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First we eat. Then we do everything else.

First we eat. Then we do everything else.

by Elise Wachspress

One of the goals of the Duchossois Family Institute (DFI) is to understand how our own individual genes, those of the microbes cohabiting with us, and the many metabolites they produce all work together to create healthy, robust biological systems—or fail to do so.

Over the past century, medical science has shown great success in creating drugs and other treatments that address human ailments and extend lifetimes. It excels in rescuing people from acute disease and fighting pathogens (like developing multiple vaccines against a new and evolving virus within less than a year). The important challenge before us now—less apparently heroic, but potentially much more powerful—is to reduce vulnerability to chronic diseases, a problem escalating all over the world, even in developing countries.

The DFI was created around a central question: what if we could tune the factors involved in human health to achieve and maintain vigor throughout our lives? If science could help humans become their most robust selves, societies around the world stand to gain in happiness and productivity, rather than just increased longevity.

To achieve this goal depends on a new kind of interdisciplinary science, one that can make sense of the endlessly complex interactions among human gene products, microbial genes and metabolites, the foods we eat, and the chemicals in our environment. To do this most rationally and efficiently, Arjun Raman, MD, PhD, wants to focus on discovering the most basic principles that underlie the structure, function, and adaptability of these relationships.

We have, he believes, a surfeit of data already captured in electronic health records, complex genetics studies, and many more sources. Now we must leverage these data, using computation, theory, and experiment, to unearth the biological “wiring diagram” that will allow us to rationally engineer solutions for human health.

In a recent paper in Science, Raman and colleagues proposed to attack this issue at the level of one critical “food web,” one both simple and complex: the “triad” of mother, newborn, and breastmilk.

We know that breastfeeding supports infant health and development and influences later cognitive ability or risk for conditions like obesity or diabetes. Studies have also suggested that nursing seems to provide lifelong health benefits to the mother, including decreased risk of sex-related cancers and cardiometabolic disorders.

While vast caches of data at the population level demonstrate these correlations, we still don’t really understand exactly how these work. By figuring out the mechanisms involved, we can identify the most critical elements, so moms—and whole societies—can set their children on a path for vigorous good health. This is especially important in cases where babies are born prematurely or in resource-limited environments, when mothers’ bodies are unready or unable to provide the nutrition babies need.

In their paper, Raman and company argue that breastfeeding is a co-adaptive system and breastmilk a “live tissue” with not only macro- and micro-nutrients, but also essential bioactive compounds (like the chemicals that give structure to the fat droplets critical for brain development), micro RNAs, even cells and microbes. In fact, the nutrients in breastmilk may initially be more important in feeding the essential microbes in babies’ guts as they are for the children themselves.

What are the factors most important for the child’s microbial community to thrive and spur robust development? In babies born too early or at an environmental disadvantage, what are the best ways to repair the gut community? How does breast milk change over the nursing arc? How do the interactions between the genomes—mother, child, microbes—and the environment work together—or not—to maximize healthy growth?

Finding the answers to these questions can help us figure out how to save the lives of babies at risk. But Raman is looking for much more. By figuring out the basic principles that guide these factors and how they relate to each other in the earliest days of life, perhaps science can develop theoretical constructs that can accelerate breakthroughs, much like the theory of gravity or the periodic table or Darwinian evolution have provided powerful “shortcuts” to discovery in physics or chemistry or biology.

Raman was attracted to come back to UChicago—where he earned two undergraduate degrees—after years of study in medicine, clinical pathology, and molecular biophysics, at Washington University and University of Texas Southwestern, because he believed the resources at the DFI, with access to great expertise in computation, microbiology, genetics, and diverse clinical populations, is the perfect place to start generating useful theory.

One day, he believes, we will be able to develop health strategies and risk stratification for individuals in a data-driven way. Perhaps we’ll be able to use inflammatory markers to help create a “tuning device” for health, with personalized combinations of foods providing the “push” to adapt and repair the gut microbiome of people at genetic and environmental risk for disease.

