Meet the 2013 HHMI Investigators
Michael Rape, PhD
Michael Rape’s love of science began in the basement of his parent’s house, where he used to conduct rudimentary biochemistry experiments. Today, he uses far more sophisticated methods to understand a complex process critical to nearly all organisms: ubiquitylation. The term describes the attachment of a regulatory protein called ubiquitin—named for its ubiquity—onto other proteins. Ubiquitin tags communicate a wealth of information to the cell about what a protein’s fate should be. Rape’s work has uncovered many details about how ubiquitin gets attached to its target proteins and helped elucidate the crucial roles ubiquitin tags play in cell division and cell fate.
In human cells, getting ubiquitin on and off the right proteins at the right times involves hundreds of enzymes acting on thousands of targets. When the labeling system goes awry, diseases like cancer and Parkinson’s can result. The loss of activity of one such ubiquitin-attaching enzyme is enough to cause breast and ovarian cancers, for example. If scientists can figure out how to manipulate ubiquitylation, they might be able to develop therapies for many of these diseases. Rape developed a screening method to identify enzymes involved in ubiquitylation and in the removal of ubiquitin. He plans to use his setup to identify targets for potential drugs that activate or inhibit these enzymes.
Peter W. Reddien, PhD
Scientists working to solve the mysteries of regeneration often look to starfish or salamanders to gain insight, but Peter Reddien is committed to a less photogenic organism: the humble planarian. These tiny flatworms have amazing regenerative powers. Just a sliver of tissue can give rise to a whole new worm. Reddien's work is revealing the secrets of planarians’ success.
Reddien's group found that planarians are equipped with stem cells with the capacity to become any type of cell in the worm's body, and that these cells give rise to new tissue during regeneration. Just one such cell is enough to regenerate an entire worm. His lab has also discovered how wounded planarians manage to regrow body parts in the right places. When a planarian is wounded, a signaling pathway called Wnt instructs the regenerating cells to grow a tail. When the worm needs a head, a gene called notum kicks in, dampening the Wnt pathway. Silencing notum or genes in the Wnt pathway generates worms with multiple heads or tails were generated.
Using the molecular tools he has developed for identifying genes controlling regeneration, Reddien is continuing to investigate the sources of the worm's extraordinary regenerative powers. The insight he gains may lead to new understanding of the genes and pathways that control tissue repair and stem cell biology in humans. It will also help reveal what limits the human body's ability to regenerate lost or injured tissue.
Aviv Regev, PhD
Molecular networks are the information-processing devices of cells and organisms, transforming extra- and intracellular signals into coherent cellular responses. Aviv Regev uses computational and experimental approaches to investigate how the molecular networks that regulate gene activity rewire themselves in response to genetic and environmental changes—in the short term and over millennia. She has developed techniques to analyze how genes and regulatory networks in yeast have changed over the course of 300 million years and how circuits change as immune cells respond to pathogens or differentiate. Her algorithms are used in labs around the world to analyze gene expression data and other information. Not content to work solely in silico, her lab is also using cutting-edge experimental techniques, such as inserting genes into cells with silicon nanowires, to chart the molecular circuitry of T cells.
The computational wizardry of Regev and her colleagues has enabled them to identify circuits and regulatory pathways that they can test and manipulate at the lab bench. Data from the experiments in the lab can then be used to improve the computational models. Working with dendritic cells (antigen-presenting cells of the immune system), blood cells, and yeast, Regev has identified dozens of regulators. Her group has confirmed some of these molecular regulators by knocking out the corresponding genes in mice. She and her colleagues are beginning to define which regulatory circuits have changed and which have stayed the same over millions of years of evolution.
David Reich, PhD
Ever since modern humans evolved, groups of them have been on the move, mixing with other groups they encountered. Geneticist David Reich is a world expert at finding evidence of mixing between human populations. He has shown that this mingling of genes is a profound part of human evolutionary history.
His studies have also exposed some surprising dalliances in our species’ past. In 2010, Reich co-led a team that was the first to sequence and analyze the genome of Neandertals. The data showed that the Neandertals weren’t just our cousins—they were occasionally our mates, the source of about 2 percent of the DNA in the genomes of present-day non-Africans. After isolating DNA from a preserved finger bone, Reich and coworkers found that a mysterious group called the Denisovans, who dwelled in Siberia around 50,000 years ago, also left their genetic mark in the DNA of some present-day people. His team has also applied its methods to medical questions. They uncovered seven DNA alterations that might explain why prostate cancer is about twice as common in African American men as in men of European ancestry.
This year, Reich and colleagues opened a state-of-the-art laboratory for analyzing ancient DNA, which requires special precautions to prevent contamination with modern DNA. He plans to use the facility to probe European history and Native American history and to dig deeper into the origins of India’s inhabitants, who are descended from people who lived in northern India and a distinct group his team has identified from the southern part of the country.
|Russell E. Vance, PhD
University of California, Berkeley
The human body is rife with microbes. They cover our skin, colonize our digestive tracts, and coat our teeth. Not all cause harm. In fact, some of these hitchhikers are helpful. To protect the body from disease, the immune system must decide which invaders should be destroyed and which should be ignored. But friendly microbes often look a lot like foes. How does the immune system distinguish between the two?
