Research Stories

Blood Vessels in Your Brain Don’t All Act the Same

by Kim Krieger


Certain blood vessels in the brainstem constrict when blood vessels elsewhere in the body would dilate. And that contrary behavior is what keeps us breathing, according to a new paper by UConn researchers published in the journal eLife.

Neuroscientists studying the brainstem have historically focused on neurons, which are brain cells that send signals to one another and all over the body. Recently, neuroscientists have come to understand that astrocytes, cells once thought to simply provide structure to the brain, also release signaling molecules, which regulate neuron function. But until now, no one even considered the possibility that blood vessels may be similarly specialized.

For more than a century, doctors and scientists have known that blood vessels dilate when cellular waste products like carbon dioxide build up. Widening the vessels allows fresh blood to flush through, carrying in oxygen and washing away the acidic carbon dioxide. This has been shown to be true throughout the body, and is standard dogma in undergraduate physiology classes.

Neuroscientists have come to understand that astrocytes release signaling molecules that regulate neuron function. Until now, no one even considered the possibility that blood vessels may be similarly specialized.

UConn physiologist Dan Mulkey was teaching exactly that to undergraduates one day when he realized that it couldn’t possibly be true in the part of the brainstem he studies. The retrotrapezoid nucleus (RTN), a small region in the brainstem, controls breathing. Mulkey has shown in the past that RTN neurons respond to rising levels of carbon dioxide in brain tissue by stimulating the lungs to breathe. But if the blood vessels in the RTN dilated in response to rising carbon dioxide the same way blood vessels do everywhere else, it would wash out that all-important signal, preventing cells in the RTN from doing their job of driving us to breathe.

Mulkey’s team, primarily comprising UConn undergraduates, studied thin slices of brainstem and found that RTN blood vessels constricted when carbon dioxide levels rose. But blood vessels from slices of cortex (the wrinkled top part of the brain) dilated in response to high carbon dioxide, just like the rest of the body.

Mulkey guessed that astrocytes had something to do with the change in blood vessel behavior, and his hypothesis was proved right in the lab. The astrocytes in the RTN were behaving differently than astrocytes anywhere else in the body. When these brainstem astrocytes detected high levels of carbon dioxide, they released adenosine triphosphate signaling to the neurons and blood vessels that they should constrict.

“This is a big change in how we think about breathing,” Mulkey says.

A Path With Less Pain

Genetic Clues Show Which Breast Cancer Patients Are Prone to Post-Treatment Agony

By Kim Krieger

woman chooses between two marked paths


Sickness and pain go together. We think of them as a matched pair, a married couple. Pain signals sickness, sickness causes pain. But this is not always the case. Especially in early stage cancer, often there is no pain — until the patient is treated.

UConn Health researchers have discovered genetic clues that could eventually reveal which people might be vulnerable to post-treatment pain, they reported in the June issue of Biological Research for Nursing.

“We’ll hear women say ‘If I knew the pain would be this bad, I’d have rather died of breast cancer,’” says Erin Young, a UConn Health pain geneticist. Young and her research partners wondered: Can we really call such treatment a “cure”? It would be better if we could know in advance which patients might suffer from which treatments.

Young worked with data collected as part of a broader study involving nurse-scientist and director of UConn’s Center for Advancement in Managing Pain Angela Starkweather, neuroscientist Kyle Baumbauer, and colleagues at the University of Florida and Kyung Hee University in Seoul, South Korea. Young’s analysis found that common variants in two genes contribute to certain symptoms during and after chemotherapy treatment for breast cancer. The results could one day help patients, and their nurses and doctors, make informed treatment decisions and prepare for — or avoid — damage to patients’ quality of life.

The researchers looked at the genetics of 51 women with early-stage breast cancer who had no previous chemotherapy and no history of depression. The women rated their well-being both before and after treatment for cancer, reporting on their pain, anxiety, depression, fatigue, and sleep quality. Young and her colleagues then looked for connections between genes and symptoms.

Can we really call treatment a “cure”? It would be better if we could know in advance with patients might suffer from which treatments.

They looked at three genes in particular: NTRK1, NTRK2, and COMT. These genes are already associated with pain from other research. NTRK1 is connected to rapid-eye-movement sleep (dream sleep), and a specific variant is linked to pain insensitivity. NTRK2 is associated with the nervous system’s role in pain, fatigue, anxiety, and depression. And some common versions of COMT are linked to risks of developing certain painful conditions. The researchers also chose these genes because the variants associated with pain, fatigue, and other symptoms are fairly common, making it possible to get meaningful results from a sample size of just 51 people.

After the analysis, a couple results jumped out at them. Two of the genes, COMT and NTRK2, had significant correlations with pain, anxiety, fatigue, and sleep disturbance. The other gene didn’t.

