Striepen works with CTEGD colleague Jessica Kissinger, an expert in parasite genomics, to help figure out which genes in Crypto are doing what. With collaborators at the University of Pennsylvania, Kissinger is funded to make a database of all known apicomplexan genes, and this includes “CryptoDB”—a database containing the estimated 4,000 genes present in each of the two Crypto species. This database allows Kissinger to do “data mining,” which she describes as a systematic way of “looking for a needle in a haystack.”

Striepen will run experiments based on a genetics question that Kissinger is trying to answer, and Kissinger will search in her database for a gene that pops up in one of Striepen’s experiments. “The experimental and the computational approaches each have their own strengths and weaknesses, but combining them is very powerful,” Striepen said.

Parallel to Striepen and Kissinger’s interest in understanding basic parasitic biology is their hunt for potential drug targets—agents that can be used to treat individuals with Crypto infections. The scientists’ strategy is to identify areas in which the biology of the parasite is radically different from that of the host.

“Because Cryptosporidium sits on the same branch of the tree of life as we do, this makes an infection hard to treat,” said Striepen. “We have really good drugs against bacteria, which are completely different from humans, but we don’t have as good, as specific, or as effective drugs for pathogens that are more similar to ourselves.”

Striepen and Kissinger decided that the most straightforward avenue for finding exploitable differences is metabolic activity—the modification of chemical compounds within a cell. “For example, if we make a certain amino acid and parasites make it using completely different enzymatic machinery, then we could theoretically hit that system without fearing that we’d interfere with our own metabolism, which could cause side effects,” Striepen said.

This strategy appears to be succeeding. Striepen and Kissinger’s teamwork has already led to one potential drug target, and a novel discovery. They found that Crypto is a genetic mix of species—a lot of protozoan and a little bit of bacteria, with apparently something borrowed from the plant world as well.

Unlike the typical mode of “vertical” genetic transmission, in which the genes of an infant are derived from its two parents, nature sometimes exhibits “horizontal” gene transfer—genes that jump from one living organism to another. This process is often seen in bacteria, which love to share genes that help them survive, Striepen said. “That is why there is so much antibiotic-drug resistance today and why it is spreading.”

Striepen and Kissinger published a series of studies that made the case this process happens in Cryptosporidium parvum as well.

Based on Striepen’s lab work that examined activity of the protozoan and Kissinger’s analysis of the Crypto genome, they found that Cryptosporidium parvum carries bacterial genes and that these genes are needed to help it make DNA. Their finding may help them locate biological “back doors” into Crypto—enzymes and proteins, made by bacterial genes, that can be targeted by novel drugs that will not affect human cells.

Striepen believes he has already found such a potential Crypto Achilles heel. Working with scientist Lizbeth Hedstrom from Brandeis University, he tested 45,000 different chemicals for the ability to inhibit the bacterial enzyme that helps assemble the parasite’s DNA. So far, they have identified 10 good candidates—compounds that can block the enzyme.

The transporters that the parasite uses to bring in material it needs from the host cell might also make a good drug target, Kissinger said, so she and her research team are assembling a diagram of metabolic activity associated with the parasitic genome, a process they dub “metabolic-profiling.”

“If we can figure out which transporters are bringing in sugars, which ones bring in amino acids, how this thing eats and makes the compounds it needs, that could give us a variety of ways to disrupt their activity,” she said.

EMAIL THIS     PRINTABLE VERSION