Posted on by Lawrence Tabak, D.D.S., Ph.D.
Hi everyone, I’m Larry Tabak. I’ve served as NIH’s Principal Deputy Director for over 11 years, and I will be the acting NIH director until a new permanent director is named. In my new role, my day-to-day responsibilities will certainly increase, but I promise to carve out time to blog about some of the latest research progress on COVID-19 and any other areas of science that catch my eye.
I’ve also invited the directors of NIH’s Institutes and Centers (ICs) to join me in the blogosphere and write about some of the cool science in their research portfolios. I will publish a couple of posts to start, then turn the blog over to our first IC director. From there, I envision alternating between posts from me and from various IC directors. That way, we’ll cover a broad array of NIH science and the tremendous opportunities now being pursued in biomedical research.
Since I’m up first, let’s start where the NIH Director’s Blog usually begins each year: by taking a look back at Science’s Breakthroughs of 2021. The breakthroughs were formally announced in December near the height of the holiday bustle. In case you missed the announcement, the biomedical sciences accounted for six of the journal Science’s 10 breakthroughs. Here, I’ll focus on four biomedical breakthroughs, the ones that NIH has played some role in advancing, starting with Science’s editorial and People’s Choice top-prize winner:
Breakthrough of the Year: AI-Powered Predictions of Protein Structure
The biochemist Christian Anfinsen, who had a distinguished career at NIH, shared the 1972 Nobel Prize in Chemistry, for work suggesting that the biochemical interactions among the amino acid building blocks of proteins were responsible for pulling them into the final shapes that are essential to their functions. In his Nobel acceptance speech, Anfinsen also made a bold prediction: one day it would be possible to determine the three-dimensional structure of any protein based on its amino acid sequence alone. Now, with advances in applying artificial intelligence to solve biological problems—Anfinsen’s bold prediction has been realized.
But getting there wasn’t easy. Every two years since 1994, research teams from around the world have gathered to compete against each other in developing computational methods for predicting protein structures from sequences alone. A score of 90 or above means that a predicted structure is extremely close to what’s known from more time-consuming work in the lab. In the early days, teams more often finished under 60.
In 2020, a London-based company called DeepMind made a leap with their entry called AlphaFold. Their deep learning approach—which took advantage of 170,000 proteins with known structures—most often scored above 90, meaning it could solve most protein structures about as well as more time-consuming and costly experimental protein-mapping techniques. (AlphaFold was one of Science’s runner-up breakthroughs last year.)
This year, the NIH-funded lab of David Baker and Minkyung Baek, University of Washington, Seattle, Institute for Protein Design, published that their artificial intelligence approach, dubbed RoseTTAFold, could accurately predict 3D protein structures from amino acid sequences with only a fraction of the computational processing power and time that AlphaFold required . They immediately applied it to solve hundreds of new protein structures, including many poorly known human proteins with important implications for human health.
The DeepMind and RoseTTAFold scientists continue to solve more and more proteins [1,2], both alone and in complex with other proteins. The code is now freely available for use by researchers anywhere in the world. In one timely example, AlphaFold helped to predict the structural changes in spike proteins of SARS-CoV-2 variants Delta and Omicron . This ability to predict protein structures, first envisioned all those years ago, now promises to speed fundamental new discoveries and the development of new ways to treat and prevent any number of diseases, making it this year’s Breakthrough of the Year.
Anti-Viral Pills for COVID-19
The development of the first vaccines to protect against COVID-19 topped Science’s 2020 breakthroughs. This year, we’ve also seen important progress in treating COVID-19, including the development of anti-viral pills.
First, there was the announcement in October of interim data from Merck, Kenilworth, NJ, and Ridgeback Biotherapeutics, Miami, FL, of a significant reduction in hospitalizations for those taking the anti-viral drug molnupiravir  (originally developed with an NIH grant to Emory University, Atlanta). Soon after came reports of a Pfizer anti-viral pill that might target SARS-CoV-2, the novel coronavirus that causes COVID-19, even more effectively. Trial results show that, when taken within three days of developing COVID-19 symptoms, the pill reduced the risk of hospitalization or death in adults at high risk of progressing to severe illness by 89 percent .
On December 22, the Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for Pfizer’s Paxlovid to treat mild-to-moderate COVID-19 in people age 12 and up at high risk for progressing to severe illness, making it the first available pill to treat COVID-19 . The following day, the FDA granted an EUA for Merck’s molnupiravir to treat mild-to-moderate COVID-19 in unvaccinated, high-risk adults for whom other treatment options aren’t accessible or recommended, based on a final analysis showing a 30 percent reduction in hospitalization or death .
