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
Gene editing has shown great promise as a non-heritable way to treat a wide range of conditions, including many genetic diseases and more recently, even COVID-19. But could a version of the CRISPR gene-editing tool also help deliver long-lasting pain relief without the risk of addiction associated with prescription opioid drugs?
In work recently published in the journal Science Translational Medicine, researchers demonstrated in mice that a modified version of the CRISPR system can be used to “turn off” a gene in critical neurons to block the transmission of pain signals . While much more study is needed and the approach is still far from being tested in people, the findings suggest that this new CRISPR-based strategy could form the basis for a whole new way to manage chronic pain.
This novel approach to treating chronic pain occurred to Ana Moreno, the study’s first author, when she was a Ph.D. student in the NIH-supported lab of Prashant Mali, University of California, San Diego. Mali had been studying a wide range of novel gene- and cell-based therapeutics. While reading up on both, Moreno landed on a paper about a mutation in a gene that encodes a pain-enhancing protein in spinal neurons called NaV1.7.
Moreno read that kids born with a loss-of-function mutation in this gene have a rare condition known as congenital insensitivity to pain (CIP). They literally don’t sense and respond to pain. Although these children often fail to recognize serious injuries because of the absence of pain to alert them, they have no other noticeable physical effects of the condition.
For Moreno, something clicked. What if it were possible to engineer a new kind of treatment—one designed to turn this gene down or fully off and stop people from feeling chronic pain?
Moreno also had an idea about how to do it. She’d been working on repressing or “turning off” genes using a version of CRISPR known as “dead” Cas9 . In CRISPR systems designed to edit DNA, the Cas9 enzyme is often likened to a pair of scissors. Its job is to cut DNA in just the right spot with the help of an RNA guide. However, CRISPR-dead Cas9 no longer has any ability to cut DNA. It simply sticks to its gene target and blocks its expression. Another advantage is that the system won’t lead to any permanent DNA changes, since any treatment based on CRISPR-dead Cas9 might be safely reversed.
After establishing that the technique worked in cells, Moreno and colleagues moved to studies of laboratory mice. They injected viral vectors carrying the CRISPR treatment into mice with different types of chronic pain, including inflammatory and chemotherapy-induced pain.
Moreno and colleagues determined that all the mice showed evidence of durable pain relief. Remarkably, the treatment also lasted for three months or more and, importantly, without any signs of side effects. The researchers are also exploring another approach to do the same thing using a different set of editing tools called zinc finger nucleases (ZFNs).
The researchers say that one of these approaches might one day work for people with a large number of chronic pain conditions that involve transmission of the pain signal through NaV1.7. That includes diabetic polyneuropathy, sciatica, and osteoarthritis. It also could provide relief for patients undergoing chemotherapy, along with those suffering from many other conditions. Moreno and Mali have co-founded the spinoff company Navega Therapeutics, San Diego, CA, to work on the preclinical steps necessary to help move their approach closer to the clinic.
Chronic pain is a devastating public health problem. While opioids are effective for acute pain, they can do more harm than good for many chronic pain conditions, and they are responsible for a nationwide crisis of addiction and drug overdose deaths . We cannot solve any of these problems without finding new ways to treat chronic pain. As we look to the future, it’s hopeful that innovative new therapeutics such as this gene-editing system could one day help to bring much needed relief.
 Long-lasting analgesia via targeted in situ repression of NaV1.7 in mice. Moreno AM, Alemán F, Catroli GF, Hunt M, Hu M, Dailamy A, Pla A, Woller SA, Palmer N, Parekh U, McDonald D, Roberts AJ, Goodwill V, Dryden I, Hevner RF, Delay L, Gonçalves Dos Santos G, Yaksh TL, Mali P. Sci Transl Med. 2021 Mar 10;13(584):eaay9056.
 Nuclease dead Cas9 is a programmable roadblock for DNA replication. Whinn KS, Kaur G, Lewis JS, Schauer GD, Mueller SH, Jergic S, Maynard H, Gan ZY, Naganbabu M, Bruchez MP, O’Donnell ME, Dixon NE, van Oijen AM, Ghodke H. Sci Rep. 2019 Sep 16;9(1):13292.
 Drug Overdose Deaths. Centers for Disease Control and Prevention.
