The Berkeley Science Review: Articles

Funding the Future
The Howard Hughes Medical Institute contributes millions to Berkeley Research (view PDF)
by Meredith Carpenter

It's a scientist's dream: at a time when funding is scarce and many take the safest research route to guarantee results for that next grant application, you're given a million dollars a year and instructed "to take risks, to explore unproven avenues, to embrace the unknown—even if it means uncertainty or the chance of failure." Want that new $500,000 microscope? Buy it. Have an idea for an experiment that might take several years of troubleshooting? Hire a new postdoc and go for it. This scenario, while fantasy for most, has become reality for the 13 Howard Hughes Medical Institute (HHMI) Investigators at UC Berkeley.

From Spruce Goose to lab use
In 1953, the eccentric aviation magnate Howard Hughes founded a charitable research organization. He was the sole trustee of the organization and transferred all of his stock from the Hughes Aircraft Company into its coffers. As a result, the major aerospace and defense contractor effectively became a tax-exempt charity, albeit one whose goal was "to probe the genesis of life itself." The Internal Revenue Service, understandably dissatisfied with this arrangement, soon challenged the organization's non-profit status. So, in the late 1950s, the Howard Hughes Medical Institute began funding 47 medical investigators at nine different institutions.

As of 2008, the HHMI's endowment had grown to a whopping $17.5 billion that funds 354 investigators at 71 host institutions, as well as a myriad of grants that support teaching programs, international researchers, and research opportunities for predoctoral and premedical students. It is one of the largest philanthropic organizations in the United States, second only to the Bill and Melinda Gates Foundation. There are currently 13 HHMI Investigators at UC Berkeley, of whom five were appointed in 2008. In addition, in April 2009, Professor of Molecular and Cell Biology Robert Tjian was appointed the organization's new president, one of the most prestigious leadership positions in science.

The HHMI's motto is "people, not projects"—that is, it appoints scientists as "investigators" instead of awarding grants based on a specific research proposal, which is the method used by government agencies like the National Institutes of Health (NIH) and the National Science Foundation (NSF). "The main goal is to identify the best scientists doing the most original and creative work and give them enough resources for a long enough period of time to allow them to pursue their scientific curiosity," says Tjian.

HHMI Investigators are awarded a renewable, five-year appointment. They remain at their host institution, but they also become employees of the HHMI, which pays their entire salary and benefits and even compensates the host institution for their laboratory space. In addition, they receive about one million dollars in funding a year and administrative support for their labs. "We're in this incredibly privileged situation where we can give pretty substantial amounts of funding for pretty long periods of time," Tjian explains. "I've been a Hughes investigator for over 20 years—that's extraordinary generosity for any organization."

Investigator rising
Since the early 1990s, the HHMI has held periodic national competitions to search for new investigators. Prior to 2006, they would invite about 200 research institutions—universities and academic health centers—to nominate two to four researchers "in the ascending phase of their career" for each competition. Starting in 2006, however, the competitions have been "open," meaning researchers from 121 top institutions can apply directly, although institutions can still nominate researchers who do not nominate themselves. "I think it's a much more democratic way of doing it, because you don't have this middle layer of people making decisions about who should be nominated and who shouldn't," says Tjian. "I was very happy to see that happen."

Competitions usually take place every three years, but they are sometimes held more frequently, with each one focused on a particular research area or investigator career stage. A recently completed investigator competition, held in 2007, resulted in the appointment of 56 new investigators—including five from Cal. "I think it's fantastic that Berkeley got five new investigators. MIT is the only other university that got five, and everybody else got three or less, which is a real statement for Berkeley's quality," Tjian says. "Another thing I like about the Berkeley group is they're very diverse in their fields—they cover not just molecular biology, but also bioengineering and chemistry."