Additional promising anti-viral pills for COVID-19 are currently in development. For example, a recent NIH-funded preclinical study suggests that a drug related to molnupiravir, known as 4’-fluorouridine, might serve as a broad spectrum anti-viral with potential to treat infections with SARS-CoV-2 as well as respiratory syncytial virus (RSV) .
Artificial Antibody Therapies
Before anti-viral pills came on the scene, there’d been progress in treating COVID-19, including the development of monoclonal antibody infusions. Three monoclonal antibodies now have received an EUA for treating mild-to-moderate COVID-19, though not all are effective against the Omicron variant . This is also an area in which NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership has made big contributions.
Monoclonal antibodies are artificially produced versions of the most powerful antibodies found in animal or human immune systems, made in large quantities for therapeutic use in the lab. Until recently, this approach had primarily been put to work in the fight against conditions including cancer, asthma, and autoimmune diseases. That changed in 2021 with success using monoclonal antibodies against infections with SARS-CoV-2 as well as respiratory syncytial virus (RSV), human immunodeficiency virus (HIV), and other infectious diseases. This earned them a prominent spot among Science’s breakthroughs of 2021.
Monoclonal antibodies delivered via intravenous infusions continue to play an important role in saving lives during the pandemic. But, there’s still room for improvement, including new formulations highlighted on the blog last year that might be much easier to deliver.
CRISPR Fixes Genes Inside the Body
One of the most promising areas of research in recent years has been gene editing, including CRISPR/Cas9, for fixing misspellings in genes to treat or even cure many conditions. This year has certainly been no exception.
CRISPR is a highly precise gene-editing system that uses guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to cut out or correct disease-causing misspellings. Science highlights a small study reported in The New England Journal of Medicine by researchers at Intellia Therapeutics, Cambridge, MA, and Regeneron Pharmaceuticals, Tarrytown, NY, in which six people with hereditary transthyretin (TTR) amyloidosis, a condition in which TTR proteins build up and damage the heart and nerves, received an infusion of guide RNA and CRISPR RNA encased in tiny balls of fat . The goal was for the liver to take them up, allowing Cas9 to cut and disable the TTR gene. Four weeks later, blood levels of TTR had dropped by at least half.
In another study not yet published, researchers at Editas Medicine, Cambridge, MA, injected a benign virus carrying a CRISPR gene-editing system into the eyes of six people with an inherited vision disorder called Leber congenital amaurosis 10. The goal was to remove extra DNA responsible for disrupting a critical gene expressed in the eye. A few months later, two of the six patients could sense more light, enabling one of them to navigate a dimly lit obstacle course . This work builds on earlier gene transfer studies begun more than a decade ago at NIH’s National Eye Institute.
Last year, in a research collaboration that included former NIH Director Francis Collins’s lab at the National Human Genome Research Institute (NHGRI), we also saw encouraging early evidence in mice that another type of gene editing, called DNA base editing, might one day correct Hutchinson-Gilford Progeria Syndrome, a rare genetic condition that causes rapid premature aging. Preclinical work has even suggested that gene-editing tools might help deliver long-lasting pain relief. The technology keeps getting better, too. This isn’t the first time that gene-editing advances have landed on Science’s annual Breakthrough of the Year list, and it surely won’t be the last.
The year 2021 was a difficult one as the pandemic continued in the U.S. and across the globe, taking far too many lives far too soon. But through it all, science has been relentless in seeking and finding life-saving answers, from the rapid development of highly effective COVID-19 vaccines to the breakthroughs highlighted above.
As this list also attests, the search for answers has progressed impressively in other research areas during these difficult times. These groundbreaking discoveries are something in which we can all take pride—even as they encourage us to look forward to even bigger breakthroughs in 2022. Happy New Year!
 Accurate prediction of protein structures and interactions using a three-track neural network. Baek M, DiMaio F, Anishchenko I, Dauparas J, Grishin NV, Adams PD, Read RJ, Baker D., et al. Science. 2021 Jul 15:eabj8754.
 Highly accurate protein structure prediction with AlphaFold. Jumper J, Evans R, Pritzel A, Green T, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D. et al. Nature. 2021 Jul 15.
 Structural insights of SARS-CoV-2 spike protein from Delta and Omicron variants. Sadek A, Zaha D, Ahmed MS. preprint bioRxiv. 2021 Dec 9.
 Merck and Ridgeback’s investigational oral antiviral molnupiravir reduced the risk of hospitalization or death by approximately 50 Percent compared to placebo for patients with mild or moderate COVID-19 in positive interim analysis of phase 3 study. Merck. 1 Oct 2021.
