Posted on by Dr. Francis Collins
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 . 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 .
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.
 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.
 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.
 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.
 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.
 Proline-catalyzed direct asymmetric aldol reactions. List B, Lerner RA, Barbas CF. J. Am. Chem. Soc. 122, 2395–2396 (2000).
 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.
Curiosity Creates Cures: The Value and Impact of Basic Research (National Institute of General Medical Sciences/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)
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
Posted on by Dr. Francis Collins
The spinal cord, as a key part of our body’s central nervous system, contains millions of neurons that actively convey sensory and motor (movement) information to and from the brain. Scientists have long sorted these spinal neurons into what they call “cardinal” classes, a classification system based primarily on the developmental origin of each nerve cell. Now, by taking advantage of the power of single-cell genetic analysis, they’re finding that spinal neurons are more diverse than once thought.
This image helps to visualize the story. Each dot represents the nucleus of a spinal neuron in a mouse; humans have a very similar arrangement. Most of these neurons are involved in the regulation of motor control, but they also differ in important ways. Some are involved in local connections (green), such as those that signal outward to a limb and prompt us to pull away reflexively when we touch painful stimuli, such as a hot frying pan. Others are involved in long-range connections (magenta), relaying commands across spinal segments and even upward to the brain. These enable us, for example, to swing our arms while running to help maintain balance.
It turns out that these two types of spinal neurons also have distinctive genetic signatures. That’s why researchers could label them here in different colors and tell them apart. Being able to distinguish more precisely among spinal neurons will prove useful in identifying precisely which ones are affected by a spinal cord injury or neurodegenerative disease, key information in learning to engineer new tissue to heal the damage.
This image comes from a study, published recently in the journal Science, conducted by an NIH-supported team led by Samuel Pfaff, Salk Institute for Biological Studies, La Jolla, CA. Pfaff and his colleagues, including Peter Osseward and Marito Hayashi, realized that the various classes and subtypes of neurons in our spines arose over the course of evolutionary time. They reasoned that the most-primitive original neurons would have gradually evolved subtypes with more specialized and diverse capabilities. They thought they could infer this evolutionary history by looking for conserved and then distinct, specialized gene-expression signatures in the different neural subtypes.
The researchers turned to single-cell RNA sequencing technologies to look for important similarities and differences in the genes expressed in nearly 7,000 mouse spinal neurons. They then used this vast collection of genomic data to group the neurons into closely related clusters, in much the same way that scientists might group related organisms into an evolutionary family tree based on careful study of their DNA.
The first major gene expression pattern they saw divided the spinal neurons into two types: sensory-related and motor-related. This suggested to them that one of the first steps in spinal cord evolution may have been a division of labor of spinal neurons into those two fundamentally important roles.
Further analyses divided the sensory-related neurons into excitatory neurons, which make neurons more likely to fire; and inhibitory neurons, which dampen neural firing. Then, the researchers zoomed in on motor-related neurons and found something unexpected. They discovered the cells fell into two distinct molecular groups based on whether they had long-range or short-range connections in the body. Researches were even more surprised when further study showed that those distinct connectivity signatures were shared across cardinal classes.
All of this means that, while previously scientists had to use many different genetic tags to narrow in on a particular type of neuron, they can now do it with just two: a previously known tag for cardinal class and the newly discovered genetic tag for long-range vs. short-range connections.
Not only is this newfound ability a great boon to basic neuroscientists, it also could prove useful for translational and clinical researchers trying to determine which specific neurons are affected by a spinal injury or disease. Eventually, it may even point the way to strategies for regrowing just the right set of neurons to repair serious neurologic problems. It’s a vivid reminder that fundamental discoveries, such as this one, often can lead to unexpected and important breakthroughs with potential to make a real difference in people’s lives.
 Conserved genetic signatures parcellate cardinal spinal neuron classes into local and projection subsets. Osseward PJ 2nd, Amin ND, Moore JD, Temple BA, Barriga BK, Bachmann LC, Beltran F Jr, Gullo M, Clark RC, Driscoll SP, Pfaff SL, Hayashi M. Science. 2021 Apr 23;372(6540):385-393.
What Are the Parts of the Nervous System? (Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH)
Spinal Cord Injury (National Institute of Neurological Disorders and Stroke/NIH)
Samuel Pfaff (Salk Institute, La Jolla, CA)
NIH Support: National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Eunice Kennedy Shriver National Institute of Child Health and Human Development
Posted on by Dr. Francis Collins
One of the best ways to learn how something works is to understand how it’s built. How it came to be. That’s true not only if you play a guitar or repair motorcycle engines, but also if you study the biological systems that make life possible. Evolutionary studies, comparing the development of these systems across animals and organisms, are now leading to many unexpected biological discoveries and promising possibilities for preventing and treating human disease.
