Gates Grants Fund Research

Traditionally, infections are treated with conventional antibiotics. But a new treatment designed by a Harvard researcher replaces pills with light.

This out-of-the-box idea is one of four projects that received $100,000 through the Grand Challenges Exploration Initiative, a project backed by the Gates Foundation.

The initiative, which bestowed grants on 104 researchers from 22 countries, was developed to lower the barriers to funding for anyone with a transformative idea in global health. Projects that show promise in the first year will be eligible for a second phase of funding of possibly $1 million or more.

Unlike most lengthy grant applications, applicants submitted just a two-page proposal and needed no preliminary data—the focus was on the idea, not on the results, according to Andrew C. Serazin, an official at the Gates Foundation.

“Innovation can come from unexpected places and from unusual people,” Serazin said in an e-mail. “Explorations seeks to fund projects that fall outside the scope of conventional wisdom and champions high-risk, high-reward projects with the potential to transform global health.”

The Crimson contacted three of the four scientists who won grants from the Gates Foundation (the work of the fourth, Harvard Medical School professor George M. Church, has been profiled in the past) to learn about their “unconventional” research.

The professors include Sarah M. Fortune of the Harvard School of Public Health, and Tayyaba Hasan and Roy Kishony of the Medical School.

WHEN SYMPTOMS DON’T APPEAR

Though it’s well known that humans express phenotypes for characteristics like brown hair or blue eyes, far fewer people know that tuberculosis also generates different phenotypic states.

“Those phenotypic states can be...‘I need to be in some different metabolic state to survive,” said Fortune, an assistant professor of immunology and infectious diseases.

What the states have in common is their heritability—they have to be passed on to progeny, or the progeny will be eradicated.

For the Gates Foundation grant, Fortune will study a particular state known as latency, where patients can be infected as children but not develop symptoms for decades.

“We postulated that TB is tapping into a fundamental dormancy program that many different organisms—from seeds to yeast to worms—use,” Fortune said.

Specifically, there is a change in chromatin structure so that the DNA collapses and forms a crystal matrix, inhibiting gene expression. Instead of the dormant organism using energy to sense the environment, it acts as a biophysical switch—when environmental conditions change, the chromatin relaxes and gene expression can resume.

STRUCK BY LIGHT

Across the street from Fortune, another Gates recipient—Hasan, a professor of dermatology—is working on an innovative way to kill infections using photodynamic therapy.

In this therapy, a non-toxic chemical is injected or applied to a lesion where a disease is present, and then light is shone to activate the chemical. Once activated, the chemical creates compounds like free radicals that become toxic to the target cells.

“These compounds will kill anything in the vicinity,” Hasaan said. “That’s really the beauty of it.”

While research regarding photodynamic therapies has focused on cancer in the past, Hasaan said that she is now interested in using the therapy to treat infections.

“If you think of the world over, more people die of infections than of any other disease, and they die in countries which don’t have as much importance globally,” Hasaan said.

One of the major challenges to treating infections is that the pathogens often develop resistance to antibiotics, Hasaan said.

Since the mechanism of killing the infection is so different in this therapy, no resistance has been reported yet. And hopefully, Hasaan added, pathogens resistant to conventional antibiotics will be responsive to this therapy.

Hasaan is specifically targeting the gp63 protein in visceral leishmaniasis, an infection in which a parasite lives inside cells of the human immune system. The protein helps protect the parasite from immune attack and is expressed on the surface of the cells.

Hasaan hopes to synthesize a compound that, once injected, will be activated by light and only in the presence of gp63. Only compounds near gp63 will become toxic, either directly killing the parasite or destroying gp63 so that the parasite can be attacked by the body’s immune system.

REVERTING RESISTANCE

Kishony, a systems biologist and the third Gates grant recipient, is researching how using multiple drugs that suppress each other can surprisingly lead to more effective treatment.

“We’re trying to ask how the use of multi-drug treatments impacts the evolution of resistance,” Kishony said.

His proposal was based on previous work by graduate student Remy P. Chait showing that, in some cases, using certain types of drug combinations can make it unfavorable for the bacteria to become resistant to one of the drugs in the combination.

For example, if a bacteria is treated with two drugs, A and B, and becomes resistant to drug A, then drug A is no longer an effective treatment. But if drug A suppresses some of the effect of drug B, then developing a resistance to drug A might allow drug B to become more potent, thus having an overall deleterious effect on the bacteria. In effect, Kishony said, “getting beat up by one is worse than getting beat up by both.”

Kishony and Chait had previously hypothesized that bacteria that became resistant to two drug that were known to suppress each other would not fare as well.

Now, in a sense, the researchers are taking “one step backwards.”

“Rather than looking at existing drugs, we want to incorporate this feature of inherent selection into the screening of novel drugs,” Kishony said.

For the Gates foundation, Chait is developing a way to test this idea.

Under Chait’s plan, researchers would spot various small molecules on petri dishes that contain mixtures of bacteria that are either sensitive or resistant to a particular drug. The sensitive and resistant bacteria would be labeled with different colors, such as green and red.

A compound that selects for resistance will generate a red ring, while a “selection-inverting” drug—those that temper the effects of another—will generate a green ring, indicating drug-sensitivity rather than resistance, Kishony said.

—Staff writer Alissa M. D’Gama can be reached at adgama@fas.harvard.edu