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Single gene controls variety of wing patterns across butterfly species

Mon, 09/18/2017 - 14:00
butterfly-display-1

Monarch butterflies studied by Marcus Kronforst and Darli Massardo at the University of Chicago. The white patches on the wings, most prominent on the bottom left and middle right specimens, show where the WntA gene was knocked out and did not produce the characteristic orange scales. (Credit: Matt Wood, University of Chicago)

A single gene is responsible for producing different wing patterns, shapes and colors across several butterfly species, scientists report this week in a new study published in the Proceedings of the National Academy of Sciences.

Using CRISPR/Cas9 gene editing tools, researchers from seven institutions knocked out a gene called WntA in embryos from seven different butterfly species, essentially turning it off. The resulting adult butterflies developed changes in wing patterns and colors that differed in each species, suggesting that while WntA plays a fundamental role in wing patterning across butterfly species, it has been used in a variety of ways.

“Every butterfly has a unique color pattern and there is extraordinary diversity among species, but they’re not reinventing the wheel when it comes to developing those unique color patterns,” said Marcus Kronforst, PhD, associate professor of ecology and evolution at the University of Chicago and an author on the study. “In the case of WntA, they’re using that one gene again and again and again.”

Video: University of Chicago researcher Darli Massardo explains how knocking out the WntA gene changes the coloring of orange scales on monarch buttefly wings. (Credit: Kat Carlton, University of Chicago)

Previous genetic studies have identified WntA as the gene that controls patterns of melanin, or dark pigmentation, in the wings of Heliconius butterflies. The widespread group of species lives throughout the tropical and subtropical regions of North and South America. Other studies have also pinpointed the role of WntA in wing patterning of other groups, suggesting that it is widely conserved across all butterfly species.

Until recently, however, scientists lacked the tools to directly test of function of this gene in butterflies. For the new study, coordinated by Arnaud Martin from the George Washington University, each research team from seven different institutions chose a different butterfly species and used the CRISPR gene editing system to knock out WntA.

Kronforst and Darli Massardo, PhD, a postdoctoral fellow at UChicago, worked with monarch butterflies. The loss of WntA caused the monarch’s characteristic orange scales to turn white, but didn’t change the overall pattern of the wings. Another team worked with painted lady butterflies, which lost the usual black spots in the middle of their wings. Other species developed differently shaped bands across the wings.

massardo-kronforst-2

University of Chicago researchers Darli Massardo and Marcus Kronforst in the greenhouse on top of the Donnelly Biological Sciences Learning Center on the University of Chicago campus. (Credit: Kat Carlton, University of Chicago)

“When we knock out the gene, we’re seeing totally different effects,” Massardo said. “So, although WntA is involved in wing-patterning in general, it’s doing fundamentally different things in different species.”

Kronforst and Massardo say that the results of this study give scientists insight into the process of evolution, as butterflies exploit the utility of this gene to develop multiple wing patterns. The widespread use of precise genetic tools like CRISPR will allow them to explore this process further, moving beyond simple knockout experiments to more complex, functional changes.

“Now we’re just altering the gene to make it nonfunctional,” Kronforst said. “But what we’d really like to do are things like precisely put in a copy of the same gene from another species or another color pattern and see what that does. This just opens the door for us.”

butterfly-greenhouse-3

Monarch butterflies in the greenhouse on top of the Donnelly Biological Sciences Learning Center on the University of Chicago campus. (Credit: Kat Carlton, University of Chicago)

The study, “Macro-evolutionary shifts of function potentiate butterfly wing pattern diversity,” was supported by the National Science Foundation, the National Institutes of Health, the Leverhulme Trust, the Pew Charitable Trust, a Nigel Groome PhD studentship and the Smithsonian Institution. Additional authors include Anyi Mazo-Vargas, Linlin Zhang and Robert Reed from Cornell University; Carolina Concha from North Carolina State University; Luca Livraghi and Casper Breuker from Oxford Brookes University; Richard Wallbank and Chris Jiggins from the University of Cambridge; Joseph Papador, Daniel Martinez-Najera and Nijam Patel from the University of California, Berkeley; and W. McMillan from the Smithsonian Tropical Research Institute.


Tagged: Biological Sciences, butterflies, CRISPR, Darli Massardo, ecology, Evolution, genetic engineering, Genetics, Marcus Kronforst, monarch butterflies
WntA butterflies

Antibiotics weaken signs of Alzheimer’s disease in mice after just one week of treatment

Fri, 09/15/2017 - 09:00
Minter Sisodia

Neurobiologists Myles Minter, PhD, left, and Sangram Sisodia, PhD

Last year, UChicago neurobiologists Sangram Sisodia and Myles Minter made a surprising discovery: Treating mice with antibiotics long-term reduced some of the telltale signs of Alzheimer’s disease.

Mice that received high doses of broad spectrum antibiotics over five to six months had a two-fold decrease in amyloid-ß (Aß) peptides in the brain, the “plaques” or that build up and play a central role in the onset of Alzheimer’s. They also had altered inflammation of microglia, brain cells that perform immune system functions in the central nervous system.

Of course, this doesn’t mean antibiotics could be a “treatment” for Alzheimer’s disease. There may be changes occurring in the brain and central nervous system 15 to 20 years before diagnosis, and administering antibiotics for more than a few weeks to treat an infection is a bad idea anyway. But what was intriguing about that study is what it suggested about how microbes might be interacting with the brain and nervous system.

When the team analyzed the gut bacteria of the mice, they saw dramatic changes in the overall diversity of the community of microbes. Some species of bacteria were wiped out, while others thrived. A growing body of research shows how gut bacteria interact with the immune system and brain through the periphery of the nervous system. Sisodia and Minter believe that the changes they saw in the microbiome of these mice could somehow be linked to the changes in the brain—and a new study shows that the timing of when antibiotics are given may mean everything.

In a new study just published in Scientific Reports, they performed similar experiments, but instead of giving the mice antibiotics long-term, they did it for just one week when the mice were only two weeks old. The results, again, were surprising: They saw all the same changes in Aß plaques, microglia activity and gut bacteria diversity, although to a slightly lesser extent.

“The most staggering part for me was after giving one week of antibiotics very early on, we see the expansion and contraction of various strains of bacteria,” said Minter, who is a postdoctoral scholar. “But the fact that it seems to be the developmental window that can have these long-lasting effects in this mouse model is pretty exciting, and something we certainly weren’t expecting.”

Video: Sangram Sisodia and Myles Minter talk about the relationship between the microbes living in your gut and your brain, for Argonne’s Microbiome Project.

This early developmental period is believed to be crucial for the proper development of the gut microbiome, and an early blow can lead to long-term consequences. For example, earlier this year, Eugene Chang’s team showed that giving antibiotics to mice during pregnancy can increase the risk for their offspring developing a form of inflammatory bowel disease.

These changes can go both ways though. In 2015, Cathy Nagler and her team showed that probiotic formula for babies can help reverse allergies to cow’s milk by replacing certain gut bacteria.

Sisodia said that his team’s work paves the way for more experiments to understand the exact mechanisms behind how the changes in gut microbes might be related to changes in microglial nerve cells and their ability to clear plaques. Minter is working on genetic experiments to understand the molecular changes taking place that could be affecting signals between gut bacteria and the immune and nervous systems, and the group is looking at more ways the timing of antibiotics play a role as well.

“We need to design experiments where we treat animals later in life, either before they develop amyloid deposits or right about the time they do,” said Sisodia, the Thomas Reynolds Sr. Family Professor of Neurosciences. “In Alzheimer’s, the ability to clear amyloid plaques is reduced. We think microglia play a central role in that, and we want to identify what could be changing in their metabolism early in life that could be priming these cells to do their job.”


Tagged: Alzheimer's, Alzheimer's disease, antibiotics, Biological Sciences, microbiome, Myles Minter, neurobiology, Neuroscience, Sangram Sisodia

UChicago scientists create alternate evolutionary histories in a test tube

Wed, 09/13/2017 - 12:00
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University of Chicago graduate student Tyler Starr holds a vial of yeast cells engineered with a library of proteins comprising millions of possible evolutionary paths from our ancient ancestor to its modern function. (Credit: Matt Wood, University of Chicago)

Scientists at the University of Chicago studied a massive set of genetic variants of an ancient protein, discovering a myriad of other ways that evolution could have turned out and revealing a central role for chance in evolutionary history.

The study, published this week in Nature by University of Chicago graduate student Tyler Starr and his advisor Professor Joseph Thornton, PhD, is the first to subject reconstructed ancestral proteins to deep mutational scanning — a state-of-the-art technique for characterizing massive libraries of protein variants.  The authors’ strategy allowed them to compare the path that evolution actually took in the deep past to the millions of alternative routes that could have been taken, but were not.

Starting with a resurrected version of an ancient protein that evolved a new function some 500 million years ago – a function critical to human biology today — the researchers synthesized a massive library of genetic variants and used deep mutational scanning to analyze their functions.  They found more than 800 different ways that the protein could have evolved to carry out the new function as well, or better than, the one that evolved historically.

The researchers showed that chance mutations early in the protein’s history played a key role in determining which ones could occur later.  As a result, the specific outcome of evolution depended critically on the way a serial chain of chance events unfolded.

“By comparing what happened in history to all the other paths that could have produced the same result, we saw how idiosyncratic evolution is,” said Starr, a graduate student in biochemistry and molecular biology, who performed the paper’s experiments. “People often assume that everything in biology is perfectly adapted for its function.  We found that what evolved was just one possibility out of many that were just as good, or even better, functionally than what we happened to end up with today.”

Molecular time travel

Over the last 15 years, Thornton, senior author on the new study and a professor of ecology and evolution and human genetics at UChicago, led research that pioneered “molecular time travel” using ancestral protein reconstruction.  In 2013, his team resurrected and analyzed the functions of the ancestors of a family of proteins called steroid hormone receptors, which mediate the effects of hormones like testosterone and estrogen on sexual reproduction, development, physiology, and cancer.  The body’s various receptors recognize different hormones and, in turn, activate the expression of different target genes, which they accomplish by binding specifically to DNA sequences called response elements near those targets.

Thornton’s group inferred the genetic sequences of ancient receptor proteins by statistically working their way back down the tree of life from a database of hundreds of present-day receptor sequences. They synthesized genes corresponding to these ancient proteins, expressed them in the lab, and measured their functions.