The 2007 competition specified that applicants be between years four and ten of tenure-track faculty appointments. In contrast, the recent 2009 competition focused on early career scientists who have been faculty for only two to six years. And unlike in previous competitions, applicants for the 2009 competition were not required to already be receiving one or more active national research grants. The goal, according to the competition announcement, was "to identify the nation's best biomedical scientists at a critical early stage of their faculty careers, and to provide them with flexible funding to develop scientific programs of exceptional merit." The award recipients, announced in late March, included Associate Professor of Molecular and Cell Biology Kristin Scott, who studies the biology of taste perception.

For all investigator competitions, applicants must submit a curriculum vitae, a summary of their research plans, and five publications reflecting their most important scientific contributions. The selection process takes about a year. "If you start at 1,000 and you need to choose 50, you can imagine it's a really rigorous review process," says Tjian. Once the list is narrowed to a few hundred, it is sent to the HHMI Scientific Review Board, which consists primarily of non-HHMI scientists. This group creates lists of the top applicants; however, the final decisions are made by the President and one or two of the Vice Presidents of Scientific Research.

Kicking it up a notch
For those lucky few who are selected, how does the money actually change their research? "The really big difference the Hughes can make is that if you have one or two NIH grants, and they're limited to $250,000 each, you're at half a million and you're pretty much tapped out," Tjian explains. "Well, our research might really need $1.5 to $2 million, if you run a really aggressive research operation. The Hughes was that lifeline that allowed me to buy instruments and get into a kind of science I couldn't do otherwise. It kicked me up a couple of notches, and I think most people's experiences are like that."

Tjian also emphasizes that the HHMI hopes the funding will not benefit the recipient lab alone. "It allows you to hire the right people, get the right kind of equipment, and then make the equipment available to your colleagues. The whole idea is that within any given department, only a small percentage are Hughes investigators, but we hope that the Hughes funds get used in a more equitable way." For example, several years ago Tjian used his HHMI funds to start a mass spectrometry facility, which consists of a set of instruments used to determine the exact mass or sequence of amino acids in a protein (among other tasks); this facility is now open to the university community.

In his new role as HHMI President, Tjian is contemplating his goals for the organization, especially in light of the recent economic downturn. "A lot of it is trying to figure out where we can make the most difference—what fields and which scientists should we be supporting that we're not supporting today, and how much should we be doing outside of the borders of the United States in the international scene," he explains. "There's no doubt that there's tremendous talent all over the world that the Hughes has not supported, and how much should we be viewed as an international organization rather than a national one? That's something I'm going to be thinking about hard."

Clearly, the HHMI has been a major force in biomedical science, particularly in the last few decades. The idea of awarding grants to people instead of specific projects is still unique in the realm of research funding. Regardless, the strategy seems to be working—12 of the current HHMI investigators are Nobel laureates. "We don't know where the discoveries are going to happen," says Tjian. "So you just have to find people who are really passionate about what they're doing. They don't really see it as work—they see it as their life, and all they need are the resources."

Meredith Carpenter is a graduate student in molecular and cell biology.

To Christopher Chang, copper isn't just the stuff pennies are made of. In fact, trace amounts of copper, as well as other metals like iron and zinc, are required for proper functioning of the human nervous system, though the reasons for this are still poorly understood. "It's interesting to us because brain tissue actually contains more of these metals than any other part of your body," says Chang. The Chang lab uses chemistry to study neurobiology, with the goal of better understanding how the brain works on the molecular level.

To study the role of copper in the brain, the lab is working on ways to visualize the metal in living cells, particularly under conditions of neural activity, neural stem cell development, injury, and disease. "We're approaching it from a chemical point of view, where we develop a fluorescent probe that will selectively detect copper, and use that new tool to do experiments that were previously inaccessible due to experimental limitations," says Dylan Domaille, a graduate student in the Chang lab. "It's been observed that copper is released during synaptic activity, and recent evidence suggests some sort of neuroprotective effect," he explains. "That's probably one of the predominant hypotheses now in terms of what's happening in the brain, but we want to know what's happening on the molecular level at a higher resolution."

