease. Here, also, I mean, even in the treatment area, if you think about all the diseases, there are very, very few diseases that we can treat and cure. So many of the things, we can alleviate, delay, postpone, but not cure.

There is not a single diabetes drug in the market, for example, that cures diabetes. So all the drugs actually alleviate high levels of blood glucose. So, even in the drug discovery area, there are many examples that we haven’t been able to reach the root causes.

And in the preventive arena, the problem is even more challenging. Because, for a long period of time, this has not really entered even the arena of preventive medicine. But this has now firmly and strongly entered. And this is the transformational force for global health practices.

And so those who actually incorporate this into their schools and programs and companies and agencies and foundations and NGOs, they will turn out to be successful. And those who cannot will not. It’s as simple as that.

NOAH LEAVITT: I know your lab has done a lot of recent work on cholesterol, for example. So is cholesterol an example where we’re seeing this play out, where you’re looking to understand how the body interacts with cholesterol at this basic, molecular level? And what have you found, in that regard?

GOKHAN HOTAMISLIGIL: Yeah. So, when we were searching for these built-in mechanisms, we needed to develop a model, a place to ask this question, so that we can actually go after a potential defense mechanism or a switch or dimmer that tunes our responses. And one part of our program is very much interested in the function of small functional units within the cells, called “organelles.” So those are, like, mini organs inside every cell that are charged with certain tasks.

And there’s one organelle, called “endoplasmic reticulum,” which I refer to this as the “master of all of the organelles” or all of the mini functional units inside the cell, and also a place that is extremely critical in a cell’s ability to monitor its metabolic environments, its food and carbon sources, and what kind of stress responses it should emanate to establish balance and health.

And so the reason we are obsessed with this structure is because we think this is where you would find the most powerful defense mechanism. Because this is like an octopus with millions of tentacles, reaching every part of the cell and essentially all functional units of a cell. So, when we were thinking about this, we realized that there’s an important gap in management of one nutrients, one critical nutrient and building block, in the cells, which is cholesterol.

And so cholesterol is, on one hand, extremely essential. So a cell cannot function or even construct itself without cholesterol. On the other hand, it is a volatile molecule. It’s very toxic and reactive. So the cell does not have tolerance to have free cholesterol molecules floating around, because they will cause a lot of damage.

And so, when we look at the approach to cholesterol homeostasis, the whole paradigm actually is built on the fact that cells need cholesterol. Therefore, when there is a reduction in the cholesterol, a mechanism kicks in to replenish it immediately. But we realize that the other side of the coin has an important knowledge gap. Because the cell cannot drive its vehicles just by hitting the gas. It needs a break. Because if you push the cholesterol upwards, then how do you stop before it becomes generating its toxic effects?

So we thought this was a good intellectual framework to look for that break. And we thought this would be present in the endoplasmic reticulum, because this is a place where it can accommodate a sensor. And then it would be responsive to cholesterol, and then it will have the capability to launch an adaptive program or countermeasures to mitigate the toxic effects of cholesterol.

So we searched for this for a very long time. And sometimes, it’s easier said than done– many, many, many years. But finally, a couple of years ago, we found this molecule.

It turned out to be what we envisioned in the beginning, which is very rare– we can come back and talk about this– because most of the things we envision turn out to be incorrect. And this, at least the larger concept, in this case, turned out to be correct. Details turned out to be, of course, far from what we had imagined.

But there was a molecule sitting in the ER, sensing, monitoring, and sensing cholesterol. And when cellular cholesterol reached a dangerous level, it gets activated and kicks in a program which neutralizes all the damaging effects of this. And, very interestingly–
So you asked me, why do you do basic science? How do you go from basic science to something relevant to human disease? And it may be a preventive or therapeutic measure. So, in this case, of course, we are far from that. But even this basic discovery immediately helps us to make sense out of many things.

