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Going with the flow

Going with the flow

 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 inability 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


Uncovering the benefits of herbal medicine

Uncovering the benefits of herbal medicine

by Kate Dohner

One in three Americans uses herbal therapies. Yet less than one in 3,000 scientific studies focus on this increasingly popular therapy.

Researchers at the Tang Center for Herbal Medicine Research at the University of Chicago are changing that. Established in 2000 through generous donations from the foundations of Cyrus Tang, the Tang Center seeks to uncover the benefits and potential dangers of herbal therapies.

“The majority of prescription medications are derived from natural products,” explained Chun-Su Yuan, MD, PhD, Cyrus Tang Professor and director of the Tang Center. “At the Tang Center, we apply a scientific approach to identify new herbal therapies and gain a better understanding of how they might help patients.”

Yuan and his colleagues were among the first to point out that—because most herbal medicines are taken by mouth (as capsules or teas)—they must be digested and absorbed by the microbiome, the trillions of bacteria that live in each person’s gut.

One of the most popular herbal medicines worldwide, ginseng has been used for centuries to treat a variety of ailments. In recent years, it was discovered that after ginseng is consumed, its original compounds are transformed by certain gut bacteria into new substances called metabolites—one of which, “compound K,” has significant cancer prevention potential.

Yuan and his team are studying ginseng’s ability to fight colorectal cancer, one of the most common cancers worldwide. This work, previously supported by a $6 million grant from the National Institutes of Health, led to an important discovery: When ginseng was fed to mice with colorectal cancer, it not only significantly reduced inflammation in the colon but also restored the bacterial community to a healthy state.

In a related study, Yuan’s team examined how American ginseng (one of the main species of ginseng) affects the microbiomes of people who eat different diets. They studied six volunteers in the Chicago area—half of whom regularly ate an Asian diet of largely vegetables and rice, and half who ate a high-fat, Western diet. Each of the participants took ginseng capsules by mouth for seven days.

The researchers found that those on the Western diet had much higher levels of cancer-fighting compounds compared to those on the Asian diet. This preliminary study suggests ginseng may be even more beneficial for those who eat a Western diet.

“This was not what we expected,” offered Yuan. “However, the high-fat diet appears to affect the composition of gut bacteria, and in turn, allows for better absorption of ginseng’s anti-cancer compounds.”

Looking ahead, Yuan seeks to study ginseng’s influence on the microbiome in greater depth, eventually moving into clinical trials. But more animal studies are needed first.

“The general public is very enthusiastic about dietary supplements and herbal medicine,” said Yuan. “With continued research, we hope to provide unbiased scientific findings to help inform the medical community, patients, and health-conscious consumers.”

Kate Dohner is a senior writer for the University of Chicago Medicine & Biological Sciences Development office.


When ‘as easy as breathing’ isn’t

When ‘as easy as breathing’ isn’t

by Elise Wachspress

Stop for a minute and breathe, just breathe. Now envision what your lungs are doing.

In your mind’s eye, do you see big pink balloons filling and deflating?

Close. What’s really going on is hundreds of millions of tiny little pink balloons filling and deflating—ten to twenty times a minute, even more often for babies and small children. Your lungs actually look more like foamy, pulsating soap bubbles than balloons.

In between these bubbles—the alveoli—is a flexible web that allows the little sacs to expand and contract, taking in air, grabbing the oxygen, and dispelling the carbon dioxide waste products.

Unless the web starts to harden. That’s what happens in the case of interstitial lung diseases (ILD). Alveolar expansion gets more and more difficult, until patients begin to feel their lungs are made of concrete. The damage is usually progressive and irreversible. In some cases, certain medications can slow ILD, and some people may be candidates for lung transplants. Otherwise, it’s not hard to see where this condition leads. When you can’t breathe, you can’t live.

ILD can be caused by exposure to hazardous materials like asbestos. Sometimes autoimmune diseases, like rheumatoid arthritis, can trigger the disease. Unfortunately, in most cases, especially for a subset of the disease called idiopathic pulmonary fibrosis (IPF), the cause is unknown.