They found that the ancestor of the family behaved like an estrogen receptor – recognizing only estrogens and binding to estrogen response elements – but during one specific interval of history, they evolved into a descendant group capable of recognizing other steroid hormones and binding to a new class of response elements. The researchers found that three key mutations before the emergence of vertebrate animals caused the ancestral receptor to evolve its ability to bind to the new target sequences.

That work set the stage for the current study.  Knowing precisely how evolution played out in the past, Thornton’s group asked: Was this the only evolutionary path to evolving the new function? Was it the most effective one, or the easiest to achieve?  Or was it simply one of many possibilities?

tyler-starr-lg-3

Graduate student Tyler Starr works in a lab at the University of Chicago Gordon Center for Integrative Science. (Credit: Matt Wood, University of Chicago)

Alternate histories

Starr began working on the project during his first year as a graduate student, developing the technique to assess massive numbers of variants of the ancestral receptor for their ability to bind the new response element.  First, he engineered strains of yeast in which the ancestral or new response elements drive expression of a fluorescent reporter gene.  He then synthesized a library of ancestral proteins containing all possible combinations of amino acids at the four key sites in the receptor that recognize DNA – 160,000 in all, comprising all possible evolutionary paths that this critical part of the protein could have followed – and introduced this library into the engineered yeast.  He sorted hundreds of millions of yeast cells by their fluorescence using a laser-driven device, and then used high-throughput sequencing to associate each receptor variant with its ability to carry out the ancestral function and the new function.

Most of the variants failed to function at all, and some maintained the ancestral function.  But Starr found 828 new versions of the protein that could carry out the new function as well, or better than, the one that evolved during history.  Remarkably, evolution could have accessed many of these even more easily than the historical “solution,” but it happened not to, apparently wandering around the space of possible mutations until it arrived at the version of the protein in our bodies today.

Joe Thornton, PhD

Joe Thornton, PhD

“We all share the same gene sequence for this protein, so it might seem like evolutionary destiny, as if we’ve arrived at the best possible version.  But there are hundreds of other directions that evolution could just as well have taken,” Thornton said.  “There’s nothing special about the history that happened, except that a few chance steps brought us to this singular chance outcome.”

Thornton said that deep mutational scanning will be a powerful tool for evolutionary biologists, geneticists and biochemists, and he looks forward to using the approach on successive ancestors at different points in history to see how the set of possible outcomes changed through time.

“We have a molecular time machine to go back to the past, and once we’re there, we can simultaneously follow every alternate history that could possibly have played out,” Thornton said. “It’s a molecular version of every evolutionary biologist’s dream.”

The study, “Alternate evolutionary histories in the sequence space of an ancient protein,” was supported by the National Institutes of Health and the National Science Foundation. Lora Picton, a former research scientist in Thornton’s lab at the University of Chicago, was also co-author.


Tagged: biochemistry, Biological Sciences, Evolution, Genetics, Joe Thornton, molecular biology, proteins, Tyler Starr

Systems analysis points to links between Toxoplasma infection and common brain diseases

Wed, 09/13/2017 - 09:48
toxoplasmosis

The protozoan Toxoplasma gondii, tissue cyst in brain (Photo: D. Ferguson, Oxford University)

More than 2 billion people – nearly one out of every three humans on earth, including about 60 million people in the United States – have a lifelong infection with the brain-dwelling parasite Toxoplasma gondii.

In the September 13, 2017, issue of Scientific Reports, 32 researchers from 16 institutions describe efforts to learn how infection with this parasite may alter, and in some cases amplify, several brain disorders, including epilepsy, Alzheimer’s and Parkinson’s diseases as well as some cancers.

When a woman gets infected with T. gondii during pregnancy and passes the parasite on to her unborn child, the consequences can be profound, including devastating damage to the brain, nervous system and eyes.

There is growing evidence, however, that acquiring this infection later in life may be far from harmless. So the researchers began looking for connections between this chronic but seemingly dormant infection and its potential to alter the course of common neurologic disorders.

“We wanted to understand how this parasite, which lives in the brain, might contribute to and shed light on pathogenesis of other brain diseases,” said Rima McLeod, MD, professor of ophthalmology & visual science and pediatrics and medical director of the Toxoplasmosis Center at the University of Chicago.

Rima McLeod, MD

Rima McLeod, MD

“We suspect it involves multiple factors,” she said. “At the core is alignment of characteristics of the parasite itself, the genes it expresses in the infected brain, susceptibility genes that could limit the host’s ability to prevent infection, and genes that control susceptibility to other diseases present in the human host. Other factors may include pregnancy, stress, additional infections, and a deficient microbiome. We hypothesized that when there is confluence of these factors, disease may occur.”

For more than a decade, researchers have noted subtle behavior manipulations associated with a latent T. gondii infection. Rats and mice that harbor this parasite, for example, lose their aversion to the smell of cat urine. This is perilous for a rodent, making it easier for cats to catch and eat them. But it benefits cats, who gain a meal, as well as the parasites, who gain a new host, who will distribute them widely into the environment. An acutely infected cat can excrete up to 500 million oocysts in a few weeks’ time. Even one oocyst, which can remain in soil or water for up to a year, is infectious.

A more recent study found a similar connection involving primates. Infected chimpanzees lose their aversion to the scent of urine of their natural predator, leopards.

The research team decided to search for similar effects in people. They focused on what they call the human “infectome” – plausible links between the parasite’s secreted proteins, expressed human microRNAs, the neural chemistry of the human host, and the multiple pathways that are perturbed by host-parasite interactions.

Using data collected from the National Collaborative Chicago-Based Congenital Toxoplasmosis Study, which has diagnosed, treated and followed 246 congenitally infected persons and their families since 1981, they performed a “comprehensive systems analysis,” looking at a range of parasite-generated biomarkers and assessing their probable impact.

Working with the J Craig Venter Institute and the Institute of Systems Biology Scientists, they looked at the effect of infections of primary neuronal stem cells from the human brain in tissue culture, focusing on gene expression and proteins perturbed. Part of the team, including Huan Ngo from Northwestern University, Hernan Lorenzi at the J Craig Venter Institute, Kai Wang and Taek-Kyun Kim at the Institute for Systems Biology and  McLeod, integrated host genetics, proteomics, transcriptomics and circulating microRNA datasets to build a model of these effects on the human brain.

Using what they called a “reconstruction and deconvolution,” approach, the researchers identified perturbed pathways associated with neurodegenerative diseases as well as connections between toxoplasmosis, human brain disorders and some cancers.

toxo-localization

T. gondii (I, II, III) infection of S-NSC alters localization of p50-NFkB(red) and Stat 3 (second panel, red): SAG1 (Green), Hoechst (blue); T. gondii, in NSC, expresses or alters host cells’ neurotransmitters. Tyrosine Hydroxylase (red) in the infected NSCs that synthesizes dopamine is present in T. gondii (middle panels 40X, 60X). This is further exemplified in the furthest right panel by a dopamine-like immunostaining pattern in the parasite (green). The red arrow in the dopamine-like staining image points to a host cell dense perinuclear distribution of label. This suggests potential to influence neurotransmission in human NSC.

They also found that:

  • Small regulatory biomarkers – bits of microRNA or proteins found in children with severe toxoplasmosis – matched those found in patients with neurodegenerative diseases like Alzheimer’s or Parkinson’s disease.
  • The parasite was able to manipulate 12 human olfactory receptors in ways that mimicked the cat-mouse or the chimp-leopard exchange.
  • Evidence that gondii could increase the risk of epilepsy, “possibly by altering GABAergic signaling.”
  • gondii infection was associated with a network of 1,178 human genes, many of which are modified in various cancers.

“Our results provide insights into mechanisms whereby this parasite could cause these associated diseases under some circumstances,” the authors wrote. “This work provides a systems roadmap to design medicines and vaccines to repair and prevent neuropathological effects of T. gondii on the human brain.”

“This study is a paradigm shifter,” said co-author Dennis Steinler, PhD, director of the Neuroscience and Aging Lab at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. “We now have to insert infectious disease into the equation of neurodegenerative diseases, epilepsy and neural cancers.”

“At the same time,” he added, “we have to translate aspects of this study into preventive treatments that include everything from drugs to diet to life style, in order to delay disease onset and progression.”

This work was funded by the National Institutes of Health, the Mann Cornwell Family, the Engel family, the Rooney, Drago, and the Morel families, and “Taking out Toxo.” The Institute for Systems Biology is partially supported by research contracts from the Defense Threat Reduction Agency and the Department of Defense. The J. Craig Venter Institute sequencing and analysis was funded by the National Institute of Allergy and Infectious diseases, as was parts of the work at the University of Chicago.

Additional authors include Ying Zhou, Kamal El Bissati, Ernest Mui, Laura Fraczek, Fiona L. Henriquez, Kelsey Wheeler, Ian Begeman, Carlos Naranjo-Galvis, Ney Alliey-Rodriguez and Shawn Withers from the University of Chicago; Huan Ngo, Gwendolyn Noble and Charles N. Swisher from Northwestern University; Hernan Lorenzi and Seesandra V. Rajagopala from the Craig Venter Institute; Kai Wang, Taek-Kyun Kim, Yong Zhou and Leroy Hood from the Institute of Systems Biology, Seattle; Craig W. Roberts from the 6University of Strathclyde, Glasgow; Alexandre Montpetit from Genome Quebec, Montréal, Canada; Jenefer Blackwell from McGill University; Sarra Jamieson from the University of Western Australia; Roderick Davis from the University of Illinois-Chicago, Liliana Soroceanu from California Pacific Medical Center, Charles Cobbs from Tufts University, Kenneth Boyer and Peter Heydemann from Rush University Medical Center, Chicago; Peter Rabiah from Northshore University Health System, Evanston, IL; and Patricia Soteropoulos from Rutgers University.


Tagged: Alzheimer's disease, Biological Sciences, epilepsy, Infectious Disease, neurology, Neuroscience, parasites, Parkinson's disease, Rima McLeod, toxoplasmosis

Graduate students in biological sciences attend computation bootcamp

Mon, 09/11/2017 - 16:14
uchicago-bsd-bootcamp-students

UChicago students Matt Trendowski and Hallie Sussman attend the Biological Sciences Division bootcamp. (Photo byMegan Costello)

As biology increasingly transforms into a discipline driven by ever-expanding datasets and computational analysis, students need new forms of training to follow best practices and build a successful research career. With a new award from the National Science Foundation, the University of Chicago Biological Sciences Division will test an innovative curriculum, which it piloted at the Marine Biological Laboratory, that focuses on hands-on learning in computational methods and how to use these tools in a rigorous and reproducible way.

