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Dr. Francis Collins

Congratulations on 2020 Nobel Prize in Chemistry

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Congratulations to Jennifer Doudna and Emmanuelle Charpentier on sharing the 2020 Nobel Prize in Chemistry “for the development of a method for genome editing.” Doudna, a biochemist with the University of California, Berkeley and a genome editing pioneer, has received continuous NIH funding since 1997. Charpentier is a French microbiologist and a fellow genome editing pioneer with the Max Planck Institute for Infection Biology, Berlin, Germany. Here, I am with Doudna on December 12, 2018 during a U. S. Senate NIH Caucus Meeting on CRISPR and Gene Editing. Credit: Berkeley News


Congratulations to an NIH Nobelist

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Congratulations to an NIH Nobelist
Yesterday was a fantastic day for NIH and Harvey Alter, a co-recipient of the 2020 Nobel Prize in Physiology or Medicine for his contributions to the discovery of the hepatitis C virus. Harvey, a senior scholar at the NIH Clinical Center’s Department of Transfusion Medicine, shares this year’s award with Michael Houghton, University of Alberta, Canada; and Charles Rice, Rockefeller University, New York, who is an NIH grantee. I congratulated Harvey on winning the prize, and we took some photos, including this one on the front steps of NIH’s James Shannon Building. Harvey has been with the Clinical Center for more than 50 years, doing remarkable work to keep the blood supply safe. His research to identify the hepatitis C virus led to tests and treatments that have saved millions of lives. Credit: NIH

Rogue Antibodies and Gene Mutations Explain Some Cases of Severe COVID-19

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SARS-CoV-2
Caption: Colorized scanning electron micrograph of a dying cell (blue) heavily infected with SARS-CoV-2 virus particles (yellow), isolated from a patient sample. Credit: National Institute of Allergy and Infectious Diseases, NIH

One of the many perplexing issues with COVID-19 is that it affects people so differently. That has researchers trying to explain why some folks bounce right back from the virus, or don’t even know they have it—while others become critically ill. Now, two NIH-funded studies suggest that one reason some otherwise healthy people become gravely ill may be previously unknown trouble spots in their immune systems, which hamper their ability to fight the virus.

According to the new findings in hundreds of racially diverse people with life-threatening COVID-19, a small percentage of people who suffer the most severe symptoms carry rare mutations in genes that disrupt their antiviral defenses. Another 10 percent with severe COVID-19 produce rogue “auto-antibodies,” which misguidedly disable a part of the immune system instead of attacking the virus.

Either way, the outcome is the same: the body has trouble fending off SARS-CoV-2, the novel coronavirus that causes COVID-19. The biological reason is there’s not enough of an assortment of signaling proteins, called type I interferons, that are crucial to detecting dangerous viruses like SARS-CoV-2 and sounding the alarm to prevent serious illness.

The research was led by Jean-Laurent Casanova, Howard Hughes Medical Institute and The Rockefeller University, New York; and the Imagine Institute, Necker Hospital, Paris. Casanova and his team began enrolling people with COVID-19 last February, with a particular interest in young adults battling severe illness. They were curious whether inherent weaknesses in their immune systems might explain their surprising vulnerability to the virus despite being otherwise young and healthy. Based on earlier findings in other infectious illnesses, they were especially interested in a set of 13 genes involved in interferon-driven immunity.

In their first study, published in the journal Science, researchers compared this set of genes in 659 patients with life-threatening COVID-19 to the same genes in 534 people with mild or asymptomatic COVID-19 [1]. It turned out that 23, or 3.5 percent, of people with severe COVID-19 indeed carried rare mutations in genes involved in producing antiviral interferons. Those unusual aberrations never turned up in people with milder disease. The researchers went on to show in lab studies that those genetic errors leave human cells more vulnerable to SARS-CoV-2 infection.

The discovery was certainly intriguing, but given the rarity of those mutations, it doesn’t explain most instances of severe COVID-19. Still, it did give Casanova’s team another idea. Perhaps some other people who suffer from severe COVID-19 lack interferons too, but for different reasons. Perhaps their bodies were producing rogue antibodies that were crippling their own antiviral defenses.

In their second study, also in Science, that’s exactly what researchers found in 101 of 987 (over 10 percent) patients from around the world with life-threatening COVID-19 [2]. In the bloodstreams of such individuals, they detected auto-antibodies against an assortment of interferon proteins. Those antibodies, which blocked the interferons’ antiviral activity, weren’t found in people with more mild cases of COVID-19.

Interestingly, the vast majority of patients with those harmful antibodies were men. The findings might help to explain the observation that men are at greater risk than women for developing severe COVID-19. The patients with auto-antibodies also were slightly older, with about half over the age of 65.

Many questions remain. For instance, it’s not yet clear what drives the production of those debilitating auto-antibodies. Might there be more mutations in antiviral defense-related genes that researchers have yet to discover? Is it possible that interferon treatment may help some people with severe COVID-19? Such treatment may be difficult in patients with auto-antibodies, although some clinical trials to explore this possibility already are underway.

The findings, if confirmed, have some potentially immediate implications. It’s possible that screening patients for the presence of damaging auto-antibodies might help to identify those at greater risk for progressing to severe disease. Treatments to remove those antibodies from the bloodstream or to boost antiviral defenses in other ways also may help. Ideally, it would be a good idea to make sure donated convalescent plasma now being tested in clinical trials as a treatment for severe COVID-19 doesn’t contain such disruptive auto-antibodies.

