Sep 18, 2019 | Genetics, Immunology, Microbiome
In 2017, the University of Chicago Medicine established the Duchossois Family Institute: Harnessing the Microbiome and Immunity for Human Health (DFI). The institute is dedicated to developing new knowledge about human biological defense systems, including the microbiome, and their potential for preventing disease and maintaining lifelong wellness.
After a national search, renowned physician-scientist Eric G. Pamer, MD, was recruited to become DFI’s inaugural director in July 2019. Formerly with Memorial Sloan Kettering Cancer Center, Pamer is tasked with building the DFI’s research capabilities, from recruiting new faculty and building core facilities to translating discoveries into treatments that can be used in the clinic. UChicago Medicine spoke to him about his plans, and what he hopes to see the DFI accomplish.
Read the full Q&A on “The Forefront” >>
Sep 16, 2019 | Cancer, Immunology, Microbiome
by Elise Wachspress
In the world of cancer research, Thomas Gajewski, MD, PhD, is a rock star. And not just because he plays lead guitar for The Checkpoints, an all-cancer-researcher band that includes his longtime colleague Jim Allison, last year’s Nobel Prize winner for physiology or medicine (and professor at the MD Anderson Cancer Center) on harmonica.
Named a Giant of Cancer Care in 2017, Gajewski has, for more than two decades, worked in cancer immunotherapy, a field only recently recognized as the most promising for actual cancer cures—a word that makes most clinicians nervously back away.
Gajewski has dedicated his career to figuring out how to help patients’ immune systems fight cancer from within. Much of his work has focused on checkpoint inhibitors, proteins which our bodies use to keep immune responses in check, so we don’t attack beneficial bacteria or our own cells. But checkpoint inhibitors can also keep our immune system from killing cancer cells (and thus the name chosen for Gajewski’s band).
Over the past century, the idea of fighting cancers with immunotherapies has fallen in and out of favor multiple times. But oncologists are now watching the field—and Gajewski’s work—with excitement. Recent research shows that, in metastatic melanoma and many other solid cancers, immunotherapies cause tumors to regress or even disappear in 30-50% of patients. These treatments are often significantly less toxic than surgery, radiation, or traditional chemotherapy. And by training the body to recognize and kill cancer cells, immunotherapies offer an opportunity for truly durable results, offering patients a chance at living long, healthy, cancer-free lives.
But Gajewski, the AbbVie Foundation Professor of Cancer Immunotherapy, is focused past these success stories. What drives his curiosity and his passion is understanding why immunotherapies fail. And one of his most remarkable findings is that the bacteria patients carry in their guts—their microbiome—can strongly influence whether or not cancer immunotherapy works.
As with most scientific breakthroughs, this one came through a combination of dogged dedication, careful observation, and wonder. When Gajewski and his team implanted mice with melanoma tumors, they noticed immunotherapy response differed depending upon the commercial source of the animals themselves; one supplier’s mice fared much better, even though they were identical strains. The team finally found that the mice were delivered to the lab carrying a certain type of gut bacteria responded much better to the therapy.
Even more tantalizing: when the two sets of mice were housed together, outcomes improved for the mice from the other supplier. Sharing these healthy gut bacteria was key to therapeutic success.
Gajewski and team are now working to identify bacteria found in humans that can produce these effects in mice. The team will use a system in which germ-free mice are colonized with microbial material from patients, implanted with tumors, and then treated with immunotherapy drugs. The goal is to figure out the exact mechanism of how bacteria promote or restrict anti-tumor immunity—knowledge that will provide a foundation for new therapeutics. By developing computational algorithms which integrate genomic sequencing of the microbiota, the tumor oncogenes, and germline polymorphisms, they aim to get a comprehensive view of immunotherapy success versus resistance in each individual patient.
The goal is a diagnostic approach that will help clinicians—like Gajewski himself—decide the most effective way to use immunotherapy for each patient and tumor, perhaps by simply introducing new types of bacteria to a patient’s gut. While we commonly think of probiotics as a way to improve digestion or alleviate allergies, we may one day find an avenue to use much more sophisticated, designer probiotics to treat some cancers.
Gajewski recently received a promise of nearly half a million dollars from the Melanoma Research Alliance to advance this research. However, securing this award requires him to match the grant with similar funding from other sources.
For anyone ready to invest in much more effective, less debilitating treatments—perhaps even cures—for cancer, Gajewski has a strategy ready for prime time, a track record of unusual research success, and a group of musicians ready to sing about it.
Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office
Mar 28, 2019 | Commercialization, Immunology, Microbiome, News Roundup
A selection of health news from the University of Chicago and around the globe curated just for you.
