by Matthew Eckwahl, PhD
Postdoctoral fellow in the Department of Biochemistry & Molecular Biology
Take a look at the people around you: besides identical twins, you’ll likely see an array of differences, from height to hair color. Humans vary extensively, not only in appearance but also in less tangible traits. Not surprisingly, these differences often have at least some genetic basis. The immune system is no exception. Individuals differ considerably in their ability to fight off infections and their risk of autoimmune diseases, like type 1 diabetes and inflammatory bowel disease. What’s more, the human immune response has been shaped over time by evolution.
Luis Barreiro, an associate professor at the University of Chicago, seeks to understand how natural selection influences the evolution of our species; in particular, he’s interested in how past evolutionary events affect the immune response. By identifying the genetic factors contributing to infectious disease susceptibility, Barreiro aims to uncover new genes and pathways linked to disease, opening the door to fresh research approaches and novel therapeutic targets.
In an influential 2016 report, Barreiro, then at the University of Montreal, helped shed light on differing disease rates between Americans of African and European descent. His team’s findings are particularly important given some troubling health disparities in autoimmune disorders such as multiple sclerosis and lupus. Young women of African ancestry, for example, are three times more likely than women of European descent to be affected by lupus, a chronic disease in which the body’s immune system attacks its own healthy tissues.
While factors such as environment and socioeconomic status undoubtedly play a role in these health discrepancies, Barreiro’s group showed that the immune response itself differs unexpectedly between people of African and European ancestry. How did they do this?
They first collected blood samples from both groups and isolated their macrophages, immune cells that “eat” bacteria and other parasites. Next, they infected these immune cells with bacterial pathogens—either Salmonella or Listeria, both common culprits of food poisoning—and used leading-edge genomic sequencing techniques to see how infection altered gene activity. Remarkably, they discovered that about one-third of genes active in macrophages showed different activity in people of European versus African descent.
It turns out that many of these genes are involved in activating the immune system: people of African ancestry showed much higher expression of genes associated with inflammation compared to those of European origin. While some of these are linked to known immune diseases like celiac and Crohn’s disease, they also provided at least one advantage: macrophages from African Americans were far better at devouring bacterial invaders and eliminating infection.
Incredibly, interbreeding with another human species—Neanderthals—also plays a role in this story. Although Neanderthals went extinct around 40,000 years ago, they left an indelible mark on the human genome, contributing to about 2 percent or less of human ancestry. Barreiro’s team identified immune variants that were preferentially passed on from Neanderthals to people of European—but not African—ancestry. Notably, these DNA variants are associated with reduced inflammation. (In a complementary report, the Barreiro lab explored a specific immunity gene that protects against viral infection and also appears to have been obtained from Neanderthal interbreeding.)
One mystery remains: what evolutionary pressures gave rise to these divergent immune responses? One possibility is that humans who migrated out of Africa experienced fewer exposures to potentially dangerous microbes, making a robust inflammatory response less valuable or even harmful. In contrast, Africa’s tropical environment may have favored a stronger immune response to combat more frequent pathogen exposure.
Regardless of the ultimate cause, each population seems to have ended at a different “balance point.” The immune system operates somewhat like a smoke alarm, keeping us safe from possible disaster. And like a smoke alarm, the system should respond proportionally to the threat at hand: not sensitive enough, and you risk being unaware as fire engulfs your house. But too sensitive, and the alarm shrieks at the first hint of burnt toast. There’s always a tradeoff. While an overactive immune system is better at fending off parasites, it may also lead to higher risk of autoinflammatory and autoimmune diseases.
Carl Sagan, a famous astronomer and science popularizer, once said, “You have to know the past to understand the present.” By highlighting how long-ago evolutionary events affect our genome, Barreiro’s findings expose a key influence that human ancestry has on immunity. Further, his research underscores the necessity of expanding racial diversity in clinical trials, where commonly more than 80 percent of participants are white. Together, by helping us better understand the evolutionary forces shaping our species, the work of Barreiro and others may contribute to the eventual dream of precision medicine.
by Claire Stevenson
Graduate student in the Committee on Development, Regeneration and Stem Cell Biology
Two University of Chicago-based startups, Oxalo Therapeutics and ImmunArtes, recently beat out fierce competition to be chosen for MassChallenge Boston, a global start-up accelerator with a focus on high-impact entrepreneurs. With 1600 teams vying for a spot and an 8 percent acceptance rate, this was the most competitive year yet, so getting into the program says a lot about the excitement around these two companies.
MassChallenge is a not-for-profit accelerator that offers world-class programming. The vision of its founders is toward a “creative, inspired society in which everyone is empowered and has the resources to maximize their impact.” Through its flagship location in Boston, and many others worldwide, MassChallenge runs programs and draws teams from around the world.
A sought-after feature of MassChallenge is the opportunity to make connections with top corporate partners and build a network of expert mentors. The program culminates with teams competing for up to $1.5 million in cash prizes to help grow their businesses, but according to Yang Zheng, co-founder and COO of Oxalo Therapeutics, “the real prize is getting in the Challenge and all the connections you make.”
Oxalo and ImmunArtes both formed less than a year ago and have hit the ground running with investment from the University of Chicago Polsky Center for Entrepreneurship and Innovation. Though Polsky’s Innovation Fund, Oxalo and ImmunArtes won $250,000 and $175,000, respectively, in new venture funding. Oxalo was also awarded $25,000 through the Polsky Center’s New Venture Challenge, the top university accelerator program in the nation. “Chicago is great for STEM and entrepreneurship,” noted Zheng. “The resources here helped us get to this stage.”
