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Nobel Laureate

NIH’s Nobel Winners Demonstrate Value of Basic Research

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Credit: Niklas Elmehed © Nobel Prize Outreach

Last week was a big one for both NIH and me. Not only did I announce my plans to step down as NIH Director by year’s end to return to my lab full-time, I was reminded by the announcement of the 2021 Nobel Prizes of what an honor it is to be affiliated an institution with such a strong, sustained commitment to supporting basic science.

This year, NIH’s Nobel excitement started in the early morning hours of October 4, when two NIH-supported neuroscientists in California received word from Sweden that they had won the Nobel Prize in Physiology or Medicine. One “wake up” call went to David Julius, University of California, San Francisco (UCSF), who was recognized for his groundbreaking discovery of the first protein receptor that controls thermosensation, the body’s perception of temperature. The other went to his long-time collaborator, Ardem Patapoutian, Scripps Research Institute, La Jolla, CA, for his seminal work that identified the first protein receptor that controls our sense of touch.

But the good news didn’t stop there. On October 6, the 2021 Nobel Prize in Chemistry was awarded to NIH-funded chemist David W.C. MacMillan of Princeton University, N.J., who shared the honor with Benjamin List of Germany’s Max Planck Institute. (List also received NIH support early in his career.)
The two researchers were recognized for developing an ingenious tool that enables the cost-efficient construction of “greener” molecules with broad applications across science and industry—including for drug design and development.

Then, to turn this into a true 2021 Nobel Prize “hat trick” for NIH, we learned on October 12 that two of this year’s three Nobel winners in Economic Sciences had been funded by NIH. David Card, an NIH-supported researcher at University of California, Berkley, was recognized “for his empirical contributions to labor economics.” He shared the 2021 prize with NIH grantee Joshua Angrist of Massachusetts Institute of Technology, Cambridge, and his colleague Guido Imbens of Stanford University, Palo Alto, CA, “for their methodological contributions to the analysis of causal relationships.” What a year!

The achievements of these and NIH’s 163 past Nobel Prize winners stand as a testament to the importance of our agency’s long and robust history of investing in basic biomedical research. In this area of research, scientists ask fundamental questions about how life works. The answers they uncover help us to understand the principles, mechanisms, and processes that underlie living organisms, including the human body in sickness and health.

What’s more, each advance builds upon past discoveries, often in unexpected ways and sometimes taking years or even decades before they can be translated into practical results. Recent examples of life-saving breakthroughs that have been built upon years of fundamental biomedical research include the mRNA vaccines for COVID-19 and the immunotherapy approaches now helping people with many types of cancer.

Take the case of the latest Nobels. Fundamental questions about how the human body responds to medicinal plants were the initial inspiration behind the work of UCSF’s Julius. He’d noticed that studies from Hungary found that a natural chemical in chili peppers, called capsaicin, activated a subgroup of neurons to create the painful, burning sensation that most of us have encountered from having a bit too much hot sauce. But what wasn’t known was the molecular mechanism by which capsaicin triggered that sensation.

In 1997, having settled on the best experimental approach to study this question, Julius and colleagues screened millions of DNA fragments corresponding to genes expressed in the sensory neurons that were known to interact with capsaicin. In a matter of weeks, they had pinpointed the gene encoding the protein receptor through which capsaicin interacts with those neurons [1]. Julius and team then determined in follow-up studies that the receptor, later named TRPV1, also acts as a thermal sensor on certain neurons in the peripheral nervous system. When capsaicin raises the temperature to a painful range, the receptor opens a pore-like ion channel in the neuron that then transmit a signal for the unpleasant sensation on to the brain.

In collaboration with Patapoutian, Julius then turned his attention from hot to cold. The two used the chilling sensation of the active chemical in mint, menthol, to identify a protein called TRPM8, the first receptor that senses cold [2, 3]. Additional pore-like channels related to TRPV1 and TRPM8 were identified and found to be activated by a range of different temperatures.