For a week before their first courses begin, incoming graduate students from every BSD graduate program will travel to Marine Biological Laboratory in Woods Hole, Mass. for a weeklong “bootcamp” session. This training experience—combined with a responsible research course taught later in the academic year—will prepare students with the programming, statistics and documentation practices needed to produce cutting-edge science.

Read more about the bootcamp at UChicago News.


Tagged: big data, Biological Sciences, biostatistics, computation, computer programming, computer science, Marine Biological Laboratory, statistics

UChicago researcher receives Fulbright award to study toxoplasmosis in Morocco

Thu, 08/24/2017 - 09:00

kamal-el-bissati

Kamal El Bissati, PhD, a faculty member in the department of Ophthalmology and Visual Sciences at the University of Chicago, has been awarded a Fulbright U.S. Scholar Award in Medical Sciences and Public/Global Health for 2017-2018.

El Bissati is a microbiologist who studies how parasites that cause diseases interact with their hosts, specifically toxoplamosis. Toxoplasmosis is a serious, potentially fatal parasitic disease. While some people carry the Toxoplasmosis gondii parasite without showing any symptoms, it can cause blindness, developmental disabilities and epilepsy in infants born to mothers infected with it.

Toxoplasmosis is a serious issue in the developing world, including Bissati’s native Morocco, where as many as half of pregnant women carry the parasite. Under the Fulbright program, he will travel to Morocco for the 2017-18 academic year to collect genetic variation data on the parasite in North Africa to support his ongoing research with Rima McLeod, MD, Medical Director of the Toxoplasmosis Center at UChicago and one of the world’s leading experts on the disease.

The Fulbright Program is the flagship international educational exchange program sponsored by the U.S. government. Each year more than 800 U.S. citizens teach, conduct research, and provide expertise abroad in over 160 countries worldwide.

Read more about Kamal El Bissati’s research here on Science Life.


Tagged: Biological Sciences, Fulbright, Fulbright Scholar Program, Global Health, Infectious Disease, Kamal El Bissati, Microbiology, morocco, toxoplasmosis

Scientists identify gene that controls immune response to chronic viral infections

Tue, 08/15/2017 - 11:00
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Image: Immunity

For nearly 20 years, Tatyana Golovkina, PhD, a microbiologist, geneticist and immunologist at the University of Chicago, has been working on a particularly thorny problem: Why are some people and animals able to fend off persistent viral infections while others can’t?

Mice from a strain called I/LnJ are especially good at this. They can control infection with retroviruses from very different families by producing specific antibodies that coat viruses and render them innocuous.

Golovkina, a Professor of Microbiology, was interested in what makes these mice special, so she began searching for the genes responsible for their remarkable immune response. In a new study published this week in the journal Immunity, she and her colleagues identify this gene. They also began to uncover more clues how it might work to control anti-virus immune responses.

Using a process called positional cloning, in which researchers progressively narrow down the location of a gene on the chromosome, they pinpointed it within the major histocompatibility complex (MHC) locus. The MHC locus is a well-known region of the genome involved with the immune system so it makes sense that the gene was located there, but this was a disconcerting discovery.

“It was a bummer at first because there are tons of genes within the MHC locus all controlling immune response, not only against viruses, but also many other microbial pathogens and non-microbial disorders,” she said. “Most of the time when people map a gene to the MHC they give up and stop there, with an assumption that the gene encodes for one of the two major MHC molecules, MHC class I or and MHC class II.”

But with the help of a biochemist, Lisa Denzin from Rutgers University, and a computational biologist, Aly Khan from the Toyota Technological Institute at Chicago, Golovkina and her team identified a gene called H2-Ob that enables this resistance. Together with another gene called H2-Oa, it makes a molecule called H2-O in mice and HLA-DO in humans.

H2-O has been known for years as a negative regulator of the MHC class II immune response, meaning that it shuts down the immune response. Most researchers thought it was there to prevent autoimmune responses, which attack the body’s own tissues. But in this case, none of the I/LnJ mice showed signs of autoimmunity, so H2-O must have another purpose.

Golovkina and her team discovered another interesting thing when they crossed I/LnJ mice that were resistant to infections with ones that were more susceptible. The resultant F1 mice were susceptible to infection. This indicated that the I/LnJ H2-Ob gene was recessive; both parents had to have a copy of the mutated gene to pass it on their offspring, and the product of the gene should be a non-functional protein.

Tanya Golovkina

Tanya Golovkina, PhD

“That was really surprising,” Golovkina said. “Almost all pathogen-resistant mechanisms discovered so far are dominant, meaning that something needs to be gained to resist.”

The immune system response to a virus in susceptible mice lasts three to four weeks, then the H2-O molecule tells it to stop. But the I/LnJ mice, which respond vigorously to infections, have a mutation on H2-Ob that makes it inactive. So, after they launch an immune response, it never shuts off. This keeps persistent retroviruses in check.

Golovkina hypothesizes that while letting the immune response keep running may keep chronic infections in check, such as retroviruses or hepatitis B and C, other pathogens like tuberculosis can take advantage of a persistent immune response because they can get access to certain cells when they’re coated with antibodies (and I/LnJ mice happen to be susceptible to TB and produced anti-TB antibodies).

At some point during the evolution of these genes, it was more advantageous to be able to switch off the immune response to some infections (such as intracellular bacterial pathogens), but it came at the cost of not being able to fight other long-term infections.

Now that her team has identified the gene underlying anti-retrovirus and potentially anti-hepatitis B and C responses, Golovkina says that further research should be done to create genetic therapies to manipulate the function of this gene, or develop molecules that could interfere with the function of H2-O to allow the virus-specific response in chronically infected people.

Until then, she’ll continue working on this problem, just as she has for the past 20 years.

“I have a very persistent nature in the way I do research,” she said. “If I sincerely believe there is a very interesting biological question, nothing will prevent me from uncovering it.”

The study, “Neutralizing Antibody Responses to Viral Infections Are Linked to the Non-classical MHC Class II Gene H2-Ob,” was supported by the United States Department of Health and Human Services, the National Institutes of Health and the Robert Wood Johnson Foundation. Additional authors include Francesca Virdis from Rutgers University; Jessica Wilks, Melissa Kane, Helen Beilinson, Stanislav Dikiy, Laure Case, Michele Witkowski and Alexander Chervonsky from the University of Chicago; and Derry Roopenian from the Jackson Laboratory, Maine.


Tagged: Biological Sciences, Genetics, immune system, immunology, Microbiology, retroviruses, Tatyana Golovkina, viruses

First winged mammals from the Jurassic period discovered

Wed, 08/09/2017 - 12:00
 A mother with a baby in suspending roosting posture, climbing on tree trunk, and in gliding (Reconstruction by April I. Neander/UChicago).

Maiopatagium in Jurassic forest in crepuscular (dawn and dusk) light: A mother with a baby in suspending roosting posture, climbing on tree trunk, and in gliding (Reconstruction by April I. Neander/UChicago).

Two 160 million-year-old mammal fossils discovered in China show that the forerunners of mammals in the Jurassic Period evolved to glide and live in trees. With long limbs, long hand and foot fingers, and wing-like membranes for tree-to-tree gliding, Maiopatagium furculiferum and Vilevolodon diplomylos are the oldest known gliders in the long history of early mammals.

The new discoveries suggest that the volant, or flying, way of life evolved among mammalian ancestors 100 million years earlier than the first modern mammal fliers. The fossils are described in two papers published this week in Nature by an international team of scientists from the University of Chicago and Beijing Museum of Natural History.

“These Jurassic mammals are truly ‘the first in glide,’” said Zhe-Xi Luo, PhD, professor of organismal biology and anatomy at the University of Chicago and an author on both papers. “In a way, they got the first wings among all mammals.”

“With every new mammal fossil from the Age of Dinosaurs, we continue to be surprised by how diverse mammalian forerunners were in both feeding and locomotor adaptations. The groundwork for mammals’ successful diversification today appears to have been laid long ago,” he said.

Adaptations in anatomy, lifestyle and diet

The ability to glide in the air is one of the many remarkable adaptations in mammals. Most mammals live on land, but volant mammals, including flying squirrels and bats that flap bird-like wings, made an important transition between land and aerial habitats. The ability to glide between trees allowed the ancient animals to find food that was inaccessible to other land animals. That evolutionary advantage can still be seen among today’s mammals such as flying squirrels in North America and Asia, scaly-tailed gliders of Africa, marsupial sugar gliders of Australia and colugos of Southeast Asia.

The Jurassic Maiopatagium and Vilevolodon are stem mammaliaforms, long-extinct relatives of living mammals. They are haramiyidans, an entirely extinct branch on the mammalian evolutionary tree, but are considered to be among forerunners to modern mammals. Both fossils show the exquisitely fossilized, wing-like skin membranes between their front and back limbs. They also show many skeletal features in their shoulder joints and forelimbs that gave the ancient animals the agility to be capable gliders. Evolutionarily, the two fossils, discovered in the Tiaojishan Formation northeast of Beijing, China, represent the earliest examples of gliding behavior among extinct mammal ancestors.

Click to view slideshow.

The two newly discovered creatures also share similar ecology with modern gliders, with some significant differences. Today, the hallmark of most mammal gliders is their herbivorous diet that typically consists of seeds, fruits and other soft parts of flowering plants.

But Maiopatagium and Vilevolodon lived in a Jurassic world where the plant life was dominated by ferns and gymnosperm plants like cycads, gingkoes and conifers – long before flowering plants came to dominate in the Cretaceous Period, and their way of life was also associated with feeding on these entirely different plants. This distinct diet and lifestyle evolved again some 100 million years later among modern mammals, in examples of convergent evolution and ecology.

“It’s amazing that the aerial adaptions occurred so early in the history of mammals,” said study co-author David Grossnickle, a graduate student at the University of Chicago. “Not only did these fossils show exquisite fossilization of gliding membranes, their limb, hand and foot proportion also suggests a new gliding locomotion and behavior.”

