Center Takes Aim at Infectious Diseases

by Kathleen M. Wong

For much of the world, death comes couched in an everyday event: a cough, an insect bite, lovemaking with an unfaithful partner. From these ordinary incidents, millions of people every year contract HIV, tuberculosis, and malaria. These "big three" killers, plus a dozen other neglected diseases such as river blindness and dengue fever, place a terrible medical and economic burden upon the people of Latin America, sub-Saharan Africa and Southeast Asia.

Yet vaccines and treatments for many of these diseases do not exist. Bringing new drugs to market is extremely expensive, and developing nations cannot afford to buy costly medicines. Uncertain about recouping their development costs, big pharmaceutical companies have turned their research efforts elsewhere.

UC Berkeley is stepping into the breach with the Center for Emerging and Neglected Diseases (CEND). Launched this May, the Center aims to overcome the hurdles between innovative ideas and patient treatments. It will act as an international hub for academic laboratories, commercial biotechnology companies and clinical researchers to bring promising treatments to patients.

"To me, the role of the university here is absolutely essential," says W. Geoffrey Owen, dean of the Biological Sciences Division, who nurtured the Center into being over the past three years. "So many people die every year from diseases that aren't treated. Meanwhile, we're facing potential disaster with multi-drug resistant tuberculosis, HIV, and staphylococcus. With this collaboration between world-class scientists, hopefully we can feed the pipeline with discoveries of new drugs."

"We're ensuring that faculty members who have basic research ideas can connect with people who know biotechnology or neglected diseases to produce useful products," says Temina Madon, executive director of CEND. "You feel there's an imperative, an urgency, because there are tens of thousands of people dying every day from just a few diseases."

Madon has already been knocking on doors to connect faculty with complementary interests. The Center now has nearly 50 affiliated faculty in the sciences as well as public policy, law, business, and economics. CEND is also part of the Berkeley Alliance for Global Health, along with the Center for Global Public Health, an effort spearheaded by the School of Public Health.

"The technology and science are far enough advanced that we're ready to attack neglected diseases on a global scale," says Tom Alber, faculty Director of CEND and a Berkeley professor of biochemistry and molecular biology who studies tuberculosis. "The university can bring together the best thinking about what new knowledge is needed, what approaches need to be invented to eradicate malaria and resistant strains of tuberculosis."

CEND will extend Berkeley's neglected disease research far beyond campus gates. The Center will help Berkeley faculty collaborate with scientists and physicians in countries most affected by neglected diseases. Foreign exchange programs for students and scientists studying neglected diseases will be a top priority. For example, engineering graduate students from the Indian Institute of Technology, Kharagpur will visit Berkeley this summer. The goal is to make Berkeley's first-class scientific equipment, training, and facilities available to neglected disease researchers in countries around the world.

Meanwhile, Berkeley students and faculty will travel to countries afflicted by these diseases. Witness firsthand how these diseases are treated and patients respond will help them identify fruitful research approaches. For example, Alber graduate student Lisa Prach came across a collection of TB patient records, disease strains and tissues in South Africa, where extremely drug-resistant TB is on the rise. She will use the collection to determine whether the TB molecule she is studying is in fact associated with sickness in humans.

A forum to connect scientists studying infectious disease will make a world of difference, Alber says. "One person will say, here's a problem. The next will say, I can get fifty percent of the way to the solution, and the third person will say oh, the rest is really easy-and then you're there. Groups working together sometimes have traction on something that none of them could have solved on their own."

The bottom line is to bring solutions to these devastating diseases into the realm of possibility. "People don't think about solutions to projects that they know in their hearts are impossible," Alber says. "The Center will free our faculty to think on a scale that they wouldn't alone."

Related Web Sites

• Center for Emerging and Neglected Diseases
• Berkeley Alliance for Global Health

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A Fairer Fight Against Pathogens

by Kathleen M. Wong

To learn how the body fights infections, Daniel Portnoy studies at the tiny feet of the masters.

"Pathogens are the best cell biologists. They've spent many millions of years figuring out our cells," says Portnoy, a Berkeley professor of molecular and cell biology and public health.

Among the most challenging to fight are the intracellular pathogens, which include the microbes that cause AIDS, tuberculosis and malaria. These organisms can spread from cell to cell without being detected by antibodies, rendering traditional vaccines largely ineffective against them.

Portnoy is working to tip the scales of this fight in our favor. His studies of the food-borne bacterium Listeria monocytogenes are revealing how intracellular pathogens interact with the immune system. His findings are leading to new insights into the infection process and the development of vaccines against diseases such as cancer.

A human cell that encounters listeria will encase it in a cellular bubble and swallow the package whole. Once inside the cell membrane, the microbes will break out of their transport vehicle and enter the cytosol, or inner sanctum of the cell.

Portnoy and his colleagues found that listeria hijacks the cell's own cytoskeleton-the internal scaffolding that allows cells to move and divide-so that it can spread from cell to cell. It deploys one component of this system, a protein called actin, to form tiny bacteria-laden projections on the surface of its host cell. Neighboring cells envelop these projections and wind up infected themselves.

Portnoy isolated strains of listeria with mutations that halted this process at each stage of the cell infection process. He then infected mice with the mutants and observed what happened.