 Coronavirus (COVID-19) Update: FDA authorizes first oral antiviral for treatment of COVID-19. Food and Drug Administration. 22 Dec 2021.
 Coronavirus (COVID-19) Update: FDA authorizes additional oral antiviral for treatment of COVID-19 in certain adults. Food and Drug Administration. 23 Dec 2021.
 4′-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication. Sourimant J, Lieber CM, Aggarwal M, Cox RM, Wolf JD, Yoon JJ, Toots M, Ye C, Sticher Z, Kolykhalov AA, Martinez-Sobrido L, Bluemling GR, Natchus MG, Painter GR, Plemper RK. Science. 2021 Dec 2.
 Anti-SARS-CoV-2 monoclonal antibodies. NIH COVID-19 Treatment Guidelines. 16 Dec 2021.
 CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. Gillmore JD, Gane E, Taubel J, Kao J, Fontana M, Maitland ML, Seitzer J, O’Connell D, Walsh KR, Wood K, Phillips J, Xu Y, Amaral A, Boyd AP, Cehelsky JE, McKee MD, Schiermeier A, Harari O, Murphy A, Kyratsous CA, Zambrowicz B, Soltys R, Gutstein DE, Leonard J, Sepp-Lorenzino L, Lebwohl D. N Engl J Med. 2021 Aug 5;385(6):493-502.
 Editas Medicine announces positive initial clinical data from ongoing phase 1/2 BRILLIANCE clinical trial of EDIT-101 For LCA10. Editas Medicine. 29 Sept 2021.
Structural Biology (National Institute of General Medical Sciences/NIH)
The Structures of Life (NIGMS)
COVID-19 Research (NIH)
2021 Science Breakthrough of the Year (American Association for the Advancement of Science, Washington, D.C)
Posted In: News
Tags: 4'-fluorouridine, Accelerating COVID-19 Therapeutic Interventions and Vaccines, ACTIV, AI, AlphaFold, amino acids, artificial antibodies, artificial intelligence, biochemistry, Christian Anfinsen, Chronic Pain, computational biology, coronavirus, COVID pill, COVID-19, CRISPR, CRISPR/Cas9, DeepMind, Delta variant, Editas Medicine, EUA, gene editing, hereditary transthyretin amyloidosis, Hutchinson-Gilford progeria syndrome, Intellia Therapeutics, Leber congenital amaurosis, Merck, molnupiravir, monoclonal antibodies, Omicron variant, pandemic, Pfizer, progeria, protein structure, rare disease, Regeneron, RoseTTAFold, SARS-CoV-2, Science Breakthrough of the Year, Science Breakthroughs of 2021, structural biology
Posted on by Dr. Francis Collins
Over the course of this pandemic, significant progress has been made in treating COVID-19 and helping to save lives. That progress includes the development of life-preserving monoclonal antibody infusions and repurposing existing drugs, to which NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership has made a major contribution.
But for many months we’ve had hopes that a safe and effective oral medicine could be developed that would reduce the risk of severe illness for individuals just diagnosed with COVID-19. The first indication that those hopes might be realized came from the announcement just a month ago of a 50 percent reduction in hospitalizations from the Merck and Ridgeback drug molnupiravir (originally developed with an NIH grant to Emory University, Atlanta). Now comes word of a second drug with potentially even higher efficacy: an antiviral pill from Pfizer Inc. that targets a different step in the life cycle of SARS-CoV-2, the novel coronavirus that causes COVID-19.
The most recent exciting news started to roll out earlier this month when a Pfizer research team published in the journal Science some promising initial data involving the antiviral pill and its active compound . Then came even bigger news a few days later when Pfizer announced interim results from a large phase 2/3 clinical trial. It found that, when taken within three days of developing symptoms of COVID-19, the pill reduced by 89 percent the risk of hospitalization or death in adults at high risk of progressing to severe illness .
At the recommendation of the clinical trial’s independent data monitoring committee and in consultation with the U.S. Food and Drug Administration (FDA), Pfizer has now halted the study based on the strength of the interim findings. Pfizer plans to submit the data to the FDA for Emergency Use Authorization (EUA) very soon.
Pfizer’s antiviral pill is a protease inhibitor, originally called PF-07321332, or just 332 for short. A protease is an enzyme that cleaves a protein at a specific series of amino acids. The SARS-CoV-2 virus encodes its own protease to help process a large virally-encoded polyprotein into smaller segments that it needs for its life cycle; a protease inhibitor drug can stop that from happening. If the term protease inhibitor rings a bell, that’s because drugs that work in this way already are in use to treat other viruses, including human immunodeficiency virus (HIV) and hepatitis C virus.