“I always like having a yes/no answer — if we get some nos, then we know the analysis wasn’t just confirming what we wanted to see,” says Young.

Such a quick look at a small sample of cancer patients can’t give all the answers as to who is going to develop postoperative and post-chemotherapy pain. But what they did find is very suggestive. Some of the gene variants were associated with symptoms before surgery. For example, women with two copies of the A variant of COMT reported more anxiety than other women did. COMT was also linked with pain, both during and after cancer treatment: women with one variant of COMT reported more pain, while women with a different variant reported less.

Fatigue also seems to have a genetic component. Women with one copy of the T variant of NTRK2 reported more posttreatment fatigue than others, and women with two copies reported much more.

Surprisingly, the genes linked to various symptoms worked independently, and didn’t work together to increase overall pain and discomfort. In other words, they weren’t synergistic; they didn’t make each other worse.

The gene variants predicted pain and fatigue above and beyond any differences explained by treatment effects.

The genes’ effects were also independent of the type of treatment the women received; the 51 women followed a number of different types of treatments: different surgeries, different chemotherapies. The gene variants predicted pain and fatigue above and beyond any differences explained by treatment effects. Other experiments by other researchers have shown the COMT variants are connected to the development of skeletal muscle pain.

“So it’s not just our study but the entire literature that suggests COMT could be playing a role in how sensitive you are to many different types of pain,” says Young.

“We are focusing on how we can identify women who are at risk of experiencing persistent pain and fatigue, as these symptoms have the highest impact on reducing quality of life after treatment,” says Starkweather. “It’s a great example of how we can make progress toward the goal of personalized health care. The next piece of the puzzle is to identify the most effective symptom-management interventions based on the patient’s preferences and genetic information.”

Young, Starkweather, and their colleagues say further research, ideally looking at a person’s whole genome, is needed to refine the connections between genetic profiles and the risk of pain. With that knowledge, patients could work together with their care team to develop individualized symptom-management plans. Properly prepared patients would feel more control and less suffering. And perhaps the cure would no longer hurt worse than the disease.

Matching Medicine to the MS Patient

UConn Health researchers have discovered why drugs for an aggressive form of multiple sclerosis work in the lab but fail in real patients: Each primary progressive multiple sclerosis patient has uniquely defective stem cells, perhaps making the debilitating illness a prime candidate for precision medicine.

By Kim Krieger

Illustration by Katie Carey

illustration of stylized silhouettes holding their perfectly matched medication


At first, Christine Derwitsch thought she was just really out of shape. She and her husband had gone out for a hike. They went hiking often, but this time, by the summit of the first hill she had to sit down. Her legs were so heavy.

She laughed it off, saying she’d been spending too much time sitting at a desk. But over the next few months, walking became harder and harder. And gradually, Derwitsch realized something was wrong.

“I went on Facebook, and I looked at what I’d been able to do before — hiking, my sister’s wedding — and I couldn’t do that anymore. I thought, ‘This isn’t right.’”

It took her almost a year, but 29-year-old Derwitsch was finally referred to a neurologist at UConn Health, who diagnosed her with primary progressive multiple sclerosis (PPMS). It was a relief to finally understand what was happening to her legs, but the news wasn’t good; there were very few treatment options available.

Most cases of multiple sclerosis have a pattern of illness and then remission: symptoms flare up, then go away, then flare up again. There are effective drugs that help patients extend the periods of remission, and someone diagnosed with MS in his or her 20s may live comfortably for decades.

But PPMS is a different story.

“It’s a harder diagnosis to make because there are no attacks,” says Dr. Matthew Tremblay, Derwitsch’s neurologist at UConn Health, who specializes in treating MS.

And the same thing that makes PPMS harder to diagnose makes it harder to treat.

Most drugs for MS are designed to prevent relapses by suppressing the immune system. But PPMS patients don’t have relapses. To help them, a drug would need to help them regrow myelin, the insulation around our nerves that people with multiple sclerosis can’t reliably repair. Doctors seeking this kind of drug for PPMS keep chasing a mirage.

It’s like you bring in the National Guard to stop a riot, and [instead] they all sit down and start having lunch.

For PPMS, many researchers look for possible treatments among medications that have already been approved for other illnesses. That way they can go right from lab to patient if they show promise. And so far many medications have shown promise — in the lab. But no matter how well a compound works in the lab, it never seems to help many people in the clinic. It’s a conundrum that frustrates both doctors and patients.

But researchers at UConn Health now think they know why the drugs coming out of labs are duds. And they have an idea of how to fix it.

