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Faculty awarded funding for high-risk, high-reward research  external link

The National Institutes of Health (NIH), the primary funding agency for biomedical research in the United States, recently recognized three University of Wisconsin–Madison faculty members with its New Innovator Award. The agency announced a total of 58 awards and UW–Madison is tied for second place among all public universities in the nation for the number of faculty receiving them.

Darcie Moore, professor of neuroscience; Nasia Safdar, professor of medicine; and Srivatsan “Vatsan” Raman, professor of biochemistry, will receive more than $6.8 million in total funding for studies that are unconventional yet carry the potential to transform the medical field. Unlike standard research project grants, the New Innovator awards do not require preliminary data and pay out in full in the first year of each five-year project so that work can move forward swiftly.

“Having three UW faculty members awarded highly competitive NIH Director’s New Innovator Awards speaks to the success of our campuswide efforts to recruit the best and brightest early-career research investigators to UW–Madison,” says Cynthia Czajkowski, a neuroscience professor and associate vice chancellor for research in the biological sciences.

The award is part of NIH’s High-Risk, High-Reward Research Program, a funding mechanism the agency says is designed to “(catalyze) scientific discovery by supporting compelling, high-risk research proposals that may struggle in the traditional peer review process despite their transformative potential.”

The three New Innovator Award recipients join Jan Huisken, a professor of biomedical engineering at the Morgridge Institute for Research, who will receive one of 10 Transformative Research awards under the NIH High-Risk, High-Reward Research Program.

Funding from the umbrella program is drawn from the NIH Common Fund, which was established by the NIH Reform Act of 2006 with the idea of supporting forward-thinking cross-disciplinary research. UW–Madison has also taken similar steps to provide incentives for research projects that are risky but may to lead to significant outcomes.

For instance, in 2015, UW–Madison launched the UW2020 Initiative, which uses proceeds from the university’s technology transfer office to fund multidisciplinary teams of researchers proposing innovative research that hasn’t yet received federal grants. Moore and Raman are among UW2020 co-investigators.

In 2017, the university also established strategic funding for the UW Microbiome Initiative; Safdar is among 12 principal investigators supported by that program.

For the NIH High-Risk, High-Reward Research Program, Moore is using novel approaches to determine why aging stem cells become less effective at regeneration; Safdar is leading a team of health care researchers and systems engineers to create a computational model that fights the spread of Clostridium difficile (C diff), a gastrointestinal germ that stubbornly persists in hospitals; and Raman is using high-throughput experiments and computational tools to define the rules by which proteins switch between active and inactive states.

Read more about each project:

Not all stem cells are equal: Understanding the toll of aging on neural stem cells

Moore’s study focuses on why neural stem cells segregate certain proteins unevenly between their two daughter cells when they divide and on why neural stem cell proliferation and new neuron production decrease in the brain with age.

She initially discovered the asymmetry during her postdoctoral fellowship in Zurich, Switzerland, while investigating a diffusion barrier she identified in dividing cells. In the neural stem cells of old mice, this diffusion barrier becomes weaker and the cells are less able to compartmentalize proteins associated with cellular aging. Because aged neural stem cells divide less and make fewer neurons, this may contribute to dysfunction.

“We found polyubiquitinated proteins, or proteins destined for degradation, were segregated to only one daughter cell after the cell divided, and we have subsequently identified many other cargoes that behave similarly,” she says.

With the funding, Moore’s team will assess the mechanisms of asymmetric cargo segregation, use automated microscopy to identify segregated cargoes and further assess their roles, and determine how these processes function in the adult mouse brain.

“Understanding how neural stem cells function normally, as well as in disease and with aging, will help us to identify ways to therapeutically target them to improve their numbers, potentially improving cognitive function,” Moore says.

These findings are critical to developing future therapeutic options for people, she adds: “If you don’t set the foundation, you can’t build a house.”

—Andrew Hellpap

Computer-based simulation helps hospitals stop germ transmission

As an epidemiologist and infectious disease physician, Safdar has seen far too many patients suffer from Clostridium difficile (C diff) infections, which affect half a million Americans each year. The bacterium causes debilitating, difficult-to-treat diarrhea and infections can also be fatal, causing 29,000 deaths in the U.S. and costing over $1 billion annually.

In a cruel twist of fate, the bacterium thrives in hospitals.

“It got the name because it’s difficult to culture in the laboratory, but its spores are resistant to almost any disinfectant you can think of,” says Safdar.

Hospitals have tried a multitude of interventions to prevent transmission of the bacteria to hospitalized patients, including rapid testing and treatment when cases are first suspected, rigorous cleaning protocols, protective gear for health care workers, and emphasizing correct hand hygiene techniques.

“Unfortunately, the effects of these interventions have been highly variable and modest,” says Safdar.

Safdar is collaborating with a team that includes two UW–Madison engineering professors, Oguzhan Alagoz and Pascale Carayon, to take a systems engineering approach to address the ways the germ spreads.

In 2015, the team created a computational model to simulate C diff transmission in a hospital ward over time. The team will strengthen the simulation model with more data sets from an acute-care hospital, a veteran’s hospital and a children’s hospital, which differ in their C diff transmission risks.

