Turning on a scientific dime

Tim Bates, a fourth-year Ph.D. candidate at OHSU, began his graduate research three years ago in the lab of Fikadu Tafesse, Ph.D., investigating ways to stop tuberculosis infections. In the past six months, however, Bates’s work has shifted to SARS-CoV-2. While most labs on the OHSU campus remained empty for months after non-essential research was put on hold, Tafesse’s team realized that they had the tools and perspective to contribute to COVID-19 research. Fikadu Tafesse, Ph.D., honored with 2020 Innovation Award
On Nov. 12, 2020, Fikadu Tafesse received an American Lung Association 2020 Innovation Award to advance his research into the ways M. tuberculosis alters lipid metabolism in order to invade, persist and propagate inside immune cells. The goal is to help in developing new therapies for tuberculosis infection, which infects almost one-third of the world’s population. One signature tool that allowed them to turn on a scientific dime: alpaca antibodies.

Why this camelid?

“All infectious bacteria and viruses have to solve the same problems,” said Bates. “They have to find a cell to get inside the host.” One of the body’s most effective defense mechanisms is the production of antibodies, small proteins that attack invading viruses and bacteria. Most animals, including humans, produce antibodies that are made up of two components. But alpacas and their relatives are an evolutionary anomaly: They generate antibodies that are just as effective at shutting down viruses and bacteria — but the antibodies have only one component.

The power of antibodies comes from their ability to recognize and “stick” to invaders. A virus or bacteria covered with stuck antibodies becomes unable to infect other cells or tissues and becomes a target for other immune cells in the body. Despite their smaller construction, alpacas one-component antibodies are as sticky as conventional two-component antibodies.

Smaller and simpler

“The main advantage here is that since these are evolutionarily designed to be effective as single component antibodies, when we isolate that single binding domain it’s much closer in binding power to a conventional antibody,” said Jules Weinstein, another fourth-year Ph.D. candidate in the Tafesse lab also working on this project.

In other words, the smaller size of these alpaca antibodies allows researchers to easily isolate just the gene for the sticky part of the antibody and engineer flasks of bacteria to mass-produce those virus-sticky segments, called “nanobodies,” by the billions.

The power, the beauty of these nanobodies lies in their size and their simplicity.

“These nanobodies are amenable for all sorts of things, from a bioengineering and a chemical synthesis point of view”, said Tafesse, assistant professor of Molecular Microbiology and Immunology, School of Medicine.

If a nanobody that can attack a specific invader — a coronavirus, for instance — were properly characterized, labs could re-engineer nanobodies to carry and deliver drugs or other therapeutics directly to the target viruses in the patient. Even without the extra bells and whistles, however, using just the purified nanobodies as a way to cover and neutralize pathogens holds promising medical potential.

What makes a successful pivot possible?

The flexibility of alpaca antibodies was not the only key to the Tafesse lab’s successful research shift; their cooperative and collaborative spirit greatly contributed to how quickly they were able to hit the ground running with their SARS-CoV-2 experiments.

This detour into coronavirus research almost didn’t happen, said Tafesse. “I wasn’t sure it was the right call, because I thought it might be a distraction from [the graduate students’] theses.” Ph.D. candidates at OHSU like Bates need to complete three to four years of research on their chosen scientific topic to form their mandatory dissertation thesis, so departures from that work threaten to delay graduation. “But I called them, and I just discussed these ideas and they just said ‘OK, we’re going to do this’. It was amazing how excited they were.”

Scotty Farley, a fifth-year Ph.D. candidate in the lab, remembers how their research group experienced the early, stressful days of the lockdown as motivating: “It was those three weeks of really intensive reading and thinking about [how to approach our coronavirus research] that set it all up. We would have a normal lab meeting, but then we’d have a ‘journal club’ where we all brought in new coronavirus papers and read and talked through everything we were reading. We were all learning this completely new field together.”

Farley’s work on how viruses and bacteria interact with cell membranes laid the groundwork for the lab’s first coronavirus research proposals, and that opened the door for subsequent steps like the nanobody experiments. This momentum says a lot about how well the lab is composed and led. Farley continues, “I really respect the way that Fikadu has designed the lab to have different people with different areas of expertise, in a lovely way that makes it possible for the entire lab to work together and pivot together.”

At the bench with SARS-CoV-2

Back at his lab bench in a heavy white lab coat and two layers of purple nitrile gloves, Bates is in the process of isolating the antibodies from the blood samples of alpacas that have been vaccinated with an important coronavirus piece called the “spike” protein. With these antibodies isolated and identified, he and Weinstein will be purifying and then generating large amounts of similar nanobodies in Petri dishes that will be used for coronavirus research. Being in one of the only labs in Oregon with the clearance and tools to work with the coronavirus so directly, Bates is happy to be able to contribute to the pandemic research efforts. “I feel very fortunate to have been in a position where we could very quickly shift our focus. Pretty quickly, we knew we could contribute to coronavirus research, and we just said ‘let’s get that started’.”