Congenital insensitivity to pain (National Center for Advancing Translational Sciences/NIH)
Opioids (National Institute on Drug Abuse/NIH)
Mali Lab (University of California, San Diego)
Navega Therapeutics (San Diego, CA)
NIH Support: National Human Genome Research Institute; National Cancer Institute; National Institute of General Medical Sciences; National Institute of Neurological Disorders and Stroke
Posted on by Dr. Francis Collins
If laughter really is the best medicine, wouldn’t it be great if we could learn more about what goes on in the brain when we laugh? Neuroscientists recently made some major progress on this front by pinpointing a part of the brain that, when stimulated, never fails to induce smiles and laughter.
In their study conducted in three patients undergoing electrical stimulation brain mapping as part of epilepsy treatment, the NIH-funded team found that stimulation of a specific tract of neural fibers, called the cingulum bundle, triggered laughter, smiles, and a sense of calm. Not only do the findings shed new light on the biology of laughter, researchers hope they may also lead to new strategies for treating a range of conditions, including anxiety, depression, and chronic pain.
In people with epilepsy whose seizures are poorly controlled with medication, surgery to remove seizure-inducing brain tissue sometimes helps. People awaiting such surgeries must first undergo a procedure known as intracranial electroencephalography (iEEG). This involves temporarily placing 10 to 20 arrays of tiny electrodes in the brain for up to several weeks, in order to pinpoint the source of a patient’s seizures in the brain. With the patient’s permission, those electrodes can also enable physician-researchers to stimulate various regions of the patient’s brain to map their functions and make potentially new and unexpected discoveries.
In the new study, published in The Journal of Clinical Investigation, Jon T. Willie, Kelly Bijanki, and their colleagues at Emory University School of Medicine, Atlanta, looked at a 23-year-old undergoing iEEG for 8 weeks in preparation for surgery to treat her uncontrolled epilepsy . One of the electrodes implanted in her brain was located within the cingulum bundle and, when that area was stimulated for research purposes, the woman experienced an uncontrollable urge to laugh. Not only was the woman given to smiles and giggles, she also reported feeling relaxed and calm.
As a further and more objective test of her mood, the researchers asked the woman to interpret the expression of faces on a computer screen as happy, sad, or neutral. Electrical stimulation to the cingulum bundle led her to see those faces as happier, a sign of a generally more positive mood. A full evaluation of her mental state also showed she was fully aware and alert.
To confirm the findings, the researchers looked to two other patients, a 40-year-old man and a 28-year-old woman, both undergoing iEEG in the course of epilepsy treatment. In those two volunteers, stimulation of the cingulum bundle also triggered laughter and reduced anxiety with otherwise normal cognition.
Willie notes that the cingulum bundle links many brain areas together. He likens it to a super highway with lots of on and off ramps. He suspects the spot they’ve uncovered lies at a key intersection, providing access to various brain networks regulating mood, emotion, and social interaction.
Previous research has shown that stimulation of other parts of the brain can also prompt patients to laugh. However, what makes stimulation of the cingulum bundle a particularly promising approach is that it not only triggers laughter, but also reduces anxiety.
The new findings suggest that stimulation of the cingulum bundle may be useful for calming patients’ anxieties during neurosurgeries in which they must remain awake. In fact, Willie’s team did so during their 23-year-old woman’s subsequent epilepsy surgery. Each time she became distressed, the stimulation provided immediate relief. Also, if traditional deep brain stimulation or less invasive means of brain stimulation can be developed and found to be safe for long-term use, they may offer new ways to treat depression, anxiety disorders, and/or chronic pain.
Meanwhile, Willie’s team is hard at work using similar approaches to map brain areas involved in other aspects of mood, including fear, sadness, and anxiety. Together with the multidisciplinary work being mounted by the NIH-led BRAIN Initiative, these kinds of studies promise to reveal functionalities of the human brain that have previously been out of reach, with profound consequences for neuroscience and human medicine.
 Cingulum stimulation enhances positive affect and anxiolysis to facilitate awake craniotomy. Bijanki KR, Manns JR, Inman CS, Choi KS, Harati S, Pedersen NP, Drane DL, Waters AC, Fasano RE, Mayberg HS, Willie JT. J Clin Invest. 2018 Dec 27.
Video: Patient’s Response (Bijanki et al. The Journal of Clinical Investigation)
Epilepsy Information Page (National Institute of Neurological Disease and Stroke/NIH)
Jon T. Willie (Emory University, Atlanta, GA)
NIH Support: National Institute of Neurological Disease and Stroke; National Center for Advancing Translational Sciences
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