Oxalo Therapeutics is developing a first-in-class therapeutic to treat kidney stones, a painful condition that damages the kidneys and increases risk of chronic disease. Oxalo’s preventative drug, derived from a natural gut bacterium, will offer significant advantages over current treatment methods. The Oxalo team’s scientific lead is Hatim Hassan, MD, PhD, a UChicago nephrologist; Zheng, an MBA candidate at the UChicago Booth School of Business, leads the business side.
At MassChallenge Boston, Zheng is particularly excited about the relationships Oxalo is forming with new mentors. They are getting strategic advice about the condition they aim to treat and the drug development route they are pursuing. “The mentors are the biggest help so far,” he said.
ImmunArtes, Chicago’s other competitor, has developed a novel vaccine against staph infections, including the antibiotic resistant strain known as MRSA. Staph infections are a major issue in health care, yet no vaccine currently exists. The team at ImmunArtes, led by Olaf Schneewind, MD, PhD and Dominique Missiakas, PhD, both professors of microbiology at UChicago, has engineered a staph protein that will enable them to overcome hurdles faced by previous attempts at vaccine development.
ImmunArtes is benefiting from the excellent mentorship opportunities at MassChallenge Boston and a nice sense of community that the program provides. “It’s helpful to interact with the other teams and fun to see when you can help them,” notes Chloe Schneewind, manager of ImmunArtes’s communications at MassChallenge.
The team is learning a lot from their time in Boston, but they want to maintain their connection to the Midwest. “Chicago is important to the identity of the company,” Chloe emphasized. “Boston has an entrepreneurial culture and we want to bring this back to Chicago. The Midwest doesn’t yet have the biotech startup culture it deserves.”
But Chicago’s entrepreneurial reputation is growing. “There was a push to get Chicago companies involved in MassChallenge,” Zheng pointed out. “They recognize that there is good technology here, the strong research institutes are drivers [of that].”
A prime example of this is the Duchossois Family Institute, which is making paradigm-shifting investments to push discovery forward and build toward a future in which Chicago is on the map as a center for innovative biotechnology.
by Elise Wachspress
One of the more frustrating terms in the medical jargon is “idiopathic.” The word means “arising spontaneously from an unknown cause.”
How do you fight a disease when you don’t understand how it started or what drives its progress?
Idiopathic pulmonary fibrosis (IPF), a progressive, irreversible lung disease, is especially frustrating. What starts as shortness of breath and a dry cough leads progressively to scarring and hardening of the tissue in the lungs. Patients with IPF find breathing increasingly difficult, until, gradually, they cannot breathe at all.
Pulmonary rehabilitation and supplemental oxygen can bring patients some comfort, and a few drugs may slow disease progress somewhat. Younger patients strong enough to undergo major surgery can benefit from a transplant, if a lung is available. But sadly, once a patient is diagnosed with IPF, life expectancy averages between three and four years, with mortality rates higher than most cancers.
The University of Chicago has a strong contingent of researchers and physician-scientists—pulmonologists, immunologists, microbiome specialists, big data experts—studying the disease. The University also has a growing cadre of chemists and molecular engineers focused on creating the cellular and nano-scale tools to unwind the causes of IPF and ultimately operationalize new diagnostic and treatment strategies.
In research reported last year, Catherine Bonham, MD, and Anne I. Sperling, PhD, demonstrated that patients with high levels of a certain immunological biochemical called ICOS in their blood samples had markedly better lung function than those with lower levels. They also found patients with a very low level of a second biomolecule tended to do especially poorly. Assessed in tandem, blood levels of these two substances might offer a valuable diagnostic indicator of IPF prognosis and who would most benefit from early and aggressive disease management.
Interestingly, both substances are attached to and regulate the activity of T-cells, an immune cell known to fight cancer.
The researchers also discovered another tantalizing fact. ICOS levels were exceptionally high—much higher than in the blood—in the lungs and chest lymph nodes of patients with IPF, suggesting some kind of direct connection between ICOS and the disease. “But we don’t understand what these molecules are doing there, or if their response to flood the lungs is helpful,” Bonham said.
With strong institutional expertise in immunology, UChicago researchers are well-placed to unwind the mechanisms involved, which could set the stage for developing more effective treatments. So this week, Joel Africk, President and CEO of the Respiratory Health Association (RHA) visited the University to present Bonham and her team with a grant to advance this work. The RHA called the research “high-quality, innovative, and translational.”
Because UChicago treats a significant number of patients with IPF, the team can now undertake a controlled, longitudinal study to determine whether high ICOS levels in patients is linked to improved survival over the long-term. The team will also look to explore the effects of ICOS directly in the lungs, using lung samples—both from patients with and without IPF—collected and banked laboriously by the team has over many years.
Certainly, the cross-over between the activity of T-cells in both IPF and cancer is exciting. If the disease mechanisms are indeed related, IPF scientists and clinicians will be able to stand on the shoulders of those here and elsewhere driving an explosion of research on using the immune system to fight cancer.
The Duchossois Family Institute is just the kind of shared research environment where knowledge will be pooled and inspire innovative approaches to “idiopathic” diseases. It is an investment that stands to serve thousands, now and for years to come.
Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office