Discoveries made this year by Rockefeller scientists will someday lead to new medicines and help us conquer infectious diseases, cancer, neurodegenerative disorders, and many other afflictions. Each represents a step toward a future in which people live longer, healthier lives.
The Vosshall lab takes control of a mosquito’s DNA to fight disease
Mosquitoes have been a scourge at least since the time of King David. Besides the itchy annoyance, they transmit devastating diseases like chikungunya, dengue fever, malaria, and the Zika virus.
Unlike fruit flies, which have been used in biomedical research for more than a century, mosquitoes have been difficult to study in the lab. But Leslie Vosshall, Robin Chemers Neustein Professor and head of the Laboratory of Neurogenetics and Behavior, has applied a new gene-editing technique to elucidate the host-seeking and blood-feeding behaviors of these insects. The revolutionary technology is the CRISPR-Cas system, lifted out of bacteria where it functions as an immune defense mechanism, and adapted in Leslie’s lab to introduce mutations into the mosquitoes’ genomes.
In 2015, the researchers reported they had made it possible to edit the genome of the yellow fever mosquito, Aedes aegypti. They are now using their CRISPR-based method to search for the genes responsible for behaviors that make this organism an effective disease vector.
Ultimately, knowledge derived in this research could lead to the development of sophisticated strategies to intervene with the mosquito’s disease-transmitting behaviors. The method might also be applicable to similar studies in other disease-spreading organisms.
Published in Cell Reports, April 2015.
The de Lange lab sifts through the remnants of a genetic explosion
In recent years, cancer biologists have noticed a strange phenomenon. In many tumor types, there are cells in which a part of a chromosome looks like it has been pulverized, then put back together incorrectly. This year, Rockefeller’s Laboratory of Cell Biology and Genetics, led by Leon Hess Professor Titia de Lange, found a possible explanation for this molecular explosion, which can be a precursor to cancer.
Titia’s lab is focused on telomeres—the protective ends of chromosomes—and the discovery came as part of an investigation into a cancer-promoting event known as a telomere crisis, in which the tips of two chromosomes stick together.
The scientists showed that when such cells try to divide, the linked chromosomes stretch and stretch and stretch and form a threadlike structure called a bridge. The cells treat that bridge the same way they would any abnormal and potentially harmful DNA—they chop it up. Each daughter cell is then left with a ragged end of damaged DNA. Many of these daughter cells die from the trauma, and those that survive now have multiple mutations in their genomes.
“The ‘old’ idea in cancer is that the disease arose from a first bad mutation, and then a second mutation, and a third, and so on, until the cells divide uncontrollably,” Titia says. “Our findings provide a whole new view of how cancer can arise—a bomb goes off in part of a chromosome, and you get multiple mutations at the same time.”
Published in Cell, December 2015.
The Freiwald lab probes the complex machinations of seeing a face
Winrich Freiwald studies one of the most basic ways in which we interact with others—by looking at their faces. “A face isn’t just any object,” he says. “It demands special attention, and conveys very potent social and emotional information.”
With other members of his Laboratory of Neural Systems, he has identified the regions in our brains that are activated when we recognize a still image of a face—for instance, a photo of a friend. Among the lab’s latest achievements is a study that shows that the same regions, which he calls face patches, are also responsible for processing the visual information we receive when we watch certain facial movements—a raised eyebrow, a disdainful smirk, or a conspiratorial wink.
Winrich works with macaque monkeys, whose brains have face patches similar to those of humans. His team made movies of macaques making communicative expressions, such as aggressively baring their teeth or contentedly smacking their lips. They showed these movies to other monkeys, and used functional magnetic resonance imaging, a high-resolution brain scan, to see how their brains responded. The monkeys’ face patches, which appear as red and yellow spots in scans, show more activity when viewing moving faces than with other moving objects, such as toys.
“Our work reveals how the macaque face-processing system reunites two streams of visual information—face form and face motion—as it recreates the social reality of a face,” Winrich says. He studies face processing both to understand the phenomenon in its own right and as an entry point to exploring fundamental aspects of human nature, including the range of qualities we call intelligence.
