Pollastri is focused—single-mindedly focused—on finding cures for neglected diseases, such as African sleeping sickness, Chagas disease, leishmaniasis, and other chronic, crippling, and sometimes fatal ailments widespread in sub-Saharan Africa, Latin America, and other intertropical zones.
“The motivating factor for me is a moral thing,” he says. “I have all these skills and enthusiasm. I’ve been afforded all these opportunities, so I want to use all that to solve a problem that affects the poorest of the poor.”
Pollastri’s colleagues consider him a pioneer in medicinal chemistry, advancing an approach that has the potential to transform drug discovery in neglected diseases. Since he arrived at Northeastern in 2009, he has been working with like-minded scientists to find magic bullets among existing pharmaceutical compounds developed for more mainstream conditions.
Today, Pollastri has more company—neglected diseases are no longer quite so neglected. The Gates Foundation’s focus on malaria has helped, and the World Health Organization has made tropical-disease research a global priority. As Pollastri puts it, “A rising tide raises all boats.”
“When we started, relatively few groups were doing this,” says Robert Campbell, a molecular and evolutionary biologist and Pollastri collaborator. “But now, multiple research initiatives have sprung up, and Mike is shaping the field.”
Campbell is a researcher with EMD Serono and a faculty member at the Marine Biological Laboratory in Woods Hole, Mass. He was also the catalyst for Pollastri’s career move from industry to academia from an environment that was bottom-line driven, to just plain driven.
THE PERFECT FIT
Pollastri spent about nine and a half years at Pfizer, including his last four as a lab head in its Research Technology Center in Cambridge, Mass., which was, at the time, a cutting-edge facility that developed new chemical “tools” for the company’s other drug-discovery units.
He enjoyed his work and liked the company.
But by the fall of 2006, he was starting to feel ambivalent about staying there—increasingly drawn by the notion of devoting his skills to a larger global health cause, and increasingly concerned about looming cutbacks to the industry’s multibillion-dollar research budgets.
That was Pollastri’s mindset when he decided to drop in on a faculty seminar at Brandeis University in Waltham, Mass. Campbell was presenting on a project he’d been working on with a Brandeis graduate student: identifying possible drug targets in tropical disease parasites to discover potential matches to known drug targets in humans. It was, and is, a technology-intensive process, using computer analytics to compare DNA sequences and break down other complex genetic data.
For Pollastri, the effect was like that snatch of music that you can’t get out of your head. He was “appalled” to think about people dying for lack of basic sanitation, and he started thinking about it all the time, “wondering what [researchers] had been doing in drug discovery in these areas.”
Nearly nothing, it turned out: When Pollastri perused the research on African trypanosomiasis, he found so little chemistry work that he initially thought he was entering the wrong key words in his searches.
By March 2007, he had emailed Campbell at the MBL to propose that they work together; they started a partnership that is now in its seventh year. That summer, resolved to focus on what he really cared about, Pollastri left Pfizer.
He accepted an appointment from Boston University, essentially to set up the same kind of medicinal chemistry laboratory that he’d been running at Pfizer.
Pollastri spent two years at BU, constrained by having to oversee the core lab and itching for more freedom to pursue his passion. In the second year, two things happened: The National Institutes of Health approved a grant proposal that he had submitted with Campbell for a project on neglected diseases—and Northeastern came recruiting.
“It all just fell into place,” says Pollastri. “The perfect fit.”
CLEARING A PATH
Pollastri acknowledges that he still misses industry’s single focus: no need to chase after grants or oversee a lab full of scientists-in-training.
But it’s all outweighed by the carte blanche to pursue his own work in a research culture that supports innovative problem solving. And the repurposing approach is both: innovative and problem solving.
Pollastri and his collaborators identify enzymes in humans that match with enzymes essential to a given disease parasite, then search for drugs—either approved or in late-stage development—that are inhibitors of the human enzymes.
Biologists like Campbell or Kojo Mensa-Wilmot, a professor and department chair in cellular biology at the University of Georgia, test the inhibitors against the parasite in vitro to determine their effect. In at least one project, testing has advanced to live animals. If the results show promise, Pollastri’s lab will seek to fine-tune the chemistry of a particular compound in whatever direction the test data suggest.
It’s a painstaking process, but the advantages of working with known drugs are obvious. Many initial questions that would normally require screening tens of thousands of compounds—Can they be optimized as drugs? Are they toxic to healthy human cells?—have been answered.
“The pharmaceutical companies have cleared a path; they’ve cut down the huge trees and bushes and we’re going through the waist-high grass now,” says Pollastri.
While the standard approach to drug discovery takes about 15 years, “we hope to clip off about three years, which in this resource-limited area is pretty significant.”
And Pollastri and colleagues have managed to flatten a fair amount of that waist-high grass.
For example, Mensa-Wilmot and Pollastri, working with a breast cancer drug developed by GlaxoSmithKline, have created a promising derivative against Trypanosoma brucei, the parasite that causes African sleeping sickness. And other, separate derivatives of the drug are active against Chagas, leishmaniasis, and malaria—potentially making it “a four-for-one,” Pollastri says.
Campbell and Pollastri are collaborating on an NIH-funded project, examining a class of inhibitors developed for a range of cardiovascular and pulmonary conditions for their potential to cure African sleeping sickness. They have tested some 400 different drug designs, says Campbell, and are getting good results in terms of killing T. brucei.
Of the nine research groups Pollastri is working with on neglected-disease projects—four on African sleeping sickness, three on Chagas disease, one on leishmaniasis, and one on malaria—eight are pursuing active leads.
Still, he chafes at the slow pace. But he has yet another idea that could speed things up.
To reap the full benefits of the repurposing approach, many more researchers need to be involved, says Pollastri, because each project can yield hundreds of compounds with potential, all needing to be analyzed and tested, refined and retested. Big Pharma is providing some assistance: Pollastri and his partners have some significant, active projects with a GlaxoSmithKline lab in Spain, dedicated to research for neglected diseases.
The larger solution, according to Pollastri, is a data-sharing model for drug discovery, in which researchers post their data in real time for other researchers in the field to build upon. There is nothing inherently new in that: A malaria group in Australia, to cite one example, already posts its data on a public website, with nary a password required.
But that wide-open model is too open for Pollastri’s purposes. He is trying to attract former industry researchers like himself, medicinal chemists in particular, who “get hives when you start to talk about sharing data openly.”
It is not about money—there is no money to be made curing these diseases. But intellectual property is intellectual property and has the potential to yield big NIH grants and papers in prestigious science journals.
So Pollastri is promoting a hybrid open model of drug research for neglected diseases, “where we’ll all put our data into a database” accessible only to researchers who agree to certain privacy terms upfront. He hopes that middle ground will provide a sufficient comfort zone of security to those wary of having their data misappropriated by other scientists.
Even in the less competitive world of academic research, forging successful collaborations among colleagues in the next lab—never mind strangers a continent away—is no simple task. Mensa-Wilmot believes Pollastri is the right man for the job.
“He is a very talented chemist—idealistic and he has boundless energy—a fantastic asset for this project,” says Mensa-Wilmot.
For Pollastri’s part, the stakes are too high for this small wing of the research community not to pool its resources. Getting credit is secondary to getting solutions.
“If we discover a molecule that the Gates Foundation or the Drugs for Neglected Diseases Initiative can pick up and turn into a drug, more power to ’em,” he says.“Hopefully, they’ll mention us in their press release.”
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