Greetings! The new year is off to an impressively cold start, with temperatures in the single digits over the weekend followed by yesterday’s storm. Much more positively, Ashton Murray arrived last week as the university’s inaugural chief diversity officer (CDO) and vice president for diversity, equity, and inclusion (DEI). His arrival is timely, just ahead of yesterday’s national holiday celebrating the life and work of Martin Luther King, prompting reflection on how far Dr. King brought us and how far we have yet to go to achieve equality and justice throughout our ethnically and racially diverse society. In particular this year, I believe he would be shocked to see we are struggling to preserve the guarantee of voting rights and election integrity first enacted by federal legislation in 1965.
In the last month, the Omicron wave of the COVID pandemic has spread remarkably rapidly across the globe and through communities, resulting in a tidal wave of cases that makes the peaks of prior waves look like mere ripples. Global cases number 3 million per day, including 800,00 cases and 2,000 deaths per day in the U.S. New cases in NYC increased from ~1500 per day at the end of November to 50,000 per day by the end of December, dwarfing the prior high of ~6,600 last January. This viral variant spreads readily through modest contact, and vaccination without booster shots provides only modest protection from infection, in part due to the virus’s highly mutated spike protein that evades pre-existing antibodies. Over the last week, case numbers and the percentage of positive tests in NYC have peaked and are declining significantly, though we continue to have more than 20,000 new cases per day, still 10-fold more than we had at the peak of the Delta wave.
Fortunately, vaccines continue to provide significant protection against severe disease, hospitalization, and death, and a booster shot of the same mRNA vaccines used for doses one and two markedly raise this protection to very high levels. Boosters also produce very high antibody levels, substantially reducing the risk of infection and risk of transmitting infection to others. While cases nationally are ~5-fold higher than at the peak of the Delta wave last summer, ICU admissions and deaths are only at the same level seen at the peak of the Delta wave, driven by unvaccinated cases, with the risk of hospitalization and death about 90% lower for those who are vaccinated and boosted.
The course of Omicron at Rockefeller has paralleled the experience in NYC. Prior to Omicron, the peak number of new cases in a two-week period was 25, occurring last January. In the two weeks ending last Friday, we had 187 new cases, and 285 cases over the last month, far more than we had in the entire prior 21 months of the pandemic. Interviews by OHS staff indicate that there have likely been many viral transmissions on campus, which were previously nearly non-existent. The vast majority of new infections likely occur via maskless contact with an infected person, including a few via contact outdoors. The clinical course ranges from mild cold-like symptoms to a nasty illness with fever, body aches, cough, and extreme fatigue. Fortunately, we have had zero hospitalizations during the Omicron wave, and only one hospitalization throughout the pandemic. We are grateful that nearly 100% of on-campus Rockefeller employees have been fully vaccinated and that 80% have had booster shots.
To help mitigate the exceptional transmission of Omicron, in December the University obtained and distributed KN95 masks for all employees and students. The KN95s offer significantly more protection than surgical or cloth masks, and you are encouraged to use these indoors on campus and also when indoors in a public setting or in larger groups off-campus. Throughout the pandemic, the university has offered N95 respirators – which provide the highest level of protection when properly fitted and worn – to anyone who commutes to work by public transportation. If you want to be fit tested and trained on use of N95s for use when commuting on public transportation, please ask your head of laboratory or department to send a request to email@example.com. If you are already enrolled in the program and need replacement N95s, please contact firstname.lastname@example.org.
Most importantly for our campus, booster shots are available on-campus for all employees who are at least 5 months beyond completion of SARS-CoV-2 vaccination. Boosters are extremely safe, with effects like the prior vaccine doses. Boosters are highly effective in dramatically increasing neutralizing antibody levels, reducing risk of primary infection, and providing substantially increased protection from the risk of hospitalization and death from Omicron. Also, people who have received booster shots are, if infected, less likely to transmit the virus to others. Thus, getting a booster shot will increase your protection and will also contribute to protecting your families, your colleagues at work, unvaccinated children in the CFC and elsewhere, and members of your broader communities. Reducing case numbers also reduces the opportunity for the virus to mutate to new variant forms that could cause the next wave of infection. If you have had a booster shot, be sure to send documentation to OHS at email@example.com. If you have not had a booster shot, please sign up to get yours right here on campus via the online scheduler. We all have an opportunity and obligation to contribute to our collective well-being. Having all gone through getting vaccinated and knowing that it’s not onerous, I urge everyone to get boosted!
While we do our best to prevent the spread of infection, we will continue to ask those people who can effectively work from home do so through January 31. All winter/spring semester classes will be virtual for now. Many events which were scheduled to take place in person have also transitioned to Zoom meetings for the time being. We hope these changes will be short-lived and that we can return to fully on-campus operations in the coming weeks.
In the meantime, our vital mission continues. Last week, we hosted the first group of six new faculty candidates for a day-long research symposium, followed by a second day featuring chalk talks by the candidates. It was inspiring to hear from and discuss innovative science with a terrifically talented group of young scientists. A second group of candidates will participate in another symposium on February 9-10. We are indebted to Nat Heintz, who has done a great job leading this year’s open search, to Jill Benz and her colleagues who have gracefully handled the complex logistics following the shift to virtual meetings, and to the hard work of all members of the open search committee in selecting this year’s finalists.