“The goal is to create a simulation model that can be generalized. Every hospital is different, so we want a hospital representative to be able to enter parameters about their facility and predict which steps will be most effective for reducing C diff infections at their site,” Safdar says.

—Robyn Perrin

Sensing a switch: Defining the rules and playbook of protein function

Raman’s project is focused on protein allostery, which is the process by which a protein senses and conveys a signal that causes a change in a different part of itself. This shift controls its subsequent activity.

“Allosteric proteins are nature’s switches,” Raman, explaining that allostery is a fundamental property of all proteins. “Allosteric proteins regulate many essential cellular processes required for life.”

When a protein switches between “off” and “on” states, there can be dramatic consequences for gene expression. And just like a broken light switch plunges a room into darkness, unresponsive allosteric proteins can be responsible for many diseases because they can no longer effectively regulate activities inside a cell.

Almost half of all current drug targets are allosteric proteins, says Raman, and yet little is understood about how allostery itself works. His laboratory is deciphering the fundamental rules governing the process by using machine learning and other strategies to look for patterns among different allosteric proteins, probing the role of every amino acid.

If successful, computer modeling could allow Raman’s team to predict the impact of a mutation in an allosteric protein, and how to alleviate any detrimental effects. Deducing these molecular rules could prove challenging, but Raman doing so has applications in biomedicine and biotechnology. Additionally, drug discovery projects informed by allostery data could lead to more specific drugs with fewer side effects, he says.

“The broader vision of my laboratory is to develop these tools to advance precision medicine,” Raman says. “Every day we sequence the genomes of patients with diseases, but we have no clue which protein mutations affect function, and how they do so. Wouldn’t it be great if we could create a ‘lookup table’ or a database of mutations that a physician could use to interpret a patient’s genome?”

—Kaine Korzekwa

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Recovering from a heart attack? Hold the antibiotics  external link

The community of microorganisms that live in the human gut has been shown to confer all kinds of health benefits. Now, an international team of researchers has shown in mice that a healthy gut microbiome is important for recovery after a heart attack.

Writing today (Oct. 8, 2018) in the journal Circulation, a team led by surgeon Patrick Hsieh of the Institute of Biomedical Sciences at Academia Sinica in Taipei, Taiwan, in collaboration with researchers from the University of Wisconsin-Madison, reports on experiments that show mice recovering from heart attacks are more likely to die if treated with antibiotics, a common intervention in hospitalized patients.

Timothy Kamp

“This is a new thing to add to the list of potential complications” for recovery from a heart attack, says Timothy Kamp, a UW-Madison professor of medicine and cardiologist who contributed to the new study.

It is common, Kamp explains, for hospitalized patients to be dosed with broad spectrum antibiotics to treat a variety of infections, and some of these patients have heart attacks. But antibiotics can be indiscriminate and eliminate not only bad microbial players, but also the microbes we depend on to stay healthy, including the trillions of fungi and bacteria that help make up the gut microbiome.

Working in collaboration with microbiome expert and UW-Madison Professor of Bacteriology Federico Rey, Hsieh and Kamp treated mice with antibiotics to deplete the gut microbiome a week prior to experimentally inducing myocardial infarction or heart attack.

The depleted microbiome, the team found, tamps down the production of a set of three short-chain fatty acids, which are produced as the gut’s community of microorganism’s metabolizes food and which act as important chemical messengers to the body’s immune system.

The diminished response, says Hsieh, “impacts the immune response and the repair response after myocardial infarction.”

Conversely, when the mouse microbiome is restored through a fecal transplant, the researchers observed an uptick in mouse physiological well-being and survival. And in mice that had their microbiomes boosted through the use of probiotics or other interventions prior to a heart attack, increased cardioprotective effects and survival were the hallmark effects.

Previous studies in healthy mice have shown that the microbiome influences gene expression and the deployment of the short-chain fatty acids that help regulate immune response.

The current study showed that production of a small set of short-chain fatty acids was diminished by a depleted microbiome, but there likely are many more players – perhaps thousands – that may also be affected and that play a role in the immune response to a heart attack, says Kamp.

The research also showed that heart attacks themselves influence the health of the microbiome: “We found changes after myocardial infarction even without any antibiotics,” notes Rey. “Your microbiome changes as a result of a heart attack.”

However, the key finding – that a depleted microbiome and its diminished production of short-chain fatty acids blunts recovery from a heart attack –  suggests that clinical intervention to manipulate the microbiome through a more nuanced use of antibiotics and supplementing it with probiotics will help human patients recover faster and more robustly from heart attacks, says Kamp.

He adds that the study also identifies the short-chain fatty acids themselves as a potential therapeutic target to bolster a favorable immune response in the context of cardiovascular disease, one of the leading causes of death in industrialized societies. “The immune system and inflammation play a role in repair from a heart attack. We’ve known about the relationship between the microbiome and immune response. Now we’re getting at how that relationship works after a heart attack.”

The study was supported by a grant from the University of Wisconsin-Madison’s Microbiome Initiative administered by the Office of the Vice Chancellor for Research and Graduate Education.



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Researcher wins “high risk, high reward” NIH grant  external link

Jan Huisken is part of an ambitious project to develop a complete cellular blueprint of zebrafish development, from the first ball of cells to an adult fish. The project could have great benefit to regenerative biology.