Raman’s work has already helped colleagues have made inroads in this effort for malnourished children in Bangladesh. It’s an effort that could help completely change the way we think about medicine. And elevate opportunities for vigor in people everywhere.

Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office


The ecosystems within us

The ecosystems within us

by Elise Wachspress

Among the most beloved spaces on the UChicago campus is Botany Pond, created by the first chairman of the University’s Botany Department. Tucked between the University’s iconic Reynolds Club, where everyone meets for food and performances, and the Anatomy Building, Botany Pond provides both a natural respite and a physical reminder of Chicago’s storied—and ongoing—research in ecology and evolution. This pocket woodland enclave, so popular it has its own live YouTube channel, provides a home for a surprisingly wide assortment of life, with trees, plants, fish, turtles, ducks, birds, and insects, right in the middle of a busy urban environment.

UChicago scholars have studied Botany Pond—and many other environmental niches around the world—for over a century, but the field of ecology really came into broad public consciousness with the work of Rachel Carson, a marine biologist for the US government. Her passionate, graceful writing, first in The Atlantic and later in popular books that culminated in the blockbuster Silent Spring, popularized understanding of how ecosystems work and how changing single factors in an ecosystem could resonate in unexpected and dramatic ways.

Sam Light, PhD, is himself an ecosystem explorer, though his targets present some very particular challenges. Light studies the relationships among members of the ecosystems inside our bodies. Understanding the inter-relationships among these organisms, so tiny, transient, and specialized to their micro-environments, depends on developing strategies and tactics even more inventive and dogged than Carson’s.

These internal micro-environments are as many and diverse as any woodland. There are high-acid niches (like in our stomachs) and others with no oxygen (as in most of our gut). Microbes inhabit the sticky mucosal surfaces of our intestines, ride through the alimentary canal with dietary fiber, or glom onto particles of fat. But what is hard to fathom is just how many gradient niches there are between these and many other micro-environments, each with very specific local conditions that provide discrete sweet spots for various types of bacteria to thrive.

For context: imagine a wildflower seed blown into a woodland environment. If the ground is fertile enough, the moisture right, and the seed’s not eaten by a bird or trampled by a raccoon, it may sprout. To capture the energy it needs to grow, the seedling can “lean” into the dappled sunlight and send its roots toward the moistest sections of the soil, using all the talents accumulated over its evolutionary history to do what all living things “want” to do: live.

Now imagine if this little plant could actually pick itself up and move to a sunnier, more amenable location. Or if it could reproduce every hour and scoot its “babies” off to a slightly more felicitous nook. What if successive generations could gravitate to the ever-so-slightly cooler air fostered by the moss a few centimeters away? Or benefit from the negligibly increased acidity provided by a nearby decaying leaf? Or inch toward the animal scat that could provide better nutrients?

You get the idea. Our inner bacteria can do just this sort of thing, optimizing their environmental position more fluidly and quickly than any wildflower seed. And unlike wildflowers, many are also adept at sharing genes—what is known as horizontal gene transfer—adapting to their environment by borrowing pieces of genetic code from their next-door neighbors. All these abilities make for a remarkably dynamic and complex ecosystem.

And just as in macroscopic ecosystems, there are food chains. One microbe digests a certain kind of carbohydrate (corn sugar from your taco?) and then excretes a fermented version, which turns out to be the perfect energy source for a neighboring bacterium. And of course when that second microbe metabolizes the fermented sugar, it puts out its own waste products, which are just the sort of nutrients that yet another member of the microbial community loves to consume. The more symbiotically the microbes can arrange themselves in each specialized niche, the better and more efficiently the entire gut community works.

The end products of this microbial food web eventually make it into our blood stream. These digested molecules provide our cells energy and vitamins, act as links in our cellular communications, help control our neurological responses and appetites, activate or tamp down our immune responses, prompt our system to release hormones, even break down drugs into the molecules that intervene in disease processes. So the more diverse our microbial communities, the healthier we tend to be.

