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UW Changes Lives: Campus-born fertility company seeks to improve women’s health care, Wisconsin economy  external link

What started as a side project in a laboratory in the University of Wisconsin–Madison Department of Biochemistry is now a successful Wisconsin startup that’s closer than ever to giving women a way to easily track their hormone levels and help overcome difficulties conceiving a child.

Propelled by an abundance of resources on campus and in the city of Madison, Katie Brenner — a former UW–Madison postdoctoral researcher in biochemistry — and her co-founders at their company BluDiagnostics are seeing their idea become a reality.

Photo: Katie Brenner

Katie Brenner in the lab of biology professor Doug Weibel. Photo: Bryce Richter

“We believe that when women’s health care wins, our whole economy wins,” Brenner, chief executive officer, says. “We are committed to making women’s health better. We started with the customer in mind because we were the customer, myself in particular having faced these issues.”

BluDiagnostics wants to deliver a product to help women accurately monitor two key hormones, estradiol and progesterone, every day in the comfort of their home. The goal is to equip women with medically relevant data to help triage diagnosis and treatment for fertility-related conditions.

Brenner started her postdoctoral research at UW–Madison in 2012, in the lab of former UW–Madison biochemistry Professor Doug Weibel. Originally from Illinois, she spent her undergraduate years at Stanford University studying electrical engineering and received her Ph.D. from Caltech in biological engineering.

In Madison, she studied nutrition for preterm infants, even leading a clinical study of more than 400 preterm infants to test their urine for early signs of illness.

After acquiring promising data from a side project on fertility, Brenner decided to pursue the idea that would become bluDiagnostics: Can there be a device that allows women to easily, quickly, safely and accurately measure and track their hormones?

“We believe that when women’s health care wins, our whole economy wins.”

Katie Brenner

Brenner, Weibel and Jodi Schroll were original co-founders. Today, Schroll is serves as chief business officer and Tong Xie is the company’s chief operating officer. The methodology bluDiagnostics employs involves testing for hormones in saliva.

“I thought it was a super idea and was surprised that there were no comparable tests available,” says Weibel, now at Amazon but still involved in the company. “It’s incredibly difficult to make this kind of test for detecting extremely low levels of hormones so to do it in a widely varying sample such as saliva is a remarkable achievement … I figured that if a solution was possible, Katie was positioned to find it.”

Weibel adds: “The culture of tech development and commercialization on campus and in Biochemistry was helpful.”

Opportunities on campus and in the state of Wisconsin helped flesh out Brenner’s idea, provide initial funding, and bridge the science with her business idea. The Morgridge Entrepreneurial Bootcamp and Business and Entrepreneurship Clinic, as well as other resources from the Wisconsin School of Business and Wisconsin Alumni Research Foundation (WARF), aided immensely.

“UW–Madison has been incredible for us,” she says. “It really started with having a great advisor who was open and willing to say ‘you should try it.’ And because those first results were promising, I was able to find so many more resources on campus. These were programs and opportunities already showing up in my inbox. All I had to do was click. These campus resources really helped me figure out what to do next and get where we are today.”

The company received many early accolades, such as winning first prize in the 2015 Wisconsin Governor’s Business Plan Contest, and its innovation and drive hasn’t slowed. Now, after a few more years of work and expansion of the team from two people to nine, bluDiagnostics is armed with a device undergoing preclinical trials. The company hopes to manufacture the device for sale in a couple of years.

Opportunities on campus and in the state of Wisconsin helped flesh out Brenner’s idea, provide initial funding, and bridge the science with business. 

The device, Brenner explains, consists of several components: a disposable piece that collects saliva and a small reusable reader small enough to be kept at a bedside. It delivers hormone data to a smartphone app so users can see and share it with their physicians. It could help them determine the best time of the month to conceive, whether a woman needs fertility drugs, or if in vitro fertilization may be necessary.

The device’s hormone measurements are as accurate as blood testing, Brenner says.

“We have grown significantly and really made a huge leap from this pie-in-the-sky idea to an actual piece of hardware undergoing preclinical trials,” Brenner says. “It’s now a product that can be tested by real people. And it works, which is incredible. I really credit being in Madison and having the support of Midwestern investors who understood our mission.”

The company draws inspiration from large biotech and health firms headquartered in Madison and has relied on research connections available thanks to UW–Madison’s elite medical school, Brenner says. UW–Madison also provides a pipeline to hire great talent who then stay and work in the state, she adds, and sale of the device can put money back into the state’s economy

“Startup companies are the engines of economies — they grow up into big companies, create local jobs, and inject money into the economy,” Weibel says. “Success for bluDiagnostics means joining the ranks of exciting health-related successes, including Propeller Health and Exact Sciences, that will stimulate the local economy.”

“It’s now a product that can be tested by real people. And it works, which is incredible. I really credit being in Madison and having the support of Midwestern investors who understood our mission.”

Katie Brenner

But Brenner also believes the company’s larger impact is on the state’s women, their spouses and families. Fertility issues can affect a woman’s productivity in the workplace or cause her to leave the workforce altogether.

“The obvious savings related to improving women’s health are really incalculable,” she says. “The monitoring required during fertility diagnosis takes a lot of time and they miss too much work or they believe the cause is stress so they leave their job. Examples like this are pervasive and common.”

Hormones underlie many conditions, from infertility and obesity, to depression and migraines. BluDiagnostic sees potential in including others, such as testosterone. The team imagines a future in health care where these hormones and others are frequently monitored so women and their doctors can be proactive about health and interventions at all life stages.

“If we can help women at every phase of their lives do better at uncovering health issues early and taking positive and proactive steps to be in better health, we are going to improve outcomes and economic conditions for their offspring and their entire family,” Brenner says. “And with all the resources the university provided and continues to provide us, we are excited to see what the future holds.”

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Lost since 1943 crash, WWII pilot returned to Alabama family  external link

Mark Stone was on his way to the tractor supply store near Pensacola, Florida, in February when his father called and asked him if he was sitting down.

“He was so excited. I said, ‘Of course I’m sitting down. I’m driving!’” Stone recalls. “And he said, ‘They found Uncle Buster.’ I just couldn’t believe it.”

Photo: Stone posing in bomber jacket

Buster Stone became a fighter pilot because the P-47s protected bombers, and one of his brothers was a navigator on a bomber in the European theater.

It had been more than 75 years since 2nd Lt. Walter B. “Buster” Stone, a 24-year-old pilot from Andalusia, Alabama, disappeared with his P-47 Thunderbolt into a cloud bank 16,000 feet over northern France.