One complicating factor is that copper can actually exist in two forms depending on its number of electrons—while it mainly takes the form of copper(II) in nature and outside the cell, it is changed into copper(I) at the cell membrane, and this is the predominant form inside the cell. "We've got a few copper(I) detectors, but copper(II) is more difficult," Domaille explains. "It's easy to make a molecule that fluoresces and then turns off when it binds copper(II). But practically, that's difficult to use because you're looking for a dark spot in a bright background, and you'd rather look for a bright spot on a dark background. We're still working on that."

Domaille plans to use these sensors to study the distribution of copper in cells in culture, and eventually even in live animals, to understand more about its function, storage, and distribution in the brain. "We're looking at what I'd call waves or packets of metal pools moving around," says Chang, "things you wouldn't normally think that copper would do, so it must have its own channels, transporters, and targets." Misregulation of copper pools in the brain has also been linked to diseases such as Alzheimer's and Lou Gehrig's, so work in the lab may aid in the understanding of those disorders.

The Chang lab is also looking into the role of reactive oxygen species, and particularly hydrogen peroxide, in normal brain function. Reactive oxygen species are molecules that can produce free radicals, which can damage DNA and other cellular components. However, "we've been interested in this idea that in certain places, generated at certain times and at certain levels, hydrogen peroxide has a role in neurotransmission and stem cell growth and development in the brain," says Chang.
To study the role of hydrogen peroxide, members of the lab are taking a similar approach to how they study copper—designing fluorescent sensors that can report on the presence of the molecule. "We have a small molecule that fluoresces in the presence of hydrogen peroxide, so it's a way of asking if there's any hydrogen peroxide in what you're looking at," explains Evan Miller, another graduate student in the lab. "We're particularly interested in living systems because hydrogen peroxide is part of how cells talk to each other." In fact, Miller has already used one of these molecules to map molecular pathways of hydrogen peroxide production in living brain cells.

Ultimately, these studies have implications for understanding aging and neurodegeneration, in addition to illuminating how the brain works on a basic level. To Chang, the existence of signaling pathways unique to the brain is not surprising. "You have something that's really unique in terms of controlling senses like sight, hearing, thought, memory, and motor skills," he says. "So because it's so complex, it makes sense that it would need different chemistry than you would find anywhere else."

Abby Dernburg
Associate Professor of Molecular and Cell Biology and Faculty Scientist in LBL's Life Sciences Division
Abby Dernburg studies a type of cell division called meiosis, which produces gametes (eggs and sperm) in sexually reproducing organisms. Gametes contain half the genetic material of the parent—in humans, one set of 23 chromosomes. That way, when two gametes are combined at fertilization, the complete complement of genetic material (in humans, two sets of 23 chromosomes, one from each parent) is restored, resulting in new genetic diversity. A key step in meiosis is the exquisitely controlled pairing of the two sets of chromosomes, each with its so-called "homolog." This step ensures that when the chromosomes are distributed to the gametes, each gamete gets one copy of every chromosome. Errors in this process, which result in missing or extra chromosomes in the offspring, can cause problems ranging from Down syndrome to miscarriage.

Using the nematode worm Caenorhabditis elegans as a model organism, members of the lab study the mechanisms underlying the pairing of homologous chromosomes. Worms are especially useful for these studies because they are transparent, giving researchers a convenient window for watching the stages of meiosis in the live organism. The Dernburg lab has already discovered that, in worms, specific sequences of DNA on each chromosome are required for the pairing of homologs during meiosis (see BSR Spring 2007). Without these sequences, the chromosomes are unable to find each other and are segregated incorrectly. In addition, Dernburg has identified proteins that bind to the sequences and help bring the two homologs together. Now, members of the lab are investigating the steps of the pas de deux that culminates in the physical pairing of each set of chromosomes. In addition, they are studying how the cell checks whether chromosomes have paired before allowing meiosis to continue.

