On the fringes of typical
UTSW Microbiology: Small department, super impact
UT Southwestern’s Department of Microbiology could be described as small but mighty, surpassing its size in terms of scientific advances against pathogenic diseases. Could that success be due in part to recruiting and collaborating in ways that reflect the University’s “no-fences” tradition of reaching across disciplines?
“It’s a group of people who collaborate well without having ‘X’ number of people who work with bacteria and ‘X’ number who work with viruses,” said Department Chair Michael Norgard, Ph.D., describing the factions that once divided the field. Traditionally, large microbiology departments split into two camps based on the thinking that, like the species they studied, bacteriologists and virologists had little in common. Research at UT Southwestern, where interchange between both groups and with faculty in disciplines all across campus is encouraged, changed that outlook.
“We’re a relatively small Department, and over the years I’ve tried to get the best people I could possibly get,” Dr. Norgard explained. “I knew that gathering exceptionally talented scientists together regardless of their subdiscipline of choice, and placing them within close proximity to one another would allow magic to happen!”
Among the most recent recruits is Assistant Professor of Microbiology Kevin Forsberg, Ph.D., one of only 15 early-career investigators across the country selected last year for the 2022-2025 class of Searle Scholars. The award, funded through the Searle Funds at the Chicago Community Trust and administered by the Kinship Foundation, supports exceptional researchers pursuing high-risk, high-reward projects.
Deciphering a timeless battle
Dr. Forsberg said the award, which provides $100,000 a year for three years, will advance his studies of what he calls the arms race between bacteria and phages, the viruses that infect bacteria. Phages transmit disease only to bacteria, not humans.
“Bacteria and phages have been locked in battle for billions of years, spurring bacteria to invent a diverse array of anti-phage defenses,” Dr. Forsberg said. “In response, phages have devised myriad counterdefenses to overcome bacterial immunity and reestablish infection.” Most of the defenses and counterdefenses are undescribed, providing a rich area for research questions with answers that might someday help make phages into better therapeutics or teach us about the early evolution of the antiviral immune responses used in humans today.
Credit: Tamanash Bhattacharya
“It’s a high honor for Kevin to have gotten the Searle Award. The Searle is such a big deal, testimony to the importance of the work he’s doing,” said Dr. Norgard, known internationally for his expertise on bacteria that cause syphilis and Lyme disease.
The Searle Award will speed Dr. Forsberg’s work studying bacteria’s molecular defensive mechanisms. Those include CRISPRs (clustered regularly interspaced short palindromic repeats), in which bacteria produce enzymes that target and destroy specific pieces of phage DNA, he said. In the past two decades, scientists have adapted that bacterial defense system into the game-changing CRISPR-Cas9 gene-editing technology that was awarded a 2020 Nobel Prize.
In response to bacterial CRISPR, phages have developed anti-CRISPR proteins to inhibit that DNA cutting. Because most anti-CRISPR proteins have yet to be revealed, the Forsberg lab runs functional genetic screens, looking for traits and tracing those phenotypes to reveal hidden genes that they can investigate.
“Kevin’s work has attracted much attention because he’s developed novel screening assays to uncover a number of potentially new anti-phage and phage counterdefenses that haven’t yet been recognized or characterized,” Dr. Norgard said. “He is studying really foundational processes that may occur in many bacterial pathogens and likely are central to their ability to be infectious.”
Growth of a scientist
Dr. Forsberg grew up outside Madison, Wisconsin, where he credits his father and a high school teacher with convincing him that he could become a scientist. He earned his undergraduate degree from Arizona State University and his Ph.D. from Washington University in St. Louis, studying antibiotic resistance genes in soil.
Though Dr. Forsberg entered graduate school with the notion that he might pursue a career in neuroscience, that changed when he became exposed to the staggering diversity of unexplored genes and functions in the microbial world. To him, the genomes of bacteria (and their viruses, the phages) felt like uncharted frontiers. Though he didn’t know what he’d find, Dr. Forsberg was confident that a career devoted to exploring these wild spaces would turn up discoveries that were utterly new.
He was a postdoctoral researcher at the Fred Hutchinson Cancer Center in Seattle before joining UTSW as an Endowed Scholar in 2021. Dr. Forsberg’s work required him to hit the ground running, networking with faculty in and out of the Microbiology Department, including colleagues specializing in genetic evolution and advanced screening techniques, Dr. Norgard said.
Luckily, the UTSW Microbiology Department has a great track record of building relationships across disciplines. In fact, one of Dr. Norgard’s early recruits did groundbreaking work that helped lead to today’s harmony between bacteriologists and virologists.
Lonely no more
Among the virologists greeting Dr. Forsberg was Professor of Microbiology Julie Pfeiffer, Ph.D., then studying polio, a nearly eradicated RNA virus found in the intestinal tract. Like Dr. Forsberg, Dr. Pfeiffer also worked hard to form alliances upon arrival at UTSW. Dr. Norgard had recruited her in 2006 to be one of three virologists in the Department, although by her second year, she was the Department’s only one.
In response, Dr. Pfeiffer forged many alliances with bacteriologists across campus, including a collaboration with Lora Hooper, Ph.D., now Chair of Immunology and a Professor with additional appointments in Microbiology and in the Center for the Genetics of Host Defense. Dr. Hooper is also a Howard Hughes Medical Institute Investigator and runs the University’s colony of germ-free mice raised without exposure to pathogens.
Dr. Pfeiffer’s courage was tested most dramatically while exploring a question that straddled virology and bacteriology. A graduate student working on the project reported a confounding experimental result.
She and the student had given mice antibiotics to knock out friendly gut bacteria, which were considered protective against the growth of harmful bacteria. They hypothesized that without gut bacteria, the mice would lose protection from viruses, too. Using polio, a virus known to replicate in the gut, they found the opposite of what they expected. Animals lacking intestinal bacteria survived polio better than control mice.
That led to months of follow-up experiments to grapple with what was going on. Ultimately, Dr. Pfeiffer suggested a technique used in polio research in the 1960s. The researchers inserted a light-sensitive dye into the poliovirus so that only viruses that had undergone replication in mice would survive light exposure.
Conducting their experiments in the dark by the glow of a photographer’s red light, she and her graduate student observed minuscule levels of replication occurring in the antibiotic-treated mice. Ultimately, they showed that gut bacteria promote viral replication rather than protect against it.
The Pfeiffer lab’s discovery of alliances between gut bacteria and intestinal viruses like polio, published in 2011 in Science, shook up the world of microbiology as scientists got their minds around the idea that rather than protect against viral replication, friendly bacteria could promote it.
Those celebrating the UTSW advance included scientists who study norovirus, a common cause of vomiting and diarrhea that spreads quickly among people in confined groups, such as those on cruise ships or at evacuation centers during disasters. Despite four decades of effort, norovirus had resisted being grown in culture, meaning that the only way to study viral replication was with humans who volunteered to get sick.
As described in a 2014 study in Science, that all changed when a norovirus researcher who had read Dr. Pfeiffer’s work added gut bacteria to norovirus cultures and the virus grew, creating a more humane way of studying the nasty bug’s replication.
It’s amazing what can happen when the fences come down.