The rest of his World War II bomber-escort mission never saw him again, but in August 2018 a team from the University of Wisconsin–Madison’s Missing in Action Recovery and Identification Project unearthed the wreckage of Stone’s plane and his remains from a crash site in a national forest near Saint-Omer, France. And the Stone family had Buster back.

Through genetic testing, the Department of Defense POW/MIA Accounting Agency (DPAA) confirmed the remains to be Stone’s in February. He was interred May 11 with military honors in Andalusia in a family plot near his mother Lilla’s grave.

Four of Lilla’s seven sons served in World War II at the same time. Only one of them was killed. Mark Stone, son of one of Buster’s nephews, was told Buster became a fighter pilot because the P-47s protected bombers, and one of Buster’s brothers was a navigator on a bomber in the European theater.

“In his mind, his brother was in one of those bombers he was escorting. Everybody in the family has heard stories like that about Buster,” says Mark Stone, now 55. “Mama Stone, my great-grandmother, died when I was in my 20s, but we all knew she always thought he would come home. I can’t tell you how it feels to be able to do that for her, and the day before Mother’s Day. We couldn’t be more grateful.”

After months of preparation, members of UW–Madison’s MIA Project spent three weeks in the woods near Saint-Omer, carefully clearing trees and tons of earth from a site where in 2017 DPAA investigators had found Walter Stone’s identification tags.

Digging for clues

On Aug. 3, 2018, Charles Konsitzke (left), associate director of the UW Biotechnology Center, and Michael MacLaren (right), retired U.S. Army, use shovels to remove soil from the dig site. Photo by: Bryce Richter

UW-Madison student Samantha Zinnen (right) sifts through soil taken from the dig site. Photo by: Bryce Richter

UW-Madison student Torrey Tiedeman (center) uses a pickaxe to remove soil. Photo by: Bryce Richter

Team members are pictured during the soldier recovery mission, which was a joint effort between the University of Wisconsin–Madison and the U.S. Department of Defense POW/MIA Accounting Agency (DPAA). Photo by: Bryce Richter

Using picks and shovels they carried into the forest every day, hauling dirt by buckets to sifting stations they built alongside the dig, the MIA Project group worked 10 to 12 hours a day, six days a week. They recovered identifying parts of Stone’s plane (like .50 caliber machine guns, gnarled by the force and heat of the crash) along with the pilot’s remains and some of the personal items he was carrying.

“It’s hard work and long hours, but everyone is so careful,” says Charles Konsitzke, associate director of the UW Biotechnology Center and facilitator for the MIA Project. “The reason you’re there and what you’re looking for is always on your mind.”

UW–Madison’s first search was in 2013, and the university became DPAA’s first academic partner in 2016. Stone is the third missing member of America’s armed forces the MIA Project has successfully removed from the rolls of WWII missing — a list that still runs more than 72,000 names.

Photo: Stone in plane cockpit

Stone disappeared with his P-47 Thunderbolt into a cloud bank 16,000 feet over northern France. The rest of his World War II bomber-escort mission never saw him again.

“It’s been almost 75 years since these soldiers were lost, and that means every day there are fewer people left who have personal connections to them,” Konsitzke says. “That’s motivating. It makes us want to do what we can to help find people, so we can bring them home to families that remember them.”

This year, as many as 30 colleges and universities will follow UW–Madison’s lead, lending expertise in disciplines including history, languages and archaeology to DPAA’s search efforts.

Key to UW–Madison’s success in Lt. Stone’s case, according to Konsitzke, were students who joined the MIA Project as undergraduates, like recent grads Tristan Krause, Torrey Tiedeman and Samantha Zinnen. But help comes from across campus and Wisconsin.

Ryan Wubben, medical director of UW Med Flight, is a mainstay on excavations. Daniel Hummel, a postdoctoral fellow in history, contributed research before the team left for France. Erin Womersley of Sun Prairie served as interpreter. Gregg Jamison, a UW–Milwaukee at Waukesha anthropology professor, was the principal investigator on site. Even DPAA lead forensic anthropologist William Belcher — a professor of anthropology who brought some of his students from the University of Hawaii–West Oahu to France — earned his doctorate at UW–Madison.

While many of them have familial ties to the military, none of them are from Andalusia. And none of them are members of the Stone family, as large and close-knit as it may be.

“It means so much that there are people out there in this country — from Wisconsin, from the military — that would work so hard to do something like this, to do right by someone who served his country, and for his family,” says Mark Stone. “We owe them a lot. It makes us proud we’re all Americans.”

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Resilience of Yellowstone’s forests tested by unprecedented fire  external link

Photo: Fire burning trees

The Maple Fire burns at Yellowstone National Park in 2016. The fire affected forests recovering from the park’s historic 1988 fires. Photo: National Park Service / Jennifer Jerrett

In August 2016, areas of Yellowstone National Park that burned in 1988 burned again. Shortly after, in October 2016, ecologist Monica Turner and her team of graduate students visited the park to begin to assess the landscape.

“We saw these areas where everything was combusted and we hadn’t seen that previously,” says Turner, a professor of integrative biology at the University of Wisconsin–Madison who has closely studied Yellowstone’s response to fire since 1988. “That was surprising.”

In a study published this week [May 20, 2019] in the Proceedings of the National Academy of Sciences, Turner and her team describe what happens when Yellowstone —  adapted to recurring fires every 100 to 300 years — instead burns twice in fewer than 30 years. Yellowstone as we know it faces an uncertain future, the researchers say, and one of the big questions they hope to answer is whether the forests can recover.

Photo: The pile of rocks with the nail in the middle signifies a long-term study plot Monica Turner and her research group established at Yellowstone National Park in 1990 following the park’s historic 1988 fires. This same plot burned again in 2016. Historically, fires burn in Yellowstone only every 100 to 300 years.

The pile of rocks with the nail in the middle signifies a long-term study plot Monica Turner and her research group established at Yellowstone National Park in 1990 following the park’s historic 1988 fires. This same plot burned again in 2016. Historically, fires burn in Yellowstone only every 100 to 300 years. Photo by: Monica Turner

With Rapid Response Research funding from the National Science Foundation, Turner and her team returned to Yellowstone in the summer of 2017 to study the areas that re-burned. These include the Maple Fire, which burned 28-year-old lodgepole pines that regenerated following the 1988 North Fork Fire, and the Berry Fire, which contained 28-year-old lodgepole pines that had regenerated after the 1988 Huck Fire and 16-year-old trees that regenerated following the 2000 Glade Fire.

In each area, they compared to areas that burned in 1988 or 2000 but did not burn again in 2016.

In some areas, fire burned so severely that nothing but the stumps of young trees remained. Logs that had once been scattered on the forest floor combusted, leaving negatives of their former selves — ghost shadows — where they’d fallen.

“Everything was gone,” Turner says. “That was astonishing.”