Polsky Center’s Life Science Launchpad partners with faculty to launch startups
The Launchpad bridges the gap between academic research and entrepreneurship by forming hands-on partnerships with life sciences researchers who seek to convert their research products into business ventures. Cathryn Nagler and Eugene Chang featured. (Polsky Center for Entrepreneurship and Innovation)
How the microbiome could be the key to new cancer treatments
The effectiveness of drugs that help the immune system fight cancer cells appears to depend on bacteria in the gut. (Smithsonian magazine)
Training cells to attack
Groundbreaking CAR T-cell therapy engineers cells to target tumors. Michael Bishop featured. (Chicago Health)
How to reduce the chances of being hospitalized for Crohn’s disease
Take these steps to lessen the risk of complications from the inflammatory bowel disease. David Rubin featured. (U.S. News and World Report)
Real innovation is going to be centered on how we collect, standardize, and harmonize data
Bridging the gap between clinical care and research means creating two-way collaboration, and improving the way in which data is collected, organized, shared. Sam Volchenboum featured. (Outsourcing-Pharma.com)
Nov 21, 2018 | Immunology, Microbiome, Research
by Elise Wachspress
If you think the invention of the microscope was a pivotal moment in the development of biological knowledge, you might be pretty impressed with the flow cytometer.
This technology allows scientists to “see” an entire stream of individual cells, detecting the features of each as they rush single file through a tiny tube. A laser (or sometimes several) shines through or bounces off the cells as they pass by. Depending on the specific kinds of fluorescent indicators applied, flow cytometry can efficiently characterize 30 or more factors in hundreds of thousands of individual cells and even sort them as they surge through the tube.
For scientists studying the microbiome, the immune system, and their intersection, flow cytometry—we celebrate its 50th anniversary this year—was a breakthrough. The tool provides an efficient way to both distinguish the various bacteria in a sample and identify human immune cells and the particular antibodies they carry.
Last fall, a team led by Jeffrey Bunker (a student in the University of Chicago’s revered Medical Scientist Training Program) and his mentor, Albert Bendelac, MD, PhD (A.N. Pritzker Professor of Pathology) used flow cytometry to understand an important interaction between the gut and the bacteria that live there.
The gut is the source of large quantities of immunoglobulin A (IgA), the most abundant antibody protein in mammals. In our intestines, where we depend on a diverse community of bacteria to digest our food and make important by-products like vitamins, IgA sticks to the surfaces of the microbes, allowing them do their work while keeping them from settling in on the mucous membranes that line the gut. These membranes are the critical barrier that separates the energy furnace in our intestines from the rest of our bodies.
But how do IgA proteins—which defang bacteria with a kind of key-in-lock technique—recognize the many different kinds of bacterial locks and latch so specifically on to each? Thanks to flow cytometry, the team could identify the many types of bacteria involved, so they knew the complicated job IgA was up against.
What they found was that IgA cells in the gut were “polyreactive”: they could clasp very specifically onto many different types of bacteria. This Swiss-army-knife ability was not the result of intervention by other parts of the immune system or hyperactive mutations within the IgA cells themselves. Even changes in diet (and the presumed alterations in the balance of bacteria induced by these changes) did not significantly affect their ability as quick-change artists.
This research demonstrated that IgAs, part of our adaptive immune system, actually have the innate—born in—ability to recognize individual types of bacteria, even new ones, and do what they need to do to create the right latch. The takeaway is that the bacteria in our guts and our own immune systems have clearly been evolving together, probably for millennia, and that the immune systems of new humans have innate ability to recognize “old” bacteria—those that have been fellow travelers with the human race for generations.
This is just one more bit of evidence that none of us are truly individuals. Each human being is a colony of species living together in community—communities with very long histories and intense cultures—and we’re wise to go with the flow.
This past summer, Bunker and Bendelac went on to publish a major review article on IgA biology for the journal Immunity. There they presented a new framework integrating two distinct types of immunity that protect the gastrointestinal mucus membranes: the polyreactive IgA described above and much more “bespoke” key-and-lock responses to pathogens and vaccines provided by other kinds of immune cells.
Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office
Oct 31, 2018 | Immunology, Microbiome, News Roundup, Research
A selection of health news from the University of Chicago and around the globe curated just for you.