Light wants to figure out the details of the connections between these microbial metabolisms, how they structure beneficial communities, and the how their end products affect our health. One type of bacterium Light has been studying recently is Listeria, known for causing a food-borne infection that can be fatal.

Light’s work has demonstrated that Listeria’s peculiar metabolism can end by directly ejecting electrons out of the cell. In the absence of oxygen, this property allows Listeria to respire an unusual set of chemicals that includes mineral iron. In the lab, these electrons can be captured with an electrode and used to convert microbial metabolism into electricity.

In the oxygen-free gut, Light has found that electron-ejecting properties give Listeria an advantage over others in the intestinal community—problematic in the case of this bad citizen. Light is hoping to understand the effects of this electron-ejecting property and determine how to tilt the ecological balance in favor of other, friendlier bacteria.

Learning how to effectively manage our internal ecosystems—a goal of the Duchossois Family Institute—may be just as important as optimizing those larger ones we inhabit.

Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office



Tracking our inner allies against disease

Tracking our inner allies against disease

by Elise Wachspress

Aside from the obvious, COVID-19 has taught us a lot of things we might never have thought would interest us. Now we all know what Zoom is (even if we don’t know who might be wearing pajama bottoms). We know how Instacart works and that Amazon delivers toilet paper. We get the basics of making face masks and the safest materials to use. Even the Oxford English Dictionary is pointing out words surging in usage after decades of disuse.

For better or worse, we also now know a lot more about intensive care units. Some of us might have been familiar with surgical ICUs, when friends or family needed special post-operative care. But the many media stories about COVID have brought us—intellectually—into medical ICUs, for patients who need long-term, intensive observation and treatment. We’ve heard endless reporting of the many machines, monitors, ventilators, tubes, and wires involved, and stories of the armies of medical professionals treating those who are critically ill.

But the tiniest players in the ICU—short of the virus itself—can be overlooked. The microbes that live within us are major factors in keeping us healthy, and nowhere is understanding their involvement more important than in the ICU.

Critically ill patients are often those most at risk for alterations in their microbiome. Unlike surgical patients, who come into the hospital with digestive systems largely intact, patients admitted to the medical ICU have likely been under stress for a while, with perhaps major changes in diet and treatment with multiple medications which expand in the ICU.

Among these treatments, antibiotics are the most disruptive to the microbial community, killing off good bacteria along with the problematic ones and further unbalancing the microbial diversity that supports good immune function and health. Once that harmony is upset, those bacteria that are left may pump out metabolites—end products—that seriously compromise the chemistry of the entire gut and exacerbate the patient’s illness.

Then the really bad microbes, those resistant to antibiotics, can take over. Resistant bacteria can invade the blood stream via compromised gut tissue and spread to the bloodstream and throughout the body, potentially leading to sepsis.

When a patient has an infection serious enough to land in the ICU, antibiotics may be absolutely necessary. But by understanding the mechanics of these microbial interactions, intensivists can provide better, more nuanced care.

John P. Kress, MD, is an intensive care specialist widely recognized as an innovator in his field. He was among the first in the US to demonstrate that helmet-based respiratory assistance was often more effective—and less distressing—than intrusive ventilators for some ICU patients. So it is no surprise that he is actively investigating how treatments in the ICU affect and are affected by the patient’s microbiome—and how managing this balance can improve outcomes.

With his postdoctoral fellow, Matthew Stutz, MD, Kress’s team are providing stool and blood samples collected during the ICU stay to Duchossois Family Institute Director Eric Pamer, MD. The DFI team is studying the bacterial composition of each, looking for correlations over time.

How does the microbial balance correlate with the development of sepsis? Can certain bacteria found in the stool or blood predict the length of ICU stay or the need for a ventilator? Do changes in the microbiome track readmission to the ICU or mortality? Do the microbes present affect the patient’s function and strength after discharge, including long-term cognition and mental health?

As with most studies, this one will involve a lot of data-crunching. To the huge amount of information collected on each ICU patient–vital signs; clinical notes; lab, microbiology, pathology, pharmacy, and respiratory support reports—the DFI team will add vast stores of genomic data on the bacteria they find. The team will also integrate evaluations of long-term outcomes like functional status, cognition, and mental health for a year after discharge from the ICU.