Taken together, these breakthrough discoveries have opened the door for researchers around the world to study in greater detail how our nervous system detects the often-painful stimuli of hot and cold. Such information may well prove valuable in the ongoing quest to develop new, non-addictive treatments for pain. The NIH is actively pursuing some of those avenues through its Helping to End Addiction Long-termSM (HEAL) Initiative.

Meanwhile, Patapoutian was busy cracking the molecular basis of another basic sense: touch. First, Patapoutian and his collaborators identified a mouse cell line that produced a measurable electric signal when individual cells were poked. They had a hunch that the electrical signal was generated by a protein receptor that was activated by physical pressure, but they still had to identify the receptor and the gene that coded for it. The team screened 71 candidate genes with no luck. Then, on their 72nd try, they identified a touch receptor-coding gene, which they named Piezo1, after the Greek word for pressure [4].

Patapoutian’s group has since found other Piezo receptors. As often happens in basic research, their findings have taken them in directions they never imagined. For example, they have discovered that Piezo receptors are involved in controlling blood pressure and sensing whether the bladder is full. Fascinatingly, these receptors also seem to play a role in controlling iron levels in red blood cells, as well as controlling the actions of certain white blood cells, called macrophages.

Turning now to the 2021 Nobel in Chemistry, the basic research of MacMillan and List has paved the way for addressing a major unmet need in science and industry: the need for less expensive and more environmentally friendly catalysts. And just what is a catalyst? To build the synthetic molecules used in drugs and a wide range of other materials, chemists rely on catalysts, which are substances that control and accelerate chemical reactions without becoming part of the final product.

It was long thought there were only two major categories of catalysts for organic synthesis: metals and enzymes. But enzymes are large, complex proteins that are hard to scale to industrial processes. And metal catalysts have the potential to be toxic to workers, as well as harmful to the environment. Then, about 20 years ago, List and MacMillan, working independently from each other, created a third type of catalyst. This approach, known as asymmetric organocatalysis [5, 6], builds upon small organic molecule catalysts that have a stable framework of carbon atoms, to which more active chemical groups can attach, often including oxygen, nitrogen, sulfur, or phosphorus.

Organocatalysts have gone on to be applied in ways that have proven to be more cost effective and environmentally friendly than using traditional metal or enzyme catalysts. In fact, this precise new tool for molecular construction is now being used to build everything from new pharmaceuticals to light-absorbing molecules used in solar cells.

That brings us to the Nobel Prize in the Economic Sciences. This year’s laureates showed that it’s possible to reach cause-and-effect answers to questions in the social sciences. The key is to evaluate situations in groups of people being treated differently, much like the design of clinical trials in medicine. Using this “natural experiment” approach in the early 1990s, David Card produced novel economic analyses, showing an increase in the minimum wage does not necessarily lead to fewer jobs. In the mid-1990s, Angrist and Imbens then refined the methodology of this approach, showing that precise conclusions can be drawn from natural experiments that establish cause and effect.

Last year, NIH added the names of three scientists to its illustrious roster of Nobel laureates. This year, five more names have been added. Many more will undoubtedly be added in the years and decades ahead. As I’ve said many times over the past 12 years, it’s an extraordinary time to be a biomedical researcher. As I prepare to step down as the Director of this amazing institution, I can assure you that NIH’s future has never been brighter.

References:

[1] The capsaicin receptor: a heat-activated ion channel in the pain pathway. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. Nature 1997:389:816-824.

[2] Identification of a cold receptor reveals a general role for TRP channels in thermosensation. McKemy DD, Neuhausser WM, Julius D. Nature 2002:416:52-58.

[3] A TRP channel that senses cold stimuli and menthol. Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A. Cell 2002:108:705-715.

[4] Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin AE, Patapoutian A. Science 2010:330: 55-60.

[5] Proline-catalyzed direct asymmetric aldol reactions. List B, Lerner RA, Barbas CF. J. Am. Chem. Soc. 122, 2395–2396 (2000).

[6] New strategies for organic catalysis: the first highly enantioselective organocatalytic Diels-AlderReaction. Ahrendt KA, Borths JC, MacMillan DW. J. Am. Chem. Soc. 2000, 122, 4243-4244.