Working at the interface of immunology and microbiology, Russell Vance has discovered that the location of the microbe plays a key role in the immune system's decision. Many pathogens access the interior of host cells to wreak havoc, while harmless bacteria tend to be relegated to the spaces between cells. To detect invaders, the immune system employs sensors called inflammasomes. By confining these sensors inside cells, the immune system avoids setting off false alarms.
Vance recently discovered that immune cells called macrophages contain an inflammasome sensor that can detect flagellin, the protein that makes up the whip-like appendages that many bacteria use to motor around. When this sensor signals the presence of flagellin-containing invaders, the macrophages self-destruct to prevent the infection from spreading. But that's not the whole story. In the coming years, Vance will continue to explore the mechanisms that underlie the immune system's ability to destroy harmful bacteria and disregard the harmless ones. Those mechanisms could be the key to understanding why certain pathogens, like the bacterium that causes tuberculosis, can be so deadly.
Johannes C. Walter, PhD
Imagine you are a scribe tasked with copying every book in the library of Alexandria. You would probably recruit thousands of fellow scribes and ask each one to work on one chapter. But how would you insure that every book is copied and no mistakes are made? Living systems face exactly that challenge. Before dividing, cells must copy, or replicate, six billion units of genetic information that are strung together in the DNA double helix. Avoiding mistakes during DNA replication is critical to prevent cell death and diseases such as cancer.
To understand the molecular events underlying DNA replication, Johannes Walter’s laboratory takes a unique approach in which purified DNA molecules are added to extracts of frog eggs, where they undergo replication outside the confines of a cell. Using this highly tractable experimental system, Walter has uncovered how an enzyme called the MCM2-7 helicase separates the two strands of DNA in preparation for genome duplication. Another question he has addressed is how cells avoid making more than one copy of their DNA. He showed that the process of genome duplication triggers the destruction of a key initiator of DNA replication, thus preventing a second round of replication.
His team has also unraveled how cells repair chemical damage to DNA, which causes mutations and disease if left unrepaired. One form of damage, called an interstrand cross-link, is particularly hazardous because it glues the two strands of DNA together, and thereby blocks the process of DNA replication. Walter and his colleagues determined the detailed steps underlying cross-link repair and how this mechanism fails in Fanconi anemia, a human genetic disease. More recently, Walter's lab has turned its attention to understanding how defects in the DNA repair proteins BRCA1 and BRCA2 cause hereditary breast cancer.
Rachel I. Wilson, PhD
After a few molecules waft into your nostrils, you know whether you’re standing next to a fresh-baked apple pie or a pile of rotting apples. Rachel Wilson aspires to learn how the brain translates sensory information such as these aromas into impulses it can interpret and act on.
In the lab, Wilson and her team work to understand sensory processing using fruit flies as their model organism. Her toolbox for studying fly perception is well stocked. She devised a delicate technique for recording the electrical activity of individual neurons in a fruit fly’s tiny brain, which consists of about 100,000 neurons. Not only can she and her colleagues eavesdrop on specific neurons, they can also pinpoint a neuron or group of neurons, delete a cell from a neural circuit to gauge its function, and tamper with genes to assay the roles of particular proteins.
Her team is now probing the function of a brain structure in fruit flies called the antennal lobe, an olfactory relay station that is analogous to the olfactory bulb in mammals. Wilson’s lab has discovered that the antennal lobe reformats or “transforms” signals to allow the brain to better extract information about odors in the environment. Some of the steps in this transformation are similar to what occurs in the visual system, suggesting that a core set of fundamental principles are shared by different sensory systems. Wilson’s research group is continuing to branch out from olfaction to study the rules of information processing in the auditory system of fruit flies. This change in direction will permit Wilson to compare and contrast which rules and algorithms are used by two very different sensory systems.
Yukiko Yamashita, PhD
Stifled by conflicting expectations for women scientists in Japan, Yukiko Yamashita found a welcoming home in the United States. As a postdoctoral fellow at Stanford University, she learned “laid-back confidence,” she recalls, and began a period of creative discovery that led her to the University of Michigan, where she is now transforming the study of stem cells.
A central question that has fascinated Yamashita is now her main research focus: When stem cells divide, what determines which daughter cell will remain a stem cell and which will differentiate into sperm or other tissue types? Maintaining a balance between stem and differentiating cell populations is critical because an excess of stem cells can lead to tumorigenesis, whereas too many differentiated cells can deplete the stem cell pool, reducing tissue regenerative capacity.
Examining cells in the fruit fly testis, Yamashita discovered the choice of stem cell fate was regulated by cellular asymmetries. When a stem cell divides, the daughter cell that retains the original “mother” copy of a cell structure called the centrosome is the one that remains a stem cell.
Yamashita’s lab has also uncovered a key checkpoint in asymmetric stem cell division–showing that the position of the centrosome determines whether cell division will continue. Yamashita looks forward to designing and carrying out experiments that are curiosity driven and that may yield new examples of unappreciated asymmetries during stem cell division and unexpected links between biological processes.