Thriving among dinosaurs
Vilevolodon_Eating_lg

A gliding mammaliaform feeding on the soft parts of a bennethelian plant of the Jurassic. (Illustration by April I. Neander/UChicago)

Early mammals were once thought to have differences in anatomy from each other, with limited opportunities to inhabit different environments. The new glider fossils from the dinosaur-dominated Jurassic Period, along with numerous other fossils described by Luo and colleagues in the last 10 years, however, provide strong evidence that ancestral mammals adapted to their wide-ranging environments despite competition from dinosaurs.

“Mammals are more diverse in lifestyles than other modern land vertebrates, but we wanted to find out whether early forerunners to mammals had diversified in the same way,” Luo said. “These new fossil gliders are the first winged mammals, and they demonstrate that early mammals did indeed have a wide range of ecological diversity, which means dinosaurs likely did not dominate the Mesozoic landscape as much as previously thought.”

The study “New Gliding Mammaliaforms from the Jurassic” was supported by the Beijing Science and Technology Commission and the University of Chicago. Additional authors include Qing-Jin Meng, Qiang Ji, Di Liu, Yu-Guang Zhang and April I. Neander.

The study “New Evidence for Mammaliaform Ear Evolution and Feeding Adaptation in a Jurassic Ecosystem,” was supported by the Beijing Science and Technology Commission, and the University of Chicago. Additional authors include Qing-Jin Meng, Qiang Ji, Yu-Guang Zhang, Di Liu and April Neander.


Tagged: Biological Sciences, China, David Grossnickle, dinosaurs, fossils, Jurassic Period, paleontology, Zhe-Xi Luo
Flying mammal fossil reconstruction

Big data yields surprising connections between diseases

Mon, 08/07/2017 - 10:00
Andrey Rzhetsky

Andrey Rzhetsky, PhD, the Edna K. Papazian Professor of Medicine and Human Genetics

Using health insurance claims data from more than 480,000 people in nearly 130,000 families, researchers at the University of Chicago have created a new classification of common diseases based on how often they occur among genetically-related individuals.

Researchers hope the work, published this week in Nature Genetics, will help physicians make better diagnoses and treat root causes instead of symptoms.

“Understanding genetic similarities between diseases may mean that drugs that are effective for one disease may be effective for another one,” said Andrey Rzhetsky, PhD, the Edna K. Papazian Professor of Medicine and Human Genetics at UChicago who was the paper’s senior author. “And for those diseases with a large environmental component, that means we can perhaps prevent them by changing the environment.”

The results of the study suggest that standard disease classifications–called nosologies–based on symptoms or anatomy may miss connections between diseases with the same underlying causes. For example, the new study showed that migraine, typically classified as a disease of the central nervous system, appeared to be most genetically similar to irritable bowel syndrome, an inflammatory disorder of the intestine.

Rzhetsky and a team of researchers analyzed records from Truven MarketScan, a database of de-identified patient data from more than 40 million families in the United States. They selected a subset of records based on how long parents and their children were covered under the same insurance plan within a time frame most likely to capture when children were living in the same home with their parents. They used this massive data set to estimate genetic and environmental correlations between diseases.

Next, using statistical methods developed to create evolutionary trees of organisms, the team created a disease classification based on two measures. One focused on shared genetic correlations of diseases, or how often diseases occurred among genetically-related individuals, such as parents and children. The other focused on the familial environment, or how often diseases occurred among those sharing a home but who had no or partially matching genetic backgrounds, such as spouses and siblings.

FigureSupplement_5_GvEBaseTree2

New disease classifications created by analyzing genetic and environmental correlations among family members

The results focused on 29 diseases that were well represented in both children and parents to build new classification trees. Each “branch” of the tree is built with pairs of diseases that are highly correlated with each other, meaning they occur frequently together, either between parents and children sharing the same genes, or family members sharing the same living environment.

“The large number of families in this study allowed us to obtain precise estimates of genetic and environmental correlations, representing the common causes of multiple different diseases,” said Kanix Wang, a graduate student at UChicago and lead author of the study. “Using these shared genetic and environmental causes, we created a new system to classify diseases based on their intrinsic biology.”

Genetic similarities between diseases tended to be stronger than their corresponding environmental correlations. For the majority of neuropsychiatric diseases, such as schizophrenia, bipolar disorder and substance abuse, however, environmental correlations are nearly as strong as genetic ones. This suggests there are elements of the shared, family environment that could be changed to help prevent these disorders.

Rzhetsky ICD-9 phenotypic

Two traditional disease classifications, ICD-9 (left) and a phenotypic model (right) based on symptoms

The researchers also compared their results to the widely used International Classification of Diseases Version 9 (ICD-9) and found additional, unexpected groupings of diseases. For example, type 1 diabetes, an autoimmune endocrine disease, has a high genetic correlation with hypertension, a disease of the circulatory system. The researchers also saw high genetic correlations across common, apparently dissimilar diseases such as asthma, allergic rhinitis, osteoarthritis and dermatitis.

The study, “Classification of common human diseases derived from shared genetic and environmental determinants” was supported by the Defense Advanced Research Projects Agency (DARPA) Big Mechanism program, the National Institutes of Health, and a gift from Liz and Kent Dauten. Additional authors include Hallie Gaitsch from the University of Chicago, Hoifung Poon from Microsoft Research, and Nancy J. Cox from Vanderbilt University.


Tagged: Andrey Rzhetsky, big data, bioinformatics, Biological Sciences, biostatistics, disease classification, Genetics, nosology

Gene therapy via skin could treat many diseases, even obesity

Thu, 08/03/2017 - 11:00

wu-epidermal-cells-graphical-abstract

A research team based at the University of Chicago has overcome challenges that have limited gene therapy and demonstrated how their novel approach with skin transplantation could enable a wide range of gene-based therapies to treat many human diseases.

In the August 3, 2017 issue of the journal Cell Stem Cell, the researchers provide “proof-of-concept.” They describe gene-therapy administered through skin transplants to treat two related and extremely common human ailments: type-2 diabetes and obesity.

Xiaoyang Wu, PhD

Xiaoyang Wu, PhD

“We resolved some technical hurdles and designed a mouse-to-mouse skin transplantation model in animals with intact immune systems,” said study author Xiaoyang Wu, PhD, assistant professor in the Ben May Department for Cancer Research at the University of Chicago. “We think this platform has the potential to lead to safe and durable gene therapy, in mice and we hope, someday, in humans, using selected and modified cells from skin.”

Beginning in the 1970s, physicians learned how to harvest skin stem cells from a patient with extensive burn wounds, grow them in the laboratory, then apply the lab-grown tissue to close and protect a patient’s wounds. This approach is now standard. However, the application of skin transplants is better developed in humans than in mice.

“The mouse system is less mature,” Wu said. “It took us a few years to optimize our 3D skin organoid culture system.”

This study, “Engineered epidermal progenitor cells can correct diet-induced obesity and diabetes,” is the first to show that an engineered skin graft can survive long term in wild-type mice with intact immune systems. “We have a better than 80 percent success rate with skin transplantation,” Wu said. “This is exciting for us.”

Using CRISPR and skin grafts, researchers boost insulin levels to reduce weight

The researchers focused on diabetes because it is a common non-skin disease that can be treated by the strategic delivery of specific proteins.

They inserted the gene for glucagon-like peptide 1 (GLP1), a hormone that stimulates the pancreas to secrete insulin. This extra insulin removes excessive glucose from the bloodstream, preventing the complications of diabetes. GLP1 can also delay gastric emptying and reduce appetite.

Using CRISPR, a tool for precise genetic engineering, they modified the GLP1 gene. They inserted one mutation, designed to extend the hormone’s half-life in the blood stream, and fused the modified gene to an antibody fragment so that it would circulate in the blood stream longer. They also attached an inducible promoter, which enabled them to turn on the gene to make more GLP1, as needed, by exposing it to the antibiotic doxycycline. Then they inserted the gene into skin cells and grew those cells in culture.

wu skin graft

Immunofluorescence imaging shows normal skin differentiation and tissue architecture of transplanted skin grafts

When these cultured cells were exposed to an air/liquid interface in the laboratory, they stratified, generating what the authors referred to as a multi-layered, “skin-like organoid.” Next, they grafted this lab-grown gene-altered skin onto mice with intact immune systems. There was no significant rejection of the transplanted skin grafts.

When the mice ate food containing minute amounts of doxycycline, they released dose-dependent levels of GLP1 into the blood. This promptly increased blood-insulin levels and reduced blood-glucose levels.

When the researchers fed normal or gene-altered mice a high-fat diet, both groups rapidly gained weight. They became obese. When normal and gene-altered mice got the high-fat diet along with varying levels of doxycycline, to induce GLP1 release, the normal mice grew fat and mice expressing GLP1 showed less weight gain.

Expression of GLP1 also lowered glucose levels and reduced insulin resistance.

“Together, our data strongly suggest that cutaneous gene therapy with inducible expression of GLP1 can be used for the treatment and prevention of diet-induced obesity and pathologies,” the authors wrote.

When they transplanted gene-altered human cells to mice with a limited immune system, they saw the same effect. These results, the authors wrote, suggest that “cutaneous gene therapy for GLP1 secretion could be practical and clinically relevant.”

This approach, combining precise genome editing in vitro with effective application of engineered cells in vivo, could provide “significant benefits for the treatment of many human diseases,” the authors note.

“We think this can provide a long-term safe option for the treatment of many diseases,” Wu said. “It could be used to deliver therapeutic proteins, replacing missing proteins for people with a genetic defect, such as hemophilia. Or it could function as a metabolic sink, removing various toxins.”

wu mice

When normal and gene-altered mice ate the high-fat diet—along with varying levels of doxycycline to induce GLP1 release—mice expressing GLP1 (left) gained less weight gain while normal mice (right) grew fat

Skin progenitor cells have several unique advantages that are a perfect fit for gene therapy. Human skin is the largest and most accessible organ in the body. It is easy to monitor. Transplanted skin can be quickly removed if necessary. Skins cells rapidly proliferate in culture and can be easily transplanted. The procedure is safe, minimally invasive and inexpensive.

There is also a need. More than 100 million U.S. adults have either diabetes (30.3 million) or prediabetes (84.1 million), according the Centers for Disease Control and Prevention. More than 2 out of 3 adults are overweight. More than 1 out of 3 are considered obese.

Additional authors of the study were Japing Yue, Queen Gou, and Cynthia Li from the University of Chicago and Barton Wicksteed from the University of Illinois at Chicago. The National Institutes of Health, the American Cancer Society and the V Foundation funded the study.