Typically, most trees killed by fire remain standing for years. Surface fires leave dead needles on trees. Crown fires burn needles off but leave standing trunks. However, four of the 18 re-burned plots Turner’s team sampled saw fire so severe they had to come up with a new name to describe them: crown fire plus. In these, 99 percent of the stems of previous trees combusted.

Photo: Graduate student and study co-author Kristin Braziunas samples dead wood in an area that burned in Yellowstone’s historic 1988 fires but did not re-burn in 2016.

Graduate student and study co-author Kristin Braziunas samples dead wood in an area that burned in Yellowstone’s historic 1988 fires but did not re-burn in 2016. Photo by: Monica Turner

In 2011, modeling work by Turner’s group challenged pre-existing notions that young forests lack enough fuel in the form of trees and downed logs to sustain severe fire. The 2016 fires confirmed their predictions.

“The idea was that if fires are recurring more frequently, we will we see some self-limitation, young forests will not be able to re-burn,” says study co-author, graduate student Kristin Braziunas. “We definitively saw this was not the case — even at just 16 years old, there was sufficient fuel for these forests to burn at the highest possible level of severity.”

The team also found a six-fold decline in the number of lodgepole pine tree seedlings that re-established in the first year following the 2016 fires. In some patches of re-burned forest, regeneration rates were significantly lower. Dense, young forests were converted into much sparser ones.

Lodgepole pine trees are known for their serotinous cones, which are adapted to open in fire and release their seeds, replenishing the forest with a thick blanket of new trees once the blaze has fizzled. Historically, the 100-to-300-year fire intervals gave trees the chance to mature and build up their seed banks.

Photo: The serotinous cone of a lodgepole pine, opened by the flames of the Maple Fire.

The serotinous cone of a lodgepole pine, opened by the flames of the Maple Fire. Photo: NPS / Jennifer Jerrett

But younger trees have not yet built up their savings, so a quick re-burn is like dipping into a bank account before the funds have been replenished.

The researchers also found that the re-burned forests lost significant carbon storage capacity. Nearly two out of three logs on the forest floor were consumed in the 2016 fires. These pieces of dead wood were carbon sinks, storing carbon that the tree took up while alive. When burned, they release carbon into the atmosphere.

Turner explains that once an old forest burns, it takes about 90 years for the forest to recover its lost carbon.

“We care about carbon storage and recovery because forests play a very important role in the global carbon cycle,” says Braziunas, who before joining Turner’s research group spent more than seven years working as a municipal firefighter in Oberlin, Ohio.

Braziunas adapted a model previously created by Turner’s collaborator, Rupert Seidl, to estimate how long it would take for the forest to recover the carbon it had lost to the atmosphere in the 2016 fires, between tree loss, downed wood consumption, and reduced tree regeneration density. She found it would take more than 150 years, assuming the forests do not burn again in that time.

Photo: Researchers and field assistants stand in the middle of a very dense stand of lodgepole pines that regenerated following Yellowstone’s historic fires of 1988. In 2016, patches of forest like this burned so severely that only stumps remained, earning a new name for the type of fire: “crown fire plus.”

Researchers and field assistants stand in the middle of a very dense stand of lodgepole pines that regenerated following Yellowstone’s historic fires of 1988. In 2016, patches of forest like this burned so severely that only stumps remained, earning a new name for the type of fire: “crown fire plus.” Photo by: Monica Turner

“We were essentially able to reconstruct what the forest looked like before the fire happened, how many trees there were and how big they would have been,” Braziunas says. “Because we also measured nearby stands (of trees) that didn’t burn, we could compare what happens after the reburns and game out the scenarios in the model.”

The estimate, she and Turner say, represents a best-case, conservative scenario. With a warming climate and increased frequency of drought, the forests are likely to burn again in short intervals.

However, the forest has long shown itself to be resilient.

“The landscapes are going to look different than they have in the past,” says Turner, “but that doesn’t mean they won’t be beautiful. There will be species that benefit and species that see their ranges contract.”

“Change is going to happen and change is going to happen more quickly than we thought it would,” she adds. “We are learning how the system responds, but we don’t know to what degree it will be resilient or adapt in the future. But I am not ready to write it off. We have been surprised in the past.”

The study was supported by NSF grant DEB-1719905, the Joint Fire Science Program 16-3-01-4, the University of Wisconsin–Madison Vilas Trust, the Wisconsin Alumni Research Foundation UW2020 initiative, the Earth Institute at Columbia University and Columbia University’s Center for Climate and Life. Other co-authors include Winslow Hansen at Columbia University and Brian Harvey at the University of Washington.

The fires that ravaged Yellowstone National Park in 1988 were large and severe, but they were still within the normal limits of fire patterns in the West. Following those fires 30 years ago, University of Wisconsin–Madison Professor of Integrative Biology, Monica Turner, immediately got to work studying the recovery of the forests and she has continued to do so in the decades since. UW–Madison video

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UW–Madison and Extension collaborate on Wisconsin’s water quality  external link

Photo: Sailboats on Lake Mendota on sunny day

Lake Mendota during an autumn morning in 2017. “The value and importance of water is what brought us together today,” said the Division of Extension’s Tricia Gorby at the event “Improving Surface Water and Groundwater Quality.” Photo: Jeff Miller

On Friday, May 3, 2019, nearly 100 people packed a room at the Memorial Union on the University of Wisconsin–Madison campus, appropriately overlooking the world’s best-studied lake, Lake Mendota.

They were there to think about and to talk about water. Not just any water, but Wisconsin’s water, in a year that Governor Tony Evers has declared the Year of Clean Drinking Water and also at a time that UW–Madison and the recently reintegrated Division of Extension are looking to forge new partnerships and strengthen existing ones.

It was the second in a series of events designed to be “intentional about creating exactly the right conditions to encourage collaboration,” said Matt Mayrl, chief of staff to Chancellor Rebecca Blank, in a welcoming statement to the audience.

“There are few issues more urgent than safeguarding the quality of our freshwater,” Mayrl said, “and few issues more complex.”

Participants included representatives from Extension programs around the state and UW–Madison researchers working on water-related projects across academic disciplines.

The event, called Improving Surface Water and Groundwater Quality, is one of several funded this year by the Chancellor’s Office. The first, centered on the state’s opioid crisis, took place in March, and four others are planned for fall.

The idea is to help connect the research, scholarship and resources of UW–Madison with the people and on-the-ground expertise of Extension, which has a presence in each of the state’s 72 counties.

“Extension is a great asset to UW–Madison, and it embodies the Wisconsin Idea,” said Karl Martin, dean of the Division of Extension. “We meet people where they live, with evidence-based resources and facilitation skills. It’s not just about pushing information out; the goal of Extension is to use those local connections to engage with citizens to address their issues and figure out what their needs are at the local level.”