He found that mutants unable to hijack actin weren't infectious because they were marooned in their original host cells. Even so, they triggered a strong immunological response among the T-cells of mice. Part of the body's cell-mediated immune system, T-cells can kill infected body cells without involving antibodies. The T-cells Portnoy found were primed to attack proteins or antigens that listeria release outside of the cell.

The finding helps explain why only live listeria trigger an immune response among mice and humans. "If a bacterium isn't alive or growing, it doesn't make or secrete the antigens. So you may make some immunity with dead microbes, but it targets the wrong antigens," Portnoy says.

Vaccines against HIV and the bacterium that causes tuberculosis have proven notoriously difficult to develop. Understanding why live microbes are better at triggering immunity will help break this impasse.

Though unable to spread and cause disease, Portnoy's mutants could still train the immune system to attack infected body cells. They could not only activate T-cells but also cause the release of chemicals that attract immune cells to the site of infection.

Portnoy's mutant listeria strains have also been conscripted in the battle against cancer. Just as the mutants can teach T-cells to attack cells producing listeria proteins, they can sensitize the immune system to kill cancer cells manufacturing proteins characteristic of cancer. Because they are targeted directly at cancer cells, these treatments promise to cause fewer side effects than traditional chemotherapies. Anza Therapeutics is using the approach to sensitize the immune system against a protein expressed in pancreatic cancer cells; the product is already in clinical trials among humans. Portnoy has a consulting relationship with and a financial interest in Anza.

After working on listeria for so long, Portnoy says, "It's extremely gratifying to see work that I've done for 20 years being translated to help humans."

Related Web Sites

• The Portnoy Lab
• Daniel Portnoy—Department of Molecular and Cell Biology
• "Listeriosis's path to miscarriage traced to placental infection," by Liese Greensfelder, Berkeley NewsCenter, 29 June 2006
• "Cancer vaccine based on pathogenic listeria bacteria shows promise targeting metastases," by Robert Sanders, Berkeley NewsCenter, 29 September 2004
• "This Portnoy Has No Complaints," by Jessica Li, Berkeley NewsCenter, 04 April 2003

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Tracing Evolution in Genes

by Kathleen M. Wong

How do humans differ from chimpanzees? The average Homo sapiens has no trouble counting the ways. Just for starters, we're taller, less hairy, and-a point no one fails to mention-far brainier than our closest primate relatives.

All of these differences and more have emerged over the past five million years, when the common ancestor of both species reached an evolutionary fork in the road. How early hominids came to walk the savannah, while early chimpanzees returned to the forests, has fascinated professional scientists and armchair anthropologists alike.

The best way to answer those questions, according to Rasmus Nielsen, is to study our respective genomes. "Evolutionary biology is an historical science," says Nielsen, a Berkeley professor of integrative biology. "But in the absence of a time machine, we can't really go back and show exactly why certain evolutionary events occurred. All we have to work with is what we observe today. So we look at the DNA to see the evidence for past Darwinian selection."

Nielsen uses the power of statistics and computing to compare the DNA of different species or populations. By identifying which sets of genes have changed, or mutated, he can describe how ancestral populations diverged step by tiny genetic step. His work not only recasts the story of human evolution but promises to uncover the genetic roots of many diseases.

Nielsen's approach sorts genetic mutations into two general categories. The first involves changes that have little or no effect on the fitness of an organism. Mutations in these sequences tend to accumulate at a relatively slow background rate, so they tend not to be dramatically different between organisms. Other mutations do have a direct impact on an organism's survival, because they alter the structure or function of a gene or its protein. Exposed to the pressures of the real world, these traits tend to get amplified or weeded out at a much faster rate. In a practical sense, the genes with the most dramatic differences are also those that have undergone intensive evolutionary selection.

With this approach, Nielsen is revising the story of what drove humans and chimpanzees apart. "Biology has had a lot of just-so stories about why something might have been adaptive," he says. "Having the genomic data from many species gives us the opportunity to test some of these hypotheses."

In a recent study, Nielsen compared more than 13,000 genes common to both chimpanzees and people. The types of genes that differed the most, he found, had to do with the immune system, sensory perception, long-bone growth, and cancer control. By contrast, the genes that affect humanity's most prized possession-the brain-had changed very little.

"It was a big surprise," Nielsen says. "We would expect brain development to be one of the big areas of differences between humans and chimpanzees." This suggests that relatively few genetic changes may be responsible for the differences in the brain between humans and chimpanzees.

Nielsen is now using this approach to flag genetic mutations associated with hereditary diseases. On average, individuals with disease-causing mutations will leave behind fewer offspring. These disease-causing mutations are under especially intense Darwinian selection pressure. "By looking at which genes are under selection, we can actually flag which particular mutations are more likely to cause diseases." Nielsen says.

Conditions such as cardiovascular disease and autism have resisted useful genetic analysis because they are likely caused by multiple, interacting genetic components. Nielsen's techniques, which make statistical associations between multiple genes, are ideal for the job. Once a suite of genes is linked with a disease, scientists can make far more rapid progress developing cures that could someday benefit human and chimpanzee alike.

Related Web Sites

• Rasmus Nielsen-Department of Integrative Biology
• "Human and Chimp: Can our Genes Tell the Story of Our Divergence?" PLoS, 3 May 2005

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Last updated January 8, 2008.

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