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Successful mouse couples talk out infidelity in calm tones  external link

California mice are relatively solitary animals, but put two in a room and they’ll talk each other’s ears off.

And while all the cooing, chirping and barking they use to woo mates or drive off enemies is at too high a frequency for human eavesdroppers to hear, they may speak volumes about the way the mice form relationships. The quality of their conversations after one partner has been unfaithful can help predict which mouse pairs will successfully produce a litter of mouse pups and which males are good fathers, according to a study published recently by the journal Frontiers in Ecology and Evolution in a special issue on the evolution of monogamy.

“These mice are not gregarious. They’re loners,” says Josh Pultorak, who studied the mice while earning his doctorate in zoology at the UW–Madison. “They’re highly territorial and aggressive — both sexes.”

One of the ways they communicate that aggression is through what Pultorak calls barks.

“The barks are just nasty,” he says. “It’s like a combination of a dog bark and a lion’s roar.”

That is, when the ultrasonic barks are slowed down to the point that humans can make them out — typically 5 percent of their original speed.

While notorious for their ferocity, the California mouse is also known for its monogamy. Most rodents are promiscuous, but in the wild, infidelity is unheard of among the California mouse. Once they’ve bonded with a partner in their natural habitat (scrubby woodlands in California and northern Mexico), they don’t mate with other another mouse unless their partner dies.

Pultorak and his collaborators paired up 55 male and 55 female California mice, recording their body language and vocalizations when they met and again after two weeks.

There were plenty of barks in the beginning. But as the pairs bonded, according to Pultorak, their communication was less aggressive and more affiliative.

“They’re making a lot of what we call simple sweeps — which are like quick, one-syllable bird chirps — and more sustained vocalizations, which sound almost like whale noises when they’re slowed down enough for a human ear,” Pultorak says. “The aggressive vocalizations, the barks, go way down after they know each other.”

Then, the researchers introduced an otherwise unknown factor in California mouse relationships: cheating.

Some of the males were moved to live with new females, and some of the females were moved to live with new males. Another group was separated, but not housed with new potential mates. A fourth group was left together.

After a week, the mice given the opportunity for infidelity were reunited, and the researchers set about recording interactions again.

“Compared to when they were nice and sweet before separation, when they came back with their original mates the pairs were aggressive,” Pultorak says. “But there was a range. Some of the pairs that had the infidelity encounter were barking a lot, but some of them were much closer to their pre-separation levels of simple sweeps and sustained vocalizations.”

The pairs that simply lived alone for a week slipped back into their old communication routines, highlighting infidelity (not separation) as the cause of the bump in aggression among the potential cheating cases.

Importantly, it was how the reunited couples worked out the events of their separation that predicted whether they’d have baby mice together.

“The pairs that successfully produced litters were the ones that were affiliative when reunited,” Pultorak says. “The ones that showed more aggression were far less likely to produce offspring. That’s a big deal. Arguably, it’s the whole point of forming pair bonds in the first place.”

The researchers also gave the males a fatherhood test, moving a newborn away from the family to see how quickly the dad would respond to comfort, groom and warm the pup.

“The more affiliative or ‘loving’ and resilient a pair was after that infidelity experience, the faster the male was in responding to a pup’s needs,” Pultorak says. “They were better dads.”

While quality of communication provides a window into the way the mice bond, it’s hard for Pultorak to say whether these resilient pairs had what a human couple might consider a better relationship.

“Do they not bark at their partner because they have a stronger bond that’s able to withstand the infidelity? Or is it instead a weaker bond, and they don’t really care so much about what this other mouse has been doing?” he says. “Maybe they’d be a better match with a different partner anyway, and that’s playing into it. We don’t yet know that.”

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Changes to federal IP disclosure requirement prompt campuswide response  external link

This month, many employees at the University of Wisconsin–Madison will receive an email asking them to acknowledge that they agree to comply with UW–Madison research policies establishing rights to intellectual property that arise from their extramurally funded research activities.

This is in response to amendments to regulations issued under the Bayh-Dole Act, which gives universities, nonprofits and other small businesses the ability to claim patents to inventions arising from federal funding, such as research grants from federal agencies (e.g., NIH, NSF, DOE). UW–Madison currently holds over $600 million in federal research awards.

The email will contain a link to an electronic tool in which employees can read some background information on the Bayh-Dole Act and certify that they agree to comply with UW–Madison policy and federal regulations related to intellectual property.

“By completing the form, we can all help to avoid any unnecessary surprises down the road with respect to patent ownership, and assist in maintaining uninterrupted and continued research funding,” explains Norman Drinkwater, interim vice chancellor for research and graduate education.

“This requirement does not reflect a change in UW–Madison policy, but does help bring the university into compliance with federal changes to the Bayh-Dole Act regulations,” says Kristin Harmon, UW–Madison intellectual property disclosure specialist.

UW–Madison research policy has long required employees to disclose inventions and assign patent rights to the Wisconsin Alumni Research Foundation (WARF) if required by relevant grants or agreements.

Harmon notes that an added benefit of having the electronic acknowledgement is that it simplifies the reporting process and makes it easier for PIs and others who need to track compliance.