Also, last week we had a virtual version of the annual Talking Science event for high school students, led by Jeanne Garbarino and her colleagues in RockEDU. The students heard presentations by Jeremy Rock, Leslie Vosshall, and Christian Gaebler on infectious disease and immunology—including tuberculosis, mosquito-borne illnesses, and antibody therapies. Our thanks to all three for their terrific talks!
And our labs continue to produce amazing science. Among many recent great advances, I will highlight an extraordinary paper just out from Jue Chen’s lab on cystic fibrosis (CF). CF is a genetic disease that until recently has been fatal by about age 30 due to recurrent lung infections that lead to respiratory failure. CF is caused by mutations that eliminate function of both copies of a gene encoding a chloride channel, CFTR, that is normally expressed in lung epithelia. Mutations impair the normal folding of the protein such that it doesn’t get delivered to the plasma membrane, or prevent the channel from opening normally, or both.
The biotech company Vertex recently developed a combination of three small molecule drugs that restore about 50% of normal function to this broken gene product and has dramatic effects to restore lung function, prevent hospitalization, improve well-being, and markedly increase longevity of CF patients. One of these helps open the defective channel, while the other two help the protein fold normally, enabling its delivery to the cell surface.
How these drugs work has been a mystery. Over the last few years, Jue Chen’s lab has determined the normal structure of CFTR, shown how the channel normally opens, and has shown how binding of the ion channel potentiator increases channel opening. She and postdoc Karol Fiedorczuk have now determined the structure of CFTR bound to one of the drugs that assist the folding of the mutant channel. Surprisingly, they found that the drug binds far away from where the most common disease-causing mutation lies and works indirectly, by stabilizing the folded structure of the first transmembrane domain of the protein. Failure of proper folding of this normal first part of the protein is the rule, with 80% of normal CFTR ultimately being degraded in the endoplasmic reticulum due to misfolding. The combination of this poorly folding domain with a mutation that impairs folding of other domains reduces the probability of folding to the final, functional structure to near zero. By stabilizing the folded structure of the first domain, this drug gives the domain with the mutation more time to fold properly, markedly increasing the likelihood of the channel folding to a stable final structure. This surprising kinetic mechanism explains why this drug can assist the folding of CFTR with many different mutations throughout the protein that disrupt folding.
This principle has profound implications for a large number of genetic diseases caused by missense mutations, which commonly disrupt normal folding. Because each gene typically has dozens to hundreds of different missense mutations that are disease-causing, it has commonly been believed that impacting these diseases with small molecule therapeutics would require dozens of different drugs to correct different mutations found in the same gene in different patients, a very impractical path. The kinetic mechanism Karol and Jue discovered suggests that many different disease-causing mutations in the same gene may be corrected by a single drug that stabilizes the proper folding of a normally rate-limiting folding intermediate.
Moreover, Karol and Jue showed that the CF drug fits snugly into a cavity in the protein, stabilizing a bundle of helices. These ‘holes’ in proteins have been proposed to be a frequent source of protein instability. Their discovery will set off a hunt for other ‘holes’ in proteins that may identify structural weaknesses that might be effective targets for drugs to stabilize folding intermediates in mutant proteins. These results thus provide optimism for the development of small molecules that can ‘fix’ broken genes that cause a wide range of genetic diseases. Congratulations to Karol and Jue for this amazing research!
Congratulations are also in order for Katya Vinogradova, who along with her MSK colleague Santosha A. Vardhana, will receive the Damon Runyon-Rachleff Innovation Award for their research targeting T cell exhaustion in solid tumors. This is a terrific award that will provide significant funding as they work toward understanding how the lung tumor microenvironment suppresses immune responses, with the ultimate goal of innovating new strategies to restore T cell function in high-risk patients.
Finally, I am delighted to announce that Paul Bieniasz, head of the Lab of Retrovirology and Investigator of the Howard Hughes Medical Institute, has been named the Purnell W. Choppin Professor, following a wonderful gift by Joan Choppin to establish this professorship at Rockefeller in memory of her late husband. This is a particularly meaningful chair, as Purnell spent 28 years at Rockefeller as an iconic physician-scientist, virologist, and professor, and also as vice president for academic programs. He and Joan met at Rockefeller, where Joan worked as a nutritionist in the Hospital. Purnell subsequently was recruited to the Howard Hughes Medical Institute in 1985, initially as vice president for science, becoming president of HHMI in 1987, a position he held until his retirement in 1999. Under Purnell’s leadership, HHMI became established as the world’s most impactful philanthropic foundation dedicated to the support of biomedical research. Paul is linked to Purnell both via their critical contributions to understanding the pathogenic mechanisms of viral infections, and also through Paul’s support as an HHMI Investigator in the program Purnell developed. We are very proud that Rockefeller’s long association with Purnell is memorialized with this prestigious chair, and we send our deep appreciation to Joan and our congratulations to Paul!
Here’s hoping the Omicron wave will pass quickly and not have a comparable successor. In these trying times I urge everyone to get boosted, stay safe, be well, and continue to support and take care of one another.
Richard P. Lifton, M.D., Ph.D.
Carson Family Professor
Laboratory of Human Genetics and Genomics
The Rockefeller University