For example, we know that, in humans, there are mutations identified, genetic variations identified, in this gene, which are also associated with the same metabolic problems that we observed in the cells. And then, when we make these mutations in the animals, the animals develop metabolic disease, and particularly, for example, a very severe form of fatty liver disease, in the liver, and other metabolic problems if it spreads to other organs.

So suddenly, by identifying a molecule from a very basic question, I mean, you can immediately find the path to a condition in humans that creates metabolic problems– a combination of metabolic diseases. So the next step, of course, is very challenging.

So, OK, we find the switch or the lever or the counter or the dimmer– whatever you call it. But how are we going to really develop the tools, to manage this controlled mechanism? So that is, for example, now what we are working on, in our lab, including understanding things that naturally engaged us, including natural nutrients and metabolites. We are collaborating with industry, to see if we can find ways to replenish this molecule. Because what’s amazing is, in the preclinical setting, if we take the most severe form of fatty liver disease and then deliver this molecule through gene therapy right to the liver, in two weeks that liver can turn into completely normal liver, completely normal liver, with no sign of disease, no sign of inflammation, no sign of fibrosis, no sign of metabolic abnormalities, no sign of lipid accumulation. But can we translate this into humans?

So we don’t know the answer to this question. But we’re, for example, at that stage. This is not something we can do here. So we form an alliance with industry. And, I mean, this, here, I have to also say, one of the greatest things, at least in my experience in Harvard University, is the presence of Office of Technology Development. And so the group here, they have been so helpful for us.

When we discovered things like this, they bring us together with the interested parties in industry. And then, when we sit in the table, then we have the opportunity to form alliances. And they set the table for us. And I’m very grateful for that. And we had many successful examples of this.

NOAH LEAVITT: This is obviously probably the major question, but, I guess, for someone who’s really maybe not familiar with this process, what is the biggest barrier, then, from that standpoint: OK, we understand what’s happening mechanistically, but we still are far away from a treatment. What is the biggest gap, there? Is it finding an effective target? Is it finding a way to deliver a therapy? What is the biggest barrier, there, to bring you from the discovery to a treatment, way down the line?

GOKHAN HOTAMISLIGIL: If you look at the general trends for a discovery and what kind of path it follows to reach an application, it greatly varies from one discovery to the other, one molecule to the other. So, for example, if you find a protein that controls an important process, and you need to develop a new chemical to turn this protein on or off– which is basically the classic drug-development framework– this is very challenging.
It is very difficult to define how exactly you’re going to do that, then find the molecules, make sure the molecules are consumable, safe, and effective, and then translate into clinical practice– especially for chronic diseases, which is a very, very, very big problem, because of the cost, cost of the clinical trials and approval process– so that is very challenging.
Sometimes you find very easy things. For example, a number of years ago, we find a very simple lipid that has fascinating biology in the body. But this is one out of thousands of lipids. So it took us 15 years to find this lipid. And it took someone three months to produce and sell it. And it is now– without even going through any of the difficulties that I mentioned for a synthetic molecule, it is now sold. You can go and buy it, if you want.
So sometimes it’s extremely fast. This is also unhealthy. So the nature of the discovery really is a big determinant. So that’s why, actually, I mean, one of the things we really able to do in the [INAUDIBLE] Care Center is to find a platform where we can find more of this kind of molecules, simple molecules that are easy to make, safe to consume, and cheap for distribution to large sections of the society.

But it requires a large investment, and time-wise, to really identify these needles in the haystack. But once you identify, it’s absolutely fascinating how quickly they can find very strong applications in humans. And so we are screening and trying to identify more of these.

Another example, for example, that, again, a product similar to this platform came five or six years ago– again, we were looking at molecules that can influence this organelle network called “endoplasmic reticulum.” And then we found a chemical– it turns out to be it’s a natural bile acid. It’s just conjugated, with a simple entity. So now, for example, it is in clinical trials for type 1 diabetes and neural degeneration.