“The electronic acknowledgement will replace paper-based acknowledgements that the PI has been responsible for collecting from project staff each time a new grant was received, and which had to be maintained in physical files in the past,” Harmon says. ”You also will only have to sign the agreement once in your career at UW–Madison.”

Nick Novak, UW–Madison assistant vice chancellor for research services, says the Office of the Vice Chancellor for Research and Graduate Education has reviewed employment categories and official titles and identified those employees most likely to be required to sign the agreement. Those employees will receive an email and link to the form.

To learn more about the Bayh-Dole Act and the changes, go to research.wisc.edu/bayhdole/.

To sign the agreement, visit: go.wisc.edu/bayhdole.

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National Academy reports seen as beacons for civil public discourse  external link

In an era of fake news and widespread disinformation campaigns aimed at confusing and polarizing public discourse in the United States, a new study provides a glimmer of hope and a roadmap for fostering honest public debate, at least around issues of science and technology.

Writing this week (Oct. 2, 2018) in the journal Politics and the Life Sciences, communication experts Dominique Brossard of the University of Wisconsin-Madison and Kathleen Hall Jamieson of the Annenberg Public Policy Center of the University of Pennsylvania report on an effort to closely track public discourse on a contentious topic – genetically engineered crops – in the wake of a National Academies of Sciences, Engineering, and Medicine (NASEM) consensus report.

Photo: Dominique Brossard

Dominique Brossard

Using national survey data and large-scale social media content analysis, the study explored public conversations on genetically modified crops both before and after the May 2016 release of the NASEM report, “Genetically Engineered Crops: Experiences and Prospects.”

The question, says Brossard, a UW-Madison professor of Life Sciences Communication, is are these reports useful in terms of fostering informed public conversation on a divisive technology?

The answer, according to the results produced by Jamieson, Brossard and their colleagues, is yes.

“The goal of a consensus report is to start a public conversation,” explains Brossard, who served as a panelist on the GMO crops report contributing expertise on communicating science in new media environments. “It has to be used.”

Jamieson is an authority on political communication and directs the Annenberg Public Policy Center.

When the GMO crops report was released, there was a concerted effort to make the report broadly available and to publicize its conclusions. It received widespread news coverage, surfacing in at least 144 news outlets and was specifically mentioned on Twitter more than 4,000 times the month of the report’s release. The full report was made publicly available and to date has been downloaded as a pdf file nearly 44,000 times, making it one of the most highly trafficked NASEM reports in recent memory.

Corn tassels and leaves are backlit by the sun. A new study closely followed public opinion on genetically modified crops following the release of a consensus report. Photo: Jeff Miller

Seizing an opportunity to measure the effect of an independent, credible report from the nation’s leading scientific academy on a polarizing issue, Brossard and Jamieson mapped out a strategy to systematically assess the reach and impact of the report as it was publicized and disseminated through social media. Their goals were to capture English language coverage of the report in both traditional and social media, peg the report’s release to broader patterns of discussions of GMOs on Twitter, and measure fluctuations of negative and positive sentiment in conversations of GMOs in both social and traditional media.

“The GMO report looked at the technology in all its dimensions,” says Brossard, noting that all of the known issues associated with transgenic crops were factored in, including potential environmental impacts, economic and social influences, agricultural productivity and concerns related to human health. “Interestingly enough, for the American public conversations around GMOs center on health. That was a big part of the sentiment expressed in Twitter conversations.”

On Twitter, between March and July of 2016, there were more than 1.1 million tweets that referenced GMOs. Notably, spikes in Twitter conversations about GMOs occurred when public figures like then-presidential candidate Bernie Sanders weighed in on the topic arguing for labeling of GMO foods, even in the absence of evidence that consuming GMOs may be harmful. “You can see that events impact the conversation and content,” notes Brossard.

There was a sharp increase in Twitter conversations when the NASEM report was publicly released in May of that year, according to the new study. That, says Brossard, suggests that the report gained currency with the public and had the desired effect of fostering informed public conversation.

The GMO report was produced by a panel that included broad expertise and was aimed at achieving scientific agreement or “consensus” on the state of technology and its varied impacts. Its primary conclusions were that there was no evidence that eating GMO foods was harmful to human health, that the technology was increasingly important to modern agriculture but context-dependent, that the technology was powerful but not a magic bullet that would “feed the world,” that the technology was changing rapidly and regulations need to keep pace, and that there are environmental tradeoffs, with both risks and benefits.

Those expert conclusions, say Jamieson and Brossard, not only percolated through traditional and social media, fueling conversations on Twitter and elsewhere, but were also changing the tenor of the debate.

“We observed spikes of conversation. We observed spikes in opinion,” says Brossard. It shows that authoritative reports like those produced by NASEM “can influence the conversation if the communication is well done.”

That was reflected in the data gathered by Brossard, Jamieson and their colleagues, which showed a greater degree of ambivalence about GMOs after the NASEM report’s release.

“That’s what you want,” Brossard says. “The number one lesson is that a consensus report can have an impact beyond just being discussed in polarized arenas. It is uniquely positioned to facilitate these public conversations.”