Enrolling patients in this study will be somewhat complicated: close to 40 percent of patients admitted to the ICU may not be conscious enough to provide truly informed consent. Fellows like Dr. Stutz will need to carefully explain the study to distraught family members who hold the patient’s power of attorney, with the assurance that patients can always opt out of the study at a later date.

But Kress and his team agree that the ongoing coronavirus pandemic offers an exceptional opportunity. The team can both identify changes over time in the microbiota of patients in the ICU with any illness and compare these to patients isolated in intensive care for COVID-19. This study may lend greater clarity in treating—and saving—patients seriously ill from this novel virus.

Because of the large number of patients treated in UChicago Medicine’s medical ICU, the team has been enrolling about 50 patients a month. Their goal of studying 500 patients over the next year would make this the largest study ever of the effect of the microbiome in the intensive care unit. By generating insights into patients’ “inner allies,” they can better restore health to these most vulnerable patients.

Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office


Transplanting hearts for a lifetime

Transplanting hearts for a lifetime

by Elise Wachspress

Imagine you need a new heart to survive.

First, there is the drama of waiting for a donor heart that is a good match—knowing that your chance at life depends on someone else losing theirs.

Then, there is the actual surgery—having your chest opened and an entire team implanting this new organ, followed by both the euphoria of success—one year survival rates are now over 85 percent—and the realization that rehabilitation will require strength of body, mind, and will.

Next comes an intense drug regimen to protect your new heart from being rejected by your body’s immune system. The early danger is that your body’s specialized T-cells will attack the new heart itself. Over the past few decades, transplant specialists have developed a number of strategies to tamp down these cellular incursions, balanced with vigorous antibiotic management to address opportunistic infections. So your chances of thriving through this early stage are strong.

Yet even with a carefully calibrated drug regimen, a significant number of patients still fall prey to serious problems later, especially later during the first five years after surgery. Most common is a condition known as cardiac allograft vasculopathy (CAV). In CAV—known as the Achilles heel of heart transplantation—fibers grow down the inside of the cardiac artery wall, thickening the vessels, not dissimilar to how old galvanized pipes in a home’s plumbing eventually corrode and slow the flow of water to a trickle. Though this kind of thickening can happen in other types of cardiac disease, it progresses much more quickly in patients with heart transplants and often leads to failure of the graft.

Transplant specialists like Ann Nguyen, MD, have suspected for a while that CAV results from an attack not by the body’s immune cells, but by immune proteins—antibodies—circulating in the blood. Growing evidence suggests that certain sensitizing events, like a blood transfusion or pregnancy, can cause the body to create new donor-specific antibodies. Fewer than 10% or so of patients have these antibodies before transplant, but up to three times that many develop these antibodies afterward, and their presence can increase the odds of a failed heart graft fivefold.

Nguyen and her fellow, Mark Dela Cruz, MD, have been following the work of Duchossois Family Institute Director Eric Pamer, MD. His research has shown that certain gut microbes can protect against infections in patients receiving a bone marrow transplant and that bacterial diversity in the gut decreases mortality after the transplant. Nguyen and Dela Cruz are interested in understanding how a patient’s individual microbiome might affect the production of donor-specific antibodies and the outcomes patients experience after heart transplants.

To do so, they have designed an observational clinical study, with one fairly simple change in each patient’s regimen: the addition of one more type of sample—stool—to the blood and urine samples normally collected to monitor patients before and for months after heart transplant. The stool samples will allow Pamer and the DFI team to assess the patient’s microbiome before surgery and track any changes after transplant. They will then correlate what they learn about each patient’s microbiome with the progress of their cardiac transplant for at least the first two years after each patient’s transplant.

UChicago is extremely well-positioned to conduct this study. Not only does the University of Chicago Medicine perform 40 heart transplants per year—with the best survival rates in the state—but the DFI provides facilities for microbial characterization and study matched by few other research centers. Nguyen and Dela Cruz aim to enroll as many patients as possible within one year.

