Summary

Meet the new 2015 HHMI Investigators.

Sue Biggins Sue Biggins, PhD 
Fred Hutchinson Cancer Research Center

Sue Biggins studies the machinery that dividing cells use to ensure their daughter cells receive the correct allotment of chromosomes. Getting it right is crucial: cells with too many or too few chromosomes can cause cancer, birth defects, or miscarriage. Much of Biggins's work focuses on kinetochores, structures that connect chromosomes to the long, thin microtubules that tug them to the appropriate ends of a dividing cell. She has shed light on how cells make sure that these structures – which comprise hundreds of proteins and must be reassembled every time a cell divides – are positioned in the right spot on chromosomes. She also showed how a protein called Aurora B forces cells to stop and fix things if microtubules are incorrectly attached to a kinetochore, before cell division can proceed. In 2010, Biggins purified kinetochores from yeast cells and reconstituted their attachments to microtubules for the first time. Suddenly, a variety of questions became accessible. Her first success with the system was the surprising finding that tension helps stabilize microtubules' attachment to kinetochore. Electron microscopy images of the purified kinetochores revealed the structures' shape for the first time. The images showed that each kinetochore has multiple microtubule attachment sites and a ring that encircles the microtubule, which helps explain how they establish and maintain their grip.

Squire Booker

Squire J. Booker, PhD
Pennsylvania State University, University Park

Squire Booker is bringing to light how enzymes accelerate some of the most reluctant chemical transformations inside cells. What he is learning has opened up new opportunities to improve human health. Booker is particularly interested in how enzymes use cofactors, such as metal clusters or simple metal ions, to increase their catalytic capabilities. His lab team is well known for its work with so-called radical S-adenosylmethionine enzymes – proteins that use iron-sulfur clusters to generate highly reactive molecules that, in turn, initiate a mind-boggling array of chemical reactions. Booker wants to elucidate the mechanism behind some of those reactions, including many involved in the synthesis of natural products with antibacterial or anticancer properties. His team has also unraveled details of the enzyme-catalyzed reaction that attaches a chemical group called a methyl to bacterial RNA, a modification that makes the microbes resistant to several classes of antibiotics. Booker's team is now working to generate inhibitors of this reaction.

Olga Boudker

Olga Boudker, PhD
Cornell University

As soon as a neuron in the brain communicates with a neighboring neuron by releasing a burst of the neurotransmitter glutamate, those molecules must be cleared away rapidly to shut off the signal and ready cells for the next communication. Glutamate transporters handle this task, bringing the neurotransmitter back inside cells so effectively that there can be a million times more glutamate inside the cell than outside. Olga Boudker's work is revealing how this happens. Studying a closely related transporter from bacteria, Boudker captured a detailed structure of the protein in its inward-facing state, in which its glutamate-binding region would be exposed to the interior of a cell. Boudker studied the structure and compared it to the protein's outward-facing state, then proposed that the glutamate transporter operates like an elevator, with a large portion of the protein gliding back and forth inside a membrane-embedded scaffold as it shuttles its cargo. The model was entirely different from how other transporters were known to function. But within a few years, real-time single-molecule imaging spearheaded by Boudker's lab had confirmed that model. Boudker's ongoing work investigating the glutamate transporter and related molecules could steer drug developers toward new strategies for treating diseases.

Yifan Cheng

Yifan Cheng, PhD
University of California, San Francisco

Cryo-electron microscopy (cryo-EM), in which biological samples are flash frozen and then visualized with an electron microscope, offers scientists a nearly atomic-level glimpse of proteins in their native state. For a long time, the technique's advantages were offset by its limited resolution compared to x-ray crystallography, a more traditional method of determining protein structures. But Yifan Cheng's innovations have amplified cryo-EM's potential beyond what was once thought possible, enabling his lab and others to discern detailed structural information for proteins that are difficult to study with x-ray crystallography. In 2013, Cheng's lab developed an algorithm to correct for motion-induced blurring in images, allowing users to take full advantage of sensitive new electron detectors and obtain high-resolution information from their samples. With this and other technical advances, Cheng is revealing the structures of proteins so small and asymmetrical that many thought they could not be studied using cryo-EM. His structures of TRPV1, an ion channel embedded in the membranes of nerve cells that detects temperature changes and the pungent chile-pepper component capsaicin, show three different conformations of the protein with atomic-level detail. As the first such structures for any transient receptor potential (TRP) channel, they provide a blueprint for understanding this large, diverse family of proteins.