While there are many evolutionary questions to ask, Brenda Bass, a distinguished biochemist at University of Utah, Salt Lake City, has set her sights on a particularly profound one: How has innate immunity evolved through the millennia in all living things, including humans? Innate immunity is the immune system’s frontline defense, the first responders that take control of an emerging infectious situation and, if needed, signal for backup.
Exploring the millennia for clues about innate immunity takes a special team, and Bass has assembled a talented one. It includes her Utah colleague Nels Elde, a geneticist; immunologist Dan Stetson, University of Washington, Seattle; and biochemist Jane Jackman, Ohio State University, Columbus.
With a 2020 NIH Director’s Transformative Research Award, this hard-working team will embark on studies looking back at 450 million years of evolution: the point in time when animals diverged to develop very distinct methods of innate immune defense . The team members hope to uncover new possibilities encoded in the innate immune system, especially those that might be latent but still workable. The researchers will then explore whether their finds can be repurposed not only to boost our body’s natural response to external threats but also to internal threats like cancer.
Bass brings a unique perspective to the project. As a postdoc in the 1980s, she stumbled upon a whole new class of enzymes, called ADARs, that edit RNA . Their function was mysterious at the time. It turns out that ADARs specifically edit a molecule called double-stranded RNA (dsRNA). When viruses infect cells in animals, including humans, they make dsRNA, which the innate immune system detects as a sign that a cell has been invaded.
It also turns out that animal cells make their own dsRNA. Over the years, Bass and her lab have identified thousands of dsRNAs made in animal cells—in fact, a significant number of human genes produce dsRNA . Also interesting, ADARs are crucial to marking our own dsRNA as “self” to avoid triggering an immune response when we don’t need it .
Bass and others have found that evolution has produced dramatic differences in the biochemical pathways powering the innate immune system. In vertebrate animals, dsRNA leads to release of the immune chemical interferon, a signaling pathway that invertebrate species don’t have. Instead, in response to detecting dsRNA from an invader, and repelling it, worms and other invertebrates trigger a gene-silencing pathway known as RNA interference, or RNAi.
With the new funding, Bass and team plan to mix and match immune strategies from simple and advanced species, across evolutionary time, to craft an entirely new set of immune tools to fight disease. The team will also build new types of targeted immunotherapies based on the principles of innate immunity. Current immunotherapies, which harness a person’s own immune system to fight disease, target infections, autoimmune disorders, and cancer. But they work through our second-line adaptive immune response, which is a biological system unique to vertebrates.
Bass and her team will first hunt for more molecules like ADARs: innate immune checkpoints, as they refer to them. The name comes from a functional resemblance to the better-known adaptive immune checkpoints PD-1 and CTLA-4, which sparked a revolution in cancer immunotherapy. The team will run several screens that sort molecules successful at activating innate immune responses—both in invertebrates and in mammals—hoping to identify a range of durable new immune switches that evolution skipped over but that might be repurposed today.
Another intriguing direction for this research stems from the observation that decreasing normal levels of ADARs in tumors kickstarts innate immune responses that kill cancer cells . Along these lines, the scientists plan to test newly identified immune switches to look for novel ways to fight cancer where existing approaches have not worked.
Evolution is the founding principle for all of biology—organisms learn from what works to improve their ability to survive. In this case, research to re-examine such lessons and apply them for new uses may help transform bygone evolution into a therapeutic revolution!
 Evolution of adaptive immunity from transposable elements combined with innate immune systems. Koonin EV, Krupovic M. Nat Rev Genet. 2015 Mar;16(3):184-192.
 A developmentally regulated activity that unwinds RNA duplexes. Bass BL, Weintraub H. Cell. 1987 Feb 27;48(4):607-613.
 Mapping the dsRNA World. Reich DP, Bass BL. Cold Spring Harb Perspect Biol. 2019 Mar 1;11(3):a035352.
 To protect and modify double-stranded RNA – the critical roles of ADARs in development, immunity and oncogenesis. Erdmann EA, Mahapatra A, Mukherjee P, Yang B, Hundley HA. Crit Rev Biochem Mol Biol. 2021 Feb;56(1):54-87.
 Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Ishizuka JJ, Manguso RT, Cheruiyot CK, Bi K, Panda A, et al. Nature. 2019 Jan;565(7737):43-48.
Bass Lab (University of Utah, Salt Lake City)
Elde Lab (University of Utah)
Jackman Lab (Ohio State University, Columbus)
Stetson Lab (University of Washington, Seattle)
Bass/Elde/Jackman/Stetson Project Information (NIH RePORTER)
NIH Director’s Transformative Research Award Program (Common Fund)
NIH Support: Common Fund; National Cancer Institute