In a new study, UConn Health neuroscientist Stephen Crocker and his colleagues collected blood cells from patients with PPMS, as well as the patients’ siblings or spouses. Then in the lab, they “reprogrammed” the cells and turned them into neuroprogenitor stem cells.

Stem cells can turn into any type of cell in the body; neuroprogenitor stem cells are found only in the brain and specialize in turning into new brain and nerve tissue, such as the oligodendrocyte cells that re-myelinate nerves. These neuroprogenitor stem cells are known to protect the brain from injury, but this recent study was the first to ask whether these stem cells from someone with PPMS had the same ability to protect the brain as those from someone without the disease.


Christine Derwitsch

While primary progressive multiple sclerosis is harder to treat than typical MS, UConn Health researchers have found why drugs that work in the lab fail on real patients with PPMS, like Christine Derwitsch (pictured). Photo: Tina Encarnacion


To explore this question, the researchers first tried adding the stem cells to brain tissues in animals with damage similar to PPMS. Stem cells from the healthy relatives and spouses started repairing the damaged areas. But the PPMS stem cells didn’t do anything.

“It’s like you bring in the National Guard to stop a riot, and [instead] they all sit down and start having lunch,” Crocker says.

Crocker and his colleagues then tested how these stem cells were different by growing them in dishes in the lab. They collected the soup that the cells grew in, called conditioning media, and tested how this affected other cells grown in it afterward. The stem cells had left behind chemicals and proteins in the conditioned media, little messages that tell other cells that come later what they need to do.

Oligodendrocyte cells grown to maturity in media conditioned by healthy stem cells matured into nice, big oligodendrocytes with no problems. But the cells added to dishes conditioned by PPMS stem cells didn’t mature at all. Something about the neural stem cells from PPMS patients was messing up the young oligodendrocytes, leading them astray.

So members of Crocker’s research team next tested some drug candidates for PPMS and added them to the young oligodendrocytes. The drugs absolutely helped the young oligodendrocytes mature when they were growing in media conditioned by stem cells from healthy people. But the same drugs didn’t help the young oligodendrocytes when they were grown in media conditioned by diseased stem cells. In those cases, the cells responded differently every time.

As Tolstoy might have said, healthy stem cells are all alike, but stem cells with PPMS are all unhealthy in their own way. It might appear to be the same disease from the symptoms, but each patient’s PPMS seems to be caused by a different problem with that specific patient’s cells.

But that means that doctors may be able to screen drugs for brain repair on a patient-by-patient basis, Crocker says. He and his colleagues published their findings in the Feb. 1 issue of Experimental Neurology.

Tremblay has begun collaborating with Crocker as they plan the next steps to this research, looking to recruit patients for future studies.

And in the lab they’ve already found that some drugs that have been dismissed as ineffective when tested using more typical techniques may have the potential to work very well for certain PPMS patients — patients like Derwitsch.

Derwitsch hasn’t participated in the study yet, but it’s exactly patients like her who could benefit from this personalized approach.

In the meantime, she is staying mobile and positive. She credits Tremblay for getting her insurance to cover her treatment — he actually got on the phone with her insurance company, she says.

“Dr. Tremblay has so much knowledge about MS, but also a dedication and passion. Every time I have a question, he has an answer.”

Scientists Pave Path for Tackling Rare Cancers

An earlier study by Dr. Andrew Arnold (center) provided the basis for the new research on parathyroid carcinoma genes.

An earlier study by Dr. Andrew Arnold (center) provided the basis for the new research on parathyroid carcinoma genes.


An international team of scientists led by the UConn School of Medicine and Icahn School of Medicine at Mount Sinai sequenced a genome for an extremely rare form of cancer, demonstrating the utility of this approach in opening the door for therapy options for rare diseases that are neglected due to scarcity of patients or lack of resources.

The team’s findings were published by JCI Insight, a journal of the American Society for Clinical Investigation.

Leading genomic scientists from UConn, Mount Sinai, and other collaborating institutions performed exome sequencing on tumors and matched normal samples from 17 patients with parathyroid carcinoma, an ultra-rare form of cancer for which there is no effective treatment.

Researchers found several mutations in known cancer-related genes and pathways. This in-depth characterization provides a clear view of genetic mechanisms involved in parathyroid carcinoma and could lead to the first therapy options for patients.

The genetic variants identified in this study have been detected in other cancers and are the subject of ongoing “basket” trials, or clinical trials focused on specific mutations rather than the tissue where the cancer formed.

“This is the largest genomic sequencing study to date for this rare and deadly cancer, and we believe it serves as important validation for using this approach to uncover clinically relevant information in any number of neglected diseases,” said Rong Chen, senior author of the paper and assistant professor in the Department of Genetics and Genomic Sciences at Mount Sinai. “Genomic analysis is opening the doors to diseases that could never have been understood through traditional biomedical research because there simply aren’t enough patients to observe.”