Links:

Basic Research – Digital Media Kit (NIH)

Curiosity Creates Cures: The Value and Impact of Basic Research (National Institute of General Medical Sciences/NIH)

Explaining How Research Works (NIH)

NIH Basics, Collins FS, Science, 3 Aug 2012. 337; 6094: 503.

NIH’s Commitment to Basic Science, Mike Lauer, Open Mike Blog, March 25, 2016

Nobel Laureates (NIH)

The Nobel Prize in Physiology or Medicine 2021 (The Nobel Assembly at the Karolinska Institutet, Stockholm, Sweden)

Video: Announcement of the 2021 Nobel Prize in Physiology or Medicine (YouTube)

The Nobel Prize in Chemistry 2021 (The Nobel Assembly at the Karolinska Institutet)

Video: Announcement of the 2021 Nobel Prize in Chemistry (YouTube)

The Nobel Prize in Economic Sciences (The Nobel Assembly at the Karolinska Institutet)

Video: Announcement of the 2021 Nobel Prize in Economic Sciences (YouTube)

Julius Lab (University of California San Francisco)

The Patapoutian Lab (Scripps Research, La Jolla, CA)

Benjamin List (Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany)

The MacMillan Group (Princeton University, NJ)

David Card (University of California, Berkeley)

Joshua Angrist (Massachusetts Institute of Technology, Cambridge)

NIH Support:

David Julius: National Institute of Neurological Diseases and Stroke; National Institute of General Medical Sciences; National Institute of Dental and Craniofacial Research

Ardem Patapoutian: National Institute of Neurological Diseases and Stroke; National Institute of Dental and Craniofacial Research; National Heart, Lung, and Blood Institute

David W.C. MacMillan: National Institute of General Medical Sciences

David Card: National Institute on Aging; Eunice Kennedy Shriver National Institute of Child Health and Human Development

Joshua Angrist: Eunice Kennedy Shriver National Institute of Child Health and Human Development


Ceremonial Nobel Presentation

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Ceremonial Nobel Presentation for Harvey Alter
It’s been such a strange year this 2020. For the first time since World War II, the 2020 Nobel Laureates didn’t receive their Nobel prizes at special presentations in Stockholm and Oslo on December 10. Because of the COVID-19 pandemic, the December 10 award presentations were held ceremonially at a number of small virtual gatherings around the world. At NIH, we streamed a ceremonial presentation in the Natcher Building for our own Harvey Alter, a senior scholar in the NIH Clinical Center’s Transfusion Medicine Department. Dr. Alter is a co-recipient of the 2020 Nobel Prize in Physiology or Medicine for his contributions in discovering the hepatitis C virus. He shares the prize with Michael Houghton, University of Alberta, Calgary; and Charles Rice, Rockefeller University, New York. Presenting the Nobel Prize medal to Dr. Alter on behalf of the King of Sweden was Swedish Ambassador to the United States, Karin Olofsdotter. In this photo, Dr. Alter (center) displays his Nobel medal, flanked by Ambassador Olafsdotter (left) and me (right). Credit: NIH

Discussing the Long Arc of Discovery with NIH’s Newest Nobelist

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Discussion with Dr. Harvey Alter

It’s been a tough year for our whole world because of everything that’s happening as a result of the coronavirus disease 2019 (COVID-19) pandemic. Yet there are bright spots that still shine through, and this week brought some fantastic news about NIH-supported researchers being named 2020 Nobel Prize Laureates for their pioneering work in two important fields: Chemistry and Physiology or Medicine.

In the wee hours of Wednesday morning, NIH grantee Jennifer A. Doudna, a biochemist at the University of California, Berkeley, got word that she and Emmanuelle Charpentier, a microbiologist at the Max Planck Institute for Infection Biology, Berlin, Germany, had won the 2020 Nobel Prize in Chemistry for developing the CRISPR/cas approach to genome editing. Doudna has received continuous NIH funding since 1997, mainly from the National Institute of General Medical Sciences and National Human Genome Research Institute.