Other lessons, she adds, are that communication matters, and that the big picture – weaving in all the dimensions of a polarizing issue – can abet public conversation and debate. For instance, she notes the GMO report would have had much less utility had it focused on just a single aspect of the debate such as human health. Such reports have the most impact when there is a commitment to sharing results as broadly as possible, says Brossard.

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Stem Cells @ 20: The Stem Cell and Regenerative Medicine center galvanizes stem cell research  external link

Photo of Tim Kamp wearing a white coat by a microscope.

Tim Kamp, shown in his research lab, is director of the Stem Cell and Regenerative Medicine Center. Photo: Jeff Miller

Since University of Wisconsin–Madison researcher James Thomson and colleagues derived the first human embryonic stem cells 20 years ago, research universities and biotechnology companies around the globe have worked to unlock their vast potential.

Through the work of the UW-Madison Stem Cell and Regenerative Medicine Center, UW-Madison has remained at the forefront of the field. Launched in May 2007, the center serves as an intellectual and collaborative hub for a broad-based, interdisciplinary research community. Today, more than 600 scientists and students in almost 100 SCMRC labs around campus are working, teaching and studying in the field.

The SCRMC encompasses faculty, staff and students across five schools and colleges, 40 departments, and 10 centers and institutes at UW–Madison. It is not housed in a single brick-and-mortar building but is a virtual center with investigators across campus. The center is jointly supported by the UW–Madison Office of the Vice Chancellor for Research and Graduate Education and School of Medicine and Public Health. An executive committee of faculty from across campus provides leadership.

Stem cells @ 20 logoMost SCRMC researchers work on much-needed basic science with both embryonic and induced pluripotent stem cells (adult cells that are converted back into naive stem cells capable of becoming nearly any cell in the body), while others are also exploring new cell culture techniques, gene editing methods, and advances in preclinical animal research and human clinical trials.

“The growth of stem cell-related research and educational programs on campus over the last two decades has been amazing,” says SCRMC director, Tim Kamp, a professor of medicine and cell and regenerative biology. “I’m delighted that the SCRMC has helped stir the pot, bringing together center members from diverse disciplines to build collaborative projects that are pushing these discoveries forward.”

SCRMC advances the field

These discoveries are both large and small. For example, SCRMC scientists have and continue to engineer specialized surfaces for growing desired cell and tissue types, define the gene regulatory networks responsible for maintaining stem cells, use stem cell derivatives as powerful tools for screening the toxic effects of drugs and chemicals, and engage in a myriad of preclinical studies bringing stem cell-based therapies closer to clinical applications.

Early after it’s founding, WiCell, in partnership with the SCRMC, began holding science camps providing hands-on learning experiences with human embryonic stem cells. In 2008, a student peers into a microscope at one of the camps.

Researchers at SCRMC have also developed better ways to culture stem cells and optimized methods to derive a broad array of specialized cell types from human pluripotent stem cells. These include retinal cells, heart muscle cells, a variety of neurons, insulin producing islet cells, numerous blood cell types and more.

In 2017-2018, stem cell research drew more than $42 million in NIH grants. Since 2017 alone, SCRMC scientists have published close to 500 research articles. Overall, its researchers have garnered more than 120 research patents and executed more than 70 commercial license agreements to 47 entities through the Wisconsin Alumni Research Foundation.

Globally, nearly 20 clinical trials are underway involving human embryonic stem cells and their derivatives, intended to advance treatments for heart disease, diabetes, Parkinson’s disease and more. Another 42 trials involve the use of induced pluripotent stem cells.

And stem cells have also been a boon for business, including in Wisconsin, where at least 10 Wisconsin companies rely on pluripotent stem cells.  These include Cellular Dynamics International Inc., BrainXell, Opsis Therapeutics and others.

SCRMC is a team effort

After Thomson published his landmark paper describing the first isolation of human embryonic stem cells in November 1998, campus leaders understood they needed to develop new programs to realize their promise, overcome some of the obvious barriers and empower laboratories to engage in related research.

This led to the creation of WiCell in 1999, a Madison-based non-profit that supports stem cell research at UW–Madison. WiCell provided hands-on training intended to help laboratories embark on research in the field. However, it soon became clear that more was needed to address the explosion in interest.

“A campus effort was needed to bring the best and brightest minds together to foster collaborative, multidisciplinary research, as well as provide needed educational programs and outreach in the nascent field,” says Kamp.

This began with a cluster hire to recruit more faculty in stem cell and regenerative medicine, and was followed by the formation of the Wisconsin Stem Cell Program to provide pilot grants and foster collaboration. Then, on May 17, 2007, the SCRMC was launched with an event that included a keynote talk from Scottish biologist and Nobel laureate Ian Wilmut, the scientist who cloned Dolly the Sheep.

“The new SCRMC sought to facilitate resource-sharing, offer pilot and training grants, build philanthropy and public support, and host scientific meetings,” Kamp says. “An education committee would provide clear pathways to careers for the growing number of students entering into the university and excited about studying stem cells and regenerative medicine.”

Woman peers into microscope.

In 2008, a student peers into a microscope while participating in a summer science camp run by WiCell, in partnership with the SCRMC.

A year after its formation, the SCRMC helped ensure Madison remained prominent on the international stage. Madison was chosen that year to host the third World Stem Cell Summit, which brought together the broad research, policy, patient advocacy and business communities. It was attended by nearly 1,000 people and included a unique public outreach experience at the Pyle Center called “Lab on the Lake.”