Tagged: Biological Sciences, CRISPR, Diabetes, Genetics, immune system, immunology, Obesity, skin grafts, skin transplantation, Xiaoyang Wu

New ecological model generates diversity with chain of head-to-head battles

Thu, 07/27/2017 - 10:41

 

allesina-header

A new mathematical model of ecology created by University of Chicago scientists provides the most accurate reproduction to date of natural biodiversity, according to a new paper in the journal Nature.

For almost a century, ecologists have conceptualized an ecosystem as the sum of pairwise interactions, such as predator and prey, herbivore and plant, or parasite and host. However, equations based on that theory failed to replicate the diversity and resilience of natural ecosystems.

Building upon previous work that modeled competition between species as similar to a game of rock/paper/scissors, a team led by Stefano Allesina, Professor of Ecology & Evolution at the University of Chicago, found that adding additional competitors could generate stable and robust model ecosystems.

“Ecologists feel more comfortable with pairs, but that doesn’t mean that nature operates in pairs,” said Allesina, who is also a Computation Institute fellow and faculty. “No one had proposed equations for triplets or quadruplets. We wanted to test if these relationships really make a difference, and the answer is a resounding yes; they make a huge difference.”

Ecologists have long debated the existence and importance of higher-order interactions, where the relationship of two species can be influenced by a third. For example, the trio of a carnivore, a herbivore, and a plant would be treated as independent carnivore-herbivore and herbivore-plant pairs. But the presence of a carnivore could force the herbivore into hiding, affecting its consumption of the plant — a higher-order interaction that disrupts the pairwise model.

“If you measure these pairs and put them together, they don’t explain the system,” Allesina said. “Basically the presence of the predator modifies the relationship between the plant and the herbivore. Something emerges that cannot be explained by pairs.”

In the Nature paper, Allesina, postdoctoral researchers Jacopo Grilli and György Barabás, and graduate student Matthew Michalska-Smith considered a simple scenario. In a hypothetical forest where every so often one tree dies and leaves a hole in the canopy, who will win a battle of species to fill that ecological gap?

Jacopo Grilli (left) and Stefano Allesina

Jacopo Grilli (left) and Stefano Allesina

If a pair of species compete for each opening, the dominant competitor will eventually drive the other extinct and lower ecosystem diversity, unless they are perfectly equal. In the “rock paper scissors” model proposed by Allesina’s group in 2011, overlapping dominance (e.g. rock beats scissors but loses to paper) of multiple species can maintain a rich ecosystem, but the biodiversity cycles between high and low in a pattern not observed in nature.

To instead model the system with higher-order interactions, the team simulated competition using a “stepladder tournament” format similar to that used in televised bowling events. Here, the winner of a two-way match goes on to play against a third competitor, and the winner of that match plays a fourth, and so on, for any number of competitors. With an equation that aggregates all possible outcomes of one of these “chain of competitions,” the researchers found they could produce a system with high and stable biodiversity, similar to observations from the real world.

Unlike other ecological models, their equation produced realistic results under a wide range of starting conditions, as well as in both a closed system — akin to bacteria competing in a laboratory dish — and an open system, where new species enter and leave the ecosystem over time.

“When there is even the probability of just three species interacting, it completely changes the dynamics,” Grilli said. “As long as there is a very small probability for higher-order interactions to happen, then there are going to be huge changes. It’s really an effect that is super robust.”

The researchers now hope to test their new equation in laboratory experiments, observing whether actual competition between bacterial species follows their model’s predictions. In the meantime, by mathematically proving the strong influence of these higher-order interactions, Allesina expects the model to further push theoretical ecology into new territory.

“I think that this opens the door for a number of models that people had not considered before, that are maybe even simpler than this one,” Allesina said. “It is very rare in ecology to see a model that has this kind of global stability, such that wherever you start you end up in the same point.”

rock-paper-scissors

The new model also led Allesina’s group back to familiar territory: the world of competitive rock paper scissors.

“If you apply this equation to come up with rules to play rock paper scissors with three people, these turn out to be the official rules that they use,” Grilli said. “In fact, we have a way to generalize for any number of players, so if you want to play the game with 8 people, we can do that.”


Tagged: biodiversity, Biological Sciences, computational biology, ecology, ecology and evolution, Evolution, George Barabas, Jacopo Grilli, Matthew Michalska-Smith, stefano allesina

UChicago Medicine and Biological Sciences faculty receive named professorships

Fri, 07/14/2017 - 12:20

Twenty-four University of Chicago faculty members have received named professorships or were appointed distinguished service professors, including seven from UChicago Medicine and the Biological Sciences Division.

Zeray AlemsegedZeresenayZerayAlemseged has been named the Donald N. Pritzker Professor in Organismal Biology and Anatomy and the College.

A noted paleoanthropologist, Alemseged studies the origin of early human ancestors and the environmental factors that influenced their evolution. He established and led the Dikika Research Project, in which Alemseged made several breakthrough findings, including the discovery of the almost-complete fossilized remains of “Selam,” a 3.3-million-year-old child of the species Australopithecus afarensis. Now known as “the world’s oldest child,” it is the most complete skeleton of a human ancestor discovered to date and represents a major advancement in the understanding of human and pre-human evolution.

Alemseged is a fellow of the American Association for the Advancement of Science, and the co-founder and president of the East African Association of Paleontologists and Paleoanthropologists. He was a senior scientist at the Max Planck Institute and recently the Irvine Chair and senior curator of anthropology at the California Academy of Sciences.

joy bergelsonJoy Bergelson has been named the James D. Watson Professor in Ecology and Evolution and the College.

Bergelson’s work focuses on the plant Arabidopsis thaliana and the community of bacteria that inhabit it, with particular interest in understanding how the ecology of these interactions shapes evolutionary change. Her studies combine molecular evolutionary research with functional genomics under natural field conditions to test models of host-pathogen co-evolution. Along with colleagues she also has pioneered the development of Arabidopsis thaliana as a system for genome-wide mapping studies, which culminated in the Arabidopsis 1001 project. She received the 2017 BSD Distinguished Investigator award for this body of work.

The chair of the Department of Ecology and Evolution, Bergelson is a member of three UChicago committees, and has served on dozens of other departmental, divisional and university committees, National Science Foundation and U.S. Department of Agriculture panels, international advisory boards and journal editorial boards. She is a fellow of the American Association for the Advancement of Science and has served as chair of the AAAS Biology section.

John cunninghamJohn M. Cunningham has been named the George M. Eisenberg Professor in Pediatrics and the College.

Cunningham is an internationally known expert in the treatment and research of childhood cancers and blood diseases. He has particular expertise in treating leukemia, immunodeficiencies, sickle cell disease and thalassemia. He is a recognized leader in the field of pediatric stem cell transplantation and has developed novel uses for this life-saving treatment. Cunningham studies the transcriptional mechanisms operative in hematopoiesis and leukemia, and the development of clinical trials for the treatment of leukemia and genetic diseases.

Cunningham’s research has received support from the National Heart, Lung, and Blood Institute; the American Society of Hematology; and other prominent scientific organizations. He is a member of the scientific council of the American Cancer Society and a member of the editorial board of The Oncologist.

tom gajewski

Thomas F. Gajewski has been named the first AbbVie Foundation Professor of Cancer Immunotherapy in Pathology.

Gajewski’s team members study ways to overcome a tumor’s ability to elude the immune system, with a focus on drugs that help the immune system, especially T cells, gain access to tumor sites. They have discovered genetic clues that correlate with response versus resistance, enabling them to identify new therapies to overcome resistance and expand efficacy. They also discovered that certain components of the gut microbiota—microbes that live in a patient’s digestive tract—could stimulate the immune system to attack tumor cells. They are now refining this approach and analyzing a large cohort of human samples.

Earlier this year, Gajewski received an outstanding investigator award from the National Institutes of Health for productivity in cancer research. Gajewski is an editor for Cancer Research and the Journal for Immunotherapy of Cancer and past president of the Society for Immunotherapy of Cancer.

rex haydonRex Haydon has been named the Simon and Kalt Families Professor in Orthopaedic Surgery.

An orthopedic surgeon and physician-scientist, Haydon specializes in the comprehensive treatment of tumors in bone or soft tissue. He works closely with patients hoping to avoid limb amputation as well as those who need reconstructive surgery on their upper and lower extremities. Haydon’s research focuses on advancing the treatment of musculoskeletal tumors. He’s the author of more than 120 articles and book chapters and has accepted career development awards from both the Orthopaedic Research and Education Foundation and the National Institutes of Health.

Beyond his work in the University of Chicago’s Department of Orthopaedic Surgery and Rehabilitation Medicine, Haydon is also the associate director of the University of Chicago Medicine Molecular Oncology Laboratory.

sonali smithSonali M. Smith has been selected as the first Elwood V. Jensen Professor in Medicine.

The director of the lymphoma program, Smith is an expert on lymphoma treatment and has made outstanding contributions to the field through clinical care, education and clinical research. She studies new agents and combinations in the management of both treatment-naïve and relapsed/refractory lymphomas. She is currently studying the role of stem cell transplantation for patients with high-risk follicular lymphoma.

Smith is vice chair of the Southwest Oncology Group Lymphoma Committee, where she oversees clinical trial development and mentors faculty. She chairs the American Society of Oncology’s Women in Oncology Subcommittee and is the incoming chair of ASCO’s Continuous Professional Development Committee. She is co-editor of ASCO’s Hematology and co-chair of the Center for International Blood and Marrow Transplant Research Lymphoma Working Group. Smith serves on the editorial board of the Journal of Clinical Oncology and Cancer. She is an elected fellow of Pritzker’s Academy of Distinguished Medical Educators and a senior faculty scholar in the Bucksbaum Institute. She has more than 140 publications and lectures extensively to peers and patients nationally and internationally.

nir urielNir Uriel has been named the Louis Block Professor in Medicine.

Uriel, who is director of the Heart Failure, Transplant and Mechanical Circulatory Support program, is a leader in the field of heart failure, mechanical circulatory support and heart transplantation. He specializes in caring for patients who require mechanical circulatory support, including ventricular assist devices. Uriel’s research focuses on advanced heart failure physiology, heart transplant and mechanical circulatory support. Uriel specialized and reported physiological changes and developed treatment algorithms for patients supported with Mechanical Circulatory Support that are being used worldwide. These findings were published in the Journal of American College of Cardiology.

