Scientists at the University of Wisconsin–Madison have uncovered a possible way to protect key cells in the pancreas that are targeted during the development of Type 1 diabetes.

The researchers found that deleting a single stress-response gene in insulin-producing cells protects mice that are genetically predisposed to Type 1 diabetes from developing the disease. The findings suggest a new path to reduce stress inside those cells and alter how the immune system responds, potentially opening new avenues for early intervention or prevention.

Type 1 diabetes occurs when immune cells destroy pancreatic beta cells, leaving the body unable to produce enough insulin to regulate blood sugar. To date, most treatments have focused on suppressing immune activity.

“Historically, because it’s an autoimmune disease, scientists and clinicians have focused on preventing the immune attack,” says Feyza Engin, a professor in the UW–Madison Department of Biomolecular Chemistry who led the research, which was recently published in Nature Communications. “We looked at it from another angle and asked: Why are beta cells specifically targeted?”

The new research centers on a protein called XBP1. It’s part of a cellular stress response system that helps cells cope with inflammation, environmental toxins and the buildup of misfolded proteins. Earlier work from Engin’s lab showed that deleting a related stress sensor, Ire1α, in beta cells also prevented diabetes in mice. The new study builds on that foundation.

Using a mouse model that spontaneously develops Type 1 diabetes, Engin and her colleagues deleted the Xbp1 gene specifically in beta cells before immune assault. Although the mice initially showed elevated blood glucose, they later returned to normal glucose levels and remained healthy for as long as a year.

“What was really interesting is that early on they show hyperglycemia, but then they recover from it,” Engin says. “They actually go from diabetes back to normal blood glucose levels.”

An analysis revealed that beta cells lacking the Xbp1 gene temporarily lost features that mark them as mature insulin-producing cells. During this phase, immune cells were less likely to recognize and attack them. Over time, the beta cells regained their identity, inflammation decreased and insulin production recovered.

“They’re losing their beta cell identity and look nothing like a typical beta cell,” Engin says. “That’s why immune cells don’t recognize them.”

Importantly, the protective effect occurred without any changes to another stress-related process involving Ire1α, helping to clarify how different components of cells’ stress response influence the disease.

To better understand those differences, the team compared beta cells lacking Xbp1 with those missing Ire1α under identical environmental conditions — an important part of Type 1 diabetes research, where environmental conditions like housing and diet can affect disease rates in mice. Using single-cell sequencing from these mouse models and gene regulatory network analysis performed by UW–Madison collaborator Sushmita Roy’s lab, the team identified both shared stress pathways and ones involving only Xbp1.

“We found unique gene regulatory networks specific to Xbp1 that was never discovered before,” Roy says.

The findings add to evidence that beta cells play an active role in Type 1 diabetes rather than serving as passive targets.

“Our findings further support that beta cells are actually not victims,” Engin says. “They actively participate in their own destruction.”

While the study was conducted in mice, Engin says the work is designed with human disease in mind. People at high risk for Type 1 diabetes can often be identified years before symptoms appear through blood tests.

“If you identify these people who will develop diabetes at that stage, can we interfere?” she said. “Can we inhibit XBP1 and prevent or delay their diabetes?”

The lab is now actively pursuing those questions in further studies, Engin says, both in mice and in lab-grown human pancreatic cells.

This research was supported by the National Institutes of Health (T32 GM007215; DK130919; DK128136; 3-SRA-2023-1315-S-B; 3-SRA-2025-1654-S-B; and R01 GM144708), Greater Milwaukee Foundation and the University of Wisconsin Stem Cell and Regenerative Medicine Center.

Research at the University of Wisconsin–Madison drives innovation, saves lives, creates jobs, supports small businesses, and fuels the industries that keep America competitive and secure. It makes the U.S.—and Wisconsin—stronger. Federal funding for research is a high-return investment that’s worth fighting for.

Learn more about the impact of UW–Madison’s federally funded research and how you can help.

A new study by researchers at the University of Wisconsin–Madison provides the first empirical evidence connecting the chromosomal location of genes to natural selection, indicating the arrangement of genes can influence how quickly populations can adapt to rapid environmental change.

Published Friday in the journal Nature Communications, the study analyzed the genomes of three sibling copepod species (Eurytemora affinis species complex) to map how certain mutations — called chromosomal fusions — moved the location of genes as the tiny aquatic crustaceans evolved. The research team was surprised to find that even though these fusions occurred millions of years ago, they have implications for a contemporary species’ ability to adapt.