Job Dekker

Job Dekker, PhD
University of Massachusetts Medical School

Job Dekker has added new dimension to how scientists think about genomes. As a postdoctoral researcher, he developed a method to determine the folded shape of a chromosome with unprecedented resolution. He later extended the technology, which he calls chromosome conformation capture (3C), to enable genome-wide analysis, and to construct the first three-dimensional map of the human genome. That map made clear that human chromosomes fold into a series of chromatin domains that play roles in regulating gene expression. It also revealed genome neighborhoods that compartmentalize the active regions of chromosomes, away from inactive domains. Dekker and scientists around the world have used 3C to find physical connections between regions of the genome that, when viewed as a linear DNA sequence, appear distant from one another, thus explaining how genes can be influenced by seemingly faraway regulatory elements. He has also used his methods to show how the genome's three-dimensional organization differs when cells are preparing to divide compared to the period between cell divisions. In that state the chromosomes fold as arrays of chromatin loops. Since chromosomes must transition between these two fundamental states, Dekker is now investigating how cells fold, unfold, and refold their genomes under different circumstances.

Xinzhong Dong

Xinzhong Dong, PhD
Johns Hopkins University

Xinzhong Dong knew the family of proteins he discovered as a postdoctoral researcher was diverse. But he couldn't have known that, by continuing to study those proteins in the ensuing years, he would revolutionize the field of itch research by revealing how the brain discriminates itch from pain, and by uncovering why certain drugs cause allergy-like side effects despite not triggering a true allergic reaction. The proteins Dong studies are cellular receptors called Mrgprs. Several members of the Mrgpr family are found only in sensory neurons, and Dong showed that they function as itch receptors. His team has shown that itch-sensitive nerve cells are distinct from pain-sensing neurons. Dong's team recently discovered that another Mrgpr is produced exclusively on mast cells – immune system first responders that recruit other immune cells to the site of an injury. This receptor is sensitive to a variety of compounds that trigger the mast cells' call to arms, the researchers found, including components of animal venoms, therapeutic drugs, and inflammation-triggering peptides. Pseudo-allergic drug responses, which are common for a variety of drugs and can range from local inflammation to life-threatening anaphylaxis, are eliminated in mice whose mast cells lack Mrgpr receptors.

Loren Frank

Loren M. Frank, PhD
University of California, San Francisco

Loren Frank wants to understand how the brain forms memories and how those memories help guide decisions. His lab team has discovered distinct patterns of neural activity in the brain's hippocampus in response to new experiences and shown that neurons can repeat that firing pattern within a burst of neural activity, after an event has occurred. That burst of activity appears to replay a memory of the event and may help stabilize the memory for more permanent storage. Frank's team showed that this replay happens in awake animals, not just during sleep, as previously thought. His lab also demonstrated a link between recall of these memories and decision making. The team's work in rats suggests that the hippocampus broadcasts information about future options to the rest of the brain in the form of replayed memories. The more intensely that relevant memories are reactivated, the more likely the animals are to correctly navigate a maze they've previously explored. Now, Frank's group is developing new research tools to measure and manipulate brain activity across entire brain regions, to better understand how such information is processed.

Levi Garraway

Levi A. Garraway, MD, PhD
Dana-Farber Cancer Institute

Levi Garraway conducts detailed studies to reveal how genetic and molecular alterations that lurk inside tumor cells cause cancers to grow and spread – and how this knowledge might inform new therapeutic avenues. His team's studies of melanoma and prostate cancers have turned up entirely new classes of cancer-causing genes. Garraway's research group was also the first to identify prevalent cancer-promoting mutations in parts of the genome that do not encode proteins. That led to the discovery that more than 70 percent of melanomas harbor mutations in a stretch of regulatory DNA that switches on production of telomerase, an enzyme that helps determine cells' longevity. Garraway is also intent on learning how tumors become resistant to cancer drugs. He and his colleagues have used systematic genetic screens to identify the ways cells are most likely to become resistant to targeted therapies. These findings are informing the design of clinical trials to evaluate combination therapies for melanoma and other cancers. Garraway's lab is also helping to propel the nascent field of precision medicine. His team has adapted genomic technologies to survey patients' tumors for hundreds of cancer gene alterations, creating tumor profiles that can be used to identify the best candidates for clinical trials and, in the future, to tailor treatments to individual patients.