Mount Sinai’s work built upon research by Dr. Andrew Arnold of UConn, published in the New England Journal of Medicine in 2003. In the earlier study, Arnold reported on the first gene discovered in non-familial parathyroid cancer.

“Some of the tumor-specific genomic vulnerabilities we found turn out to be shared with much more common cancers, so drugs already being developed for other cancers may prove valuable in parathyroid cancer,” said Arnold, the study’s co-leader, who serves as the Murray-Heilig Chair in Molecular Medicine, director of the Center for Molecular Medicine, and chief of endocrinology at UConn School of Medicine. “This offers new hope for our patients and serves as a model for approaching other rare and neglected diseases.”

The study was funded by the Icahn Institute of Genomics and Multiscale Biology at Mount Sinai and the Murray-Heilig Fund in Molecular Medicine at UConn School of Medicine through the UConn Foundation.

UConn Health research image of a parathyroid gland (darker) located on the thyroid gland (pink background) during a research experiment where scientists genetically engineered mouse models, knocking out the CDC73 gene to test if cancer would then develop.

UConn Health research image of a parathyroid gland (darker) located on the thyroid gland (pink background) during a research experiment where scientists genetically engineered mouse models, knocking out the CDC73 gene to test if cancer would then develop.

Aches, Age & Influenza:

What We Know About Flu-Induced Muscle Loss and How to Prevent It

By Kim Krieger

the Flu


Why does age impact flu-related muscle loss, and how can we prevent it? UConn Health researchers are on the case.

Muscle mystery

Most of us have seen it happen to a relative, friend, or patient. A formerly healthy senior gets a bad case of the flu. When they recover, they’re weak from muscle loss, sometimes permanently disabled. We don’t know exactly why the muscle loss happens, but UConn researchers are finding ways to prevent it.

It used to be that losing muscle was just a part of getting old. It’s considered normal aging. You can’t get a drug approved by the FDA to treat aging, because aging isn’t considered a disease. But influenza, the virus that causes the flu, is. If getting the flu speeds up muscle loss in seniors, then muscle loss is potentially preventable. But how could a virus that only infects the lungs cause muscle loss?

Wasting away

When immunologist Laura Haynes first came to UConn Health, she knew that when mice get the flu, they lose weight. In fact, that’s the way researchers can tell that a mouse has the virus. Some mice lose more, some less. Haynes’ work had previously shown that older mice with the flu not only get much sicker, but also lose more weight than younger mice. But as an immunologist, her research focused on how aging immune systems decline. Differences in weight loss were an afterthought. But when she sat down with Dr. George Kuchel, director of the UConn Center on Aging, they made the connection that weight loss might indicate future disability.

Haynes teamed up with kinesiologist Jenna Bartley to further investigate. They confirmed that a significant amount of the weight lost by mice infected with the flu was muscle. And older mice infected with influenza lost more muscle than younger mice, and continued to lose it over a longer period of time.

It’s really hard to improve elderly immune response. So if we can’t prevent them from getting the flu, maybe we could at least prevent muscle loss and future disability.

“In mice there are changes in gene expression in muscle during influenza infection. Genes that degrade muscle go up, genes that build muscle go down. But in young mice, the gene expression goes back to normal more quickly,” says Haynes. The older mice, on the other hand, had higher levels of inflammation, muscle wasting, and atrophy, and it all persisted longer.

Exacerbated muscle loss wasn’t the only problem experienced by the older mice recovering from the flu. They also moved less and took fewer, narrower steps. It was as if they had become frailer and more easily tired. Decreasing gait speed, or how fast someone walks, indicates increasing frailty in humans, and taking narrower steps also increases the risk of falling. [See ‘UConn Pilots Quick Gait-Speed Measurement’]

Haynes and Bartley’s research was the first that directly linked flu-induced inflammation in a controlled setting to muscle atrophy and functional impairment. It was published in the April 2016 issue of the journal Aging. But now that they knew flu really was causing muscle wasting, how could they stop it? Even yearly vaccination doesn’t provide 100-percent protection.

“It’s really hard to improve elderly immune response. So if we can’t prevent them from getting the flu, maybe we could at least prevent muscle loss and future disability,” says Bartley.

Stemming the tide

Haynes and Bartley suspected that influenza-induced inflammation was related to, and possibly the cause of, the destruction of muscle tissue in the elderly mice. They theorized that if they could stem the tide of inflammation in the body, they might prevent the muscle tissue from degrading so much. But there was a catch: inflammation helps mobilize the immune system. If you block inflammation totally, you block the body’s defense against the flu virus. So Haynes and Bartley needed a more subtle tool.