Until the last 80 years, these copepods largely lived in coastal estuarine ecosystems. Recently, these crustaceans have invaded freshwater ecosystems like the Great Lakes through the transport and dumping of ship ballast water. Carol Eunmi Lee, a professor of integrative biology at UW–Madison, has been studying copepod genetics for over 20 years to understand how they can adapt and thrive in new environments.

The short lifespan and relatively small genome of copepods make them the perfect model organism to investigate these questions. Even still, it took postdoctoral researcher Zhenyong Du nearly three years to sequence the genomes and map how the chromosomal fusions relocated genes to uncover patterns of natural selection. The work also revealed that each sibling species has an entirely different number of chromosomes.

“We were absolutely shocked,” says Lee.

These three sibling species, or clades, of copepods share a common ancestor and can breed with one another, something that is rare for organisms with different chromosome numbers, explains Du, who co-authored the paper with Lee. The clade from Europe has 15 chromosomes, while the Gulf clade has seven. Meanwhile, the Atlantic clade, which now also lives in the Great Lakes, has just four chromosomes.

Du and Lee immediately set out to understand why these sibling species have packaged their genes so differently from one another.

“We looked at the evolutionary history of the chromosomes, and we found that fusions are bringing multiple chromosomes together,” says Du.

Chromosomal fusions — the joining of different chromosomes into one — are a type of mutation that can happen all the time. This process can bring genes from different chromosomes together on the same chromosome, physically linking them as a potential unit of inheritance during natural selection.

Du and Lee started to wonder if the fusions that resulted in different chromosome numbers were beneficial for survival and thus were favored by natural selection in the past.

“During the evolutionary history of these copepods, salinity is the major variable of their living conditions,” Du explains.

One of the main mechanisms that copepods use to adapt to changes in salinity are proteins called ion transporters. Du and Lee found that these ancient chromosomal fusions caused genes that code for key ion transporters to be grouped together.

They observed that these fusions also caused the groupings of genes to move away from the recombination-prone arms of the chromosome and closer to its center, where recombination would not rip apart combinations of beneficial gene variants.

Genes are often subject to recombination, a process that occurs in the exchange of DNA during procreation and allows for new combinations of genetic material in offspring. Recombination is beneficial in creating genetic diversity that can help a species survive. And sometimes the fusions are so beneficial that they become permanent in the evolutionary process.

Scientists have hypothesized for years that genomic architecture evolution, particularly chromosomal fusions, might play an important role in evolutionary adaptation. This is the first study to produce empirical evidence of that particular link. The UW researchers’ study shows as copepods evolved, natural selection seemed to favor fusions that moved these ion-transporter genes toward the center of the chromosomes.

Importantly, the findings also suggest that fusion sites that were created millions of years ago are still hot spots for natural selection in invasive populations in the Great Lakes today.

While this study focuses on copepods, Du and Lee expect there will be implications for how scientists consider genetic architecture evolution and mechanisms of adaptation in other invasive species. There are also important implications for predicting which populations will be able to survive and adapt to future climate change.

“Genome architecture likely has profound impacts on how populations respond to natural selection. It’ll affect the mechanism of natural selection in a population, and determine how quickly it can evolve and respond,” says Lee.

This project was funded by National Science Foundation grants IOS-2412790, OCE-1658517, and DEB-2055356, and French National Research Agency ANR-19-MPGA-0004.

Research at the University of Wisconsin–Madison drives innovation, saves lives, creates jobs, supports small businesses, and fuels the industries that keep America competitive and secure. It makes the U.S.—and Wisconsin—stronger. Federal funding for research is a high-return investment that’s worth fighting for.

Learn more about the impact of UW–Madison’s federally funded research and how you can help.

Shawn Wiederhoeft is a pretty regular guy in his 30s. The Madison native works as a video game developer and maintains an active lifestyle. He’s healthy — in the best shape of his life — and regularly spends time with friends and family in southern Wisconsin.

But it wasn’t always a given that Wiederhoeft would be able to participate in life so fully. In fact, “Uncle Shawn,” as he’s known to family, is healthy today thanks in large part to a new kidney he received in 2020 from his sister, Meagan Hahn, of Wauwatosa.

