DeRisi team wins $1 million Keck Award; will develop technology for vaccine designers

February 17, 2010
By Kaspar Mossman, QB3

Joe DeRisi with the ViroChip, which he co-developed in 2003. DeRisi is now developing technology based on proteins, instead of DNA, to aid scientists developing vaccines.

A team led by QB3’s Joe DeRisi, PhD, UCSF professor of biochemistry and biophysics and HHMI Investigator, recently received a $1 million award from the W. M. Keck Foundation to develop technology that will aid researchers seeking to design a vaccine for malaria and other infectious diseases. There is currently no vaccine in widespread use to prevent malaria, which the World Health Organization estimates affected 243 million people worldwide in 2008.

DeRisi’s team will develop a novel technology that will help identify which regions of the proteins produced malaria, viruses, and other infectious diseases are targets for antibodies. Antibodies are molecules produced by the immune system to neutralize pathogens and tag them for destruction. Knowing which regions (called “epitopes”) are prime antibody targets, and therefore likely to generate a response that protects the host against malaria, may enable scientists to design a custom vaccine.

DeRisi has convincing credentials: a former Macarthur Fellow, he is a co-inventor of the ViroChip, a virus-identifying array that displays 22,000 DNA sequences and was used in 2003 to tag the SARS virus as a novel coronavirus.

As a first step toward a synthetic malaria vaccine, the DeRisi team seeks to manufacture the “proteome” of P. falciparum— its complete repertoire of proteins—chopped up into “peptides” 15-20 amino acids long. Each peptide would represent an epitope. But it’s more complicated than just putting P. falciparum into a blender. The researchers plan to produce the peptides one amino acid at a time.

How will they do this? The process is simple in concept but requires technology of the highest order. DeRisi intends to use a well-established reaction to grow the peptides on the surface of plastic beads. The sheer number of epitopes—3.8 million—presents a challenge.

“There’s currently no efficient way to produce large scale peptide arrays,” DeRisi says. “Large scale DNA arrays are comparatively easy. It’s a totally commercial technology. But the same is not true for peptides.”

DeRisi’s team will reproduce the malaria proteome, and that of other infectious diseases, based on whole-genome sequencing data. First, the team will devise a barcoding scheme to label each bead with the sequence of amino acids to be added. In the proposed manufacturing process, the beads will be robotically sorted and sent to reaction chambers that add the first amino acid. The apparatus will spit out the beads into a pool that will be piped back into the input and sorted again for the next step. The process repeats 14 times, and voilà: the epitope repertoire of P. falciparum, or any other pathogen, contained in one soupy milliliter.

A robot will sort the peptide soup into an array similar to the ViroChip. Serum samples from hosts infected with malaria will be applied to the array, and the researchers will observe where the antibodies bind. The ultimate goal is to correlate this binding profile with protection against malaria. “If we’re ever going to make a vaccine that works, we have to discover which rare epitopes result in the production of neutralizing antibodies,” DeRisi says.

He has assembled what he calls a “dream team” for the project: Ron Zuckerman, PhD, an expert in combinatorial peptide synthesis at Lawrence Berkeley National Laboratory (LBNL); Rafael Gomez-Sjoberg, PhD, a LBNL specialist in microfluidics; Kurt Thorn, PhD, a UCSF scientist and Director of the Nikon Imaging facility who will design custom imaging systems; and physicist Polly Fordyce, PhD, and immunologist Charlie Kim, PhD.

DeRisi admits that, although $1 million is a lot of money, it will only go so far. “The grand experiments come later,” he says. “The Keck grant is seed money to develop the foundation of the technology—all the different components that allow us to build this peptide synthesizer.”