With what they learn about the microbiome’s effects on long-term success after cardiac transplant, they hope they can keep transplanted hearts beating healthily for many more years.

Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office


Tuning a community of bacteria for health

Tuning a community of bacteria for health

by Elise Wachspress

For those mesmerized by the early days of tech culture—with characters like Bill Gates, Steve Jobs, Sergey Brin, and Larry Page—one amazing facet of the story was how quickly the movement became democratized. It took little so capital to get into the game—just a lot of free time and access to the silicon chips that redefined how we capture, organize, and transfer data. Soon young people were developing businesses in local hacker clubs or their dorm rooms.

Dreams of launching the next Napster or Myspace attracted many of these enthusiasts into the larger “maker” culture, a kind of crossover between tech and the Arts and Crafts movement. Suddenly it became cool to make not only your own computer and programs, but all kinds of devices and products, with designs personalized to the “maker”—a refutation of mass manufacturing.

One tool that became essential to the movement—in addition to the 3D printer—was the breadboard, a handy tool that allows the user to design and test electrical circuits without having to solder them together permanently (which takes a lot of time and can involve burnt fingers). The reusable breadboard makes it easy to change the capacitors, resistors, power sources, and lights in circuits to find the most effective, energy-efficient way to provide the functions needed for a new device.

Mark Mimee, PhD, wonders: What if we could create a kind of breadboard to optimize the microbiomes in each of our systems? A tool to experiment with “tuning” various species of bacteria, all at the same time, so that the microbes in us deliver the functionalities individualized for our health?

Mimee is a synthetic biologist. He specializes in redesigning microorganisms, turning their genes off and on to change how they perform, what they consume, and the byproducts—metabolites—they produce. Synthetic biologists like Mimee are modifying bacteria to solve costly or difficult problems, like eating up oil spills or manufacturing medications. For centuries, we’ve used bacteria, yeasts, and molds as “factories” for products we use—think cheese and beer—and, within just the past few decades, have learned to engineer microbes to produce insulin. (In fact, in a weird convergence of maker culture and synthetic biology, some hackers are actually using microbes to make their own insulin!)

But Mimee has much more expansive plans. What about engineering bacteria we normally carry in our bodies to home in on inflammation and tamp down those fraught environments? Imagine, say, a microbial allergy treatment that stops the itchiness and congestion without making you sleepy. Or perhaps microbes that can measure intestinal bleeding. Or genetically altered bacteria that can deliver payloads to our resident gut microbes to make them better intestinal citizens.

Mimee and the teams of scientists with whom he works have already done some of these things. The goal now is to figure out how to develop new functionalities that work not just with one individual species, but with an entire a system of species, like a microbial breadboard. He wants to find a way to test how manipulating multiple types of microbes that normally live in the gut—right now, he’s aiming for 12—can provide valuable health functions that are both safe and reliable.

Among the candidates for Mimee’s breadboard is Bacteroides, a type of bacteria often found in the intestines, where it is sometimes associated with diarrhea. But in other parts of the body, Bacteroides can cause serious infections, and the microbe is often resistant to multiple types of antibiotics.

Strangely, however, some strains of these bacteria are found in much lower levels in patients with Crohn’s disease and ulcerative colitis. Other Bacteroides strains are enriched. Why? How are the inflammation-associated bacteria involved in disease? What are people with few Bacteroides missing? What functionality are some bugs creating that seems to make them more resistant to inflammatory bowel disease? Figuring that out may lead to treatments—or, better, preventive strategies—to save people from these painful and debilitating diseases.

Needless to say, applying what Mimee is learning about Bacteroides and their effects on other microbes in the system may be clinically useful—and quickly. Gastrointestinal immune diseases—from Crohn’s and colitis to celiac and type 1 diabetes—just happen to be among the strongest clinical and research programs at UChicago, and so Mimee will have the right partners to help advance his work on Bacteroides and how they affect other microbes in the system.