In mice there are changes in gene expression in muscle during influenza infection. Genes that degrade muscle go up, genes that build muscle go down. But in young mice, the gene expression goes back to normal more quickly.

The first drugs Bartley and Haynes found that might be good candidates are COX-2 inhibitors. They’re non-steroidal anti-inflammatories, like aspirin and ibuprofen, but COX-2 inhibitors are very specific. They block just one molecule in the body’s web of inflammatory responses. Other researchers have shown that COX-2 inhibitors can slow muscle wasting in cancer patients. And most importantly, COX-2 inhibitors don’t seem to block the body’s antiviral immune reaction.

Haynes and Bartley are currently testing the COX-2 inhibitors to see if they prevent muscle loss in geriatric mice after the flu. They’re also testing whether improving immune memory of the flu in mice — that is, vaccinating them — protects them against muscle wasting.

Their work is intriguing, but Kuchel cautions that adult humans are more complicated than lab mice.

“Factors that may contribute to an older individual becoming more vulnerable to losing muscle function during or after flu infection are complex but may include a sedentary lifestyle, slow walking speed at baseline, low muscle mass, poor nutrition, plus chronic inflammation as a result of any number of chronic infections, being frail, etc.,” he says.

Bartley and Haynes agree. They’re applying for more grant money to explore how COX-2 inhibitors interact with other factors such as exercise. And they hope to eventually test muscle-protection strategies in people. Because while influenza is one of the most common serious infections in the elderly, it probably isn’t alone in causing muscle wasting.

“We’re trying to establish the relationship between any infection and inflammation, and how it leads to muscle loss and disability,” says Bartley. “Overall, we’re trying to help people get better and stay stronger for longer.”

Free to Be Imperfect

For patients and their families who live with Glycogen Storage Disease, a new gene therapy nearing clinical trial at UConn Health will mean freedom from the constant countdown to the next dose of medication.

By Julie Bartucca
Photography by Peter Morenus

Alyssa Temkin, 11, takes a break during a basketball game

Alyssa Temkin, 11, takes a break during a basketball game to drink Tolerex, the special formula that keeps her blood sugar from crashing to dangerously low levels. Alyssa has Glycogen Storage Disease and must drink the formula every 90 minutes to stay alive. Photo: Peter Morenus


Imagine never being able to hit the snooze button or oversleep, never being able to cheat on your diet or fall asleep in front of the TV because it could mean life or death — for you, or worse, your child.

That’s what the 1 in 100,000 people worldwide with Glycogen Storage Disease (GSD), a genetic liver disorder — and their parents — live with every day.

Dr. David Weinstein, who in January moved his world-renowned GSD program from the University of Florida to UConn Health and Connecticut Children’s Medical Center, has dedicated his life to giving these families hope. Although a life-saving treatment was discovered in the 1970s — taking a cornstarch mixture every few hours — research had halted for decades after that. And today, patients are still slaves to the clock; the effects of cornstarch last only a few hours, and even an extended-release form has its pitfalls.

But soon, that could change. Weinstein and his team are on the verge of testing in a human clinical trial the first GSD gene therapy, which has worked for canines and mice with the illness.

For the patients and their families who live in a constant countdown to the next feeding, the new therapy would mean freedom. A normal life, where mistakes can be made. Where they no longer have to be perfect.

There was no research going on anywhere in the world in this disease. And if there’s no research, that means there’s no hope.

Fatal Mistakes

Healthy livers store excess sugar from food and release it into our bloodstreams when we need it, as processed sugar enzymes called glycogen. However, in the seven forms of GSD, the liver fails to break down glycogen into glucose, causing the body’s blood sugar levels to drop dangerously low, which can lead to seizure or death.

The discovery of cornstarch therapy was a huge turning point, but it wasn’t enough.

“The problem with this disease is that people need cornstarch every four hours. People have died because their parents overslept,” says Weinstein. One missed alarm and a patient could die. A malfunctioning piece of medical equipment could mean a dangerous seizure.

“One of the parents was giving a talk recently and said, ‘Do you know what it’s like to have to be perfect all the time?’” Weinstein says. “And that’s what these families live with. It’s extreme stress.”

Weinstein and his team have made great strides. GSD was once considered a childhood disease — this generation is the first to survive to adulthood. Now, patients are doctors, athletes, mothers — more than 50 babies have been born to mothers with GSD since the first in 2003. But they still live under constant pressure. The disease is relentless, unforgiving.

For the patients and their families who live in a constant countdown to the next feeding, the new therapy would mean freedom. A normal life, where mistakes can be made. Where they no longer have to be perfect.

The Temkin family of West Hartford knows all too well what can happen.