Uriel has a strong interest in high-risk transplant populations, including HIV-positive patients and patients who have received mediastinal radiation due to tumors or prior transplants. He has improved treatment protocols and patient care for these high-risk groups.


Tagged: Biological Sciences, Cancer, ecology and evolution, Haydon, Heart & Vascular, John Cunningham, Joy Bergelson, Nir Uriel, Orthopedics, paleontology, Pediatrics, Sonali Smith, Thomas Gajewski, Transplant, Zeray Alemseged

Studying the shape of a protein to learn how pregnancy makes peace with the immune system

Thu, 07/13/2017 - 09:00
Dulberger HLA-F

The crystal structure of HLA-F, an immune system protein involved in pregnancy

Pregnancy presents a conundrum for the immune system. It’s built to fight off any invaders with foreign DNA, from viruses and bacteria to, unfortunately, lifesaving transplanted organs. Since a fetus has DNA from both parents, the mother’s immune system needs to have a way to remain tolerant of the father’s foreign genes and give them a pass.

One way the immune system acknowledges the special circumstances of pregnancy is with proteins produced by genes in the major histocompatibility complex (MHC), which help the immune system identify foreign bodies. In most situations, MHC proteins on healthy cells present little pieces of proteins called peptides, which are like badges to show to the body’s security guards, roaming immune T cells. If they see a human or “self” peptide, everything checks out; but if they see a peptide from a virus or foreign tissue, the guards sound the alarm and trigger an immune response to kill the cell.

But during pregnancy, the fetus doesn’t express a lot of these classical MHC proteins that are recognized by T cells responding to specific peptides, perhaps as a way to avoid rejection. Instead, fetal and uterine cells express related, but slightly different, non-classical MHC proteins that regulate maternal NK (natural killer) cells that supervise the extensive changes that occur in the uterus during pregnancy.

Charles Dulberger is a PhD candidate in the department of Biochemistry and Molecular Biophysics at the University of Chicago (and Science Life contributor) who studies the three-dimensional structures of proteins that control immune responses. The shape and surface topology of proteins is important to how they function. They have unique notches and grooves that allow them to interact with other proteins or bind molecules with matching shapes, like puzzle pieces fitting together.

In a paper published last month in the journal Immunity, Dulberger led a team that described the structure of HLA-F, one of the specialized MHC proteins involved in pregnancy, for the first time. It hasn’t been studied as thoroughly as some of its neighbors, and while it turns out that it functions in many of the same ways, it has some interesting differences that may be tied to the evolution of pregnancy in humans.

Scientists haven’t been sure how HLA-F is involved in the immune system, or whether it presents peptides in the same way as other MHC proteins. Using x-ray crystallography and other biochemical methods to define its structure, Dulberger and his colleagues were able to confirm that HLA-F does bind peptides, which means it could be recognized by T cell receptors too.

“Now that we know that HLA-F can present peptides, we want to know if T cells and NK cells can use their receptors to perceive these peptides as a signal to respond to,” he said. “If T cell receptors do recognize them, that opens the door for potential therapeutics that exploit or modify this interaction, because T cells are important in a lot of diseases, including many cancers.”

Dulberger HLA-F

Changes to HLA-F converted it into a molecule that can present peptides (B), shown here with an evolutionary tree showing these changes in different primates

Most MHC molecules have a well-defined, linear groove shaped to hold peptides, like a Lego piece that snaps perfectly into place. But HLA-F has a slightly different groove that is partially blocked off, so part of the peptide protrudes out of the groove. What’s interesting is that these changes are only present in human and orangutan HLA-F, who notably both have nine month pregnancies—they’re not there in HLA-F for chimpanzees, which have a shorter eight-month gestation.

Dulberger said that the differences may contribute to how the mother’s immune system tolerates a longer pregnancy. The structure and function of HLA-F is important to understanding aspects of pregnancy, he said, but learning more about its specific shape (and of others like it) will also help us understand diseases that manipulate the immune system, like cancer.

“We can learn a lot about how cells communicate by understanding the structure of proteins and protein complexes because proteins are kind of like the eyes, ears and mouth of the cell,” Dulberger said. “They sense their environment and signal to each other via protein-protein interactions.”

Understanding protein structure is also really important for the development of new medicines because most drugs used in the clinic target specific proteins.

“Once you understand the molecular architecture of a protein receptor and how it binds another protein, you can design drugs that interfere with that interaction or modify it in an advantageous manner,” he said. “So, you can imagine if you had a cancer that expresses HLA-F at a really high level to inhibit the immune system, you can develop an antibody or small molecule inhibitor to block that, and then the immune cells will be able to fight the cancer cells again.”


Tagged: Biological Sciences, Charles Dulberger, Genetics, immune system, molecular biology, pregnancy, protein structure

Antibiotics taken late in pregnancy can increase risk for inflammatory bowel diseases in offspring

Tue, 07/11/2017 - 11:00
Eugene B. Chang, MD

Eugene B. Chang, MD, the Martin Boyer Professor of Medicine at the University of Chicago (Photo: Dan Dry)

A study by researchers at the University of Chicago Medicine shows that when mice that are genetically susceptible to developing inflammatory bowel disease (IBD) were given antibiotics during late pregnancy and the early nursing period, their offspring were more likely to develop an inflammatory condition of the colon that resembles human IBD.

The antibiotic treatment also caused lasting changes in the gut microbiome of mothers that were passed on to their offspring. While their offspring developed disease, adult mice given antibiotics did not see an increase in IBD. This suggests that the timing of antibiotic exposure is crucial, especially during the early developmental period after birth when the immune system is undergoing maturation.

“The newborn mice inherited a very altered, skewed population of microbes,” said Eugene B. Chang, MD, Martin Boyer Professor of Medicine at the University of Chicago, Director of the Microbiome Medicine Program of the Microbiome Center, and senior author of the study, published this week in the journal Cell Reports. “None of the mothers developed IBD, but even though they had the same genetic background, the offspring with an altered microbiome during this critical period of immune development became highly susceptible to the development of colitis.”

Chang cautioned, however, that these results from an animal study should not be taken as a reason for pregnant women or those nursing newborn infants to avoid antibiotics when they are needed to treat dangerous bacterial infections. Instead, he said, it should serve as a reminder that best practices dictate avoiding casual, indiscriminant over usage ‘just to be safe’, say, for a common cold that is most likely caused by a virus.

“Antibiotics should absolutely be used judiciously when they’re indicated,” Chang said. “But we as physicians should keep in mind the importance of antimicrobial stewardship, because this study suggests that it may have long term consequences that potentially impact health and risk for certain diseases.”

Lasting changes in the gut microbiome

Several epidemiological studies have suggested that exposure to antibiotics during the peripartum period (late pregnancy and the nursing period after birth) increases the risk for IBD in humans. Direct evidence for this association has been lacking, however, because of vast differences in individual gut microbiomes, challenges in controlling for variables, and the limits of conducting clinical experiments in pregnant women and infants.

To address these issues, Jun Miyoshi, MD, PhD, a postdoctoral scholar, and Alexandria Bobe, a graduate student in Chang’s lab, designed a series of experiments with a standard genetic mouse model for IBD to study the timing of antibiotic treatment during the peripartum period and its impact on gut microbes and immune system development in offspring. The researchers gave cefoperazone, a commonly-used antibiotic, to mouse mothers in the late stages of pregnancy through the period that they nursed their pups, i.e. to mimic a common clinical scenario of early antibiotic exposure in humans. None of the adult mice treated with antibiotics developed colitis, but their pups exhibited a high risk for developing colitis compared to those from mothers that were not treated with antibiotics.

Anvi'o visualization

Visualization of the gut microbial population structure created by Anvi’o, software developed by A. Murat Eren, PhD, Marine Biological Laboratory Fellow and Assistant Professor of Medicine at UChicago. The software allows scientists to work with a visual display of genetic data. Click on the image for a fully interactive display of the data used in this study.

Using state-of-the-art, high-throughput sequencing technologies, the team also analyzed the gut microbial population structures of mothers and their offspring. The mothers showed a decrease in diversity of bacteria, and changes in the relative numbers of certain groups of bacteria. For example, there were fewer populations of Bacteroidetes and more from the phyla Firmicutes and Verrucomicrobia. Surprisingly, these changes persisted even four to eight weeks after stopping the antibiotic treatment.

The mouse pups also had similar changes in their gut bacteria, with microbial communities matching their mothers at birth. The diversity of microbes in these pups was significantly different from that of mice not treated with antibiotics, and these differences lasted into adulthood.

“What this should tell us is, at least as physicians, is that antibiotics are not as innocuous as we think they are, and injudicious, casual use of them can have consequences,” Chang said. “When they’re used during pregnancy or early childhood, they can disturb the development of a normal gut microbiome which would otherwise be essential for proper immune development. In genetically susceptible hosts, the inability to develop the immune system properly can have negative consequences like inflammatory bowel disease or any other kinds of complex immune disorders.”

Working toward a definition of health

Chang said that understanding more about the microbiome in an unhealthy state can help scientists begin to learn how to promote the development of a microbiome that sets the stage for a healthy immune system.

“What this study showed is what an ‘unhealthy’ microbiome looks like, so presumably whatever is missing may be important to promote health,” he said. “What we want to eventually develop is a microbial cocktail we can give to infants that ensures that they develop properly, metabolically and immunologically. That’s going to have a significant impact on human health, by reducing risk for many types of diseases and by promoting wellness.”

The study, “Peripartum Exposure to Antibiotics Promotes Persistent Gut Dysbiosis, Immune Imbalance, and Colitis in Genetically Prone Offspring,” was supported by the NIDDK Digestive Disease Core Research Center, the Microbiome Medicine Program of the Microbiome Center at the University of Chicago, the Peter and Carol Goldman Family Research Fund, and the GI Research Foundation of Chicago. Additional authors include, Sawako Miyoshi, Yong Huang, Nathaniel Hubert, Tom O. Delmont, A. Murat Eren and Vanessa Leone from the University of Chicago.


Tagged: antibiotics, Biological Sciences, Eugene Chang, Gastroenterology, IBD, inflammatory bowel disease, microbiome, Microbiome Center, pregnancy, ulcerative colitis

Studying the activity of the genome, one cell at a time

Thu, 07/06/2017 - 09:00
DNA_methylation

Illustration of a DNA molecule that is methylated at the two center cytosines (Image: Christoph Bock, Max Planck Institute for Informatics – Own work, CC BY-SA 3.0)

To understand how the human genome governs what a cell does and how it looks, it’s important for scientists to understand what parts of the genome are activated in different cell types, and how these parts act together to make sure the cell functions properly. To study these questions, researchers have developed tools that measure the structure and activity of genetic material in cells.