At the same time, thousands of faculty, staff and graduate students at UW–Madison, who have the capacity to engage in research that meets needs currently not being addressed, are pursuing research that affects the lives of Wisconsin residents.

Photo: People on a boat docked at a pier

Visitors to Trout Lake Station in Boulder Junction, Wisconsin, hear from UW–Madison Center for Limnology scientists during the research station’s annual open house. “We are used to having a lot of water,” Emeritus Director Stephen Carpenter said. “But our demand for water has exceeded our supply.” Photo by: Kelly April Tyrrell

“It’s huge for Extension because there is renewed attention to where we are in the state so we can get researchers here, attention, partners here,” said Danielle Hairston-Green, Extension Human Development and Relationships Institute director. “A lot of people in the community feel disconnected from the research through the lens of the institution.”

At the water-focused event — led by Martin, Dean Paul Robbins from the UW–Madison Nelson Institute for Environmental Studies, and Tricia Gorby, director of Extension’s Natural Resources Institute — participants hailed from at least 11 counties, including the cities of Green Bay, Hurley, Superior and Wausau.

They included representatives from Extension programs around the state, Wisconsin Sea Grant, Extension and UW–Madison researchers working on water-related projects across academic disciplines, from engineering and political science to global health and ecology.

“The value and importance of water is what brought us together today,” said Gorby, noting that water is one of Wisconsin’s most important natural resources.

Stephen Carpenter, director emeritus of the Center for Limnology, spoke about the richness of Wisconsin’s water, but also about the pressing issues facing it.

“Wisconsin has an extraordinary demand for water and we are used to having a lot of water,” Carpenter said. “But our demand for water has exceeded our supply.”

Photo: Algae on surface of lake

Algae blooms form on the surface of Lake Mendota near the UW campus in July 2018. Wisconsin’s lakes experience harmful algae blooms each summer as phosphorus runoff creates conditions that favor their growth. Photo: Jeff Miller

Climate change, he explained, is exacerbating the issue, bringing flooding and erosion to communities across the state; contributing to the collapse of fisheries, threatening livelihoods and recreation; adding to pollutants in surface water and groundwater; and leading to toxic algae blooms in the state’s lakes.

“It is changing our cultural and economic relationships to water,” Carpenter said. “There has been a collapse of the legendary walleye stocks in northern Wisconsin, which is the backbone of that recreational economy, and climate change is leading to the loss of brook trout, the only native trout, in southwest Wisconsin.”

Water in some Wisconsin municipalities and private wells have tested positive for elevated levels of per- and poly-fluorinated compounds, contaminants found in food packaging and nonstick cookware that present a health hazard to people. And others have tested positive for high levels of nitrates, fecal matter and antibiotic resistant bacteria.

“There is a greater need for water treatment and that’s expensive,” Carpenter said.

“We meet people where they live, with evidence-based resources and facilitation skills. It’s not just about pushing information out; the goal of Extension is to use those local connections to engage with citizens to address their issues and figure out what their needs are at the local level.”

Karl Martin

A panel of speakers followed Carpenter to highlight opportunities for Extension and UW–Madison to collaborate to preserve and protect Wisconsin’s water resources and to address the needs of residents.

Panelists included Center for Limnology director and chair of Water at UW–Madison’s Jake Vander Zanden; Water Resources Management Program Chair Anita Thompson; Professor of Civil and Environmental Engineering Steve Loheide; Jim Hurley, director of the Aquatic Science Center; Ken Bradbury, director of the Wisconsin Geological and Natural History Survey; and Ken Genskow, Extension specialist and chair of the Department of Planning and Landscape Architecture.

Out of the conversation came a big idea from Loheide, who suggested the creation of what he called an “extensionship,” in which Ph.D. students at UW–Madison might apply for funding to work with Extension agents to plan and implement an extension/outreach program based on their doctoral research.

“The Extension agent then becomes the repository of that science,” Loheide said. “I think students are where we have the bandwidth to make an impact. Someone who spends five, six, seven years studying something is invested. They want their research to benefit people.”

The Nelson Institute’s Robbins expressed his excitement for the momentum around addressing water quality — from the governor’s initiative to a bipartisan state legislative task force and a cluster hire of freshwater sustainability faculty — and for renewed focus on ways campus and Extension can work together.

“We have an envious responsibility to make an impact and water is a great venue to do it,” said Extension’s Martin. “We have done it before and now we can do it better … Everyone wants to make a difference with their work and the best way to see those differences is in your home state.”

Read a related message from Extension’s Karl Martin

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Native Nations_UW Leadership Summit highlights directions for partnerships  external link

The University of Wisconsin–Madison and the 12 Native Nations in Wisconsin met May 10 for a day of discussion about new and ongoing partnerships to improve health services, preserve the environment, develop local economies, strengthen families, and expand educational opportunities.

Among the announcements at the Native Nations_UW Leadership Summit: the university and the Tribes will collaboratively pursue the creation of a culturally responsive research center on indigenous issues, and UW–Madison will hire a tribal relations liaison to identify opportunities and facilitate communication between UW–Madison and tribal governments in Wisconsin on matters of shared interest. The position will jointly report to the Office of the Vice Chancellor for University Relations and the Division of Extension.

“It’s wonderful to see the enthusiasm in this room — and back on campus — as we explore ways we can work more closely together,” UW–Madison Chancellor Rebecca Blank said.

The summit in Madison was the second such gathering for university officials and representatives from 12 tribes. About 80 people attended.

Photo of Tribal and university leaders at Monona Terrace.

Among the leaders attending the summit were (standing from left to right) Aaron Bird Bear, assistant dean for student diversity programs, School of Education; LeAnn White, vocational/higher education transition coordinator, Lac du Flambeau Band of Lake Superior Chippewa Indians;Tribal Council Member Jessica Ryan, Brothertown Indian Nation; Don Rosin, human resources manager, Red Cliff Band of Lake Superior Chippewa Indians; Vice President Jolene Bowman, Stockbridge-Munsee Band of Mohican Indians; Patrick Sims, UW-Madison chief diversity officer; Thomas Boelter, administrator of education and culture, Forest County Potawatomi; Mic Isham, executive administrator of the Great Lakes Indian Fish & Wildlife Commission and past chairman of the Lac Courte Oreilles Band of Lake Superior Chippewa; Yvette McGeshick, education director, Sokaogon Chippewa Community Mole Lake Band of Lake Superior Chippewa; Paul Robbins, dean, Nelson Institute for Environmental Studies; Legislator Gunnar Peters, Menominee Indian Tribe of Wisconsin; Soyeon Shim, dean, School of Human Ecology; Sarah Mangelsdorf, UW-Madison provost; Larry Nesper, director of American Indian Studies and professor of Anthropology; and Jessie Conaway, co-chair of the Native Nations_UW Working Group and faculty associate, Nelson Institute. Seated from left to right are Charles Hoslet, vice chancellor of university relations; Tribal Council Member Dylan Jennings, Bad River Band of Lake Superior Chippewa; Tribal Advisory Council Member Nehoma Thundercloud, Ho-Chunk Nation; Chancellor Rebecca Blank; Chairman Tehassi Hill, Oneida Nation; Michael Decorah, NN_UW Advisory Council delegate, St. Croix Chippewa Indians of Wisconsin; and Tribal Chairman Mike Wiggins Jr., Bad River Band of Lake Superior Chippewa.