Jay Groves
Associate Professor of Chemistry and Faculty Scientist in LBL's Physical Biosciences Division
Jay Groves's research defies placement in a single department. A biophysicist by training, he is a professor in the chemistry department who studies cell membranes. Groves is interested in how large-scale collective interactions, such as the association of individual lipid molecules and proteins that make up the cell membrane, affect the overall properties of the system without changing its chemical makeup. For example, signaling across the cell membrane (i.e., relaying a signal originating from outside of the cell to the inside) occurs through specific proteins embedded in the membrane. However, in some cases, it is not simply the action of a single signaling protein that matters, but also the clustering of those proteins into patterns.

One example of this phenomenon, and a focus of research in the Groves lab, is the T cell receptor (see BSR Spring 2006). When a cell is infected by, for example, a virus, it takes pieces of proteins from that virus and displays them on receptors on its surface—a signal that helps to draw the attention of immune cells. One of these immune cells is the T cell, which uses its T cell receptor to bind to the receptors on the infected target cell. During this interaction, the bound receptors cluster into a bull's-eye configuration, and the T cell is activated to kill infected cells or help mobilize other immune system cells.

It would be difficult to study this interaction and clustering using traditional molecular biology methods, so Groves takes a very different approach. He uses live T cells, but the interacting cell is replaced by an artificial cell membrane, complete with receptor proteins, on a nanostructured surface that allows Groves to guide the movements of the interacting proteins. He then constrains the movement of the bound receptors in certain ways, creating "spatial mutations" in otherwise chemically equivalent cells, and watches how these changes affect T cell activation. Using these tools, Groves and his former student Kaspar Mossman found that the radial positioning of the receptors is required for proper signaling activity. Currently, in addition to continuing his studies of the T cell receptor, Groves is using his hybrid cell system to investigate mechanisms of cell signaling in cancer.

Yang Dan
Professor of Molecular and Cell Biology
Few UC Berkeley professors can claim to have a YouTube video of their research findings. But Yang Dan's video is understandably popular—it shows the viewer what it's like to see through the eyes of a cat. Dan studies the neurobiology of vision, specifically how visual information is encoded and processed in the brain and how neural circuits are shaped by visual experience. "We think about coding—how do you take visual input to turn it into electrical signal?" explains Dan. "And then you can also go backwards and ask how you decode information. So if you observe the neural response, can you guess what stimuli were out there?" She studies these questions on multiple levels, using mathematical models and measurements of neural activity in both individual neurons and live brains to develop models for different aspects of vision.

Dan made the video now on YouTube by recording the electrical activity of 177 neurons in the cat's thalamus, a region of the brain that receives signals from the eyes. With knowledge of how these neurons responded to light and dark, she and her collaborators then used sophisticated computer programs to translate the cells' firing into a two-dimensional recapitulation of the animal's field of vision. Though fuzzy (due to the small number of neurons sampled and the bypassing of any processing by other areas of the brain), a human face crossing the field of vision is clearly discernible in the resulting movie.

This study was actually performed about 10 years ago, but the lab continues to study similar problems. "At one level we're interested in microcircuitry—at the single neuron level, who connects to who," says Dan. "But the other half is a very new direction that has to do with the global brain state." She is interested in how the brain switches from one brain state, such as sleep or attentiveness, to another. Neuroscientists already know that in the brain, individual neurons don't fire independently; instead, they tend to fire in a coordinated way with other neurons in their circuit, and it is the overall pattern of these oscillations that determines the brain state. "We know that in the brain stem and the basal forebrain and hypothalamus, there are all these neuromodulatory circuits controlling the brain states," Dan explains. The patterns of activity (often measured by electroencephalogram, or EEG) in different areas of the brain have been correlated with different brain states. "But that's only a preliminary understanding based on the anatomy. We want to know the exact mechanism of how these neuromodulatory circuits interact and control the brain states." To answer these questions, the lab is using a combination of multi-electrode recording and imaging experiments in live animals. Although this research is relatively new in the lab, Dan says the HHMI funding will allow her to move forward faster. "When you're struggling for funding, and write grants one round after another, you're much more conservative—you don't want to branch out too fast," she says. "But with this, we can be bolder in terms of taking more risks. For me, it's about how fast you can move."