When Gayle and Steve Temkin brought baby Alyssa home from the hospital at three days old, Gayle knew something was wrong with her daughter. By the time they got to a hospital that night, Alyssa was in full liver and renal failure. Her sugars were undetectable. Without intervention, she wouldn’t survive an hour, doctors said.

It was six months, several hospitals, countless invasive tests, and second and third opinions before Alyssa was diagnosed with GSD at Mount Sinai Hospital in New York City.

Alyssa is now 11, a smiling, soft-spoken sixth-grader who enjoys playing sports, acts in plays, and is learning to play guitar and dance. She gets good grades and loves her friends. But every 90 minutes, every single day, she must check her blood sugar and drink Tolerex, a special formula that keeps her sugar up. Alyssa is the only known GSD patient who can’t tolerate cornstarch, and Tolerex doesn’t last as long, so the time between her feedings is even shorter than it is for most GSD patients.

While the Temkins do everything they can to make Alyssa’s life normal, there are constant reminders that it is anything but.

Gayle spends every day at Alyssa’s school. For years, she would go into the classroom to feed Alyssa, first through a feeding tube and, more recently, with a drinkable formula. This year, Alyssa has gained some freedom. An Apple Watch reminds her when it’s time to test her blood and drink, and she reports her sugar level to her mom via a walkie talkie. Gayle, a former social worker, stays close, just in case.

If Alyssa’s sugar gets too low, she doesn’t feel it. Unlike most people, GSD patients don’t feel shaky or get headaches when their sugar drops — at least not until it’s too late. By then, they could be moments from having a seizure.

In 2015, Alyssa suffered a near-fatal seizure after the pump that feeds her dextrose through the night failed. “There is nothing about this disease that’s forgiving,” says Gayle. “It doesn’t matter what regimen you’re on; it could be a bad batch of something — We think we’re doing everything right, and the pump malfunctions.”


Dr. David Weinstein, head of the Glycogen Storage Disease Program at UConn Health and Connecticut Children’s Medical Center, walks with Alyssa Temkin through the new clinic at Connecticut Children’s.

Dr. David Weinstein, head of the Glycogen Storage Disease Program at UConn Health and Connecticut Children’s Medical Center, walks with Alyssa Temkin through the new clinic at Connecticut Children’s. Weinstein has treated Alyssa since she was diagnosed with GSD at 6 months old. Her family and other Hartford-area philanthropists supported the move of Weinstein’s program from Florida to Connecticut. Photo: Peter Morenus


No Research, No Hope

Weinstein had no intention of dedicating his life to curing GSD. As a young physician at Boston Children’s Hospital specializing in sugar disorders in 1998, Weinstein was caring for just two patients with GSD when he was invited to a national conference of the Association for Glycogen Storage Disease.

“I showed up at this meeting and was shocked by what I saw,” he says. The conference started with a moment of silence and a reading of the names of all the children who had died from GSD that year. The research presented was decades old. And the only treatment option being discussed was liver transplantation to combat complications from the disorder.

“There was no research going on anywhere in the world in this disease,” Weinstein says. “And if there’s no research, that means there’s no hope.”

A conversation with a mother there changed the course of Weinstein’s life. Knowing no one at the conference, he sat down for lunch next to Kathy Dahlberg, who had one-year-old twin sons already on the liver transplant list. She told Weinstein how sick her children were, and that her only hope was that they’d live long enough to get their liver transplants.

“Over lunch at that conference, I decided that somebody had to care about these children. The children shouldn’t have to suffer just because it was a rare disease,” Weinstein says. “The world didn’t need another diabetes doctor. This is where I could make a difference.”


Gayle Temkin talks to her daughter Alyssa in a school stairwell.

Gayle Temkin talks to her daughter Alyssa in a school stairwell. Gayle attends school with Alyssa every day, waiting in a room off the main office for Alyssa to check in via walkie talkie every 90 minutes to report her blood sugar level and that she’s drunk her Tolerex. GSD patients don’t feel the signs of low sugar until they are moments from a seizure, so Gayle stays close around the clock. Photo: Peter Morenus


As soon as he returned to Boston, Weinstein shifted his research focus to GSD and built the program there before moving it to the University of Florida in 2005 in order to work with the veterinary program. He has successfully treated dogs with his gene therapy, turning a fatal disease into one where dogs born with GSD are thriving.

Today, Weinstein sees 500 patients from 49 states and 45 countries. With help from Alyssa’s Angel Fund — started by the Temkins when Alyssa was a baby — and other charities, he has established centers all over the world.

