A few years ago a chemist made an offer under the table to Jim McKerrow, a professor at UC San Francisco’s Mission Bay campus. McKerrow accepted and drove down to South San Francisco, backed his car up to a loading dock, filled the trunk, and drove away.
“Suddenly I think, oh wow. What if I get stopped by the highway patrol and they open the trunk and there’s all these vials with white powder,” he said, recalling the incident recently. “Now officer, these are protease inhibitors,” he joked.
Back in the mid-1990s, McKerrow adopted another protease inhibitor, K777, in a similarly altruistic maneuver with Jim Palmer, a chemist then working at the now defunct Khepri Pharmaceuticals.
Today, that compound has become a promising candidate in the fight against an infectious parasite that has been found in the Bay Area blood supply and affects millions of victims in Latin America. The culprit—Trypanosoma cruzi (trip-PAN-o-soma CREW-see) —causes the potentially-fatal Chagas disease.
If K777 is successful, which won’t be known until it goes through lengthy clinical trials, it will be the first drug out of UCSF developed independently from industry. In this case, that research was conducted by McKerrow’s lab and its collaborators at the Sandler Center for Basic Research into Parasitic Diseases, a consortium devoted to drug development for neglected diseases.
The latter are infections that are endemic but primarily affect poor people. With Chagas, it’s 8 to 12 million of them, nearly all having lived in rural Latin America at some point in their lives.
An obsolete Brazilian 10,000 cruzado note reflects the importance of the disease in that country, where it was first discovered.
“Instead of on American money – e pluribus unum – here is the life cycle of the parasite sucking blood from someone’s skin,” McKerrow said, pulling a bill out of his desk drawer and pointing to money, which shows a drawing of a benchuca and the skin of its victim, complete with bite mark and parasite-rich feces.
Spread By A Bloodsucking Vector
The T. cruzi parasite – a single-celled eukaryote – is spread by a bloodsucking subfamily of assassin bug called a benchuca, or kissing bug. It bites near a sleeping victim’s eye or mouth, hence its name.
Every time a benchuca has a blood meal, it also defecates. T. cruzi moves from bug to human host when the victim inadvertently scratches the its poop into the bite wound or a mucus membrane.
The Centers for Disease Control and Prevention believe that almost all infections happen outside of the United States, but the parasite, and the insect that spreads it, live in the Southwest and some parts of California. It can also infect animals.
If untreated, 20 to 30 percent of its victims will develop significant, sometimes fatal heart disease, according to the CDC.
No Financial Incentives to Study Chagas
Because the poor are most affected, Chagas isn’t an interesting investment for pharmaceutical development, but it remains important to researchers and countries like Brazil, Argentina, and Bolivia, which have pockets of very high incidence. It’s that importance that leads some to make calls to fellow chemists like McKerrow.
Labs have no financial incentive to look into alternatives to the available treatment for the parasite — nasty drug regimens developed around WWII that have serious side effects including vomiting, psychiatric effects, and nerve damage. But still, scientists remain interested and aware that the latter might be improved on.
So when lawyers for the closing South San Francisco life sciences company told their scientists to destroy the compounds they had been working on to avoid any legal problems, the chemist thought it worth the risk to call McKerrow.
Some of these otherwise doomed compounds, he or she suspected, might be useful to the Sandler Center in fighting parasitic diseases like Chagas and malaria. McKerrow declined to name the chemist.
“It would be a terrible shame to waste stuff in which millions of dollars had been poured into,” Jim Palmer said generally about drugs developed in industry that might get thrown away.
Years earlier, Palmer made a batch of K777 for McKerrow in his free time, hoping the compound would have potential to help treat parasitic infections.
Palmer now works in Australia and said that everything he did with McKerrow was above board, though there are indications that some higher ups in his company at the time – long since dissolved – were uninformed about the relationship initially. “I don’t know anything about that – I don’t remember,” Palmer said.
Palmer was happy about the compound´s progress. He said he named after he saw the very first Boeing 777 airplane waiting to enter service at Dulles International Airport. “It’s like my child,” he said.
K777 was one of about 20 compounds – initially investigated for applications like cancer and arthritis – that were handed over to McKerrow to match against a chemical produced by the Chagas disease parasite.
McKerrow said that the compound has since been legally secured, safe from anyone being able to take out a patent and charge huge sums for it if it.
Though getting drug company throwaways helps, having promising compounds is merely one of many steps in a long and expensive drug development process.
Sandler Center researcher at a chemical hood.
Researchers screened thousands of compounds along the way. Tests for the disease had to be created, as did an animal model, which were designed through the devoted efforts of scientist couple Patricia Doyle-Engle and Juan Engle, according to McKerrow.
The Sandler Center targeted Chagas in particular because Latin American countries have basic infrastructure, like clinics, to distribute medicines once they are developed.
McKerrow said there won’t be a vaccine, since vaccines function to boost immune function, and in later stages of the disease, the host’s own immune response to T. cruzi helps damage heart tissue. Furthermore, there are wild animals like armadillos that are reservoirs for the disease. It’s impossible to eradicate.
Instead, researchers at the Sandler Center are looking at possible drug treatment – protease inhibitors – that stop the action of a chemical the parasite requires throughout its life cycle.
So far, K777 has been shown to be effective in animal tests. The next step is a clinical trial in humans. McKerrow said that the next hurdle is raising roughly $350,000 to pay for manufacturing the drug for such a study according to FDA standards.
Parasites in the Blood Supply
Meanwhile, on the local level, other researchers are tracking Chagas through blood donations.
Studies conducted by San Francisco-based Blood Systems Research Institute found that one out of every 16,000 donors in the San Francisco area tested positive for the parasite. That’s about double the overall U.S. rate.
The CDC estimates roughly 300,000 immigrants have the parasite in the United States.
“Nobody is legally required to screen for T. cruzi in the U.S.,” said Brian Custer, an associate investigator at the institute. He estimated 75 to 80 percent of blood banks nationwide are screening for it, and probably all California blood banks screen for it.
He said he didn’t know anybody that was doing really good outreach, adding that the institute tried to form outreach partnerships with local organizations and clinics, but it was “very, very unsuccessful.”
The American Red Cross and the institute are the largest blood research entities in the country and the only blood banks studying the infection. Custer said the Blood Systems Research Institute is in an ongoing study of the parasite in Brazil, because little data exists on how Chagas disease progresses after initial infection.
“We really don’t know how it’s contributing to the overall burden of heart disease in the United States,” Custer said.
Rare cases of transmission have occurred in this country. However, infection is closely associated with substandard housing – the benchuca likes crevices that exist in thatched housing – and the vast majority of infections are linked to time spent in certain rural areas of Latin America.
Areas of Argentina have some of the highest prevalence of infection, yet “the likelihood of someone in Buenos Aires having T. cruzi is about the same as someone in San Francisco having the infection,” Custer cautioned.
It’s a disease, like many, with a long tail and may have felled one of the most famous scientists of all.
Charles Darwin wrote about being bitten by a benchuca and suffered from a mysterious illness his whole life. He died from heart failure, and some believe he may have had Chagas.