The first summit, in 2015, was convened as a centennial event commemorating the Society of American Indians’ visit to campus in 1914. This led to the creation the following year of the Native Nations_UW Working Group. The group was charged by the provosts of UW–Madison, University of Wisconsin Colleges, and the University of Wisconsin Extension to partner with Native Nations in Wisconsin on a range of educational, research and outreach initiatives.

“I really like that we’re here today, and I’m really encouraged by what’s going on,” said Mic Isham Jr., executive administrator of the Great Lakes Indian Fish & Wildlife Commission and former chairman of the Lac Courte Oreilles Band of Lake Superior Chippewa. “The partnership feels genuine. I think it will have valuable benefits, and not just on the research end, but also in how many Native students are at UW–Madison and how the university can better support them.”

Thomas Boelter, administrator of education and culture for the Forest County Potawatomi, said the most important thing is that everyone is together in the same room.

“We won’t be able to get anyplace until we at least begin the dialogue, so I believe there’s hope for the future,” he said. “I believe the UW System can help the Tribes as much as the Tribes can help them. It can be an equal partnership.”

The idea for an indigenous collaborative research center has been developing on campus for decades, said Jessie Conaway, co-chair of the Native Nations_UW Working Group and a faculty associate at the Nelson Institute. A draft planning proposal describes the governance structure as an advisory board with 50 percent representation from Native Nations and the university.

The center would build culturally responsive research capacity on campus, develop research opportunities for students, facilitate joint grant-writing opportunities, and ensure that the research is community driven and results in local benefits for Tribes.

“The center can help us build more robust research collaborations involving and supporting tribal communities, particularly in Wisconsin but throughout the Great Lakes Region,” Blank said.

Feedback on the proposed center was largely enthusiastic, with caveats. Patty Loew, a professor in the Medill School of Journalism and director of the Center for Native American and Indigenous Research at Northwestern University, said such a center, to be culturally sensitive and responsive, will need to operate differently than UW–Madison’s many other research centers. Everything from the way funds are secured to how research results are used will need to be addressed, said Loew, who has a deep history with UW–Madison and the working group.

“The university is really going to have to think about structurally changing the way it does research if it really wants to partner with Native people,” she said.

Jessica Ryan, a tribal council member with Brothertown Indian Nation, said she appreciates that all 12 tribes are at the table and that they are being included in every stage of development, including the brainstorming phase. Too often, tribes are consulted only toward the end of a planning process, she said.

“I’m grateful for the conversation from the outset — the dreaming — and I ask that you continue that so that we can come together in a meaningful way,” she said.

The summit also served to renew existing commitments. Several faculty members and students showcased projects that are helping the university meet the priorities set out in the working group’s strategic plan. Among those priorities, the university:

  • Hosts precollege programs for Tribal youth, and its admissions team now makes regular visits to high schools identified as having large Native populations — not only in Wisconsin but in New Mexico, Arizona, and North and South Dakota.
  • Has hired four new Native American faculty and will hire three more in a new research cluster that will focus on “Native American Environment, Community and Health.” Additionally, the UW System has hired an American Indian Student Success Coordinator.
  • Held its first cultural responsiveness training for faculty, staff and administrators. More are planned.
  • Welcomes tribal leaders and educators to campus through a new Elders-in-Residence Program.

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Jawless fish take a bite out of the blood-brain barrier  external link

A jawless parasitic fish could help lead the way to more effective treatments for multiple brain ailments, including cancer, trauma and stroke.

One major challenge in treating cancers and other disorders of the brain is ensuring that medicines reach their targets. A team of biomedical engineers and clinician-scientists at the University of Wisconsin–Madison and the University of Texas at Austin borrowed molecules from the immune system of the parasitic sea lamprey to deliver anti-cancer drugs directly to brain tumors.

Photo: 2 lampreys

Lampreys and humans have similar immune systems. But instead of producing antibodies to neutralize threats (that’s how vaccines help protect us against measles), they produce small defensive molecules. iStock Photo

They published their results today (May 15, 2019) in the journal Science Advances.

Unlike most currently used medicines, which target specific features on or inside individual cells in our body’s organs and tissues, the lamprey-derived molecules take aim at a different target — the extracellular matrix, a tangled mesh of proteins and sugars that supports and surrounds all cells in the brain.

The researchers believe the molecules could be adapted and combined with a wide array of other therapies, offering hope to treat numerous brain ailments beyond tumors, such as multiple sclerosis, Alzheimer’s disease or even traumatic injuries.

“This set of targeting molecules appears somewhat agnostic to the disease,” says Eric Shusta, a professor of chemical and biological engineering at UW–Madison. “We believe it could be applied as a platform technology across multiple conditions.”

The technology takes advantage of the fact that many diseases disrupt one of the body’s natural defense mechanisms: the blood-brain barrier, which lines the blood vessels of the central nervous system and protects the brain from potential threats such as circulating toxins or pathogens.

Many drugs — including the lamprey-derived molecules — cannot reach targets in the brain when they are injected into the bloodstream, because the blood-brain barrier normally prevents large molecules from leaving the blood vessels in the brain.

Photo: Ben Umlauf and Eric Shusta working at lab bench

Chemical and biological engineering professor Eric Shusta, right, and postdoctoral researcher Ben Umlauf at work in the lab, where they helped develop molecules from parasitic lamprey for use in treating disorders in the brain. UW–Madison photo by Sam Million-Weaver

Yet, in conditions such as brain cancer, stroke, trauma and multiple sclerosis, the barrier becomes leaky in and around the disease locations. A leaky barrier offers a unique point of entry. It will allow the matrix-targeting lamprey molecules to access the brain and deliver drugs precisely on target.

“Molecules like this normally couldn’t ferry cargo into the brain, but anywhere there’s a blood-brain barrier disruption, they can deliver drugs right to the site of pathology,” says Shusta.

