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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

10 Comments

  • Elizabeth F Newberry says:

    Congratulations to all the Nobel recipients, and thank you to all for all your hard scientific work to increase the understanding of our world and how our bodies work.
    Also, a huge thank you to Dr. Collins for all his years of service as Director of NIH, leading us through a tumultuous time in our history.

  • Martine Jager says:

    How do young women respond to seeing only white men getting the most important science awards? The five drawings say it all. One should add that nowadays many NIH awards go to women, which essential to make the future bright for everyone.

    • Roseanne Woo Haltresht says:

      Light a candle, but NEVER curse the darkness. Let us ask ourselves “What have we done PERSONALLY to encourage more girls and young woman to enter and stay with a career track in science and engineering?” Success is not determined by gender nor skin color. Individual drive and motivation matter.

  • Roseanne Woo Haltresht says:

    Congratulations to NIH! Best wishes to Dr Collins for your leadership and stewardship of the NIH!

    We will always remember your groundbreaking role in the Human Genome Project of the 1980’s. It will impact the fields of medicine and physiology for generations to come.

    May God bless you and your family in the Golden retirement days ahead!

  • George Nicolae says:

    I would relate the effect of capsaicin from the cayene peppers to the stereostructure of capsaicin a long molecule with an amidic group and phenol to interact with protein and generating a more stable complex, a more stable means to surrend energy as an effect sensation transmitted to the PNS as heat. (hot peppers). The menthol has an opposite effect based on its structure as a “hydrocarbon” with a tertiary alcohol classified as of a large group of terpenoid. Mentol is “stealing” energy by a rearrangement of the chain of protein with an effect “as winter” arrived to the PNS. Proteins in general have a very complicated structures not only by the long chain, but a single atom of carbon could change the chain with 180 degree and hydrogen bonds from NH or OH would be affected. Proteins in my opinion as the “chemicals” that are able as the fastest to absorn energy. You can run a simple experiment. Take a mercurium thermometer and place in hot water, remove it fast from hot medium and touch with your fingers the mercurium reservoir and see how the mercurium that indicated lt say 60-80degree C drop the fastest than anything else due of the caloric capacity of the proteins of the skin. Run another similar experiment and touch the reservoir with a cloth or other material, the mercurium would not go as fast as it does with proteins. Sorry, it is a boring experiment easy to run by anyone!

  • Zuccheri Gianni says:

    Thanks to Dr. Collins and a sincere greeting.

    Interesting discoveries that will bring advances in diagnoses and daily therapies.
    I would like to tell you about my unwelcome experience in this regard : the receptors treated in the research of the Nobel laureates, David Julius and Ardem Patapoutian.
    Instead of Capsaicin, I experienced the burning pain of jellyfish toxin.
    A month ago while I was swimming I touch a jellyfish, I feel like a barbed wire on my arm. Once out of the water, I remembered that the poison is thermolabile: the pain pushed me to quickly find a solution. On the beach without medicines or other supports, remembering that years before with the ice I had been worse, I made an instinctive gesture on my own.
    I took a hot stone from the heat of the sun and PRESSED it on the injured area. What a nice surprise!
    The burning pain in the arm almost suddenly ceases, not even bothered by the heat, which irritated the hand holding the stone!

    By repeating the application several times, only acceptable hyperemia and discomfort remains (years before episode without hot stones, it took me a month to heal).

    All this is to point out that the healthy skin area surrounding the scratches was not affected by the scorching heat.

    I feared a pejorative vasodilatation, in reality everything improved, thanks to complex circuits of receptors: painful, thermal, pressure and chemical in the tissues.

    The healthy hand did not tolerate the heat, which on the arm canceled out any discomfort, as if nothing had happened!

  • Andrew Goldstein says:

    Not only do Nobel Prizes acknowledge and reward experts in their respective fields, they also reveal to the lay public some of the extraordinary advances in science from all over the world and particularly at NIH, one of the great institutions of our federal government. Congratulations to all those who are recognized.

  • Zuccheri Gianni says:

    In medicine, Capsaicin has been studied for its peculiar properties, while for many people it represents an irresistible condiment, with an extraordinary effect of burning heat for the mouth. In the research of Dr. David Julius, Capsaicin was used for the study of thermal receptors. There will probably be important results derived from further investigations of its action at the cornea and conjunctiva level, already considered in several studies … There are no taste receptors here, but the burning heat effect … is guaranteed at the same time.

    One day, while I was cutting a pepper, a splash of juice from this hit my eye: terrible burning, subsided only after continuous washing with eye drops. As it faded, vasodilation remained with a warm sensation all over the eye, thankfully with no clear damage.

    Remaining in the ophthalmology sector, we find that the Piezo 1 receptors are involved in the complex mechanisms of regulation of ocular pressure:
    they will probably be considered for the treatment of the disease Glaucoma, in which the ocular pressure is altered.

    Finally, I ask: there will still be receptors to be discovered involved in the responses to LASERs, such as, for example, those used in physiotherapy: their electromagnetic waves emitted have an anti-inflammatory and biostimulating action (YAG, Diode, etc.).

  • Zuccheri Gianni says:

    Dear Dr. Collins – I have read with regret that your leadership of the NIH will end at the end of the year.

    A few days ago I was in the mountains, among the colors of the autumn forest, towards sunset I was listening to the pleasant sound of a stream. From the hill I forded the course of the water that flowed below, like the passing of time of our life, in that instant I wondered if I have collected more stones or more fish from the river, as disappointing defeats or radiant goals. In the medical profession, we always want to solve the problems of those who question us: unfortunately it is not always easy.

    I was reading about the NIH Nobel Prize winners: it is a beautiful message, which stimulates us to build the future.
    In the meantime, speaking of economic studies, I think of the girl who inspired me what I wrote in
    https://directorsblog.nih.gov/2021/09/16/preventing-glaucoma-vision-loss-with-big-data/#comment-29100 :
    Just 21 years old, she has been completely blind for about 2 years: She was studying Economics, her aunt shows me all the clinical documentation, MRI Brain etc. .

    From the documentation it appears an undefined neurological problem, which has caused damage to both of them
    the optic nerves. Show me the photo, the aunt makes me listen to a song that the patient sings in a very sweet way:
    if I don’t have to be moved, what could I do? In an overseas country, I will send a speaking text reader, but it is not enough for viewing . . .

  • Fahmida P. says:

    Congratulations to all the NIH’s Nobelists, and keep your good work up.

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