Britt Glaunsinger

Britt A. Glaunsinger, PhD
University of California, Berkeley

Britt Glaunsinger says we can learn a lot about ourselves by studying viruses that have evolved to infiltrate our cells. With limited genetic resources of their own, viruses are notorious for hijacking cellular machinery for their own benefit. Glaunsinger searches for functions of mammalian cells that are exploited by viruses, then investigates how those functions aid the virus, as well as their normal roles in cells. She has focused on uncovering how viruses use or target RNA to manipulate gene expression. As a postdoctoral researcher, she showed that Kaposi's sarcoma-associated herpesvirus (KSHV), the leading cause of cancer in patients with untreated AIDS, shuts off gene expression in infected cells by chopping up messenger RNA. In her own lab, Glaunsinger has continued exploring the consequences of KSHV's RNA-degrading enzyme SOX. Her studies have shed light on how cells respond to dramatic changes in the abundance of messenger RNA, both in the face of infection and in other situations. More recently, Glaunsinger has used systems-level technologies to map virus-host interactions on a global scale, revealing new features of gene regulation to be explored.

Reuben Harris

Reuben S. Harris, PhD
University of Minnesota, Twin Cities

Mutations can be beneficial or detrimental. Reuben Harris studies the physiological and pathological functions of a family of DNA-mutating enzymes. His work is illuminating the roles that these DNA-mutating enzymes play in boosting the effectiveness of immune responses, as well as spurring the growth of cancer cells. As a postdoctoral researcher, Harris discovered that an enzyme in immune cells helps produce the vast repertoire of antibodies by editing DNA in a specific way. The enzyme, AID, converts cytosines to uracils, creating an obvious error that cells attempt to repair, introducing mutations along the way. Harris also showed that several related enzymes alter DNA in the same way. As an independent investigator, he demonstrated that several of these enzymes, including APOBEC3F and APOBEC3G, restrict the growth of HIV by inducing mutations in viral DNA. In further studies of these and related enzymes, Harris detailed how HIV-1 defends itself by degrading APOBEC3 proteins. He recently determined that another family member, APOBEC3B, is a major source of genomic mutations in breast cancer, and that high levels of APOBEC3B correlate with poorer outcomes for patients. Follow-up studies from Harris and others have implicated these editing enzymes in driving mutation in many tumor types.

Michael Laub

Michael T. Laub, PhD
Massachusetts Institute of Technology

Michael Laub studies the design principles of biology's information-processing systems. His research team is solving mysteries about how bacteria can detect and respond to a bewildering array of internal and environmental conditions, integrating information from hundreds of signaling pathways, all while managing to avoid getting those signals crossed. Much of his team's work focuses on two-component signaling systems. Most bacteria have dozens or even hundreds of these systems, each with a sensor protein that monitors conditions outside the cell and a partner protein that controls how the cell responds to environmental changes. Rather than studying these two-component signaling pathways individually, Laub undertook a major effort to study all of the two-component systems present in one bacterium simultaneously; the findings offered a new view of the molecular basis for pathway specificity, how cells coordinate multiple pathways, and how new pathways evolve. His group will take a similar approach as they explore how toxin-antitoxin systems found throughout the bacterial kingdom regulate bacterial growth. Some species produce dozens of these systems, in which toxins are held inactive until a signal or stressor triggers degradation of the antitoxin, freeing the toxin to suppress cell growth while stressful conditions persist.

Hening Lin

Hening Lin, PhD
Cornell University

Genome sequencing has provided scientists with a wealth of information. But to really understand the biology, Hening Lin believes the next two important challenges are to discover the biochemical function of all proteins and to understand the regulatory roles of protein modifications. He aims to address these challenges by studying enzymes that regulate protein modifications and have unknown biochemical functions. One class of such enzymes, the sirtuins, is supposed to catalyze the removal of acetyl groups from proteins. One problem that caught Lin's attention was that only three of the seven known human sirtuins actually remove acetyl groups efficiently. By studying one of the "weaker sirtuins," Sirt5, Lin discovered that the enzyme is better suited to work with malonyl and succinyl groups that are bulkier than acetyl groups. He further demonstrated that this is a natural function of the enzyme inside cells. His work suggests that the addition and removal of malonyl and succinyl groups – previously unrecognized forms of protein modification – are likely to be important in regulating protein function. Lin later discovered that another family member, Sirt6, removes a different chemical tag from proteins and showed that this activity promotes cells' secretion of tumor necrosis factor, a signaling molecule involved in inflammation. Lin is still learning about sirtuins, but he's also investigating other enzymes of unknown function. Each one, he says, is an opportunity to understand more about physiology and disease.

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For More Information

Jim Keeley 301.215.8858 keeleyj@hhmi.org