Knowing that brain tumors often cause the barrier to leak, the researchers linked the lamprey-derived molecules to a Food and Drug Administration-approved chemotherapy called doxorubicin. The treatment prolonged survival in mouse models of glioblastoma, the incurable brain cancer that afflicted Senators John McCain and Ted Kennedy.

The matrix-targeting strategy means a wide variety of therapies could be linked to the lamprey-derived molecules. They could also be combined with techniques that temporarily open the blood brain barrier at specific brain sites. And it’s possible that drugs delivered to the matrix could accumulate to a much higher therapeutic dose than medicines aimed at the inside of cells.

“Similar to water soaking into a sponge, the lamprey molecules will potentially accumulate much more of the drug in the abundant matrix around cells compared to specific delivery to cells,” says collaborator John Kuo, a neurosurgeon-scientist and professor of neurosurgery in the Dell Medical School at the University of Texas at Austin.

Additionally, brain cells actively pump out many chemicals — a useful trick to protect against toxic compounds, but a major headache for achieving effective therapeutic doses for medicines.

Targeting the matrix that surrounds the cells sidesteps that pumping problem.

“This could be a way to hold therapies in place that don’t otherwise accumulate well in the brain so they can be more effective,” says Ben Umlauf, a postdoctoral scholar in Shusta’s group who isolated the lamprey-derived molecules.

In the future, the researchers plan to link the matrix-targeting molecules to additional anti-cancer drugs, such as immunotherapy agents that activate a patient’s own immune system to destroy tumors.

Lampreys and humans have similar immune systems. But instead of producing antibodies to neutralize threats (that’s how vaccines help protect us against measles), they produce small crescent-shaped defensive molecules called VLRs. To obtain their drug-delivery molecules, the researchers “vaccinated” lampreys with components of the brain extracellular matrix and then hunted through many thousands of VLRs to find one that stuck specifically to the brain matrix.

Importantly, in the mouse studies, the lamprey-derived molecules circulated throughout the body without accumulating in healthy brain tissue or other organs. This targeted delivery is especially important in cancer treatments, since many therapies frequently cause debilitating adverse reactions due to indiscriminate effects on healthy cells.

In the future, the researchers plan to link the matrix-targeting molecules to additional anti-cancer drugs, such as immunotherapy agents that activate a patient’s own immune system to destroy tumors.

They also see promise in using the molecules as diagnostic tools to detect blood-brain barrier disruption by linking the matrix binders with probes for advanced imaging with PET scanners or MRI machines.

And because the molecules appear to be quite adaptable, the researchers speculate that many other medicines for the brain could become more effective if they were targeted to the matrix.

“I’m excited about trying this strategy in different disease model systems,” says Kuo. “There are several disease processes that disrupt the blood-brain barrier and we could conceive of delivering a variety of different therapies with these molecules.”

Other collaborators on the study include Paul Clark, Jason Lajoie, Julia Georgieva and Samantha Bremner at UW–Madison and Brantley Herrin at Emory University.

The work was supported by grants from the National Institutes of Health (NS091851 and NS099158) and the Defense Threat Reduction Agency (HDTRA1-15-1-0012) and Falk Medical Research Trust Catalyst Award.

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A new way to wind the development clock of cardiac muscle cells  external link

These days, scientists can collect a few skin or blood cells, wipe out their identities, and reprogram them to become virtually any other kind of cell in the human body, from neurons to heart cells.  

The journey from skin cell to another type of functional cell involves converting them into induced pluripotent stem cells (iPSCs), which are similar to the developmentally immature stem cells found in embryos, and then coaxing them to mature into something different. 

Photo: Colored microscopic image of iPSC-derived crdiomyocytes

Human iPSC-derived cardiomyocytes Image courtesy of Jianhua Zhang

But the process runs on an invisible clock, one in which scientists are interested in speeding up so adult-like cells are available when needed, whether for testing drugs for precision medicine, transplanting to repair injury or defect, or better understanding basic biology. It involves an FDA-approved compound called polyinosine-polycytidylic acid, or pIC, a double-stranded RNA molecule that activates a cell’s innate defense system. The compound is commonly used to boost vaccines and chemotherapy. The researchers found that when added to induced pluripotent stem cells undergoing the process of transitioning into cardiac muscle cells, pIC accelerated cellular maturation. 

“We make beating heart muscle cells out of human iPSCs because we are interested in understanding and treating cardiac diseases,” says lead author and University of Wisconsin–Madison MD-PhD student, Mitch Biermann. “It’s important that the cells we make in a dish are as close to adult heart muscle function as we can make them. 

This is because, study leader Tim Kamp says, immature cardiac cells don’t contract as strongly as adult cardiac cells, and the electrical properties that sets their beat is different. Their metabolic characteristics are a bit different, too. 

“If you want to know how drugs, such as beta blockers, work in the adult heart, it’s better to test those in more mature, human iPSC-derived cardiomyocytes (cardiac muscle cells),” says Kamp, director of the University of Wisconsin–Madison Stem Cell and Regenerative Medicine and a professor of medicine in the School of Medicine and Public Health. 

Other researchers have made progress utilizing a variety of ways to speed up the process, including electrical stimulation, changes to the metabolic environment of the cells, and even forcing the cells into the rod-like shapes more characteristic of adult cells, but each method seems to fall a bit short. 

Biermann chose a different tack. He noticed that cardiac cells derived from iPSCs mature at different rates in a dishOther researchers found that cardiomyocytes in the heart and in blood vessels of rats matured according to the same clock, despite being distant from each other in the body. 

Maturation isn’t only controlled by what’s going on in the environment of the heart,” Biermann says. “Because of that and because maturation in a dish seems random, we started thinking about epigenetics.”  

In other words, Biermann thought maturation rates might have to do with the way timing of cellular maturation events was coordinated. He wondered whether he could essentially prime the cells at just the right time to accelerate maturation — to wind up the clock — and began looking for compounds that did so without also killing them. 

That’s how he found pIC. When he added it to early cardiac precursor cells in the lab, they formed beating heart cells two days sooner than cells without pIC. After 48 hours, the cells were removed from the compound but its effects continued to linger, leading to cells that were larger in size, had better contractility, were electrically more efficient, exhibited mature metabolic characteristics and had better-developed structures when compared to cells without pIC. 

When they looked closely at what was going on inside the cells exposed to the compound, they found that pIC had activated cellular programming that led to accelerated maturation. Specifically, it turned up the expression of the JAG1 gene (which triggers a signaling pathway called Notch), and led to a host of epigenetic changes. 

The researchers also found that early cardiomyocytes exposed to pIC before implantation in mouse hearts matured faster than those not primed with the compound. They think pIC makes the cells more receptive to the maturation cues already present. 