The transplanted kidney has given Wiederhoeft a new lease on life, and because he and his sister chose to participate in a cutting-edge clinical trial at the University of Wisconsin School of Medicine and Public Health, he’s also able to live without the need for anti-rejection medications.

With no daily medications and only occasional medical checkups, Wiederhoeft says he sometimes almost forgets he’s the recipient of a kidney transplant.

“I have to consciously remind myself that there’s a third kidney in here,” he says. “I feel healthier than I’ve ever been.”

Wiederhoeft’s remarkable journey from serious illness to a medication-free recovery is just one of a growing number of living kidney transplant success stories that an international team of physicians and researchers reported in the July issue of the American Journal of Transplantation.

Led by UW–Madison surgery professor Dr. Dixon Kaufman, who directs the UW Health Transplant Center, the team shared results of a Phase 3 clinical trial that evaluated the effectiveness and safety of a living kidney transplant tolerance protocol that also includes the transplantation of certain stem cells from the kidney donor to the transplant recipient.

These stem cells are injected into the recipient several days after transplantation and take up residence in bone marrow, where they divide and multiply into immune cells that share the genes of the donated organ. The goal is to keep the recipient’s immune system from attacking the new organ, which it would otherwise recognize as a threat.

“This procedure doesn’t replace the immune system, but it complements it with around 5 to 10% of the immune system being from the donor,” says Kaufman.

In doing so, the new method removes the need for costly anti-rejection medications that severely suppress the recipient’s immune system, carrying a whole host of lifelong side effects.

The prospect of participating in a clinical trial that carried such a possibility was surreal for some of the study’s initial participants, including Wiederhoeft and Hahn.

“It felt straight out of a science fiction novel,” says Wiederhoeft.

The feeling of entering uncharted territory was even more pronounced for the trial’s first participants, sisters Barb Okey and Brenda Quale, both of Platteville.

“To say I was nervous — that’s an understatement,” says Okey, who received one of Quale’s kidneys followed by an infusion of her stem cells in 2018. Within months of the procedure, as hoped, tests showed that Quale’s cells had begun multiplying and circulating in Okey’s blood, and Okey was eventually weaned off her anti-rejection medications. Today, the only medication Okey takes is to help control her blood pressure.

“It’s amazing,” Okey says. “To have an opportunity to continue life with a new kidney and without taking medications is pretty fabulous.”

Okey and Wiederhoeft are among the small group of kidney recipients who can forgo anti-rejection medications thanks to UW–Madison’s clinical trial, but there are plans to expand eligibility for the procedure.

The initial phase required donors and recipients to be siblings and a “perfect,” or identical, match, meaning they have compatible blood types and other physiological compatibilities. Kaufman says that the initial trial’s success means that eligibility could soon be extended to living donor transplants of non-identical matches and eventually to recipients of organs from deceased donors.

Kaufman described the trial’s positive results as “immensely gratifying” and a testament to the value of long-term investments in research.

Indeed, before the procedure could be attempted in human patients, researchers at the Wisconsin National Primate Research Center and elsewhere spent years testing its safety and effectiveness in non-human primates. In 2023, the team led by Kaufman reported promising results from its latest primate studies that could pave the way for expanding the procedure to non-identical transplant pairs.

The studies that enabled this clinical trial received substantial support over the years from the National Institutes of Health (NIH). Kaufman credits UW–Madison’s proven track record of executing complex biomedical research for the sustained federal investment.

“The clinical and research environments at UW are outstanding” he says. “I’ve been to other programs, trained at other programs, and been faculty at other programs, and the unique things that make the ability to do complicated clinical trials like this successful at the University of Wisconsin are the strong collaborative culture and fantastic resources. We’ve got a history and a tradition of advancing the field in innovative ways for the benefit of many. We want to keep reaching higher and keep making those advances.”

While the recognition and support from NIH and other funding agencies have underpinned the trial’s success, Kaufman says it’s the patients and donors who are willing to participate in new and potentially risky trials who are ultimately responsible for helping to advance the field.

“Getting [the patients] back on the road to living a happy and fulfilling life is really what this is all about,” he says.

For Hahn, who felt compelled and grateful to participate in the trial as Wiederhoeft’s donor, the results have been immeasurably positive.