In the case of 332, it targets a protease called Mpro, also called the 3CL protease, coded for by SARS-CoV-2. The virus uses this enzyme to snip some longer viral proteins into shorter segments for use in replication. With Mpro out of action, the coronavirus can’t make more of itself to infect other cells.
What’s nice about this therapeutic approach is that mutations to SARS-CoV-2’s surface structures, such as the spike protein, should not affect a protease inhibitor’s effectiveness. The drug targets a highly conserved, but essential, viral enzyme. In fact, Pfizer originally synthesized and pre-clinically evaluated protease inhibitors years ago as a potential treatment for severe acute respiratory syndrome (SARS), which is caused by a coronavirus closely related to SARS-CoV-2. This drug might even have efficacy against other coronaviruses that cause the common cold.
In the study published earlier this month in Science , the Pfizer team led by Dafydd Owen, Pfizer Worldwide Research, Cambridge, MA, reported that the latest version of their Mpro inhibitor showed potent antiviral activity in laboratory tests against not just SARS-CoV-2, but all of the coronaviruses they tested that are known to infect people. Further study in human cells and mouse models of SARS-CoV-2 infection suggested that the treatment might work to limit infection and reduce damage to lung tissue.
In the paper in Science, Owen and colleagues also reported the results of a phase 1 clinical trial with six healthy people. They found that their protease inhibitor, when taken orally, was safe and could reach concentrations in the bloodstream that should be sufficient to help combat the virus.
But would it work to treat COVID-19 in an infected person? So far, the preliminary results from the larger clinical trial of the drug candidate, now known as PAXLOVID™, certainly look encouraging. PAXLOVID™ is a formulation that combines the new protease inhibitor with a low dose of an existing drug called ritonavir, which slows the metabolism of some protease inhibitors and thereby keeps them active in the body for longer periods of time.
The phase 2/3 clinical trial included about 1,200 adults from the United States and around the world who had enrolled in the clinical trial. To be eligible, study participants had to have a confirmed diagnosis of COVID-19 within a five-day period along with mild-to-moderate symptoms of illness. They also required at least one characteristic or condition associated with an increased risk for developing severe illness from COVID-19. Each individual in the study was randomly selected to receive either the experimental antiviral or a placebo every 12 hours for five days.
In people treated within three days of developing COVID-19 symptoms, the Pfizer announcement reports that 0.8 percent (3 of 389) of those who received PAXLOVID™ were hospitalized within 28 days compared to 7 percent (27 of 385) of those who got the placebo. Similarly encouraging results were observed in those who got the treatment within five days of developing symptoms. One percent (6 of 607) on the antiviral were hospitalized versus 6.7 percent (41 of 612) in the placebo group. Overall, there were no deaths among people taking PAXLOVID™; 10 people in the placebo group (1.6 percent) subsequently died.
If all goes well with the FDA review, the hope is that PAXLOVID™ could be prescribed as an at-home treatment to prevent severe illness, hospitalization, and deaths. Pfizer also has launched two additional trials of the same drug candidate: one in people with COVID-19 who are at standard risk for developing severe illness and another evaluating its ability to prevent infection in adults exposed to the coronavirus by a household member.
Meanwhile, Britain recently approved the other recently developed antiviral molnupiravir, which slows viral replication in a different way by blocking its ability to copy its RNA genome accurately. The FDA will meet on November 30 to discuss Merck and Ridgeback’s request for an EUA for molnupiravir to treat mild-to-moderate COVID-19 in infected adults at high risk for severe illness . With Thanksgiving and the winter holidays fast approaching, these two promising antiviral drugs are certainly more reasons to be grateful this year.
 An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19.
Owen DR, Allerton CMN, Anderson AS, Wei L, Yang Q, Zhu Y, et al. Science. 2021 Nov 2: eabl4784.
 FDA to hold advisory committee meeting to Discuss Merck and Ridgeback’s EUA Application for COVID-19 oral treatment. Food and Drug Administration. October 14, 2021.
COVID-19 Research (NIH)
Posted In: News
Tags: 332, 3CL protease, Accelerating COVID-19 Therapeutic Interventions and Vaccines, ACTIV, antivirals, clinical trial, coronavirus, COVID pill, COVID-19, COVID-19 treatment, drug development, Emergency Use Authorization, EUA, FDA, Merck, molnupiravir, Mpro, novel coronavirus, pandemic, PAXLOVID™, PF-07321332, Pfizer, protease, protease inhibitor, Ridgeback, ritonavir, SARS, SARS-CoV-2, spike protein