“There is some intrinsic clock function involved as well, which, in part, is based on epigenetic changes,” says Kamp. “It’s safe to say there is much more to learn that we don’t yet understand about cell autonomous developmental clocks.” 

Developmental clocks, researchers think, dictate the amount of time it takes for a fertilized egg to develop from a single immature cell into a newborn possessing all the specialized cells of the body. Despite being composed of the same cellular stuff, a baby mouse takes 21 days to develop, a human about 280 days, and an African elephant 600 days or more.  

Biermann’s finding, Kamp says, was a surprise, because no one has thought about using pIC or compounds like it for this application. It also presents an opportunity to combine with other methods for accelerating maturation, and for doing so at a larger scale since it can be easily added to and washed out of cells. But the finding is also not without caveats. 

“One obvious question is whether this is cardiomyocyte specific or if it could be useful in making neurons of pancreatic islet cells (defects in which can lead to diabetes),” says Kamp. 

He also points out that these accelerated cardiomyocytes are still not an exact match for adult heart muscle cells. 

“We are not at the promised land yet,” he says. “We haven’t seen any aberrant effects, but we don’t know.”  

Further, they don’t yet know how these cells will continue to age.  

“If we’re turning up the clock, are they going to age faster, too?” explain Kamp. “If we can get a better handle on it, it could be used for practical purposes and for better understanding development.  

The study was supported by University of Wisconsin ICTR TL1TR002375 and MSTP T32GM008692, AHA 15PRE2577004, NIH F30 HL126452, NIH R01 HL129798, NIH 1S10RR025644 and NIH 1U01HL134764. 

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Kohl donates $10M to support La Follette School’s outreach, teaching and research  external link

Representing Wisconsin in the U.S. Senate for 24 years, Herb Kohl demonstrated his deep commitment to public service and his ethos of civility in public debate and policymaking. A $10 million gift announced today from Herb Kohl Philanthropies to the University of Wisconsin–Madison’s La Follette School of Public Affairs will extend the reach of that legacy.

Kohl’s donation, the Kohl Initiative, focuses on three priorities that will expand the School’s public outreach mission, advance the training of future public leaders and support influential research by faculty and students. It is the largest donation in La Follette School history.

Photo of former Sen. Herb Kohl

Former U.S. Senator Herb Kohl Photo: Jeff Miller

“Today, more than ever, we need strong public and private sector leaders – people like Sen. Kohl, who thoughtfully and respectfully discuss thorny policy issues,” said La Follette School Director and Professor Susan Webb Yackee. “UW–Madison has seen tremendous growth in civic engagement among its students, and this gift will allow the La Follette School to educate many more future leaders, who will tackle the world’s toughest problems with an evidence-based approach.”

Chancellor Rebecca Blank said the university is deeply grateful for Sen. Kohl’s generosity to his alma mater, his support of education across the state, and his decades-long service to the state and country in the U.S. Senate.

“Sen. Kohl has shown lifelong dedication to UW–Madison and this gift will provide tremendous opportunities for our students, faculty, staff and community,” said Blank, who holds an appointment as a La Follette School faculty member. “The Kohl Initiative embodies the Wisconsin Idea ­– especially the initiative’s outreach innovation fund, which will help expand the school’s impact in the state and the nation.”

Sen. Kohl, who was a founding member of the La Follette School’s Board of Visitors, believes the School is critically important for solving many of the country’s most difficult issues.

“Our democracy is being threatened by bitter partisanship, and the La Follette School is poised to lead by example – fostering cooperation, respectful discourse, and service to others,” said Kohl. “The school’s commitment to be a convener of thoughtful debate and evidence-based research provides a critical path for moving our country forward.”

In 2016, Sen. Kohl’s $1.5 million donation to the La Follette School launched the Herb Kohl Public Service Research Competition, which has provided financial support for collaborative faculty-student research that informs critical public policy and governance debates. Community outreach is a key component of the research competition.

Sen. Kohl’s most recent gift will extend the research competition and will support several new efforts. The Kohl Initiative will allow the school to educate more students, support undergraduate public policy internship opportunities, increase partnerships with nonpartisan organizations, host conferences on critical policy topics, and teach more high-demand classes in areas such as public and nonprofit leadership, economic development and social entrepreneurship.

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Double dipping: Dual-action ‘slippery’ catheter fights bacteria  external link

A super-slippery coating being developed at a University of Wisconsin–Madison lab could benefit medical catheters, factory equipment, and even someday, oil tankers.

The coating contains a lubricating oil that resists the attachment of bacteria. A first commercial target is catheters, which are used to deliver or remove fluids in medicine.

Catheters are frequently colonized by bacteria that form a tough “biofilm” that resists agents that would otherwise kill them.

Between 250,000 and 500,000 catheter infections in the United States each year cost billions through increased use of antibiotics, longer hospital stays, and the need to replace the catheter.

UW–Madison chemical engineering Professor David Lynn creates the patented coating by alternately dipping an object in two polymer solutions.

The Wisconsin Alumni Research Foundation holds several patents on Lynn’s work and has enrolled the project in the WARF Accelerator Program. According to WARF Accelerator director Greg Keenan, “The super-slippery surface could reduce infections, blockages and costs associated with catheters.”

David Lynn, a professor of chemical and biological engineering at the University of Wisconsin–Madison, is developing “slippery” coatings to reduce bacterial growth on implanted medical devices, such as catheters. The water-repellent coating speeds fluid movement and also deters colonization by bacteria.

WARF Accelerator aims to cut risks of promising technologies and ease the path to licensing by a business. “The goal of WARF Accelerator is to attract industry partners or investors by validating market potential, demonstrating commercial value, and de-risking the underlying technology,” says Keenan.

Revenues from licenses are the primary source of the millions of dollars that WARF sends to UW–Madison annually to support research, salaries, buildings and equipment.

Photo: Microscopic images of regular slide and SLIPS slide

After 24 hours, a bacterial pathogen, Pseudomonas aeruginosa (green), has attached to a bare glass slide, but not to a SLIPS-coated slide that contains an antibacterial agent. David Lynn, Materials Views, 2016

The new coating can also be infused with slow-release antibiotics, which could kill fungi and bacteria in the bloodstream or urinary tract where catheters are often used.

With Helen Blackwell, a professor of chemistry at UW–Madison with extensive understanding of bacterial growth, Lynn has demonstrated that the “slippery liquid-infused porous surfaces” (SLIPS) indeed prevent bacteria from growing on glass surfaces.

Lynn’s slippery coatings were inspired by certain plant leaves, which cause water to bead up into nearly spherical drops. “There’s been a lot of effort in materials science to develop synthetic mimics of those leaves,” Lynn says.