In living cells the genome is tightly packaged in a structure called chromatin. Chromatin consists of the genomic DNA itself, proteins, and RNA. When the cell is actively transcribing and replicating DNA, the chromatin is more loosely packed or accessible. Scientists can measure chromatin accessibility to tell which regions of the genome are probably active at a given time. They can also measure levels of DNA methylation, when molecules are added to DNA to “turn off” parts of the genome, to see which regions of DNA might be repressed.

Sebastian Pott, a research assistant professor in the Department of Human Genetics at the University of Chicago, is working to answer some of these questions. In a new study published in the journal eLife, he tested a tool that measures both chromatin accessibility and DNA methylation to see if it could be applied to single cells. Science Life spoke to him about the work.

Why was it important to see if this method works for single cells?

Until recently, most of these studies were performed using large samples that contained thousands of cells. This is beneficial because the starting material is not limited. However, it has become clear that even cells that are seemingly of the same type differ in subtle but important ways. These differences are lost when using bulk samples, which are more likely to reflect the average of a cell population.

It is therefore necessary to develop methods that measure these features in single cells. Because the amount of starting material [from a single cell] is very small, it is critical to modify many of the established techniques when adapting them for single cell measurements. Studying features of the genome in single cells has the added limitation that the sample cannot be divided up for multiple assays. To address these limitations, this study was designed to test whether a method that measures both chromatin accessibility and DNA methylation, called NOMe-seq, could be applied to single cells. It builds on previous work by the labs of Peter Jones [from the Van Andel Research Institute] and Michael Kladde [from the University of Florida]. In this study, I tested whether this protocol could be modified and applied to single cells; the modified protocol was named “single cell NOMe-seq,” or scNOMe-seq.

Did it work?

This study provides evidence that scNOMe-seq detects endogenous DNA methylation and chromatin accessibility at the same time from a single cell. To test the performance of scNOMe-seq the study was performed in well-characterized human cell lines.  Regulatory regions (e.g. promoters of active genes or active regulatory regions and enhancers) showed characteristic chromatin accessibility in single cells. As previously documented in bulk samples, DNA methylation in these regions was inversely correlated with chromatin accessibility. This proof-of-principle study therefore established that scNOMe-seq recovers the same features of chromatin organization observed in bulk samples.

What will scientists be able to do with a tool like this?

Many biological samples contain mixtures of cell types. As a result, it is often difficult when studying such a sample to extract a specific cell type for detailed characterization. For example, not all cell types in a tissue might be known in advance or have specific markers that would allow one to label them and separate them from the rest. In such cases, scNOMe-seq can be applied to measure regulatory activity (i.e. DNA methylation and chromatin accessibility) in individual cells without first isolating specific cell types. The resulting single cell data could then be used to classify and identify distinct cell types or states. This approach could be particularly useful when studying tumor samples which are often very heterogeneous.

What was your biggest challenge during this study?

Cells contain extremely small amounts of DNA and the biggest challenge of this work was to capture as much of the DNA in a cell to be able to measure anything at all. Only after very long process it is possible to assess whether this method works, and so it was pretty cool to see that this approach actually turned out data that were very similar to data produced from thousands of cells.

What are you working on next?

The aim of this study was to provide proof-of-principle that this method reliably obtains data from single cells. But of course, the motivation to develop the method was to use it to study biologically and clinically significant problems. For example, I am planning to apply this technique to study the activation of immune cells. I am particularly interested in understanding how responses of immune cells are regulated in individual cells and what might be different in cells of individuals with allergies.


Tagged: Biological Sciences, chromatin, DNA, DNA methylation, genes, Genetics, genome, human genetics, human genome research, Sebastian Pott

Neuroscientists call for more comprehensive view of how brain forms memories

Wed, 07/05/2017 - 10:54

Neuronal_activity_DARPA

Image: Massachusetts General Hospital and Draper Labs [Public domain], via Wikimedia Commons

Changes in the activity of neurons play crucial role forming physical memory traces in the brain

Neuroscientists from the University of Chicago argue that research on how memories form in the brain should consider activity of groups of brain cells working together, not just the connections between them.

Memories are stored as “engrams,” or enduring physical or chemical changes to populations of neurons that are triggered by new information and experiences. Traditional thinking about how these engrams form centers on the ability of connections between neurons to strengthen or weaken over time based on what information they receive, or what’s known as “synaptic plasticity.” The new proposal, published this week in the journal Neuron, argues that while synaptic plasticity establishes the map of connectivity between individual neurons in an engram, it is not enough to account for all aspects of learning. A second process called “intrinsic plasticity,” or changes in the intensity of activity of neurons within an engram, plays an important role as well.

Christian Hansel

Christian Hansel, PhD

“Synaptic plasticity does not fully account for the complexity of learning mechanisms that we are aware of right now,” said Christian Hansel, PhD, professor of neurobiology and senior author of the new paper. “There were elements missing, and with the introduction of intrinsic plasticity, all of a sudden you see a system that is more dynamic than we thought.”

Viewing activity of the brain as a whole

In recent studies using optogenetic tools, which enable scientists to control the activity of neurons with light, researchers have been able to monitor memory storage and retrieval from brain cells. Optogenetic tools give scientists a window to the activity of the brain as a whole, even in living animals. These new studies show how both individual neurons and groups, or ensembles, of neurons work together while memory and learning processes take place—often without requiring any changes to the connections between synapses.

For instance, synaptic plasticity relies on repeated conditioning to develop stronger connections between cells, meaning that an animal has to experience something several times to learn and form a memory. But, of course, we also learn from single, brief experiences that don’t necessarily trigger changes in the synapses, meaning that another, faster learning process takes place.

Heather Titley

Heather Titley, PhD

The authors point to several studies showing that intrinsic plasticity is a nearly instantaneous mechanism that likely has a lower threshold, or takes fewer experiences, to initiate. Thus, it might be more appropriate for fast learning resulting from single experiences, instead of the slow, adaptive process involved with synaptic plasticity.

Theories about memory formation also don’t account for the relative strength of activity in neurons once connections between them have been established, the authors write. If you think of how memories are stored as working like the lights in a room, synaptic connections are the electrical wiring that determine how the lights are connected and what input (electricity) they receive. Changing how the lights are wired (i.e. the synaptic plasticity) obviously affects how they function, but so do the switches and light bulbs. Intrinsic plasticity is the ability to manipulate the intensity of the light without changing the wiring, like using dimmer switches or three-way bulbs. Both kinds of changes have an effect independently, but they work together to light the room.

Nicholas Brunel, PhD

Nicholas Brunel, PhD

“They are two ideas that are very important to learning and memory and we bring them together in this paper,” said postdoctoral scholar Heather Titley, PhD, first author of the paper. “They’re not mutually exclusive.”

The authors emphasize that this new line of thinking is just a starting point. More experiments should be designed, for instance, to tease out the relative effects of synaptic versus intrinsic plasticity on learning and memory. But given the evidence produced by new technology, they argue that it’s time to expand our thinking about how memories form.

“People might argue whether this intrinsic plasticity is really something that plays a major role or not,” said Nicolas Brunel, PhD, professor of neurobiology and statistics, and another author of the paper. “But I don’t think people can argue that it doesn’t play any role, because there is an increasing amount of evidence that it does.”


Tagged: Biological Sciences, Brain, Christian Hansel, Heather Titley, memories, memory, neurobiology, Neuroscience, Nicholas Brunel

What’s in a name? Big Data approach reveals distinctive patterns in higher education systems

Mon, 07/03/2017 - 14:00
Jacopo Grilli (left) and Stefano Allesina

Jacopo Grilli (left) and Stefano Allesina

A list of professors’ last names can reveal, measure unethical hiring

Using lists of names collected from publicly available websites, two University of Chicago researchers have revealed distinctive patterns in higher education systems, ranging from ethnic representation and gender imbalance in the sciences, to the presence of academic couples, and even the illegal hiring of relatives in Italian universities.

“This study was an exercise in exploiting bare-bones techniques,” said author Stefano Allesina, PhD, professor of ecology & evolution and a member of the Computation Institute at the University of Chicago. “We wanted to analyze the simplest form of data you could imagine: lists of names. That’s all we had. We wondered what kinds of information we could extract from such a meager source of data. We also asked: how could we use this to explore real-world problems?”

For the study — “Last name analysis of mobility, gender imbalance, and nepotism across academic systems,” published July 3, 2017 in the Proceedings of the National Academy of Sciences — Allesina and postdoctoral scholar Jacopo Grilli, PhD, acquired lists of the surnames of all Italian academics in the four years 2000, 2005, 2010 and 2015. For comparison, they also gathered lists of all researchers currently working at the Centre National de la Reserche Scientifique (CNRS) in France, and those working at research-intensive public institutions in the United States.

Then they counted the number of professors in each department who shared last names and contrasted that to the number expected by chance. They found three possible explanations for an overabundance of identical last names. An unusually high proportion of name sharing could be due to geography; certain names are typical of a region. Or, immigration could have an impact, for example, the influx of Asian faculty to the United States in disciplines such as in mathematics and computer science.

If the clustering of names cannot be explained by these two factors — which was the case in certain disciplines and regions in Italy — then the data point to nepotistic hires: professors who recruit their relatives for academic positions.

The Allesina laboratory is not new to this type of analysis. In a 2011 paper published in PLoS One, Allesina demonstrated that certain disciplines (law, medicine, engineering) in Italian universities displayed a severe scarcity of last names, raising the suspicion of nepotism.

That study caused “quite a stir in Italy,” Allesina said. The publication followed a complete overhaul of the nation’s academic system. The reform, passed in late 2010, included a provision intended to prevent professors from recruiting relatives by shifting hiring and funding decisions away from the universities to independent panels. The perception at the time was that “promotions and funding were often awarded on the basis of connections rather than merit, providing mediocre and unproductive professors with jobs for life while pushing many of the country’s brightest minds abroad,” Allesina said.

Grilli and Allesina decided to take a closer look at the law’s impact since 2010 and to compare the prevalence of nepotism in Italy with other countries. They found that nepotism in Italy appears to have declined somewhat over the period from 2000 to 2015. In 2000, seven of the 14 fields measured showed clear signs of nepotism. That fell to five fields in 2010, and only two, chemistry and medicine, by 2015.