Three UChicago Scientists Earn NIH Grants to Pursue Innovative Research
Three UChicago scientists—including Jun Huang, who studies the immune system and its role in treating infectious diseases and cancer—each have been awarded $1.5 million grants over five years from the National Institutes of Health in support of their innovative, high-impact biomedical research. (UChicago News)
Noah’s Ark for Microbes
A team of researchers, including Jack Gilbert, is calling for the creation of a global microbiota vault to protect the long-term health of humanity. (Science)
These 19 MassChallenge Startups Just Won $1.65M
Nineteen early-stage startups, including Oxalo Therapeutics, won a total of $1.65 million at Wednesday night’s MassChallenge awards ceremony. (BostInno)
Polsky Opens its High-Profile Accelerator to Alumni Startups
UChicago’s New Venture Challenge, ranked among the top accelerator programs in the country, is launching an alumni track as part of its annual startup competition. (American Inno)
Meet the Carousing, Harmonica-Playing Texan Who Just Won a Nobel for his Cancer Breakthrough
This year, the Nobel Prize was awarded to James Allison, PhD—a colleague, friend, and “The Checkpoints” bandmate of Tom Gajewski—for research that laid the groundwork for the development of checkpoint inhibitor immunotherapies. (WIRED)
Sep 24, 2018 | Immunology
by Matthew Eckwahl, PhD
Postdoctoral fellow in the Department of Biochemistry & Molecular Biology
In Lewis Carroll’s Through the Looking-Glass, Alice finds herself in a perplexing circumstance: she keeps running faster and faster but goes nowhere. The Red Queen remarks, “Here, you see, it takes all the running you can do to keep in the same place.”
This whimsical story gave name to a classic evolutionary idea (posited by famed UChicago biologist Leigh Van Valen) called the Red Queen effect: that organisms must constantly adapt just to survive against other opposing organisms. This evolutionary dynamic arises not only between large, charismatic mammals—say, cheetah vs. gazelle—but also in the molecular realm. A constant “arms race” exists between viruses and their hosts, driving their co-evolution. Thus, although humans have intricate systems to detect and combat pathogens, viruses have equally cunning ways to counter these defenses and fight back.
Michaela Gack, PhD
Michaela Gack, a professor of microbiology at the University of Chicago and last year’s recipient of the prestigious Vilcek Prize, is an expert at unraveling the complex interactions between virus and host. By helping us better understand how viruses evade the immune response, Gack’s research may lay the groundwork for new vaccines and antiviral treatments that help us outpace our viral nemeses.
The first and most important step in defeating microbial invaders: detection. When viruses invade a cell, they often trip cellular alarms that distinguish “self” from “non-self.” The human immune system has two main parts, innate and adaptive. Evolutionarily older, the innate immune system provides a broad defense against bacteria and viruses. Vigilantly scanning for tell-tale features of pathogenic intruders, innate immunity is indispensable for our well-being. Once triggered, this defense system springs into action within hours to eliminate the threat and keep us safe.
One star player in the innate immune response and a recurring protagonist in Gack’s research is RIG-I. Despite its lackluster name, RIG-I proteins are present in nearly every cell of the body, functioning as viral sensors. After latching onto specific viral molecules (specifically, a unique portion of viral RNA), RIG-I undergoes a dramatic transformation: it changes shape, and another cellular protein paints it with specific chemical tags. Thus adorned, RIG-I flashes the alarm for viral invasion. (Indeed, this work, which significantly advanced our understanding of the activation process, earned Gack her PhD degree).
Of course, like any talented thief, successful pathogens have ways to circumvent the cell’s intruder warning system. Dengue virus, which the Gack lab studies along with several other viruses, is particularly adept at evading detection and represents a serious global health threat. Belonging to the same virus family as Zika and the West Nile virus, dengue is spread by mosquitoes. Alarmingly, nearly 400 million cases of dengue infection are reported each year, with about two-thirds of the world’s population at risk. While many people infected with dengue show relatively mild symptoms or none at all, for others, the virus can be life threatening—in fact, its alternative name is “breakbone fever.” Given the urgent need for better vaccines and antiviral treatments, it is critical that we better understand how dengue virus outmaneuvers the immune system.
A 2016 report by Gack and former graduate student, Ying Kai Chan, solves part of this mystery. They discovered that both dengue and West Nile make a protein that prevents RIG-I from raising the alarm.
How? One straightforward possibility—that the viral proteins directly target and destroy RIG-I—didn’t seem to happen. Instead, Chan and Gack found that the virus acts to block an intermediary messenger, the cellular protein that shuttles RIG-I to deliver its warning—operating somewhat like a classic movie villain who cuts the phone cord before the police can be called. By stopping the partner protein from interacting with RIG-I, the virus can remain hidden from the immune system.
Gack’s team took this a step further, testing what would happen if they altered the viral region that alerts the messenger and prevents the “emergency call” from connecting. They showed that the mutant dengue virus could no longer stifle RIG-I but prompted a strong immune response.
Gack’s work, with its valuable insights for future vaccine development, has broader resonance. Dengue virus is far from alone in targeting RIG-I: her additional research revealed that the measles virus and human papillomavirus also have ways to subvert this pathway. Other labs have unmasked even more strategies that Ebola and influenza viruses use to disable RIG-I as well.
Millions of years of evolutionary conflict between virus and host have given rise to an astonishingly complex immune system and elaborate viral evasion tactics. By better understanding both how cells sense pathogens and how viruses elude recognition, we can develop not only more effective antiviral treatments but also new strategies to boost the immune response. As the Red Queen reminds us, “If you want to get somewhere else, you must run at least twice as fast as that!”
