Mice differ from people in many ways. But over the last decade, scientists have succeeded in engineering mice that are more humanlike in their ability to be infected with HIV, making it possible to study the disease, and develop vaccines and therapies, in these small animals.
As Daniel Claiborne, Ph.D., a Caspar Wistar Fellow who started in August, gets his lab off the ground, these so-called humanized mice, which he worked to optimize during his postdoctoral research, will be central to his research goals. Dan will take advantage of two other technologies that have recently come of age: CAR T-cell therapy, which is used to treat certain blood cancers, and transcriptomics — or the large-scale study of gene expression, to tease apart how T cells function in these mice and, like in people, stop functioning during HIV infection. It was truly a trifecta — “none of these technologies existed, even in isolation, until fairly recently,” Dan said.
Dan clearly remembers the thrill of reading the email from The Wistar Institute inviting him for a job interview. “It felt good because I had a shot to talk about what I’m passionate about and to explain to people my vision,” Dan said. As soon as the interview was over, he had no doubt that Wistar was where he wanted to be.
In fact, the timing seemed perfect because, although the humanized mouse model has not been widely embraced, the Institute believes so strongly in its potential, as Dan does, that it is launching a research program around it. Since he has joined, Dan and his new colleagues have wasted no time discussing how they can collaborate together and capitalize on Dan’s deep experience working with the mice during his postdoc at the Ragon Institute of MGH, MIT and Harvard, and his understanding of which aspects of the immune system they recapitulate well and which they don’t. For example, Dan can help another lab take a small molecule they found has interesting properties in cells in a Petri dish and study it in these small animals.
Dan also looks forward to what he can learn and share with just the other new recruits, three assistant professors, who are also joining Wistar this fall. “You always have peers, but to have true peers that are just starting out is kind of amazing,” he said.
Mining the Data
Going into his interview, Dan already knew the Philadelphia area well. As a postdoc, he had been collaborating with James Riley at the University of Pennsylvania, combining his expertise with HIV-susceptible humanized mice and the Riley lab expertise making CAR T cells specifically designed to recognize and kill HIV-infected cells.
This collaboration will continue now that Dan is at Wistar. While the Riley lab is focused on developing CAR T cells as a potential cure for HIV, Dan sets himself apart by making use of these engineered T cells, which he calls an “untapped resource,” to tease apart how they become exhausted and lose their ability to fight off HIV, just like natural T cells do, during infection. Dan plans to use a host of molecular tools to try to prevent CAR T-cell exhaustion and then probe what the precise pathways and gene expression profiles are within these cells that allow them to retain anti-HIV activity. The experimental system is in place, Dan said, and now “we just need to mine it.” What they find could ultimately help his collaborators who are working toward a CAR T-cell HIV cure figure out ways to make the therapy more effective.
For Dan, collaborations are not just really fun but absolutely necessary. “I tend to take on more ambitious and risky projects that take a lot of labs working together. I think biomedical science has evolved into that, where the questions we are asking really involve a lot of expertise that rarely is contained in one lab.” He thinks Wistar is fertile ground for these relationships because the small private institution really embodies the spirit of partnership.
Inspired by Immunology
For Dan, being easily bored has served him well. It made the idea of science, and constantly learning something new, seem very appealing to him as he was growing up. As much as Dan always knew he wanted to be a scientist — and counts himself in the lucky minority for figuring it out early, he recharted his course as an undergraduate at Florida State University. He started off focusing on organic chemistry, but soon decided the lab work was far too dull. Then Dan took an immunology course about halfway through his degree and he was hooked. He promptly started a project in the professor’s lab and never looked back. “I was so fascinated with immunology because it was so clear that we didn’t know anything, but the things that we did know were awesome,” Dan recalled. For the first time, he was motivated to go for his Ph.D., which he got at Emory University, instead of getting a job after college.
While being easily bored turned Dan on to science, being stubborn made him stick with it. Through what he calls the “fourth year grad school slump” and the ups and downs of his postdoc, he refused to quit. “It’s just part of how I’m wired, I keep after it until I get somewhere,” Dan said. “I have been lucky that I have not suffered from a lack of conviction.”
In addition to brainstorming about collaborations with his new colleagues, Dan’s first few weeks at Wistar have involved a lot of ordering lab supplies. Even though he oversaw a small team of scientists during his postdoc, it never really occurred to him that many of the reagents they used for experiments didn’t just come with the lab space. Nevertheless, he is enjoying the experience. “It is like Christmas, you get to go on a shopping spree.”
There is plenty for Dan to set up at in his new home, too. He and his wife moved to the Philadelphia area with their three-year-old son and their infant son, who was born about the same time that Dan started his own lab. He jokes that he will get back to his old hobbies such as lifting weights one day, once he gets a handle on some kind of work-life balance. “It is all good things, just smashed into a really small timescale,” Dan said.
Written by Carina Storrs, Ph.D.