Undergraduates tailor UCSC Genome Browser to aid malaria research

Timothy Sterne-Weiler and Jonathan Deans developed the malaria genome browser. Photo courtesy of M. Ares.

Undergraduates at the University of California, Santa Cruz, have created a genome browser for studying the malaria parasite. A team of UCSC researchers used the new browser to discover previously unknown genes that could help in the search for antimalarial drugs. Their findings appear in the November issue of the journal RNA.

Timothy Sterne-Weiler and Jonathan Deans, bioinformatics majors who graduated earlier this year, based their malaria genome browser on the UCSC Genome Browser, a widely used research tool developed for studying the human genome and maintained by UCSC's Center for Biomolecular Science and Engineering. Sterne-Weiler and Deans did the work as members of the Hughes Undergraduate Research Lab, an interdisciplinary group started by Manuel Ares, Jr., professor of molecular, cell, and developmental biology, with support from the Howard Hughes Medical Institute.

Over the lab's four-year tenure, 60 undergraduates collaborated with graduate students and research staff to complete their own research. Ares said that bioinformatics students made up about a third of the group and were key to sorting through the data-rich results of experiments.

"There's a whole revolution in biology going on right now, where computer science is colliding with classic biological science approaches," Ares said. "At that interface, there's a lot that can be done."

Students typically spent two to three years in the program, which required a time commitment of one class per quarter, including summers. Ares gave the students more autonomy than typically afforded undergraduates, including keys to the lab. They worked with graduate students and postdoctoral researchers to pursue their own research, gaining an appreciation of life in academic research along the way. Ongoing projects in the lab included work on the SARS virus, malaria, and the basic biology of yeast cells.

Sterne-Weiler said he appreciated the opportunity to come to grips with real, unsolved problems. "I got into the lab and I was actually doing all the things I was really interested in, and learning a lot more than I ever could out of classes," he said. "It kind of kept me going, because I had a focus that I could see in front of me."

That's not to say they found research a breeze. One of the main skills the students learned was resourcefulness. "You're chugging along and all of a sudden you hit a wall. It's like, 'Well, what do I do now? I've never done this before,' " Deans said. "I'm not a computer administrator; I don't know what these errors mean. But you start to learn to think on your feet."

The new malaria genome browser brings together on a single screen the full DNA sequences of eight species of the malaria parasite (Plasmodium), alongside experimental results and previously discovered genes culled from the literature. The program allows users to search through the 26 million letters and 14 chromosomes of the parasite's genome, enter their own sequence data and notes, and quickly compare findings across species. In the weeks since the malaria genome browser went live, it has received more than 5,000 hits from six continents, and has been linked in a forthcoming version of PlasmoDB, the international repository for information on Plasmodium genetics.

Once the malaria browser was up and running, members of the Ares lab led by research biologist Kausik Chakrabarti used the system to search for undiscovered "structural RNA" genes. The browser enabled Chakrabarti to predict the locations of DNA regions that produce the RNA sequences he is interested in. After this computer-bound, "dry side" of the operation, he and other colleagues perform "wet side" experiments that isolate those sequences and find out if the predictions are correct.

RNA is a single-stranded counterpart of the DNA double helix. Whereas DNA stores genetic information inside a cell's nucleus, RNA copies of genes are ferried out into the cell, where structures called ribosomes use the information to assemble proteins. But some genes make small pieces of RNA that don't code for proteins. These so-called structural RNA molecules perform jobs such as splicing together other sections of RNA or combining with proteins to make specialized enzymes, such as the ribosome.

Because structural RNA performs key tasks in the cell, researchers study it for ways to disrupt disease organisms. The well-known antibiotic erythromycin, for example, works by exploiting a difference between the ribosomal RNA of humans and that of bacteria. When a patient takes erythromycin, it disrupts the bacteria's ability to make proteins, but not the patient's.

Chakrabarti hopes to find similar drug targets by studying the newfound RNA sequences and looking for differences between the human and malarial versions. Among his targets is an enzyme called telomerase that is made up of both RNA and protein. The enzyme repairs a chromosome region that happens to control malaria's virulence. If Chakrabarti can find a way to shut off the enzyme in Plasmodium but not in humans, the result could be a potent antimalarial drug.

He is also interested in telomerase because it works as a reverse transcriptase, synthesizing new DNA from RNA. That's one of the characteristics that allows HIV, the virus that causes AIDS, to commandeer human cells so successfully.

"Basically, we're trying to hit two diseases with one stone," Chakrabarti said.

The Hughes Undergraduate Research Lab finished operation in 2006, and the Ares lab's malaria work is also coming to a close. Chakrabarti hopes to get more funding, but for now the malaria genome browser is being kept alive by the volunteer work of Deans, Sterne-Weiler, and John Paul Donohue, a research specialist in Ares's lab and coauthor of the paper.

"With malaria, since it's a tropical disease, most of the funding is private," Chakrabarti said. Despite the millions malaria kills each year, federal funding priorities emphasize diseases that strike closer to home, he said. Grants increasingly come from smaller private foundations, as large philanthropic trusts focus on research into treating the disease rather than basic biology of the parasite, he said.

Sterne-Weiler is now a UCSC graduate student pursuing a master's degree in bioinformatics. Deans, who now works at Santa Cruz Biotech, also plans to pursue a graduate degree. Their accomplishments represent the kind of experience Ares had in mind when he designed the undergraduate lab.

"When someone goes through our current university system, they're actually being forced to think in a disciplinary fashion," Ares said. "The idea was to break this down, to create an experience where students learn that to solve a research problem you really can't do it with any one discipline."

In addition to Chakrabarti, Sterne-Weiler, Deans, Ares, and Donohue, the paper's coauthors include UCSC graduate student Michael Pearson and postdoctoral fellow Leslie Grate. The malaria genome browser can be accessed at the Ares Lab web site.

Note to reporters: You may contact Chakrabarti at (831) 459-4917 or kausik@darwin.ucsc.edu and Ares at (831) 459-4628 or ares@biology.ucsc.edu.