These new findings come from an international effort involving hundreds of scientists called the COVID Human Genetic Effort. Besides its ongoing efforts to understand severe COVID-19, Casanova says his team is also taking a look at the other side of the coin: how some people who’ve been exposed to severe COVID-19 in their own households manage to not get sick. A related international group called the COVID-19 Host Genetics Initiative is pursuing similar goals. Such insights will be invaluable as we continue to manage and treat COVID-19 patients in the future.

References:

[1] Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Gorochov G, Béziat V, Jouanguy E, Sancho-Shimizu V, Rice CM, Abel L, Notarangelo LD, Cobat A, Su HC, Casanova JL et al. Science. 2020 Sep 24:eabd4570. [Published online ahead of print.]

[2] Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Gorochov G, Jouanguy E, Rice CM, Cobat A, Notarangelo LD, Abel L, Su HC, Casanova JL et al. Science. 2020 Sep 24:eabd4585. [Published online ahead of print.]

Links:

Coronavirus (COVID-19) (NIH)

Interferons (Alpha, Beta) (NIH)

Interferons. Taylor MW. Viruses and Men: A History of Interactions. 2014 July 22. (Pubmed)

Video: Understanding the underlying genetics of COVID-19, Jean-Laurent Casanova (Youtube)

Jean-Laurent Casanova (The Rockefeller University, New York)

COVID Human Genetic Effort

NIH Support: National Institute of Allergy and Infectious Diseases


Discussing Cancer Health Disparities

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Cancer Health Disparities
It was my pleasure to offer virtual remarks for the opening plenary session of the 13th Annual Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved Virtual Conference. The session was hosted by the American Association for Cancer Research (AACR) on October 2, 2020. I started things off speaking about factors that influence racial health disparities, including cancer disparities, and the need for greater workforce diversity. This videoconference image shows me with the panel members for the opening session. They are (starting top left to right) John Carpten, University of Southern California Keck School of Medicine, Los Angeles; Patricia LoRusso, Yale School of Medicine, New Haven, CT; Francis Collins; Brian Rivers, Morehouse School of Medicine; Atlanta; Chanita Hughes-Holbert, Medical University of South Carolina, Charleston; Mariana Stern, University of Southern California Keck School of Medicine, Los Angeles; Clayton Yates, Tuskegee University, AL; and Robert Winn, Virginia Commonwealth University Massey Cancer Center, Richmond.

COVID-19 Can Damage Hearts of Some College Athletes

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American football Player
Credit: iStock/Serega

There’s been quite a bit of discussion in the news lately about whether to pause or resume college athletics during the pandemic. One of the sticking points has been uncertainty about how to monitor the health of student athletes who test positive for SARS-CoV-2, the novel coronavirus that causes COVID-19. As a result, college medical staff don’t always know when to tell athletes that they’ve fully recovered and it’s safe to start training again.

The lack of evidence owes to two factors. Though it may not seem like it, this terrible coronavirus has been around for less than a year, and that’s provided little time to conduct the needed studies with young student athletes. But that’s starting to change. An interesting new study in the journal JAMA Cardiology provides valuable and rather worrisome early data from COVID-positive student athletes evaluated for an inflammation of the heart called myocarditis, a well-known complication [1].

Saurabh Rajpal and his colleagues at the Ohio State University, Columbus, used cardiac magnetic resonance imaging (MRI) to visualize the hearts of 26 male and female student athletes. They participated in a range of sports, including football, soccer, lacrosse, basketball, and track. All of the athletes were referred to the university’s sports medicine clinic this past summer after testing positive for SARS-CoV-2. All had mild or asymptomatic cases of COVID-19.

Even so, the MRI scans, taken 11-53 days after completion of quarantine, showed four of the student athletes (all males) had swelling and tissue damage to their hearts consistent with myocarditis. Although myocarditis often resolves on its own over time, severe cases can compromise the heart muscle’s ability to beat. That can lead to heart failure, abnormal heart rhythms, and even sudden death in competitive athletes with normal heart function [2].

The investigators also looked for more subtle findings of cardiac injury in these athletes, using a contrast agent called gadolinium and measuring its time to appear in the cardiac muscle during the study. Eight of the 26 athletes (31 percent) had late gadolinium enhancement, suggestive of prior myocardial injury.

Even though it’s a small study, these results certainly raise concerns. They add more evidence to a prior study, published by a German group, that suggested subtle cardiac consequences of SARS-CoV-2 infection may be common in adults [3].

Rajpal and his colleagues will continue to follow the athletes in their study for several more months. The researchers will keep an eye out for other lingering symptoms of COVID-19, generate more cardiac MRI data, and perform exercise testing.

As this study shows, we still have a lot to learn about the long-term consequences of COVID-19, which can take people on different paths to recovery. For athletes, that path is the challenge to return to top physical shape and feel ready to compete at a high level. But getting back in uniform must also be done safely to minimize any risks to an athlete’s long-term health and wellbeing. The more science-based evidence that’s available, the more prepared athletes at large and small colleges will be to compete safely in this challenging time.

References:

[1] Cardiovascular magnetic resonance findings in competitive athletes recovering from COVID-19 infection. Rajpal S, Tong MS, Borchers J, et al. JAMA Cardiol. 2020 September 11. [Published online ahead of print.]

[2] Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 3: Hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and other cardiomyopathies, and myocarditis. Maron BJ, Udelson JE, Bonow RO, et al. Circulation. 2015;132(22):e273-e280.

[3] Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from Coronavirus Disease 2019 (COVID-19). Puntmann VO, Carej ML, Wieters I. JAMA Cardiol. 2020 Jul 27:e203557. [Published online ahead of print.]

Links:

Coronavirus (COVID-19) (NIH)

Heart Inflammation (National Heart, Lung, and Blood Institute/NIH)

Saurabh Rajpal (Ohio State College of Medicine, Columbus)


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