“To be able to have Uncle Shawn there for all the family events, and for it to be the most normal version of him — the most healthy version of him — I have to remind myself that this all happened and that this isn’t normal for so many people. But for us, it’s quite a blessing.” ■

Dixon Kaufman, MD, PhD, is the Ray D. Owen endowed professor in the UW–Madison Department of Surgery.

The research that supported this clinical trial occurred over 12 years, first in non-human primates before human trials, with more than $20 million in funding provided by the National Institutes of Health over that period (U01AI102456, MSN150727, T32AI25231, U54). NIH also supports the Wisconsin National Primate Research Center (P51OD011106). The Phase 3 clinical trial described here was sponsored by Medeor Therapeutics (MDR-101) in association with Stanford University.

Paul Lambert has received international recognition for his many contributions to understanding the role of HPV in cancer, leads three NIH research grants and edits the journal Virology. He says continued funding for research means “more effective therapies and greater understanding of how to fight cancer from every angle.”

Research at the University of Wisconsin–Madison drives innovation, saves lives, creates jobs, supports small businesses, and fuels the industries that keep America competitive and secure. It makes the U.S. — and Wisconsin — stronger. Federal funding for research is a high-return investment that’s worth fighting for. Learn more about the impact of UW–Madison’s federally funded research and how you can help protect it.

Paul Lambert leads the McArdle Laboratory for Cancer Research at University of Wisconsin–Madison where he has developed new anti-cancer therapies for cervical cancer and leads research to prevent and treat cancers caused by viral infections. Lambert, who also serves as chair of the Department of Oncology in the Wisconsin School of Medicine and Public Health, recently sat down for a Q&A about the importance of continued research on tumor viruses, which he says cause about 15% of all human cancers.

What is the focus of the project you’ve been leading, and why is it so important? 

This grant, originally initiated over 46 years ago by Dr. Howard Temin, supports a collaborative program focused on viruses that cause human cancer. It’s one of the few such NIH Program Project grants in the U.S. dedicated to studying tumor viruses, which are responsible for approximately 15% of all human cancers worldwide. These include viruses like HPV (human papillomavirus), Epstein-Barr virus (EBV), hepatitis B and C and Kaposi’s sarcoma-associated herpesvirus (KSHV).

This work has not only deepened our understanding of cancer biology but also directly led to preventive strategies — like vaccines and potential therapies — that save lives.

What viruses are currently the focus of your research?

Today, our research centers on HPV, EBV and KSHV, though over the years we’ve also studied hepatitis B and C viruses and Merkel cell polyomavirus. These viruses cause a range of cancers including cervical, anal, penile, head and neck cancers, liver cancer and lymphomas. Our work seeks to understand how these viruses cause cancer and, just as importantly, how we can prevent or treat those cancers.

What are some major public health impacts of your work so far?

One of the biggest examples is HPV, which alone causes about 5% of all human cancers, and most of these are preventable through vaccination. For example, cervical cancer is one of the leading causes of cancer deaths in women worldwide, yet HPV vaccines can prevent the infections that lead to it. If widely implemented, this could save hundreds of thousands of lives annually. Unfortunately, vaccination rates remain low in many areas, especially in low-resource settings.

We’re also collaborating with the Gates Foundation to develop therapeutic vaccines for use in countries where access to advanced cancer treatments like radiation or chemotherapy is limited. So, the impact of our work stretches from the lab bench to global public health solutions.

How has this research contributed to other areas of cancer science?

Our work on tumor viruses has had profound implications beyond virus-related cancers. For example, studies of HPV’s cancer-causing proteins led to the discovery of key tumor suppressors like p53, which is now known to be the most commonly mutated gene in all human cancers. Our research also uncovered mechanisms of immune evasion used by HPV — mechanisms now known to contribute to resistance to immunotherapy across many types of cancer.

Have your findings led to clinical applications or trials?

Yes. One exciting example is a clinical trial underway at UW–Madison for patients at risk of anal cancer caused by HPV. This work was inspired by basic science from Dr. Nathan Sherer’s lab (focused on HIV) and research from Dr. Evie Carchman, a GI surgeon. They discovered that HIV protease inhibitors, originally used to manage HIV, could also kill HPV-positive cancer cells. Now, these drugs are being repurposed in a trial to help prevent cancer in high-risk patients. It’s a great example of how basic lab research can translate directly into patient care.

What challenges has your research faced recently, particularly around funding?