Published in Current Biology, January 2015.
The Ravetch lab is on the trail of a universal, lifelong flu vaccine
Each year, between three and five million people around the world become seriously ill or die from seasonal flu outbreaks. Current vaccines typically last for one season only and are designed based on health experts’ estimates of which will be the main strains circulating in the coming year. When these predictions are inaccurate—and they often are because influenza viruses mutate quickly and new strains keep emerging—the result is a partially or entirely ineffective vaccine.
Generations of scientists have tried and failed to concoct a universal vaccine that would be effective against all strains of influenza. Now Jeffrey Ravetch, Theresa and Eugene M. Lang Professor and head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology, has conceived of a strategy that might bring us closer to making one. His lab’s innovation relies on spurring the immune system to generate more effective antibodies.
When we get the flu, the immune system makes a suite of different antibodies with varying degrees of potency against the virus. Vaccines, which traditionally are composed of dead or inactivated viruses, work by mimicking this process—they stimulate the immune system to generate antibodies so that when a real infection happens the body is better prepared to fight it.
Jeff’s team monitored antibody production in vaccinated volunteers, and noticed that the best responders were those whose antibodies carried a particular chemical modification, which ensures that only the most potent antibodies get amplified. When the researchers included such modified antibodies in the vaccine formulation, the vaccine granted protection against many flu strains—not only the one the vaccine was based on. “These results may represent a preliminary step toward a universal flu vaccine,” Jeff says, one that potentially could provide lifelong immunity to any strain of influenza.
Published in Cell, July 2015.
The Nussenzweig lab tests a new antibodybased HIV drug in patients
Like the flu virus, HIV has evolved sophisticated ways of challenging the body’s immune system. Rockefeller scientists in 2015 reported the first results from a clinical trial of a new treatment against the infection. Led by Michel Nussenzweig, Zanvil A. Cohn and Ralph M. Steinman Professor and head of the Laboratory of Molecular Immunology, the research has brought new optimism to the field of immunotherapy in demonstrating that the experimental therapy—an antibody called 3BNC117—can dramatically reduce the amount of virus present in a patient’s blood.
The new treatment is based on research into broadly neutralizing antibodies, powerful antiviral molecules produced by immune cells. Some people with HIV naturally start generating these antibodies after several years of infection. But, by that time, the virus has often mutated so that the antibodies no longer work against it. In the study, 3BNC117 was produced and given as a single injection to patients whose HIV had not had as long to prepare. The eight patients treated with the highest dosage showed up to a 300-fold decrease in the amount of virus in their blood.
This is the first time an HIV drug of this kind has been tested in humans, and the researchers believe it may be capable of enhancing a patient’s immune responses and potentially kill viruses hidden in infected cells that are out of reach for current antiretroviral drugs.
Published in Nature, April 2015.
The Chen lab takes a close look at bacteria’s interactions
Magnificent in its simplicity, a molecular pump that ferries proteins across a bacterium’s outer membrane has recently been under intense scrutiny in Rockefeller’s Laboratory of Membrane Biology and Biophysics, led by Jue Chen, William E. Ford Professor. Bacteria rely on efficient protein transport—they send molecules out into the world to communicate with one another, poison their enemies, or manipulate the host cells they infect.
In this image, the coils mark the outline of a molecular pump called PCAT. To determine its structure, the scientists first purified it from Clostridium thermocellum, a bacterial strain that thrives in hot temperatures, and coaxed it into forming a crystal. They then used a technique called x-ray diffraction analysis to determine the three-dimensional shape of the molecule with atomic resolution.
“The pump is composed of a single protein, a sort of all-in-one machine capable of recognizing its cargo, processing it, then burning chemical fuel to pump that cargo out of the cell,” says Jue. “Our new atomic-level structure explains for the first time the links between these three functions, and adds to our understanding of how cells send out proteins in order to interact with their environment.”
Published in Nature, July 2015.