Posted on by Dr. Francis Collins
We now know that the immune system of nearly everyone who recovers from COVID-19 produces antibodies against SARS-CoV-2, the novel coronavirus that causes this easily transmitted respiratory disease . The presence of such antibodies has spurred hope that people exposed to SARS-CoV-2 may be protected, at least for a time, from getting COVID-19 again. But, in this post, I want to examine another potential use of antibodies: their promise for being developed as therapeutics for people who are sick with COVID-19.
In a recent paper in the journal Science, researchers used blood drawn from a COVID-19 survivor to identify a pair of previously unknown antibodies that specifically block SARS-CoV-2 from attaching to human cells . Because each antibody locks onto a slightly different place on SARS-CoV-2, the vision is to use these antibodies in combination to block the virus from entering cells, thereby curbing COVID-19’s destructive spread throughout the lungs and other parts of the body.
The research team, led by Yan Wu, Capital Medical University, Beijing, first isolated the pair of antibodies in the laboratory, starting with white blood cells from the patient. They were then able to produce many identical copies of each antibody, referred to as monoclonal antibodies. Next, these monoclonal antibodies were simultaneously infused into a mouse model that had been infected with SARS-CoV-2. Just one infusion of this combination antibody therapy lowered the amount of viral genetic material in the animals’ lungs by as much as 30 percent compared to the amount in untreated animals.
Monoclonal antibodies are currently used to treat a variety of conditions, including asthma, cancer, Crohn’s disease, and rheumatoid arthritis. One advantage of this class of therapeutics is that the timelines for their development, testing, and approval are typically shorter than those for drugs made of chemical compounds, called small molecules. Because of these and other factors, many experts think antibody-based therapies may offer one of the best near-term options for developing safe, effective treatments for COVID-19.
So, what exactly led up to this latest scientific achievement? The researchers started out with a snippet of SARS-CoV-2’s receptor binding domain (RBD), a vital part of the spike protein that protrudes from the virus’s surface and serves to dock the virus onto an ACE2 receptor on a human cell. In laboratory experiments, the researchers used the RBD snippet as “bait” to attract antibody-producing B cells in a blood sample obtained from the COVID-19 survivor. Altogether, the researchers identified four unique antibodies, but two, which they called B38 and H4, displayed a synergistic action in binding to the RBD that made them stand out for purposes of therapeutic development and further testing.
To complement their lab and animal experiments, the researchers used a particle accelerator called a synchrotron to map, at near-atomic resolution, the way in which the B38 antibody locks onto its viral target. This structural information helps to clarify the precise biochemistry of the complex interaction between SARS-CoV-2 and the antibody, providing a much-needed guide for the rational design of targeted drugs and vaccines. While more research is needed before this or other monoclonal antibody therapies can be used in humans suffering from COVID-19, the new work represents yet another example of how basic science is expanding fundamental knowledge to advance therapeutic discovery for a wide range of health concerns.
Meanwhile, there’s been other impressive recent progress towards the development of monoclonal antibody therapies for COVID-19. In work described in the journal Nature, an international research team started with a set of neutralizing antibodies previously identified in a blood sample from a person who’d recovered from a different coronavirus-caused disease, called severe acute respiratory syndrome (SARS), in 2003 . Through laboratory and structural imaging studies, the researchers found that one of these antibodies, called S309, proved particularly effective at neutralizing the coronavirus that causes COVID-19, SARS-CoV-2, because of its potent ability to target the spike protein that enables the virus to enter cells. The team, which includes NIH grantees David Veesler, University of Washington, Seattle, and Davide Corti, Humabs Biomed, a subsidiary of Vir Biotechnology, has indicated that S309 is already on an accelerated development path toward clinical trials.
In the U.S. and Europe, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership, which has brought together public and private sector COVID-19 therapeutic and vaccine efforts, is intensely pursuing the development and testing of therapeutic monoclonal antibodies for COVID-19 . Stay tuned for more information about these potentially significant advances in the next few months.
 Humoral immune response and prolonged PCR positivity in a cohort of 1343 SARS-CoV 2 patients in the New York City region. Wajnberg A , Mansour M, Leven E, Bouvier NM, Patel G, Firpo A, Mendu R, Jhang J, Arinsburg S, Gitman M, Houldsworth J, Baine I, Simon V, Aberg J, Krammer F, Reich D, Cordon-Cardo C. medRxiv. Preprint Posted May 5, 2020.
 A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2. Wu Y. et al., Science. 13 May 2020 [Epub ahead of publication]
 Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Pinto D, Park YJ, Beltramello M, Veesler D, Cortil D, et al. Nature. 18 May 2020 [Epub ahead of print]
 Accelerating COVID-19 therapeutic interventions and vaccines (ACTIV): An unprecedented partnership for unprecedented times. Collins FS, Stoffels P. JAMA. 2020 May 18.
Coronavirus (COVID-19) (NIH)
Monoclonal Antibodies (National Cancer Institute/NIH)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences
Posted on by Dr. Francis Collins
Each time your cells divide, telomeres—complexes of specialized DNA sequences, RNA, and protein that protect the tips of your chromosomes—shorten just a bit. And, as the video shows, that shortening renders the genomic information on your chromosomes more vulnerable to changes that can drive cancer and other diseases of aging.
Consequently, over the last few decades, much research has focused on efforts to understand telomerase, a naturally occurring enzyme that helps to replace the bits of telomere lost during cell division. But there’s been a major hitch: until recently, scientists hadn’t been able to determine telomerase’s molecular structure in detail—a key step in figuring out exactly how the enzyme works. Now, thanks to better purification methods and an exciting technology called cryo-electron microscopy (cryo-EM), NIH-funded researchers and their colleagues have risen to the challenge to produce the most detailed view yet of human telomerase in its active form .
