From curing herpes to treating diabetes in a new way, their innovations might one day treat some of the world’s most prevalent health problems. This year’s two finalists in STAT Madness, a bracket-style competition that showcases cutting-edge research across the biomedical sciences, harnessed new approaches to devise possible therapies that could help millions of people with all-too-common maladies.
One team, from the Fred Hutchinson Cancer Research Center, developed a gene-editing technique with the potential to effectively treat and even cure herpes. The other finalist, a group from the Massachusetts Institute of Technology and Brigham and Women’s Hospital, devised a liquid solution that coats the small intestine with a temporary adhesive, a noninvasive technique with wide applications from efficient drug delivery to treating diabetes.
The competition was stiff, with well over 1 million votes cast during the month-long contest, blowing past last year’s record of almost 700,000 votes. In the end, both teams were declared winners. STAT editors made that decision in the interest of fairness, after identifying unusual voting patterns in the final round.
Martine Aubert, Keith Jerome, and their colleagues at Fred Hutch tested a new method of gene therapy to treat herpes, improving on previous research done by Jerome. Using gene editing in mice, the researchers removed over 90% of the virus from the cells that it mainly infects, they reported in a paper published in Nature.
Jerome, a virologist and a professor at Fred Hutch and the University of Washington, said that after years of improving their gene editing approach, he was “more thrilled” than surprised about the promising results. “That’s what we were going for,” he said.
Existing antiviral treatments for herpes typically address the infection temporarily, but latent virus still remains in the body, hiding in the peripheral nerves and periodically reactiving. Type 1 HSV usually causes cold sores around the mouth and lips; type 2 causes sores on the genitals. Herpes is incredibly common, affecting over two-thirds of people under age 50 worldwide. In their study, the researchers tested their treatment for the type 1 virus, but think it would also be effective for type 2.
In previous research, Aubert and Jerome had found that using a DNA-clipping enzyme called meganuclease, they could effectively target viral DNA in infected cells and damage the herpes virus. The enzymes used in the research were delivered to cells via a hollowed-out virus-like particle, called a viral vector. In the Nature study, the researchers also experimented with other gene-editing approaches, such as CRISPR/Cas9.
“You can see some signs [CRISPR/Cas9] was working a bit, but the meganucleases were way, way better,” said Jerome.
Several incremental improvements to the researchers’ original method enabled it to destroy almost all of the herpes virus in the peripheral nerve cells of mice, versus damaging 4% or less of the virus in the initial study.
In the new paper, the researchers hypothesized that if the technique works in humans, it would reduce viral shedding, which would make it harder to transmit the virus to others. In recent research, the researchers have further supported this idea using a mouse model Aubert developed that mimics viral shedding in humans. There were also some signs the technique could be improved upon even further, making it possible for it to effectively cure herpes.
“There might be a tweak in there [that would explain] why some animals do better than others,” said Aubert. For instance, some mice had no detectable disease at all.
It may take at least two-and-a-half years before the treatment enters human trials, said the researchers. They are planning to meet with the Food and Drug Administration by this summer to discuss what safety data they will need to collect before beginning a clinical trial. The researchers also said the technique might eventually be used to treat hepatitis B and HIV.
The other winning team was led by Junwei Li, a researcher at Brigham and Women’s Hospital and a visiting scientist at MIT. The researchers developed a solution that, once inside the small intestine, undergoes a reaction and coats it with a temporary adhesive. Giovanni Traverso, an assistant professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital, was the senior author of the study published in Science Translational Medicine.
Li said that using the coating to make drug delivery more efficient was one of the researchers’ main goals. Some drugs are metabolized quickly and largely go to waste before the body absorbs all the medication, he said. The coating would slow absorption of a drug, the researchers reasoned. The technology could not only make drugs more effective, said Li, but less expensive.
“If we can increase this [absorption] by, for example five times, then you can lower the cost by five times,” he said.
The solution is mainly made up of dopamine, which exists commonly in the body as a neurotransmitter. Once the dopamine enters the small intestine, it reacts with an enzyme called catalase in the intestinal lining. The reaction creates an adhesive polymer that temporarily coats the small intestine with a kind of molecular glue. “The coating can stay there for 24 hours, which really maximizes the absorption window,” Li said.
The small intestine is where most nutrients and also drugs are absorbed by the body, and also where the highest concentration of catalase is found. Because of this, the researchers found that the dopamine would not form a coating in areas they weren’t targeting, like the stomach. They tested the method in human and pig tissue in the lab, and also in live pigs, whose GI tracts are similar to those of humans. The solution was delivered into the pigs through a tube, but the researchers envision that patients would be able to drink it or swallow it as a pill or capsule.
In a series of experiments, the researchers investigated potential applications of the solution. In one, they found that the drug praziquantel, which treats the tropical, parasitic disease schistosomiasis, lasted far longer in pigs when combined with the solution. Praziquantel is normally taken three times a day, so using this technique could help decrease the dosing frequency.
Li and his team also found that in pigs, the solution created a more effective way to deliver the enzyme lactase to the digestive system, which could help lactose intolerant people, and that the coating decreased the speed at which glucose was absorbed, which could provide an alternative treatment for people with diabetes or obesity.
Safety testing of the solution in pigs and rats did not find any concerns.
The two teams emerged triumphant from nearly 130 submissions to STAT’s contest, out of which 64 entries were selected for the bracket. The submissions came from across the country and were selected based on scientific rigor, originality in their field, and potential impact.
Jerome is grateful for the large community who supported his team’s research on social media, many of whom have herpes. He said he has also enjoyed looking at all the competitors’ research projects.
“I’ve learned a lot,” he said.
Li said he enjoyed the engagement with his team’s research and learning about other teams’ studies. While some of the students in the lab were quite invested in the competition, Li said he was never especially attached to winning. He sees the competition as being about exposing people to and engaging with exciting new research. He also said the competition was a welcome distraction and a way to connect with other researchers in a time of social isolation.
“It was really fun, especially during quarantine,” said Li.