We recently experienced a seven-week delay in funding renewal, which created significant disruption. We had to pause high-cost genomic studies and animal model work, delaying some projects by months, not just weeks. While funding did eventually come through at expected levels, it highlighted how vulnerable large research programs are to even short-term interruptions. These pauses can stall progress on experiments that take years to complete — especially when working with live models or time-sensitive tissue studies.

What’s the next frontier in your research?

We’re now working on developing novel therapeutics and vaccines for viruses like HPV, especially in settings where conventional treatments are inaccessible. We’re also deepening our understanding of how viruses interact with host cells and how those mechanisms might be exploited for broader cancer therapies. Ultimately, the goal is not just to understand how cancer happens — but to stop it before it starts.

If there’s one takeaway the public should know about your work, what is it?

Many of the cancers we study are preventable. That’s the key message. Whether it’s through vaccination, treatment of viral infections, or better public health outreach, we have the tools — or are developing them — to reduce cancer risk dramatically. Continued investment in this research means more lives saved, more effective therapies and greater understanding of how to fight cancer from every angle.

Quanyin Hu poses in his lab.

Using a newly discovered byproduct of dying cancer cells, University of Wisconsin–Madison researchers are developing personalized vaccines that could help keep aggressive tumors from recurring.

Led by Quanyin Hu, a professor in the UW–Madison School of Pharmacy, the research team has already found success slowing the recurrence of tumors in mouse models of triple negative breast cancer and melanoma. Currently, the long-term prognosis for human patients with these cancers is relatively poor. That’s in part because the diseases have a tendency to recur after the initial treatments to remove the tumors.

The personalized vaccine approach is an extension of the team’s recent discovery of pyroptotic vesicles, which are tiny sacs filled with the remnants of cancer cells when they undergo programmed cell death.

Crucially, the remnants in these microscopic sacs include antigens specific to the tumor, along with other molecular bits that can help direct immune cells to find and suppress cancer cells that might remain after a tumor is surgically removed.

In their study, recently published in the journal Nature Nanotechnology, Hu and his colleagues engineered these sacs to carry an immune stimulating drug. They then embedded these engineered vesicles into a hydrogel that can be implanted into the space left behind after surgical removal of a tumor.

This image shows the formation of pyroptotic vesicles, which look like small bubbles, in cancer cells as they undergo programmed cell death. A team of researchers led by UW–Madison pharmacy professor Quanyin Hu have developed a method for harnessing these vesicles to deliver vaccines against tumors with a high rate of recurrence. Image courtesy of Quanyin Hu

Using a melanoma mouse model and two different types of mouse models for triple negative breast cancers, including one with a human-derived tumor, the researchers compared their new approach with other cancer vaccine methods being studied. The mice that received the hydrogel laden with their engineered sacs survived significantly longer than others.

“Compared to the other approaches, ours shows a much stronger immune response,” says Hu. “We were one of the first groups to identify these pyrotopic vesicles and the first to show their effectiveness in helping prevent cancer recurrence, and we are very excited about their potential.”

Hu says the approach could theoretically apply to any cancer that tends to recur, such as pancreatic cancer and glioblastoma, the most common and extremely aggressive brain tumor. This potential is because the engineered sacs contain molecular information that is unique to an individual’s cancer cells, meaning the immune response they create is uniquely positioned to attack those cells.

Another advantage of this approach is the localized nature of the treatment. Most cancer vaccines under development carry the risk for severe side effects because of how they’re given — through systemic injections. Hu says that applying the engineered vesicles directly to the site of the removed tumor greatly reduces the risk of systemic side effects.

While the approach will require more testing in mice and other animal models before it can be tested in humans, Hu is bullish about its potential. Several of the mice that received the highest doses of the experimental treatment remained cancer free throughout the course of the study.

“That’s really exciting because we demonstrated that we could essentially cure these mice with no tumor recurrence,” Hu says.

This research was supported in part by the National Institutes of Health (R01EB035992 and R01CA288851), the American Cancer Society (RSG-23-1140821-01-ET) and the METAVIVOR Foundation.

Research at the University of Wisconsin–Madison drives innovation, saves lives, creates jobs, supports small businesses, and fuels the industries that keep America competitive and secure. It makes the U.S. — and Wisconsin — stronger. Federal funding for research is a high-return investment that’s worth fighting for. Learn more about the impact of UW–Madison’s federally funded research and how you can help protect it.

