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Biomedical Research Leads Science’s 2021 Breakthroughs

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Artificial Antibody Therapies, AI-Powered Predictions of Protein Structures, Antiviral Pills for COVID-19, and CRISPR Fixes Genes Inside the Body

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 [1]. 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 [3]. 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 [4] (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 [5].

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 [6]. 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 [7].

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) [8].

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 [9]. 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 [10]. 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 [11]. 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!


[1] 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.

[2] 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.

[3] Structural insights of SARS-CoV-2 spike protein from Delta and Omicron variants. Sadek A, Zaha D, Ahmed MS. preprint bioRxiv. 2021 Dec 9.

[4] 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.

[5] Pfizer’s novel COVID-19 oral antiviral treatment candidate reduced risk of hospitalization or death by 89% in interim analysis of phase 2/3 EPIC-HR Study. Pfizer. 5 November 52021.

[6] Coronavirus (COVID-19) Update: FDA authorizes first oral antiviral for treatment of COVID-19. Food and Drug Administration. 22 Dec 2021.

[7] Coronavirus (COVID-19) Update: FDA authorizes additional oral antiviral for treatment of COVID-19 in certain adults. Food and Drug Administration. 23 Dec 2021.

[8] 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.

[9] Anti-SARS-CoV-2 monoclonal antibodies. NIH COVID-19 Treatment Guidelines. 16 Dec 2021.

[10] 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.

[11] 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)


  • Nancy Krieger says:

    It would be remiss not to celebrate another NIH milestone in 2021: on March 1, 2021, the NIH finally took a stand against structural racism in biomedical research ( — and given the rampant health inequities exposed by COVID-19 and also the profound issues of structural racism and economic adversity affecting the health and well-being of the US population, it is essential that this NIH breakthrough be celebrated, institutionalized, and supported with ample funding and leadership.

  • Ruby says:

    Biology is a fascinating thing. It’s amazing to think what a few nucleotides can do and how epigenetics can dictate very different outcomes. Something that is toxic in one species can be fairly benign in another. As the pandemic becomes endemic and there are other host animals (such as what is being seen with deer and certain zoo animals), one does have to ask about the evolutionary advantage of codon optimization and the value of pseudo-uridine. Perhaps there are lessons that can be gleaned from Gleevac?

  • Patrick Watters says:

    Thank you for carrying on this important communication that I continue to share throughout my own circle. It is vital in combatting “qanonense” and more in our time.

  • Zuccheri Gianni says:

    Happy New Year Dr. Tabak,
    Congratulations on your important work in the NIH and thank you for this special explanation on medical advances being studied.

    These goals deeply affect medical problems that are still difficult to manage, such as diseases of genetic origin.
    Even though they are sometimes rare diseases, we have to think that behind that statistical number is a face, a person, who begs for our help as doctors.
    I still remember today a young patient (visited decades ago) suffering from Leber’s congenital amaurosis who explained his tragedy to me: at the time I couldn’t find words to help him.

    Looking at future treatments for chronic pain that is sometimes devastating to the affected person, it is encouraging to know that the CRISPR gene editing tool could help these patients.

    Just yesterday, a patient who has been suffering from spinal damage for years, writes to me: he periodically updates me on the operations he is undergoing, unfortunately with poor results. Last planned, implantation of a medullary electro-stimulator.
    But the stress resulting from this situation also causes recurrent central serous chorioretinopathies, a source of serious fear for his sight.

  • John C Lepore says:

    I read tons of scientific ‘stuff’, mostly related to geo-hydromorphological, ecological and botanical, so reading outside these areas challenges my patience. I have to say, this presentation of accomplishments engages to most weary readers. So much of our science has become inaccessible from unnecessary jargon. Larry shows us how to reach out with clear, concise and understandable descriptions. It was a pleasure read! Thank you!

  • J.D says:

    It’s delightful to read, and be reminded of the incredible work that’s been done over the past 2 years, with so much promise in the years soon to come.

  • wendy says:

    Excellent, Dr. Tabak and colleagues….look forward to tracking this blog in the years ahead. Thank you from a colleague in the national and economic security world…

  • Wasi says:

    Science is a complicated thing to parlay to lay people without adequate training. The CDC serves to communicate public health concerns to the general public whereas the FDA serves as a regulatory body. Those with the background and training to make informed choices may make decisions that are different from the lay public. However with any of these organizations there needs to be a forum to communicate dissent without repercussion. If a non-majority voice is squashed either by intimidation or other measures, it hardly serves the purpose behind science. The difficult part lays in communicating the message to the majority of the “intended” population while respecting individual informed choices. Not an enviable position to be, and everyone should realize that. It’s like being given the job of a real time translator where nuances may have very different outcomes.

  • Fahmida pathan says:

    Welcome Larry Tabak. Best wishes for you & the NIH team.

  • Debra Thomas says:

    I’m a hereditary TTR patient currently taking Tafamidis daily. My son is genetically positive. Good to read about advances. Need test subjects?

  • S. says:

    Biology is a fascinating thing. It’s amazing to think what a few nucleotides can do and how epigenetics can dictate very different outcomes.

  • Phillip Huggan says:

    Some solid-state metrology advances would improve medical equipment tools. I’ve been treating improving antenna design as replacing as much of its metal construction with solid-state lattice building processes, as is efficient. Before medical equipment, there is a need for metrology to improve. Solid-state mechanical reactions have no ground truth. X-ray diffraction, Raman Spectroscopy, NMR, XANES, manometry and thermometry, may all improve solid state manufacturing if improved. They can be improved themselves by solid state advances. This virtuous cycle will lead to soft medicine and now-metal equipment both being better prototyped by the above tools developed initially for solid state metrology. Seeing how many milli-seconds a ball bearing heats a mill surface will lead to the equipment will be quieter using more lattices than metals.

  • John Lepore says:

    Sorry, I do not understand what the second sentence to stating. Please explain, restate. Thanks

  • Phillip Huggan says:

    My app was radar dishes and coils, improving them with better materials. The principle also works for say, a microscope. The eyepiece wheel on a Bruker Optics microscope is made of metal. Heavy enough to deaden some vibrations. Precision ground and buffed to have balance. Massive enough to take handling and minimize elastic forces handling wear as well as accidental impacts.
    But replace the metal with sapphire and 3/4 of the material properties improve with 1/4 being worse. Namely, a lighter microscope made in the shape of a hollow cell membrane will outperform CNC lasered metal or extruded plastic parts. Bigger lenses would throw the existing microscope off balance in months. Already I suggest making such equipment out of planetary mill constituents. I had a 1930s X-ray in 2007 and the machine took up 1/4 the room; consider how small baggage X-rays are now.

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