It won’t be soon enough for the many thousands of patients who look forward to a life without constant or unpredictable abdominal distress.

Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office


Streaking to improve human health

Streaking to improve human health

by Elise Wachspress

For those who remember the 1970’s, “streaking” might mean “running through public places naked.”

But if you’ve ever taken a microbiology class, you know one of the first lab lessons is “streaking a plate,” a technique used to spread a sample of bacteria out across a petri dish filled with agar, a Jello-like substance from seaweed also used in ice cream and some candies. Streaking is used to separate the bacteria and get them to grow in individual “colonies,” which can, perhaps with further streaking, be purified into samples of one single type of bacteria.

First perfected well over a century ago in the lab of Robert Koch, streaking samples from people infected with TB, anthrax, and cholera helped researchers make major inroads in understanding (and thus fighting) these diseases.

Claire culturing bacteria in the anaerobic chamber

Claire culturing bacteria in the anaerobic chamber.

But the technique’s limits soon become obvious. Microbes, by far the earth’s oldest life form, have evolved to live in all sorts of conditions uninhabitable by other creatures: arctic ice, volcanoes, acidic sulfur springs, even under enormous pressure at the bottom of the sea. Expecting bacteria acclimated for life in these extreme environments to survive, much less grow, on a simple plate of agar on a shelf in a lab is not going to work.

Even some bacteria that inhabit the human body are resistant to this method. Many gut bacteria die or fail to thrive in environments with oxygen. Claire Kohout and her DFI biobank team are experts at growing, purifying, characterizing, and storing these “anaerobes.”

They grow the bacteria within oxygen-free plastic bubbles that contain only nitrogen, carbon dioxide, and hydrogen; a palladium catalyst assures that any tiny bit of remaining oxygen reacts with the hydrogen and drops out of the atmosphere as water. The six- to eight-feet-long anaerobic chambers are fitted with air locks and rubber gloves to allow the scientists to work with the samples inside.

Inside, the bacteria may sometimes grow on agar plates supplemented with essential nutrients or often in a liquid broth. In both cases, the growth media must be in the anaerobic environment for at least 24 hours to ensure all traces of oxygen are gone; for particularly sensitive anaerobes, they sometimes use a special dye to indicate oxygen contamination. They purify and carefully characterize the bacteria within this oxygen-free environment and then transfer them to special tubes to be frozen and safely stored at -80° C for future research.

Eric Pamer, MD, director of the Duchossois Family Institute (DFI), started the collection several years ago when he was working at Memorial Sloan Kettering Cancer Center in New York. Now, with DFI institutional support, it will grow substantially. Since the fledgling biobank was moved to Chicago, Kohout and company worked first to establish and communicate protocols among both those collecting samples and those who will be using them. Now, as the labs move forward carefully after COVID temporarily shut down the labs, the focus is on growing the collection to support the Institute’s rapidly expanding research portfolio.

Claire culturing bacteria in the anaerobic chamber.

Claire culturing bacteria in the anaerobic chamber.

Most samples are from healthy human donors, the idea being that these can help researchers better understand how our internal bacterial communities support human well-being. Interestingly, researchers have found that, although microbial populations differ significantly from one healthy person to another, they generally have one thing in common: internal diversity. Like other ecosystems and societies, gut communities benefit from variety; samples from people who are ill tend to have fewer types of bacteria living within them.

So far, most of the samples come from routine colonoscopies. (So besides your primary reward for the undertaking that uncomfortable prep—hearing that you do not have colon cancer and you needn’t repeat the procedure for ten years—a secondary bonus is knowing you can help to advance science and medicine.) While the DFI biobank currently concentrates on gut samples—the largest conglomeration of bacteria in the body—Kohout anticipates they will eventually expand to samples from oral and skin communities.

The biobank, Kohout says, is “at the center of all the Institute’s platforms,” providing the samples for most of the research undertaken in the DFI. Under Pamer’s aggressively collaborative leadership, the DFI will even provide special samples to other research institutions which share the DFI’s central mission: to maximize good health and the economic, social, and personal benefits it delivers.

Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office