So it really varies, but we have to use multiple paths to at least see one positive outcome from our life work. So, for many labs, this one lifetime or one professional lifetime is not enough to see the results of a discovery applied to a clinic. And so I feel we’ve been very fortunate at least we are testing. So we haven’t quite seen the use of it, but at least we have lived to see our discoveries active being tested in humans. So my great hope is, I will not die before I see at least the results, positive or negative– so, not die in curiosity.


NOAH LEAVITT: And so, to jump off of that, I think– there are– you mentioned you’re kind of finding these needles in haystacks, combined with the complexity of each of these diseases. I mean, it seems like there are potentially thousands of paths to go down. So how do you, as someone who’s leading a lab, how do you set your priorities? How do you decide, this is what we’re going to investigate– this is what my scientists should be looking at? How do you balance all those priorities?

GOKHAN HOTAMISLIGIL: This is actually extremely challenging on one hand, very simple on the other hand. So, every day, of course, we have a very high level of excitement, a big appetite, about science. So we almost suffer from a scientific-intellectual version of the chronic metabolic diseases that are related to excess. So we always live with this danger that our appetite is much larger than what we can actually manage and handle.
But the way we deal with that is, we always stay in the harbor. So we never really venture into the seas, but we let go some lines and then try to bring things, the treasures of the sea, into the harbor. So this is my main principle.

So we have two main questions, in this lab. And for 25 years, we have never departed from those two main questions. And so everything else that we ventured in the wide world, we try to form some links with the main harbor. So that actually allowed us to make some advances, in those major questions, but, at the same time, diversify our approach with these little lines that extended from the main core focus.

But it is difficult, because, I mean, science has become a very big enterprise. And many questions– I think there are no low-hanging fruits anymore.


So all of those are collected. And it takes a tremendous amount of effort to understand the process. And it oftentimes attracts you to fields away from the harbor. So, in those instances, of course, we also know that discoveries– you cannot make any discovery in your comfort zone. I mean, you have to get out of your comfort zone, if you want to make a discovery.
So we collaborate. And so, rather than building platform after platform, expertise after expertise, we have chosen to be very transparent about what we are doing. So we have a really good cohort of people that we trust, both to their judgment and integrity, and we don’t mind opening our discoveries or ongoing work to the world. And we collaborate.
So these are some of the methods we use, to prioritize. And sometimes, of course, within these lines of activity, certain areas– because of our lack of imagination or lack of resource or lack of technology– we cannot make any advance. So they naturally kind of die out.

NOAH LEAVITT: We’ve talked a lot about treatment. I guess I did want to ask a little bit about prevention. So your work is you’re kind of understanding the basic biological mechanisms. Is there an opportunity to harness any of that for prevention? For example, if we notice this, you might be at a higher risk for heart disease. Is there any chance to harness what you’re doing, for prevention?

GOKHAN HOTAMISLIGIL: Actually, prevention involves every possible tool that is at our disposal. So, at least in my own personal view, I don’t have demarcation lines between, OK, from A to Z, you know, the first 13 are for prevention. The next 14 are for treatment. So, whatever tools that we have, whether they’re lifestyle-recommendation policies, nutrients, drugs, vaccines, proteins, gene transfer, gene editing– whatever is available– we shouldn’t be really limiting ourselves to the tools of prevention.
But, having said that, the classical, canonical thinking of prevention– I think a very important conceptual framework is that it is not possible to make a recommendation– let’s say, even if we are going to make a policy change– without really understanding the basic mechanistic aspects of it or without having clear scientific evidence supporting that this change will actually result in an outcome that we hope to achieve. So, for this, in my view, it is possible now for many things, even for things that we were unable to think about in the past. Like, for example, impact of environment, impact of social environment, impact of stress, emotional experiences, social determinants. Many of these actually can now be connected to specific biological-chemical mechanisms or genetic variations which push the lever one way or another.