Lynn’s SLIPS are porous materials that are made by dipping an object in two polymer solutions. The coatings are about three millionths of a meter thick, about 25 times thinner than a sheet of paper.

Many processes, such as those used in computer chips and solar panels, can coat flat objects. But Lynn’s dip-and-redip process can coat complex or curved surfaces like both surfaces of a catheter.

About a year ago, funding and support from WARF Accelerator began to support “de-risking” the coating process. Catheters, Lynn notes, “must withstand bending, sterilization, coiling, and sitting on a shelf for six months without getting dry or brittle.”

Lynn’s coatings feel ultra-smooth, but their rough interior can store chemicals. “These cargoes could kill bacteria or fungi,” Lynn says. “That could help further prevent fouling by bacteria and prolong the lifetimes of these materials.”

And because the coatings prevent the adhesion of many substances, including water, oil, ketchup and mustard, they may be useful in food processing.

Photo: David Lynn and Harshit Agarwal looking at catheter

David Lynn, left, a professor of chemical and biological engineering at the University of Wisconsin–Madison, and graduate student Harshit Agarwal discuss the super-slippery coatings they are developing to reduce bacterial growth on implanted medical devices, such as catheters. Photo: David Tenenbaum

Keenan, director of WARF Accelerator, says, “My experience at LiquiGlide, which is commercializing a different slippery coating, taught me that viscous liquids sticking on solid surfaces results in billions of dollars of waste and inefficiencies. I saw firsthand the tremendous economic, environmental, and health care benefits that can be addressed with these new liquid-infused coatings in a wide variety of applications, from consumer packaging to chemical manufacturing to medical devices.” 

Catheters carry fluid, which could pull out the lubricating oil or antibiotic additive over time, Lynn says. “We needed to look at what would happen in an artery or vein in contact with blood. Can these coatings also prevent clotting? Can they survive in the high-salt environment of a urinary catheter? How effective is the anti-bacterial activity?”

So far, one year’s examination has not unearthed serious obstacles, Lynn says. “These are the kind of tests that WARF Accelerator can support and are beyond the usual research and design work we do but are helpful for firms that may want to license this technology. The technology becomes less risky to them, and more profitable to WARF. The ultimate winner will be the university.”

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Stem cell scientists clear another hurdle in creating transplant arteries  external link

Photo: Two men look at a computer screen.

Jue Zhang, lead author on the paper published in Stem Cell Reports, discusses cell images with Matt Brown, a coauthor on the paper and former postdoctoral researcher at the Morgridge Institute. Morgridge Institute for Research

Cardiovascular disease is a major cause of death worldwide, and treating it isn’t easy.  The disease wreaks havoc on patients’ blood vessels and can require complex bypass surgery.

Scientists at the Morgridge Institute for Research at the University of Wisconsin-Madison are working toward a dream of creating artery banks — similar to blood banks common today — with readily-available material to replace diseased arteries during surgery.

The latest work in the lab of Morgridge regenerative biologist James Thomson, also a UW-Madison professor of cell and regenerative biology, puts the science one step closer to that goal.

Photo: Jue Zhang

Zhang is an assistant scientist in the James Thomson Lab at the Morgridge Institute for Research.

In a paper published online in Stem Cell Reports on May 9, 2019, the Thomson Lab highlights a better way to grow smooth muscle cells, one of the two cellular building blocks of arteries, from pluripotent stem cells. The work also identifies a potential drug for reducing post-surgical risks in patients who undergo bypass surgery.

“We decided to focus on blood vessels because cardiovascular disease is a major cause of death worldwide,” Thomson says. “In the U.S. for example, heart disease and stroke are the No. 1 and No. 3 killers, respectively. And this work also has implications beyond making vessels for transplantation; it’s sort of a stepping stone to more advanced tissue engineering.”

A vivid red and black image.

This image depicts live imaging of MYH11-Tom expression in smooth muscle cells differentiated from human pluripotent stem cells using RepSox. MYH11 is a specific protein expressed by smooth muscle cells and is a marker for the mature contractile phenotype. Morgridge Institute for Research

Producing arteries in the lab requires two essential cell types: endothelial cells and smooth muscle cells. In 2017, the lab demonstrated methods to generate and characterize endothelial cells, while the new research focuses on the smooth muscle cells.

Jue Zhang, lead author and a Morgridge associate scientist, says widely used growth factors for producing smooth muscle cells from stem cells can also cause intimal hyperplasia, one of the most common reasons a bypass graft fails.

In intimal hyperplasia, a portion of the arterial wall thickens—due to proliferation and migration of smooth muscle cells—and causes a narrowing of the blood vessel.

“We wanted to have a protocol that can reduce the risk of intimal hyperplasia,”

Zhang says. “It’s a common problem in smooth muscle cell differentiation, and if you want to make a useful artery, you don’t want that risk.”

Healthy smooth muscle cells need the ability to contract, which helps them distribute blood throughout the body and regulate blood pressure. Using a high throughput screen, the team identified a small molecule, known as RepSox, that had the best potential to produce cells with contractile properties.

RepSox was identified out of a screen of 4,804 small molecules. In contrast to current widely used growth factors, RepSox inhibits intimal hyperplasia. It’s more stable than these growth factors and is also a cheaper alternative.

The characteristics that make RepSox good for differentiating smooth muscle cells also make it a desirable drug candidate to reduce risk of post-surgery complications, like intimal hyperplasia, Zhang says. Thus, this stem cell based high throughput screen can be used as a novel strategy for identifying drugs to restrict narrowing of blood vessels.

“Even after you have a bypass surgery, you can have some problems with your artery, like restenosis (narrowing arteries) due to intimal hyperplasia,” Zhang says. “Currently there are only two FDA-approved drugs on the market [to address these problems], and they’re not cell-type specific, meaning they have side effects. We found that RepSox inhibits intimal hyperplasia and has fewer side effects.”

RepSox is cell-type specific, so it inhibits smooth muscle cells and prevents the development of intimal hyperplasia without affecting neighboring cell types like endothelial cells.

While this finding brings scientists closer to improving treatments for cardiovascular disease, Zhang says there’s still another challenge to address: cell maturity.

“Basically this cell type is better than previous efforts, but it’s still not mature yet,” Zhang says. “We need to induce these cells to become more mature, to be more similar to our native artery, to make it more functional.”

Photo: Two researchers look at a computer screen.

Mitch Probasco (left) and Brian McIntosh (right) used lab automation technology to perform a high throughput screen of 4,804 small molecules. In this screen, RepSox was identified as a potent small molecule that improved differentiation of contractile smooth muscle cells from human pluripotent stem cells. Morgridge Institute for Research

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