All the Way

In January, the GSD lab moved to UConn Health’s Farmington campus. At the same time, a clinical and research unit supported financially by the Temkins and other local philanthropists opened at Connecticut Children’s. Gayle Temkin, Alan Lazowski, and Barry Stein are the trustees for the Global Center for Glycogen Storage Disease, and through the new organization will continue to raise money to support Weinstein’s program. They are working to set up other forms of assistance for patients and their families, including a closet with free supplies at the clinic, and support programs for families once the clinical trials start.

Because GSD patients are now surviving well into adulthood, the partnership between the two institutions makes great sense. “We’re much stronger working together,” Weinstein says.

Although Weinstein is the only doctor in the world dedicated to curing GSD, he says he’s not doing it alone — far from it.

“I’ve never seen a program like ours. I only do one disease. Everybody on my team does just one disease,” he says. “This is personal. Most people have a connection to the condition, and so they’ll work until everything’s done. It’s just a dedication that I’ve never experienced anyplace else.”

The bulk of Weinstein’s Florida team came to Connecticut with him. His team includes GSD patients and parents, including several who have called him out of the blue to tell him all they want is to work with him. One, who moved to Connecticut from Minnesota to join the new center, is Kathy Dahlberg, the mother who changed Weinstein’s course all those years ago. Her twins are now sophomores in college.

And, after nearly two decades of dedicated research, Weinstein’s next step is the one he’s been working toward all along. Human safety trials of his gene therapy, in conjunction with Dimension Therapeutics out of Cambridge, Mass., are expected to start this year. UConn will coordinate the trials with collaborating centers all over the world. Full-treatment trials should start in 2020.

The ultimate goal for the gene therapy, according to Weinstein,
is to prevent low blood sugars, eliminate the dependence on cornstarch, and give patients normal lives where oversleeping isn’t the worst-case scenario.

“If we can accomplish that, we’ve come all the way,” he says.

“The cure is right at our fingertips. He knew he could do this,” says Gayle. “When we first brought Alyssa to him, he said, ‘By her Bat Mitzvah, by the time she’s 12 or 13, we should be able to cure her.’ And she’s 11.

“We’re almost there.”

Size Matters for Particles in Bloodstream

UConn Engineering Professor’s Findings Could Mean More Effective Cancer Drugs

UConn researchers used a fluorescence microscope to illuminate a microfluidic device that simulates a blood vessel to observe and measure how particles of different sizes behave in the bloodstream.

UConn researchers used a fluorescence microscope to illuminate a microfluidic device that simulates a blood vessel to observe and measure how particles of different sizes behave in the bloodstream. Their findings could aid the development of more effective cancer drugs. Photo: Anson Ma


A UConn engineering professor has uncovered new information about how particles behave in our bloodstream, an important advancement that could help pharmaceutical scientists develop more effective cancer drugs.

Making sure cancer medications reach the leaky blood vessels surrounding most tumor sites is a critical aspect of treatment and drug delivery. While surface chemistry, molecular interactions, and other factors come into play once drug-carrying particles arrive at a tumor, therapeutic medication doesn’t do much good if it never reaches its intended target.

Anson Ma, assistant professor of chemical and biomolecular engineering, used a microfluidic channel device to observe, track, and measure how individual particles behaved in a simulated blood vessel.

Ma says he wanted to learn more about the physics influencing a particle’s behavior as it travels in human blood, and to determine which particle size might be the most effective for delivering drugs to their targets. His experimental findings mark the first time such quantitative data has been gathered. The study appeared in the Oct. 4, 2016 issue of the Biophysical Journal.

Using a fluorescence microscope, Ma was able to see particles moving in the simulated blood vessel in what could be described as a vascular “Running of the Bulls.” Red blood cells race through the middle of the channel as the particles — highlighted under the fluorescent light — get carried along in the rush, bumping and bouncing off the blood cells until they are pushed to open spaces, called the cell-free layer, along the vessel’s walls.

What Ma found was that larger particles — the optimum size appeared to be about 2 microns — were most likely to get pushed closer to the blood vessel wall, where their chances of carrying medication into a tumor site are greatest. The research team also determined that 2 microns was the largest size that should be used if particles are going to have any chance of going through the leaky blood vessel walls into the tumor site.

Knowing how particles behave in our circulatory system should help improve targeted drug delivery, reducing the toxic side effects caused by potent cancer drugs missing their target and impacting the body’s healthy tissue.

“When it comes to using particles for the delivery of cancer drugs, size matters,” Ma says. “When you have a bigger particle, the chance of it bumping into blood cells is much higher, there are a lot more collisions, and they tend to get pushed to the blood vessel walls.”

The results were somewhat surprising. In preparing their hypothesis, the research team estimated that smaller particles were probably the most effective since they would move the most in collisions with blood cells, much like what happens when a small ball bounces off a larger one. But just the opposite proved true. The smaller particles appeared to skirt through the mass of moving blood cells and were less likely to experience the “trampoline” effect and get bounced to the cell-free layer, says Ma.