A major question in evolutionary biology today is how small changes, or mutations, in the DNA sequence of an organism can translate to larger changes that eventually result in new species. Most mutations are either neutral (have no effect on the organism either way) or harmful. While these do play a role in evolution, researchers have recently turned to changes in gene regulation—controlling when and where a certain gene is expressed, or activated to produce the protein it codes for—as a previously underappreciated source of evolutionary change. This idea is especially attractive because differences in the timing or distribution of expression of a gene, especially during development, could have major effects without interfering with the resulting protein itself.

Sequences of DNA flanking a gene usually contain the regulatory information for that gene, including sites for proteins to bind that enhance or reduce expression of that gene. The Eisen lab studies these regulatory sites in various species of fruit fly, one of the classic model organisms for genetics, using both computational and experimental techniques. The complete genome sequences of 12 different fruit fly species have been determined, an effort spearheaded by Eisen, allowing members of the lab to find and compare the regulatory regions of the same genes between species. In some cases, differences in these regions have been found to be directly responsible for physical differences. However, Eisen is especially interested in the regulatory regions that have retained the same function despite numerous sequence changes. As they explained in a 2008 paper in the journal PLoS Genetics, "We believe that identifying divergent [regulatory sequences] that drive similar patterns of expression, and distilling the common principles that unite them, will allow us to decipher the molecular logic of gene regulation." Ultimately, Eisen hopes that his research on fly gene regulation will shed light on not just evolution, but also on the sources of variation in the human genome.

Clearly, the HHMI has been a major force in biomedical science, particularly in the last few decades. The idea of awarding grants to people instead of specific projects is still unique in the realm of research funding. Regardless, the strategy seems to be working—12 of the current HHMI investigators are Nobel laureates. "We don't know where the discoveries are going to happen," says Tjian. "So you just have to find people who are really passionate about what they're doing. They don't really see it as work—they see it as their life, and all they need are the resources."

Meredith Carpenter is a graduate student in molecular and cell biology.

Down On the Farm
A new crop of scientists is being cultivated at Janelia Farm, the HHMI's "freestanding laboratory" located in Ashburn, Virginia. The farm-named for Jane and Cornelia Pickens, whose parents originally owned the property-is modeled after AT&T's Bell Labs, which was famous for its basic research programs that produced such innovations as radio astronomy, the transistor, the UNIX operating system, and UC Berkeley Professor/Secretary of Energy Steven Chu's work on laser cooling that earned him the Nobel Prize in Physics in 1997.

According to the HHMI's website, the objective of Janelia Farm is to allow scientists to "pursue fundamental problems in basic biomedical research that are difficult to approach in academia or industry because they require expertise from disparate areas, they are too long-term for standard funding mechanisms, or they are outside the current priorities of other funding agencies." However, rather than hosting researchers working on many unrelated topics, the Janelia Farm senior staff chose to concentrate on two main areas: the identification of general principles that govern how information is processed by neuronal circuits, and the development of imaging technologies and computational methods for image analysis.

The labs at the research center are fully funded by the HHMI and are supervised by group leaders, who, because they are not required to perform administrative duties or submit grant applications, are expected to play an active role in research in the lab. Postdoctoral fellows and graduate students can also undertake research at Janelia Farm, though the latter must first attend either the University of Chicago or Cambridge University for a year before completing their PhDs at the Farm. "The junior faculty at Janelia Farm have groups of three people only, and the senior faculty have groups of eight, so they're very small," says Robert Tjian, HHMI President. "The idea is that you have no other distractions-no teaching, no writing grants. Just do your research and train your people properly."

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