The 2008 summit also drew assistance from the newly formed Wisconsin chapter of the Student Society for Stem Cell Research. Led by their first president, Ka Yi Ling, UW–Madison undergraduates aided in summit planning and jump-started student recruitment and involvement.

The SCRMC also helped form the Wisconsin Stem Cell Roundtable, an organization for graduate students and postdoctoral researchers. Members of WiSCR help organize SCRMC’s annual fall conference, the Summer Undergraduate Research Fellowship (SURF) Program, poster competitions and cross-disciplinary student lab meetings.

“It is remarkable how many center members contribute to center programs by serving roles in various disease-based focus groups, contributing to outreach and educational programs, and organizing our conferences and symposia,” says Kamp.

Expanding opportunities for all

Today, students interested in studying and working with stem cells have a plethora of fields and majors to consider, from biology to bioengineering, bioethics to biotechnology, plus cell and regenerative biology, genetics, molecular biology, and more. Faculty of SCRMC have a combined wealth of expertise that helps prepare students for careers in academia and industry.

“The burgeoning field also needs highly-trained doctors, physician assistants, nurses, veterinarians, policy makers, entrepreneurs, teachers and science communicators to effectively move forward,” says Kamp.

Related to that goal of inclusivity, the SCRMC worked with partners around campus – with funding from an Ira and Ineva Reilly Baldwin Wisconsin Idea Endowment – to bring the world’s first organized stem cell outreach lab on campus to the public. The Stem Cell Learning Lab at the UW–Madison Biotechnology Center enables participants to view real stem cells under the microscope and use the same equipment and methods SCRMC scientists use to prepare and grow their cells.

The SCRMC also partners with the Morgridge Institute for Research to offer Rural Summer Science Camp, and works with several other campus departments and the campus stem cell student organizations to expand outreach opportunities. It’s outreach programs have now reached more than 50,000 people since 2009; most are K-12 students and teachers from Wisconsin and surrounding states.

“It’s been an incredible experience to be a part of this community from its earliest days,” says Kamp, “but we are still just at the beginning of remarkable discoveries and breakthroughs in this field which will provide new understanding of human life and remarkable new opportunities for therapies across a broad spectrum of humankind’s most devastating diseases.”

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Set in amber, fossil ants help reconstruct evolution of fungus farming  external link

Some 50 million years before humans figured it out, agriculture arrived in the world in a seemingly unlikely place: an ant hill.

Eschewing wheat or rice for feathery white fungus, the ants cultivated their fungal crop, providing it with care in exchange for nourishment. But like their human counterparts who would come after them, the ants faced the perennial problem of crop disease, in this case a parasitic fungus, which threatened to wipe out their harvests.

A fungus-farming ant is covered in white symbiotic bacteria, which the ant relies on to produce antibiotics to protect its garden from a parasitic fungus. Photo by Alex Wild

So the ant farmers evolved another partnership. They offered safe harbor and nutrition to a certain group of bacteria — the Actinobacteria — that in turn produced antibiotics capable of keeping the parasite at bay. To help the bacteria stick around, the ants’ exoskeletons evolved specialized pockets that protected and fed their partners.

These structures seemed so intricate that scientists believed they only had the chance to evolve once as the original fungal farmers eventually diverged into the 250-some ant farming species we find today. But writing today (Oct. 1) in the Proceedings of the National Academy of Sciences, University of Wisconsin–Madison researchers reveal that these bacteria-harboring structures evolved independently three times.

The results make it clear that the constant threat of crop parasites repeatedly pushed evolution in strikingly similar directions, creating structures that helped the ants reinforce their partnership with bacteria. And their successful use of protective antibiotics for eons suggests the ants may have lessons for human medicine, which has quickly come up against resistance by pathogens to our most important antibiotics.

The work was led by UW–Madison Professor of Bacteriology Cameron Currie and Hongjie Li, a postdoctoral researcher in the Currie lab. They partnered with colleagues at Arizona State University, the University of Sao Paulo, Harvard Medical School and the Smithsonian.

An ant preserved in amber.

A fungus-farming ant trapped in amber from the Dominican Republic shows bubbles on the underside of its body that are likely from bacteria that produce antibiotics capable of keeping a garden parasite at bay. Photo by Hongjie Li

“This work provides fascinating insights into an animal using bacteria to provide antibiotics over a long period of time,” says Currie, who has researched the dynamics of farming ants for 20 years.

The researchers performed an exhaustive survey of 69 ant species, sourcing diverse ant samples from the collections at Arizona State University and the Smithsonian. The research team reconstructed the ants’ evolutionary tree using pieces of their genomic sequences. The resulting tree suggested that the partnership between ants and bacteria evolved soon after the ants began farming.

Further evidence for the ancient origin of the ant-bacteria relationship came from a handful of fungus-farming ants fortuitously frozen in amber from what is now the Dominican Republic. Through the hardened tree sap, the researchers could spot the telltale signs of bacteria clinging to the ants’ bodies. With the amber dated to between 15 and 20 million years old, Currie’s team could validate their genomic data and show that the ant-bacteria symbiosis was at least as old as the amber samples.