The CRISPR/cas system, which consists of a short segment of RNA attached to the cas enzyme, provides the ability to make very precise changes in the sequence, or spelling, of the genetic instruction books of humans and other species. If used to make non-heritable edits in relevant tissues, such technology holds enormous potential to treat or even cure a wide range of devastating diseases, including thousands of genetic disorders where the DNA misspelling is precisely known.

Just two days before Doudna learned of her big award, a scientist who’s spent almost his entire career at the NIH campus in Bethesda, MD, received news that he too was getting a Nobel—the 2020 Nobel Prize in Physiology or Medicine. Harvey Alter, a senior scholar in the NIH Clinical Center’s Transfusion Medicine Department, was recognized for his contributions in identifying the potentially deadly hepatitis C virus. He shares this year’s prize with Michael Houghton, now with University of Alberta, Edmonton, and Charles M. Rice, The Rockefeller University, New York, who’s received continuous NIH funding since 1987, mainly from the National Institute of Allergy and Infectious Diseases.

In a long arc of discovery rooted in basic, translational, and clinical research that spanned several decades, Alter and his colleagues doggedly pursued biological clues that at first led to tests, then life-saving treatments, and, today, the very real hope of eradicating the global health threat posed by hepatitis C infections.

We at NIH are particularly proud of the fact that Alter is the sixth Nobel Prize winner—and the first in 26 years—to have done the entirety of his award-winning research in our Intramural Research Program. So, I jumped at the opportunity to talk with Harvey on NIH’s Facebook Live and Twitter chats just hours after he got the good news on Monday. Here’s a condensed version of our conversation, which took place on the NIH campus, but at a safe physical distance to minimize the risk of COVID-19 spread.

Collins: Harvey, let me start off by asking, how did you find out you’d won the Nobel Prize?

Alter: At 4:15 this morning. I was asleep and heard the telephone ringing. I ignored it. Five minutes later, I got another call. Now, I’m getting kind of perturbed. But I ignored it, thinking the call must be some kind of solicitation. Then, the phone rang a third time. I answered it, prepared to tell the person on the other end not to call me anymore. I heard a man’s voice say, “I’m the Secretary General of the Nobel Prize, calling you from Stockholm.” At that point, I just froze.

Collins: Did you think it might be a hoax?

Alter: No, I didn’t think it was a hoax. But I wasn’t expecting to win the prize. I knew about three years ago that I’d been on a Nobel list. But it didn’t happen, and I just forgot about it. Truthfully, I didn’t know that today was the day that the announcement was being made. The news came as a complete shock.

Collins: Please say a few words about viral hepatitis. What is it?

Alter: Sure. Viral hepatitis is an infection of the liver that causes inflammation and can lead to scarring, or cirrhosis. Early in my career, two viruses were known to cause the disease. One was the hepatitis A virus. You got it from consuming contaminated water or food. The second was the hepatitis B virus, which has a blood-borne transmission, typically from blood transfusions. In the 1970s, we realized that some other agent was causing most of the hepatitis from blood transfusions. Since it wasn’t A and it wasn’t B, we cleverly decided to call it: non-A, non-B. We did that because we hadn’t yet proven that the causative agent was a virus.

Collins: So, even though you screened donor units for the hepatitis B virus to eliminate tainted blood, people were still getting hepatitis from blood transfusions. How did you go about trying to solve this mystery?

Alter: The main thing was to follow patients prospectively, meaning forward in time. We drew a blood sample before they were transfused, and then serially afterwards. We saved those samples and also the donor samples to compare them. Using a liver function test, we found that 30 percent of patients who had open heart surgery at NIH prior to 1970 developed liver abnormalities indicative of hepatitis. That’s 1 in 3 people.

We then looked for the reasons. We found the main one was our source of blood. We were buying blood, which was then in short supply, from commercial laboratories. It turned out that their paid donors were engaging in high-risk behaviors [Note: like IV drug users sharing hypodermic needles]. We immediately stopped using these laboratories, and, through various other measures, we got the rate down to around 4 percent in 1987.