Physician-scientists at the University of Chicago are working to change that—because if you know the causes of disease, you are many steps closer to resolving it. This quest is particularly critical right now, because over the last three decades, mortality from ILD has doubled in the US.

UChicago, one of the few centers of excellence for treating the disease, draws many of the top people interested in studying it. A large team that included clinician-scientists, researchers, and radiologists from UChicago and NorthShore University HealthSystem, recently found some powerful indicators in predicting ILD outcomes—findings which will not only help physicians fine-tune treatments, but also provide clues of the disease’s mechanism.

One indicator involved the lymph nodes, the organs that 2018 Nobel Prize winner Jim Allison describe as like Rick’s Place in Casablanca: where all cells—the good guys, bad guys, reporters, and soldiers—go to hang out.

The team, led by Deji Adegunsoye, Jonathan Chung, Mary Strek, and Anne Sperling,  found that when the lymph nodes tucked between the lungs were enlarged—a condition visible on a CT scan—patients had much worse lung function and significantly increased mortality.

They also found these patients had characteristic imbalances in cells and substances associated with the immune system, some of which could be found through a blood test. In fact, patients with large numbers of one specific interleukin—a protein generated by the immune system—circulating in their blood had the worst survival rates.

Taken together, these factors are likely biomarkers of the patient’s prognosis. Both can be monitored via minimally invasive testing, as opposed to the lung biopsies currently used.

Patients who show neither of these indicators likely have a truly different form of ILD, which not only means longer survival, but may also be differentially treatable with certain immunological drugs.

This latest research is only one strand of the many ways UChicago scientists are fighting ILD. The involvement of these immunological factors seems to corroborate what many team members have suspected through years of clinical work: that a variety of triggers—both chemical and microbial—may set up an immune response that attacks the lungs. IPF patients have often reported exposure to substances like organic solvents, stone dust, and/or mold. The Chicago team is looking for funding for a dedicated occupational health consultant to extensively document patients’ life histories in hopes of identifying disease triggers. As with a similar discovery that asbestos exposure causes the universally deadly mesothelioma, they hope to make ILP preventable.

The team is also working to significantly increase their biobank of lungs, which are exceptionally fragile and require a very specialized storage regimen. The lymph node findings were only possible because of the intense support of UChicago’s technical/biobanking staff (who must often respond on a moment’s notice when a patient undergoes a lung transplant) and strong collaboration with NorthShore. The team hopes UChicago can become a regional center of lung biobanking, to drive this kind of research.

And with the help of molecular engineers, the team is also working to develop microfluidic tools to drive that lung research and develop new drugs to address the immunological effects—tools and drugs that can be commercialized for use across the world, with the help of the Polsky Center for Entrepreneurship and Innovation.

For too long, interstitial pulmonary disease, especially IPF, have been a death sentence. It’s way past time for a change.

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


News roundup: October 2018

News roundup: October 2018

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)


News roundup: September 2018

News roundup: September 2018

A selection of health news from the University of Chicago and around the globe curated just for you.

The end of an epidemic
The number of people with food allergies has exploded in recent years. A dream team of researchers from UChicago may have figured out why, and now they’re developing therapies that could end the epidemic. Cathy Nagler featured. (Chicago magazine)

UChicago startup gets $2.3 million for kidney stone prevention
Biotechnology startup Oxalo Therapeutics is closer to developing a first-of-its-kind drug to prevent kidney stones thanks to $2.3 million from the National Institutes of Health. Hatim Hassan and Yang Zheng featured. (Crain’s Chicago Business)

Science by the sea
In three weeks, there are just over 500 hours. The students in the Marine Biological Laboratory’s September intensive courses tried to use them all. Jack Gilbert featured. (UChicago Magazine)

Nasal bacteria linked to cold severity
In a study, people with certain bacteria in their noses were more likely to develop more severe cold symptoms. (U.S. News & World Report)

Brain-gut link may be way faster than we thought
New research with mice may upend our understanding of the connection between the gut and the brain, as well as appetite. (Futurity)


Tinkering with the strands of life

Tinkering with the strands of life

by Matthew Eckwahl, PhD
Postdoctoral fellow in the Department of Biochemistry & Molecular Biology

Over a decade ago, artist-scientists first used “DNA origami” to create minuscule smiley faces sculptures. It turns out that DNA’s structural diversity is perfect for building more useful tiny machinery. University of Chicago scientists have taken a lead in developing DNA nanomachines with tremendous potential to help us better understand how cells work, diagnose diseases, and test new treatments.