Earlier work had hinted at the early evolution of the ant-bacteria partnership, says Li, but “this paper provides much more evidence that this is an ancient system.”

Using ultra-high-magnification electron microscopy, the researchers examined the ants for the specialized structures housing bacteria, known as crypts. The microscopic images showed that most living species of farming ants had crypts and related structures that could support Actinobacteria. But a number of ant species were missing these structures.

When they mapped the crypt data over the reconstructed evolutionary tree, Currie’s team saw that crypts had evolved not once, but three separate times during the evolution of farming ants.

Ultra close-up of an ant.

A queen ant imaged under an electron microscope is covered in black dots, each of which is a pocket capable of housing and supporting symbiotic bacteria. Richard Noll and Hongjie Li

But the crypts were not ubiquitous. Some species have lost any obvious structures for supporting bacteria. The researchers showed that ants that have done away with crypts have also lost any trace of symbiotic Actinobacteria.

Currie and Li venture that ants that now farm in more arid areas no longer contend with the constant threat of the parasitic fungal disease. Since harboring and feeding the bacteria can use up to a quarter of an ant’s energy, it became more advantageous for the ants to part ways with their erstwhile partners.

Apparently not content to mimic the ant’s farming lifestyle, humans would later turn to the same group of bacteria, the Actinobacteria, for most of our clinical antibiotics. That the ants have, for millions of years, used similar antibiotics to protect their fungal gardens from pests suggests that we might learn from their success.

“I strongly believe there are mechanisms here that reduce the emergence of antibiotic resistance,” says Currie.

Discovering what those mechanisms are might just help us extend the useful life of our own antibiotics.

This study was funded by the National Institutes of Health (grants U19 TW009872-05, U19 AI109673, and DMR-1720415), the National Science Foundation (grants DEB 1456964 and 1654829), and the Sao Paulo Research Foundation-FAPESP (grant 2013/50954-0).


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In dangerous fungal family’s befriending of plants, a story of loss  external link

Photo of mushrooms with a red speckled cap.

With its red and white cap and hallucinogenic properties, the fly amanita has long inspired art and literature. Its friendly association with plants came about by letting go of a few key genes, new research finds. Photo by Jacqueline Hess

If Lewis Carroll had described in detail the mushroom Alice nibbles in Wonderland to shrink and grow to her rightful size, he might have noted a scarlet cap topped with white warts: the fly amanita.

This brilliant, distinctive toadstool is hallucinogenic. Eating it can distort perception and cause objects to appear to expand and contract, making this mushroom at home in Wonderland. Fly amanitas inspired the magic mushrooms in Super Mario Brothers and are littered throughout art and literature. Other members of the Amanita genus, like the death-cap mushroom, are fatal.

Yet these fanciful and sometimes dangerous mushrooms are also friendly — at least to plants. Most Amanitas can only survive by closely partnering with plants, providing their roots with minerals and nutrients in exchange for sugars. This symbiosis evolved more than 50 million years ago and helps forest ecosystems thrive.


Anne Pringle

Anne Pringle, a professor of botany and bacteriology at the University of Wisconsin–Madison, researches what genetic changes drove some Amanitas away from their ancestral, decomposing lifestyle toward this intimate relationship with plants. In new work, Pringle and her collaborators show that gene loss — not the evolution of new genes — helped drive this major change in the mushrooms’ lifestyle.

The team also suspects that they’ve identified a species of Amanita that is on its way to evolving a new symbiosis with plants. In all, the results provide further evidence that symbiosis may be a lot easier to develop than scientists once thought.

Or, as Pringle puts it: “Making friends is easy.”

The new study was published Sept. 18 in the journal Molecular Biology and Evolution. Jaqueline Hess of the University of Vienna led the study, with collaborators in Norway, the Netherlands, France and Saudi Arabia.

To get at what separated symbiotic from free-living Amanitas, the researchers sequenced the genomes of three symbiotic Amanita species — including the fly amanita — and three close relatives that aren’t symbiotic. The genomic sequences allowed them to reconstruct the evolutionary paths that led to the fungi’s different adaptations.

“We went into this thinking we’d find commonalities between the three symbiotic Amanitas,” Pringle says.

Photo of Jaqueline Hess holding mushrooms.

Jaqueline Hess

But despite their similar lifestyles, symbiotic Amanitas looked vastly different from one another on the genomic level. Some symbiotic species had almost double the number of genes as their similarly symbiotic relatives. The symbiotic mushrooms seemed to take different genomic paths after they first diverged, developing unique ways to tailor their partnership with plants.

Earlier research on other families of mushrooms had suggested that one defining characteristic of symbiotic lifestyles was the loss of enzymes capable of degrading the cellulose-laden walls of plant cells. These genes are crucial for decomposers eating through leaf litter. But for fungi that associate with plants and must avoid harming their partners, cellulose-digesting enzymes are only a liability.

So when Pringle, Hess and their team looked at this group of digestive enzymes, they were surprised to find that the free-living species Amanita inopinata was missing these genes. Although symbiotic Amanita mushrooms had indeed lost this suite of digestive enzymes, Amanita inopinata’s lack of them meant the researchers couldn’t link this loss to symbiosis itself.