That’s when Michael Houghton, then at Chiron Corp. and a co-recipient of this year’s prize, cloned the virus. Think about it, he and his colleagues looked at 6 million clones and found just one that reacted with the convalescent serum of a patient with non-A, non-B. In other words, having contracted the virus, the patient already made antibodies against it that were present in the serum. If that one clone came from the virus, the antibodies in the serum would recognize it. They did, and Chiron then developed an assay to detect antibodies to the virus.

Collins: And that’s when they contacted you.

Alter: Yes, they wanted to use our panel of patient blood samples that had fooled a lot of people who claimed to have developed a non-A, non-B assay. Nobody else had “broken” this panel, but the Chiron Corp. did. We found that every case of non-A, non-B was really hepatitis C, the agent that they had cloned. Hepatitis C was the missing piece. As far as we could tell, there were no other agents beside hepatitis B and C that would result in transfusion transmission of the disease.

Collins: This story is clearly one of persistence. So, say something about persistence as an important characteristic of a scientist. You’re a great example of someone who was always looking out for opportunities that might not have seemed so promising at first.

Alter: I first learned persistence from Dr. Baruch Blumberg, my first NIH mentor who discovered the hepatitis B virus in 1967. [Note: Other NIH researchers identified the hepatitis A virus in 1977] The discovery started when we found this “Australian antigen,” a molecular structure that the immune system recognizes as foreign and attacks. It was a serendipitous finding that could have been easily just dropped. But he just kept at it, kept at it, kept at it. He had this famous wall where he diagrammed his hypotheses with all the contingencies if one worked or failed. Then, all of a sudden, the antigen was associated with hepatitis B. It became the basis of the hepatitis B vaccine, which is highly effective and used throughout the world. Dr. Blumberg won the Nobel Prize for his work on the hepatitis B virus in 1976.

Collins: Sometimes people look at NIH and ask why we don’t focus all of our efforts on curing a particular disease. I keep answering, ‘Wait a moment, we don’t know enough to know how to do that.’ What’s the balance that we ought to be seeking between basic research and clinical applications?

Alter: There is this tendency now to pursue highly directed research to solve a problem. That’s certainly how biopharma works. They want a payoff. The NIH is different. It’s a place where you can pursue your scientific interests, wherever they lead. The NIH leadership understands that the details of a problem often aren’t obvious at first. Researchers need to be allowed to observe things and then to pursue their leads as far as possible, with the understanding that not everything will work out. I think it’s very important to keep this basic research component in parallel with the more clinical applications. In the case of hepatitis C, it started as a clinical problem that led to a basic research investigation, which led back to a clinical problem. It was bedside-to-bench-to-bedside.

Collins: Are people still getting infected with hepatitis C?

Alter: Yes, hepatitis C remains a global problem. Seventy million people have contracted the virus, though the majority are generally asymptomatic, meaning they don’t get sick from it. Instead, they carry around the virus for decades without knowing it. That’s because the hepatitis C virus likes to persist, and our immune system doesn’t seem to be able to get rid of it easily.

However, some of those infected will have bad outcomes, such as cirrhosis or cancer of the liver. But there’s no way of knowing who will and who won’t get sick over time. The trick now is to identify people when they’re asymptomatic and without obvious disease.

That involves testing. We’re in a unique position with hepatitis C, where we have great tests that are highly sensitive and very specific to the virus. We also have great treatments. We can cure everybody who is tested and found to be positive.

Collins: People may be surprised to hear that. Here is a chronic viral illness, for which we actually have a cure. That’s come along fairly recently. Say a bit more about that—it’s such a great story of success.

Alter: For many years, the only treatment for hepatitis C was interferon, a very difficult treatment that initially had only about a 6 percent cure rate. With further progress, it got up to around 50 percent. But the big breakthrough came in the late 1990s when Gilead Corp., having the sequenced genome of the hepatitis C virus, deduced what it needs to replicate. If we know what it needs and we interfere with that, we can stop the replication. Gilead came out with a blockbuster drug that, now in combination with another drug, aims at two different sites on the virus and cures at least 98 percent of people. It’s an oral therapy taken for only 12 weeks, sometimes as little as 8 weeks, and with virtually no side-effects. It’s like a miracle drug.