So when we have a clear understanding of how a problem occurs, what is the basis of a risk, then we have many more and more effective ways to address that. Whether a tool to address it– can be a piece of nutrient or a piece of medication or a vaccine, or whatever it is.

NOAH LEAVITT: This is where we’ll enter the more philosophical phase of the conversation. You mentioned, a few minutes ago, this idea that a lot of times when you start off in an area of research, where you end up might be very different from where you started. How do you encourage the young scientists in your lab to be open-minded in what they do, to kind of have a little almost creativity, if you will, as they’re approaching their science?

GOKHAN HOTAMISLIGIL: I don’t have a, like, six Cs of most creative scientists approach or anything of that nature. But there are some things that I strongly try to advocate, in our environment. And the first thing is, creativity does not come from the skies. And there’s no mystical place where you go and drink from the fountain of creativity, or the fifth dimension from which it will be transmitted to you. There is no such thing.
And so the really, I mean, number one source of creativity is exposing yourself to the existing knowledge in different dimensions to the extent possible. Most of the things that we admire are product of extremely hard work. And oftentimes I give, for example, Michelangelo’s products, or the statue David. I mean, these things, yes, they’re great, but they’re not produced in a month. Some people spend five, six, seven years, carving a piece of stone, to produce a masterpiece.

And science is no different. So that means people really need to do a tremendous amount of reading, talking, exposure to different fields, so that you can actually find where are the interesting things at the juncture of the fields. And so most often, this is where you find sources of creativity, in talking to your friends and colleagues.

And the second is actually, the second principle is, no matter how creative [LAUGH] we try to become or how creative we believe we truly are, our maximum level of creativity is far below the level of complexity of nature. And therefore it is only a fool’s game, to predict what is really happening inside a cell, inside an organ, inside an organism or human body. And therefore, the, I think, number one productive path for science is to get used to failure, or to get– really, even I say, actually enjoy being wrong. Because if you don’t enjoy being wrong, then you won’t be able to learn from the greatest creative source and complexity, which is biology itself.
So, if hypotheses– again, I mean, it’s a framework. A hypothesis, I think, is almost like gambling, [LAUGH] in an organized way. So you will build the hypothesis, but the effort has to be really not to prove the hypothesis but to disprove the hypothesis. Because the chances of it being wrong is so much higher. So, if you want to be successful, try to disprove your hypothesis. And if you want to be an average member of the community, try to prove your hypothesis.

So how can we then learn? So this is really the teaching of science, in my view– is, you really need to learn to look into your experiments and then listen, hear, see what the experiment is telling or showing you. And how can you do that? This is a place where you can control.

So you can control experiments. So you can set up your experiments so that you control as many variables as you can, so that you can actually hear the voice or see the picture. So this is something, for example, that is very important, and this is what a scientist can do.

And the more objectively you can look into your experiments, the better the chances that you will learn something very interesting about biology that you were not able to imagine in the first place.

NOAH LEAVITT: So tell us about this idea that failure isn’t necessarily a bad thing. I mean, it might be bad in the moment, but it seems like, invariably, you’ll learn something from your failures.

GOKHAN HOTAMISLIGIL: Oh, I mean, “failure” is not even a good word, actually, for science, because– and science is a task of impossibility. It’s extremely frustrating. You’re really trying to conquer something that is not possible to conquer. And so failure is given. I mean, I think it’s not a consideration.

I think more enjoying it or getting really frustrated beyond the productivity is the distinction I’m trying to make. So being wrong is given. Are you able to enjoy this– [LAUGHTER] –is the issue.

NOAH LEAVITT: So, going from that no to the question where I wanted to ask, I mean, you’ve now been doing this work for 25 years, now. You’ve talked a lot about kind of the potential stress involved, I guess. But so what excites you most about going to lab every day, as you continue to do this work? Is it working with young scientists? Or is it that possibility of kind of uncovering something new about nature? What excites you most?