Pringle says the unexpected absence of cell wall-digesting genes in Amanita inopinata’s genome may actually be a clue pointing to evolution at work. If symbiosis only develops once fungi let go of these digestive enzymes, the researchers reason, then Amanita inopinata may be primed to evolve a closer partnership with plants.

Not quite symbiotic, perhaps not fully independent, Amanita inopinata seems to be “stuck between two worlds,” says Hess, who began the work while a postdoctoral researcher in the Pringle lab and is now a senior scientist at the University of Vienna.

The evolution of Amanita inopinata — “the unexpected one,” in Latin — and the other Amanitas also seem to support a developing consensus that symbiosis, once thought to be exceptional, may actually be easy to evolve. The researchers didn’t find that Amanita needed to develop a new, complex suite of genes in order to start partnering with plants. Instead, just letting go of a few once-vital genes may be sufficient to forge new relationships in nature.

“The story of making friends is one of loss,” says Pringle.

This work was supported by the National Science Foundation (grant 1021606) and Research Council of Norway (project 221840).

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Solar cell, married to liquid battery, achieves record efficiency  external link

Photo of Song Jin, left, and graduate student Wenjie Li observing their lab-scale device for storing and releasing solar energy.

Professor Song Jin, left, and graduate student Wenjie Li observe their lab-scale device for storing and releasing solar energy. David Tenenbaum

The growing use of solar power has hit a wall in some locations: At night, or on a cloudy day, electric utilities with heavy dependence on solar must switch to an alternative source like natural gas.

The “intermittency” problem is already starting to limit adoption of solar energy in Europe.

In the journal Chem, a University of Wisconsin-Madison professor of chemistry reports on a unified solar cell-liquid battery device that returns more than 14 percent of the incoming solar energy as electricity.

Song Jin’s technology converts sunlight directly to chemical energy and then releases electricity when needed. “We are talking about a round trip, a whole cycle,” he says. “Our first proof-of-concept device two years ago achieved 1.7 percent efficiency. Now we’ve improved our design and reached 14 percent, which is the highest reported number for an integrated solar-electric and battery system.”

Jin is an expert in solar energy conversion and the reduction-oxidation reactions used in the “solar flow battery” at the heart of his new device.

Solar cells are typically rated by the efficiency of conversion from solar energy into electric energy, and the best commercially available large-area solar panels reach about 24 percent efficiency. However, the 14 percent efficiency in Jin’s system measures much more, covering the full process from incoming sunlight to electricity delivered from storage at any time, day or night.

“As the intermittency problem grows, we believe it’s important to get a metric for the complete process, from sunlight to electricity available from storage,” Jin says. “We call it solar-to-output-electricity efficiency.”

The redox-flow battery used in Jin’s system operates on the same principle as existing batteries that store energy in large liquid tanks instead of the solids used in most common batteries. Some of these “redox flow batteries” are already used to store energy for the electricity grid.

One key to efficiency arises from a streamlined conversion of energy, Jin says. “We only used two conversions – from sunlight to stored chemical energy to electricity. Combining the functions of separated devices into a single device allows us to bypass the intermediate step of electricity generation, which results in a more efficient, compact, and cost-effective approach to utilizing solar energy.”

Depending on the situation, the same device could also route electricity directly to the end use, bypassing storage, Jin says.

Jin and Ph.D. student Wenjie Li combined an efficient redox flow battery with a high-performance solar cell provided by professor Jr-Hau He and his student Hui-Chun Fu from King Abdullah University of Science and Technology in Saudi Arabia.

Although 14 percent efficiency was good, Li expects more to come. Future efforts will focus on better matching the voltage of the solar cell to the voltage of the oxidation-reduction reactions in the flow battery.

Jin compares the need to match voltage to an elevator. “Say you want to go from the first to the sixth floor, but the elevator can only take you to the eighth floor. No matter how you get down two floors, the elevator is wasting energy.”

The situation is similar in the reported device, which generated 2.4 volts, but the battery only required 1.3 volts.  As in the case of the elevator, some of the energy is wasted.

Although the highly efficient solar cell used in the current experiment is costly, “The point we are trying to make is to show what is possible,” Li says. “If, on the other hand, you used a high-efficiency solar cell and could not get high efficiency with this technology, it would not be worth following up. But we found the opposite – unprecedented efficiency, with more room at the top from fine-tuning. We already know where to look to get further improvements.”

The costly high efficiency solar cell may not be necessary, Li says. “If we use a lower efficiency solar cell that is a good match to the redox flow battery, the overall efficiency could still be quite high, and the cost lower.”

The technology Jin is advancing – unifying solar electricity generation with storage – could first be used in off-grid, standalone energy systems, Jin says, where there are no utility lines able to transmit and use extra photovoltaic electricity.

In the larger picture, the solar-power intermittency problem is already limiting plans in a growing number of locations, Jin says. “We have to work on multiple solutions for the storage of energy at a large scale. Denmark can’t use much more renewable energy because the grid is becoming unstable when the sun does not shine or the wind does not blow.”

There is no single path to optimum storage for solar electricity, Jin says. “There’s an urgent societal need to investigate every sensible alternative. Twenty years ago, solar cell development was the key to solar energy. Today, it’s storage.”

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