Collins: What would you say to somebody who is thinking about becoming a scientist? How do you pick an area of research that will be right for you?

Alter: It’s a tough question. Medical research is very difficult, but there’s nothing more rewarding than doing something for patients and to see a good outcome like we had with hepatitis C.

The best path forward is to work for somebody who’s already an established investigator and a good teacher. Work in his or her lab for a few years and get involved in a project. I’ve learned not get into a lot of projects. Get into something where you can become the expert and pursue it.
The other thing is to collaborate. There’s no way that one person can do everything these days. You need too much technology and lots of different areas of expertise.

Collins: You took on a high-risk project in which you didn’t know that you’d find the answer. What’s the right balance between a project that you know will be productive, and something that might be risky, but, boy, if it works, could be transformative? How did you decide which of those paths to go?

Alter: I don’t think I decided. I just went! But there were interim rewards. Finding that the paid donors were bad was a reward and it had a big impact. And the different donor testing, decreasing the amount of blood [transfused], there were all kinds of steps along the way that gave you a reward. Now, did I think that there would be a treatment, an eradication of post-transfusion hepatitis at the end of my line? No, I didn’t.

And it wouldn’t have happened if it was only me. I just got the ball rolling. But it needed Houghton’s group. It needed the technology of Charlie Rice, a co-recipient of this year’s Nobel Prize. It needed joint company involvement. So, it required massive cooperation, and I have to say that here at NIH, Bob Purcell did most of the really basic work in his lab. Patrizia Farci, my closest collaborator, does things that I can’t do. You just need people who have a different expertise.

Collins: Harvey, it’s been maybe six hours since you found out that you won the Nobel Prize. How are you going to spend the rest of your day?

Alter: Well, I have to tell you a story that just happened. We had a press conference earlier today at NIH. Afterwards, I wanted to return to my NIH office and the easiest route was through the parking garage across the street from where we held the press conference. When I entered the garage, a security guard said, “You can’t come in, you haven’t been screened for COVID.” I assured him that I had been screened when I drove onto the NIH campus. He repeated that I had to go around to the front of the building to get screened.

Finally, I said to him, “Would it make any difference if I told you that I won the Nobel Prize today?” He replied, ‘That’s nice, but you must go around to the front of the building.’” So, winning the Nobel doesn’t give you immediate rewards!

Collins: Let me find that security guard and give him a bonus for doing a good job. Well, Harvey, will there be that trip to Stockholm coming up in December?

Alter: Not this year. I’ve heard that they will invite us to Stockholm next year to receive the award. But there’s going to be something in the US. I don’t know what it will be. I’ll invite you.

Collins: I will be glad to take part in the celebration. Well, Harvey, I really want to thank you for taking some time on this special day to reflect on your career and how the Nobel Committee came calling at 4:30 this morning. We’re really proud of you!

Alter: Thank you.

Links:

Hepatitis C (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

The Nobel Assembly at Karolinska Institutet has today decided to award the 2020 Nobel Prize in Physiology or Medicine jointly to Harvey J. Alter, Michael Houghton and Charles M. Rice for the discovery of Hepatitis C virus,” Nobel Prize announcement, October 5,2020.

Harvey Alter (Clinical Center/NIH)

The Road Not Taken, or How I Learned to Love the Liver: A Personal Perspective on Hepatitis History” Alter HJ, Hepatology. 2014 Jan;59(1):4-12.

Reflections on the History of HCV: A Posthumous Examination.” Alter HJ, Farci P, Bukh J, Purcell RH. Clinical Liver Disease, 15:1, Feb 2020.

Is Elimination of Hepatitis B and C a Pipe Dream or Reality?” Alter HJ, Chisari FV. Gastroenterology. 2019 Jan;156(2):294-296.

Michael Houghton (University of Alberta, Edmonton)

Charles Rice (The Rockefeller University, New York)

What is genome editing? (National Human Genome Research Institute/NIH)

Jennifer Doudna (University of California, Berkeley)

Emmanuelle Charpentier (Max Planck Institute for Infection Biology, Berlin, Germany)