GOKHAN HOTAMISLIGIL: So, I think, at different stages of life I probably have different answers for this. It also, of course, like ideas not coming from the sky, scholars also don’t fall from the sky. You start as a green fruit, and hopefully you ripe a little bit, over a course. And this is very small. I mean, think about an apple. It will take 50 years to grow and then one bite to consume.

So this is what a scientist is. So, at different stages, there are different priorities. And now I feel like I’m not so green as I was maybe a while ago, so I’m learning to appreciate and enjoy different things about science and find different sources of excitement.

But one thing that doesn’t change is this small hope that you will see something that’s something for the first time, or something that hasn’t been seen or known before– I mean, however insignificant or unimportant that might be, or nobody may care about it, but it’s exciting. It’s a privilege that doesn’t exist in any other. It is difficult to enjoy this, I have to say. I mean, this is a little bit romantic way of talking about science. But normal scientific practice, it can be extremely unpleasant and stressful and frustrating, because it is a negotiation of this unearthly and noncapitalistic and very romantic view versus an extreme form of capitalistic and realistic and unromantic and brutal forces that you have to find a place to survive. And so you can shift. So I don’t want to paint a very rosy picture. So your moods and pleasures will shift. So, one day, you’ll be extremely happy to receive a good score from an NIH grant– like I did today, for example.


And so I am elated. So, even after 25 years. But this time, maybe equally, of course, both knowing that I’ll be able to do a few more experiments is very nice. But also our colleagues buying into our ideas is actually more important.

And so, beyond that– so these are some of the daily fluctuations. But, at this stage in my career, what excites me the most actually is the people– and people in two ways. One is, maybe unlike most other professions, if not all other professions, science is a place where people can unite and pay little dividends to their differences, whether they’re ethnic differences, religious differences, gender issues, political, social, lifestyle– whatever– that people discriminate each other relentlessly. There is one area which, with a little bit hope to overcome this, is science.

And this is one tremendous pleasure. I mean, when you go to learn, you find all kinds of people that can overcome what they bring as their cultural, or national, or religious baggages and leave them at the door and enter and unite. So, this, I am absolutely fascinated. And I feel that, maybe especially today, where everything is so polarized, there is nothing more really powerful than science, to overcome those polarizations and unite.
And I live that daily in my life, which I enjoy very much. But even more important than that is really these people– you have the opportunity to touch someone’s life and change its trajectory. So maybe this is a function of aging, but mentoring has become the highest, really, source of gratification for me. And in many ways, and in also some selfish ways. Because I realize that I won’t be able to finish the project that I have started, ever. No one will ever finish it.

And so, rather than focusing on my unit of success, so if I think about the problem, the more people you put on this problem, the more likely that one day it will be solved, or one day one of these people will make impact. And so I think this is really a sign of growth, to really move from self to the problem. And this, of course, is extremely difficult. I want to say again that I cannot say that I have been very successful in this, because all the forces are against it. Because all of these nice and beautiful things that I tell you cannot be converted anything tangible. So no one will give you a penny to do research, no one will publish your papers, no one will give you grants, no one will give you promotion, no one will give you lab space, et cetera, et cetera, with any one of these.

So I think maybe, to conclude, the greatest privilege for a scientist is to be shielded from this brutal world a little bit, so that actually he or she can focus on science itself. And in not a daily, monthly, yearly basis, but for a longer period of time, and with sufficient power. And this is where I want to come back to the importance of the Center for us. And the people who support science actually can make this possible. And the best example is [INAUDIBLE] Care Center.

So having the Center gives us this opportunity so that we don’t always have to describe what exactly we’re going to do to funding agencies but venture into, a little bit, uncomfortable or uncertain paths. And so this is a very critical thing, and I feel very privileged and extremely grateful, to enjoy this opportunity. And, maybe lastly, you don’t really have to be a scientist to love science. So there are many ways of loving science. [LAUGH] And so this also is a great way of loving science and advancing science and supporting science. And we have been fortunate to do it.