If the drug proves viable to treat epilepsy in humans, it would be the first to provide lasting relief from seizures even after patients stopped taking it. iStock/cagkansayin

A drug typically prescribed for arthritis halts brain-damaging seizures in mice that have a condition like epilepsy, according to researchers at the University of Wisconsin–Madison.

The drug, called tofacitinib, also restores short-term and working memory lost to epilepsy in the mice and reduces inflammation in the brain caused by the disease. If the drug proves viable for human patients, it would be the first to provide lasting relief from seizures even after they stopped taking it.

“It ticks all the boxes of everything we’ve been looking for,” says Avtar Roopra, a neuroscience professor in the UW–Madison School of Medicine and Public Health and senior author of the study, which was published last week in the journal Science Translational Medicine.

Epilepsy is one of the most common neurological diseases, afflicting more than 50 million people around the world. While there are many known causes, the disease often appears after an injury to the brain, like a physical impact or a stroke.

Some days, months or even years after the injury, the brain loses the ability to calm its own activity. Normally balanced electrical activity through the brain goes haywire.

“The system revs up until all the neurons are firing all the time, synchronously,” says Roopra. “That’s a seizure that can cause massive cell death.”

And the seizures repeat, often at random intervals, forever. Some drugs have been useful in addressing seizure symptoms, protecting patients from some of the rampant inflammation and memory loss, but one-third of epilepsy patients do not respond to any known drugs, according to Olivia Hoffman, lead author of the study and a postdoctoral researcher in Roopra’s lab. The only way to stop the most damaging seizures has been to remove a piece of the brain where disruptive activity starts.

On their way to identifying tofacitinib’s potential in epilepsy, Hoffman and co-authors used relatively new data science methods to sift through the way thousands of genes were expressed in millions of cells in the brains of mice with and without epilepsy. They found a protein called STAT3, key to a cell signaling pathway called JAK, at the center of activity in the seizure-affected mouse brains.

“When we did a similar analysis of data from brain tissue removed from humans with epilepsy, we found that was also driven by STAT3,” Hoffman says.

“[The discovery] ticks all the boxes of everything we’ve been looking for,” says Avtar Roopra (right), seated with research collaborator Olivia Hoffman.

Meanwhile, Hoffman had unearthed a study of tens of thousands of arthritis patients in Taiwan aimed at describing other diseases associated with arthritis. It turns out, epilepsy was much more common among those arthritis patients than people without arthritis — but surprisingly less common than normal for the arthritis patients who had been taking anti-inflammatory drugs for more than five-and-a-half years.

“If you’ve had rheumatoid arthritis for that long, your doctor has probably put you on what’s called a JAK-inhibitor, a drug that’s targeting this signaling pathway we’re thinking is really important in epilepsy,” Hoffman says.

The UW researchers ran a trial with their mice, dosing them with the JAK-inhibitor tofacitinib following the administration of a brain-damaging drug that puts them on the road to repeated seizures. Nothing happened. The mice still developed epilepsy like human patients.

Remember, though, that epilepsy doesn’t often present right after a brain-damaging event. It can take years. In the lab mice, there’s usually a lull of weeks of relatively normal time between the brain damage and what the researchers call “reignition” of seizures. If it’s not really epilepsy until reignition, what if they tried the drug then? They devised a 10-day course of tofacitinib to start when the mouse brains fell out of their lull and back into the chaos of seizures.

“Honestly, I didn’t think it was going to work,” Hoffman says. “But we believe that initial event sort of primes this pathway in the brain for trouble. And when we stepped in at that reignition point, the animals responded.”

The drug worked better than they could have imagined. After treatment, the mice stayed seizure-free for two months, according to the paper. Collaborators at Tufts University and Emory University tried the drug with their own mouse models of slightly different versions of epilepsy and got the same, seizure-free results.

Roopra’s lab has since followed mice that were seizure-free for four and five months. And their working memory returned.

“These animals are having many seizures a day. They cannot navigate mazes. Behaviorally, they are bereft. They can’t behave like normal mice, just like humans who have chronic epilepsy have deficits in learning and memory and problems with everyday tasks,” Roopra says. “We gave them that drug, and the seizures disappear. But their cognition also comes back online, which is astounding. The drug appears to be working on multiple brain systems simultaneously to bring everything under control, as compared to other drugs, which only try to force one component back into control.”