This structural biology advance is a critical step toward learning more about the role of telomerase in cancers, as well as genetic conditions linked to telomerase deficiencies. It’s also an important milestone in the quest for drugs targeting telomerase in different ways, perhaps to slow the growth of cancerous cells or to boost the proliferative capacity of life-giving adult stem cells.
One reason telomerase has been so difficult to study in humans is that the enzyme isn’t produced at detectable levels in the vast majority of our cells. To get around this problem, the team led by Eva Nogales and Kathleen Collins at the University of California, Berkeley, first coaxed human cells in the lab to produce larger quantities of active telomerase. They then used fluorescent microscopy, along with extensive knowledge of the enzyme’s biochemistry, to develop a multi-step purification process that yielded relatively homogenous samples of active telomerase.
The new study is also yet another remarkable example of how cryo-EM microscopy has opened up new realms of scientific possibility. That’s because, in comparison to other methods, cryo-EM enables researchers to solve complex macromolecular structures even when only tiny amounts of material are available. It can also produce detailed images of molecules, like telomerase, that are extremely flexible and hard to keep still while taking a picture of their structure.
As described in Nature, the researchers used cryo-EM to capture the structure of human telomerase in unprecedented detail. Their images reveal two lobes, held together by a flexible RNA tether. One of those lobes contains the highly specialized core enzyme. It uses an internal RNA template as a guide to make the repetitive, telomeric DNA that’s added at the tips of chromosomes. The second lobe, consisting of a complex of RNA and RNA-binding proteins, plays important roles in keeping the complex stable and properly in place.
This new, more-detailed view helps to explain how mutations in particular genes may lead to telomerase-related health conditions, including bone marrow failure, as well as certain forms of anemia and pulmonary fibrosis. For example, it reveals that a genetic defect known to cause bone marrow failure affects an essential protein in a spot that’s especially critical for telomerase’s proper conformation and function.
This advance will also be a big help for designing therapies that encourage telomerase activity. For example, it could help to boost the success of bone marrow transplants by rejuvenating adult stem cells. It might also be possible to reinforce the immune systems of people with HIV infections. While telomerase-targeted treatments surely won’t stop people from growing old, new insights into this important enzyme will help to understand aging better, including why some people appear to age faster than others.
As remarkable as these new images are, the researchers aren’t yet satisfied. They’ll continue to refine them down to the minutest structural details. They say they’d also like to use cryo-EM to understand better how the complex attaches to chromosomes to extend telomeres. Each new advance in the level of atomic detail will not only make for amazing new videos, it will help to advance understanding of human biology in health, aging, and disease.
 Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nguyen THD, Tam J, Wu RA, Greber BJ, Toso D, Nogales E, Collins K. Nature. 2018 April 25. [Epub ahead of publication]
High Resolution Electron Microscopy (National Cancer Institute/NIH)
Nogales Lab (University of California, Berkeley)
Collins Lab (University of California, Berkeley)
NIH Support: National Institute of General Medical Sciences
Posted on by Dr. Francis Collins
When you think of the causes of infectious diseases, what first comes to mind are probably viruses and bacteria. But parasites are another important source of devastating infection, especially in the developing world. Now, NIH researchers and their collaborators have discovered a new kind of treatment that holds promise for fighting parasitic roundworms. A bonus of this result is that this same treatment might work also for certain deadly kinds of bacteria.
The researchers identified the potential new therapeutic after testing more than a trillion small protein fragments, called cyclic peptides, to find one that could disable a vital enzyme in the disease-causing organisms, but leave similar enzymes in humans unscathed. Not only does this discovery raise hope for better treatments for many parasitic and bacterial diseases, it highlights the value of screening peptides in the search for ways to treat conditions that do not respond well—or have stopped responding—to more traditional chemical drug compounds.
Posted on by Dr. Francis Collins
When Dmitry Lyumkis headed off to graduate school at The Scripps Research Institute, La Jolla, CA, he had thoughts of becoming a synthetic chemist. But he soon found his calling in a nearby lab that imaged proteins using a technique known as single-particle cryo-electron microscopy (EM). Lyumkis was amazed that the team could take a purified protein, flash-freeze it in liquid nitrogen, and then fire electrons at the protein, capturing the resulting image with a special camera. Also amazing was the sophisticated computer software that analyzed the raw 2D camera images, merging the data and reconstructing it into 3D representations of the protein.
The work was profoundly complex, but Lyumkis thrives on solving extremely difficult puzzles. He joined the Scripps lab to become a structural biologist and a few years later used single-particle cryo-EM to help determine the atomic structure of a key protein on the surface of the human immunodeficiency virus (HIV), the cause of AIDS. The protein had been considered one of the greatest challenges in structural biology and a critical target in developing an AIDS vaccine .
Now, Lyumkis has plans to take single-particle cryo-EM to a whole new level—literally. He wants to develop new methods that allow it to model the atomic structures of much smaller proteins. Right now, single-particle cryo-EM has worked with proteins as small as roughly 150 kilodaltons, a measure of a protein’s molecular weight (the approximate average mass of a protein is 53 kDa). Lyumkis plans to drop that number well below 100 kDa, noting that if his new methods work as he hopes, there should be very little, if any, lower size limit to get the technique to work. He envisions generating within a matter of days or weeks the precise structure of an average-sized protein involved in a disease, and then potentially handing it off as an atomic model for drug developers to target for more effective treatment.