Yamuna Krishnan is at the leading edge of developing DNA-based tools to home in on specific structures inside the living cell and decipher what is going on there. One powerful use of this technology: identify unhealthy states before disease ravages the body.

Krishnan, the only woman to have won the Infosys Prize in the physical sciences, once aspired to become an architect, so it’s fitting she now builds tools for finding genetic maladies. Her work focuses on the lysosome, the cell’s recycling center, which breaks down useless or toxic material to make new components. Like a city with a failed garbage collection system, if a cell’s lysosomes don’t function properly, there are major problems caused by a buildup of undigested cellular waste. Not surprisingly, genetic lysosome defects can result in a variety of human diseases.

Nearly 60 lysosomal storage disorders have been identified so far. Although individually rare, these diseases collectively occur in about one in 5,000 births and can be inherited from one or both parents. Symptoms vary widely depending on the type of cellular waste that accumulates and where in the body this occurs. Ultimately, the undigested material causes the affected organ to function less efficiently, leading to physical and mental impairments such as seizures, dementia, cardiac disorders, vision and hearing loss, and bone abnormalities. Lysosomal disorders usually arise in childhood, often without obvious symptoms, and many babies die suddenly within months or years of birth.

Although there is no cure for these disorders, an increasing number of treatments are available to reduce symptoms and prolong life—if diagnosis is made early. Faster, more accurate methods to detect lysosomal defects are thus essential.

Krishnan and colleagues have developed DNA nanodevices to uncover these metabolic disorders before it’s too late. To get these DNA nanobots to work, her team overcame several major challenges. First, they needed the devices to specifically target the lysosome. Within the cell, a bustling community with many different activity centers, the nanobot must have the exact molecular address to get to the lysosomal recycling center.

Next, the bot must distinguish healthy from defective lysosomes. Since the lysosome is the most acidic “organelle” within a cell, pH was chosen as a key indicator of lysosome health—just like high blood sugar levels can indicate diabetes. If a lysosome’s pH is off, it suggests something is probably wrong. Impressively, Krishnan’s nanobots can not only find the lysosomes, but also measure their acidity—changing color at different pH levels—without disturbing the other functions in living cells.

Krishnan’s newly created company, Esya, aims to deploy these DNA nanodevices to diagnose a wide range of lysosomal disorders, all from a simple blood draw. This should considerably speed up the testing process and provide a much better outcome for those at risk for disease. This tool could also be adapted to rapidly screen new drugs that normalize the lysosome’s acidity, making it easier and faster to discover improved treatment options.

Krishnan’s lab has developed nanobots that recognize other chemical changes in diseased lysosomes as well. In research reported last year, the Krishnan group created a DNA nanodevice to measure chloride ions—what we know as part of table salt—the first tool capable of sensing this important electrolyte inside a living cell. Their research showed that normal lysosomes have much higher chloride ion levels than defective ones, revealing the unexpectedly important role chloride plays in lysosomal biology— a valuable tool for unmasking lysosomal diseases that don’t affect pH.

Earlier this year, the Krishnan team reported another nifty nanobot that directly senses congestion from undigested material building up in the lysosomes. By reporting back on the gridlocked environment that is a hallmark of lysosomal disorders, this newest device may provide early warnings for other kinds of disorders, preventing future disaster.

It’s reassuring to know that if something is going wrong with your car, a flashing light will warn you before it’s too late. Likewise, the work of Krishnan and others highlights how DNA, life’s genetic material, can also help uncover potentially fatal human diseases and save lives.