Because tofacitinib is already FDA-approved as safe for human use for arthritis, the path from animal studies to human trials may be shorter than it would be for a brand-new drug. Roopra’s epilepsy research has long been funded by the National Institutes of Health as well as key early support from Madison-based Lily’s Fund for Epilepsy Research and CURE Epilepsy.

The next steps toward human patients largely await NIH review of new studies, which have been paused indefinitely amid changes at the agency.

For now, the researchers are focused on trying to identify which types of brain cells are shifted back to healthy behavior by tofacitinib and on animal studies of even more of the many types of epilepsy. Hoffman and Roopra have also filed for a patent on the use of the drug in epilepsy.

This research was funded in part by grants from the National Institutes of Health (R01NS108756, R21NS093364, R01NS112308, NS112350, R01NS105628, R01NS102937 and R21NS120868).

Heart muscle cells grown from human induced pluripotent stem cells (in green) have successfully integrated into rhesus macaque heart muscle in this microscope image of heart tissue from a new study by UW–Madison and Mayo Clinic researchers. Photo courtesy Emborg Lab / UW–Madison

Heart muscle cells grown from stem cells show promise in monkeys with a heart problem that typically results from a heart defect sometimes present at birth in humans, according to new research from the University of Wisconsin–Madison and Mayo Clinic.

Heart disease, the No. 1 killer of Americans, can affect people at any time across their lifespans — even from birth, when heart conditions are known as congenital heart defects. Regenerating tissue to support healthy heart function could keep many of those hearts beating stronger and longer, and this is where stem cell research is stepping in.

A research team led by Marina Emborg, professor of medical physics in the UW–Madison School of Medicine and Public Health, and Timothy Nelson, physician scientist at the Mayo Clinic in Rochester, Minnesota, reported recently in the journal Cell Transplantation that heart muscle cells grown from induced pluripotent stem cells can integrate into the hearts of monkeys with a state of pressure overload.

Also referred to as right ventricular dysfunction, pressure overload often affects children with congenital heart defects. Patients experience chest discomfort, breathlessness, palpitations and body swelling, and can develop a weakened heart. The condition can be fatal if left untreated.

Nearly all single ventricle congenital heart defects, particularly those in the right ventricle, eventually lead to heart failure. Surgery to correct the defect is a temporary solution, according to the researchers. Eventually, patients may require a heart transplant. However, the availability of donor hearts — complicated by the young age at which most patients require a transplant — is extremely limited.

In their new study, the researchers focused on grafts of stem cell-derived cardiomyocytes as a possible complementary treatment to traditional surgical repair of cardiac defects. Their goal was to directly support ventricular function and overall healing.

“There is a great need for alternative treatments of this condition,” says Jodi Scholz, the study’s lead author and chair of Comparative Medicine at Mayo Clinic. “Stem cell treatments could someday delay or even prevent the need for heart transplants.”

The researchers transplanted clinical-grade human induced pluripotent stem cells — cells collected from human donors, coaxed back into a stem cell state and then developed into cell types compatible with heart muscle — into rhesus macaque monkeys with surgically induced right ventricular pressure overload. The cells successfully integrated into the organization of the surrounding host myocardium, the muscular layer of the heart. The animals’ hearts and overall health were closely monitored throughout the process. The authors noted that episodes of ventricular tachycardia (an increased heart rate) occurred in five out of 16 animals receiving transplanted cells, with two monkeys presenting incessant tachycardia. These episodes resolved within 19 days.

“We delivered the cells to support existing cardiac tissue,” Emborg says. “Our goal with this particular study, as a precursor to human studies, was to make sure that the transplanted cells were safe and would successfully integrate with the organization of the surrounding tissue. We leveraged my team’s experience with stem cells and cardiac evaluation in Parkinson’s disease to assess this innovative therapeutic approach.”

The research proved the feasibility and safety of using stem cells in the first nonhuman primate model of right ventricular pressure overload. Macaques, in particular, have been critical to advancing stem cell therapies for heart disease, kidney disease, Parkinson’s disease, eye diseases and more.

“The demonstration of successful integration and maturation of the cells into a compromised heart is a promising step towards the clinical application for congenital heart defects,” Emborg says.

The research was supported by the Todd and Karen Wanek Family Program for Hypoplastic Left Heart Syndrome and National Institutes of Health Grant P51OD011106 to the Wisconsin National Primate Research Center.