Academic hires Allesina

Changes in the ratio of the expected number of academic hires in Italy to share the same name in the same field versus the observed number. The darker blue lines show fields where the researchers saw higher than expected numbers of pairs.

The 2010 law, they point out, was not the only factor in the decrease of apparent nepotism. Much of the decline, the researchers point out, could be traced to an increase in faculty retirements and a dearth of new hires.

The Italian university system has been “virtually butchered over the last decade,” Allesina said, with a staggering 10 percent overall loss of faculty, and losses of 20 to 30 percent of the faculty at several leading universities. “This had a strong effect on new hires,” he said, “but only a limited impact on favoritism over the whole university system.”

The researchers’ focus on last names illuminates some recent changes in U.S. academics as well. When faculty last names were randomized by field, the huge impact of immigration on U.S. universities became obvious. More than half of the 5.2 million immigrant scientists, mathematicians and engineers currently working in the United States were born in Asia.

“Certain names are associated with specific academic fields and certain heritages tend to target preponderantly science and engineering,” said Grilli. Zhang, for example, is now the most common last name in the U.S. in the fields of chemistry and mathematics. It ranks third in agriculture, geology and physics, but falls to 115th in humanities. Smith, on the other hand, is among the top three in humanities, sociology and medicine, but 20th in chemistry and 47th in geology.

“Sometimes using very simple data can get you expected and unexpected results,” Allesina said. First names can reveal a field’s gender imbalance. They can also fluctuate wildly. The most common first name in the past decade for boys in Italy was Francesco, but that increased by 40 percent following the election of Pope Francis. “It was declining,” Grilli said, “but it bounced back.”

“The good and bad of Italy is the family,” Allesina said. “It protects you from collapse, but it also prevents growth. This really becomes a weight on the shoulders of young people, especially in the South, where many talented students have no choice but to emigrate.”

The National Science Foundation and the Human Frontier Science Program funded this study. Data was provided by Scopus.com.


Tagged: academic hiring, big data, Biological Sciences, Computation Institute, Computational Science, gender imbalance, higher education, Jacopo Grilli, nepotism, racial disparities, stefano allesina

What we know about how cells take out the trash could fight viruses too

Thu, 06/29/2017 - 10:52
Mouse cells norovirus

Mouse cells infected with norovirus. The black dots show the replication complexes, or compartments the viruses build for themselves to hide from the immune system.

Viruses can infect every kind of life form, from humans all the way down to bacteria. They’ve managed to spread so far and wide because they have a huge bag of tricks for getting inside cells and multiplying. Some viruses can insert genetic material into their hosts, taking over the machinery of its cells to reproduce. Others lay dormant inside a cell for years until some event triggers them to wake up and burst out of the cell to attack others.

One group of viruses, called positive-sense, single-stranded RNA (+RNA) viruses, plays a game of hide and seek to infect a host. Viruses are sometimes classified by the structure of their genetic material—positive-sense, single-stranded RNA viruses have a single strand of RNA that can act like messenger RNA that tells the host cell what proteins make so it can survive. This group accounts for about one-third of all known viruses, including some of the most well-known, disease-causing viruses out there: hepatitis C, West Nile, dengue, Zika and rhinoviruses that cause the common cold.

When a +RNA virus gets inside a cell, it manipulates the membrane of the cell to create a little compartment, called a replication complex. This compartment helps it hide from the immune system so it can replicate and move on to infect other cells.

Seungmin Hwang, PhD, an assistant professor of pathology at the University of Chicago, studies another common +RNA virus, norovirus. Norovirus is a major cause of what we call “stomach flu” or food poisoning, especially in the winter months. In 2012, while working as a postdoc with the mouse version of norovirus, Hwang discovered that the immune system can detect the replication complex where viruses are hiding inside the cell membrane and attack it. At that point, he didn’t know exactly how this worked, but when studying other +RNA viruses he saw the same thing: Somehow, the immune system could “see” the virus in its hiding spot and go after it.

In a new paper published this week in the journal Cell Host & Microbe, Hwang and his team unravel a little bit more of the mystery about how the immune system can sniff out these replication complexes. Just like a household or working office, cells regularly produce trash that needs to be thrown out or recycled. They use a process called autophagy to identify broken down components and unused proteins and wrap them up for disposal. Cells use autophagy proteins to wrap the trash in a membrane-like structure—i.e. its own little garbage bag—and mark it with another autophagy protein so the cell knows to dispose of it.

Mouse cells autophagy proteins

More cells infected with norovirus. The glowing dots are the autophagy proteins that help dispose of cellular trash and identify viruses, marked with fluorescent proteins to help researchers see how they behave.

In the new study, Hwang and his team found that cells use the same autophagy proteins to flag replication complexes where viruses are hiding so the immune system can target them. It’s like marking some trash for regular recycling, and some of it as hazardous materials for special processing. Just how the immune system distinguishes between regular cellular trash and viruses in hiding isn’t clear yet, but the researchers found that this same process works in other +RNA viruses too.

Learning more about how the immune system identifies certain types of viruses could be a big help to researchers developing anti-viral treatments. What’s more intriguing, Hwang says, is that other pathogens that aren’t viruses, like the parasite that causes toxoplasmosis and the bacteria that causes tuberculosis, also build compartments inside cells to hide from the immune system. If scientists can figure out how to target +RNA viruses, it may lead to new ways to fight these diseases too.

“We have broad-spectrum antibiotics to kill bacteria, but there’s nothing like that for viruses because they know how to survive inside our body,” Hwang said. “If what we found holds true for all other viruses, one day we may come up with a solution that would work against all positive RNA viruses and pathogens that hide inside membranous shelters, because that’s a common feature.”


Tagged: Biological Sciences, immunology, Infectious Disease, Microbiology, norovirus, pathology, Seungmin Hwang, toxoplasmosis, viruses

Computer model simulates sense of touch from the entire hand

Mon, 06/26/2017 - 14:00
Hand

Image via Flickr

Neuroscientists from the University of Chicago have developed a computer model that can simulate the response of nerves in the hand to any pattern of touch stimulation on the skin. The tool reconstructs the response of more than 12,500 nerve fibers with millisecond precision, taking into account the mechanics of the skin as it presses up against and moves across objects.

The software will allow scientists to see how entire populations of nerve fibers respond when we interact with objects. This model will allow scientists to better understand how the nerve responds to touch, and can be used to build realistic sensations into bionic hands for amputees.

“Almost everything we know about how the nerve responds to stimulation on the skin of the hand is built into this model,” said Sliman Bensmaia, PhD, associate professor of organismal biology and anatomy at the University of Chicago, and principal investigator for the new research. “Finally, you can see how all these nerve fibers work together to give rise to touch.”

Details of the model were published this week in the Proceedings of the National Academy of Sciences. The study, led by postdoctoral scholars Hannes Saal and Benoit Delhaye, along with Brandon Rayhaun, a former undergraduate in the lab, builds upon years of research by Bensmaia’s team on how the nervous system and brain perceive the sense of touch.

Previously, researchers had to conduct costly and time-consuming experiments with animals or human subjects to see how the nervous system responds to a given touch stimulus. Even then, they could only record responses from one neuron at a time. But the sensation of touch comes from thousands of nerve fibers responding in concert as the hand touches, holds, and manipulates objects. The responses of individual nerve fibers aren’t enough to convey stimulus information by themselves. Rather, information about objects we grasp is distributed over large groups of touch-sensitive nerves working together.

Video: Animation showing nerve responses on the fingertip (left) as a flat, rectangular object presses into the skin, then pulls away (right). Each column of the fingertip responses on the left shows responses from a different type of nerve fiber. The top row shows responses when the object is oriented horizontally; the bottom row, vertically.

For instance, when you hold a cell phone in your hand, some of the nerve response is driven by skin receptors located where the edges of the phone press into your fingertips. But skin deformations also radiate away from this area, down the fingers, and throughout the rest of the hand, activating many other receptors in the process. The simulation reveals how interacting with an object creates these unique, detailed patterns of nerve activity.

In addition to its impact on the basic understanding of how these sensations work, the model is also a foundation for restoring touch in bionic hands for amputees. To achieve realistic feelings of touch, neural engineers try to reproduce the natural patterns of nerve activity generated when we manipulate objects. The computer model provides engineers with the nerve output generated by a given stimulus, which can then be recreated in a prosthetic by electrically stimulating the nerve through an interface implanted in the body.

Bensmaia and his team validated the output of the model against data from a wide variety of experiments conducted by other research teams, and show that it matches their output with millisecond precision. The software will be available as a free download, so other engineers can begin using it in their own work.

“Using a model to reproduce a biological system precisely is challenging, and we have been working on this simulation for a very long time. But the final product, I think, is worth it,” Bensmaia said. “It’s a tool that will yield insights that were previously unattainable.”


Tagged: artificial touch, Biological Sciences, neuroprosthetics, Neuroscience, Sliman Bensmaia, touch
TouchSim animation

Journalists get a taste of life as a scientist through MBL fellowships

Thu, 06/15/2017 - 12:02

From hands on work in a molecular biology lab to collecting marine specimens off the coast of Cape Cod, 13 science and health journalists recently got a taste of life as a scientist through the Logan Science Journalism Fellowships from the Marine Biological Laboratory (MBL), an international center for biological and environmental research and education and an affiliate of the University of Chicago.

Now in its 31st year, the Logan Science Journalism Program (SJP) allows established science and health journalists to “step into the shoes of the scientists they cover” through immersion in hands-on research at the MBL and its affiliates. This year’s program also gave four of the journalists an opportunity to spend four days in Chicago interacting with researchers affiliated with The Microbiome Center, Argonne National Laboratory, the Field Museum and Shedd Aquarium.

During their day at UChicago, they spoke to several researchers about their work, toured the Gnotobiotic Mouse Facility used for conducting germ-free microbiome research, and visited the Polsky Center’s Fabrication Lab and its tools for building 3D prototypes.

Over the years, the Logan Science Journalism Program has granted fellowships to hundreds of journalists from prominent news organizations, including The New York Times, The Wall Street Journal, Science, National Public Radio, The Washington Post, USA Today, CNN, and Scientific American.


Tagged: Biological Sciences, Marine Biological Laboratory, microbiome, Microbiome Center

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