Ma proposed the study after talking to a UConn pharmaceutical scientist about drug development at a campus event five years ago.

“We had a great conversation about how drugs are made and then I asked, ‘But how can you be sure where the particles go?’” Ma recalls, laughing. “I’m an engineer. That’s how we think. I was curious. This was an engineering question. So I said, ‘Let’s write a proposal!’”

The proposal was funded by the National Science Foundation’s Early-concept Grants for Exploratory Research, or EAGER, program, which supports exploratory work in its early stages on untested, but potentially transformative, research ideas or approaches.

Knowing how particles behave in our circulatory system should help improve targeted drug delivery, Ma says, which in turn will further reduce the toxic side effects caused by potent cancer drugs missing their target and impacting the body’s healthy tissue.

The findings were particularly meaningful for Ma, who lost two of his grandparents to cancer and who has long wanted to contribute to cancer research in a meaningful way as an engineer.

The results may also be beneficial in bioimaging, where scientists and doctors want to keep particles circulating in the bloodstream long enough for imaging to occur. In that case, smaller particles would be better, says Ma.

Moving forward, Ma would like to explore other aspects of particle flow in the circulatory system, including how particles behave when they pass through a constricted area, such as from a blood vessel to a capillary. Capillaries are only about 7 microns in diameter. The average human hair is 100 microns.

“We have all of this complex geometry in our bodies,” says Ma. “Most people just assume there is no impact when a particle moves from a bigger channel to a smaller channel because they haven’t quantified it. Our plan is to do some experiments to look at this more carefully, building on the work that we just published.”

Ventilator-Associated Pneumonia Still a Concern, Study Says

mask holds oxygen mask to face


Contrary to data published by the Centers for Disease Control and Prevention, ventilator-associated pneumonia rates in hospital intensive care units have not declined significantly since 2005, according to a new study out of the UConn School of Medicine.

The study, published in the Journal of the American Medical Association, found that about 10 percent of critically ill patients placed on a ventilator develop ventilator-associated pneumonia (VAP). The finding is based on reviews of charts from hospitals across the country from 2005-2013.

“VAP is not going away; it still affects approximately one in 10 ventilated patients,” says the study’s lead author, Dr. Mark L. Metersky of UConn Health’s Division of Pulmonary and Critical Care Medicine. “Our findings are in stark contrast to the CDC’s report of a marked decline in VAP rates that had some believing it may no longer be an important problem.”

Researchers reviewed data compiled by the Medicare Patient Safety Monitoring System from a representative sampling of 1,856 critically ill Medicare patients, ages 65 and older, who needed two or more days of mechanical ventilation.

While the VAP rates were stable throughout that time, the rates did not correlate with the CDC’s National Healthcare Safety Network reported rates, which suggest declining rates between 2006 and 2012 in both medical and surgical ICUs. The rate of VAP is one of the metrics for patient safety and health care delivery quality that many hospitals are scored on nationally.

VAP is not going away … Our findings are in stark contrast to the CDC’s report of a marked decline in VAP rates that had some believing it may no longer be an important problem.

Patients in need of mechanical ventilation are often the most critically ill in a medical or surgical ICU hospital setting. Research has shown that up to 15 percent of patients who get it may die from VAP.
The study authors examined the prevalence of VAP in patients on a ventilator following a heart attack,
heart failure, pneumonia, or major surgery. These types of patients are at higher risk for developing pneumonia, a bacterial infection, due to the need for a tube extending down their throat and into their lungs to help them breathe.

“We have not beaten this,” says Metersky. “Current hospital interventions that are used in an attempt to prevent VAP are not working. VAP is still a significant issue, and needs more examination into how we survey its occurrence and report it, along with more research into how best to prevent this type of pneumonia in vulnerable patient populations.”

The higher-than-expected VAP rates may be leading patients to experience complications or death from their lung infection or spend more time on a ventilator or in the ICU, slowing recovery. It may also increase use of antibiotics, leading to potential resistance, and increase health care costs due to longer hospital stays.

Metersky collaborated on the study with colleagues at Qualidigm, Harvard Medical School, and Harvard School of Public Health. It was supported by the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services.

Predicting Colon Cancer:

UConn Health Researchers Redefine ‘Early Detection’

By Chris DeFrancesco

Illustration of colon with areas highlighted and given warning signs


Find cancer early enough and you can treat it. Predict it before it develops and you can prevent it altogether.

Thanks to volumes of epidemiological data they have amassed, UConn Health researchers believe they are closing in on ways to identify who’s most at risk for colorectal cancer by analyzing cells from lesions that, if they are to become cancerous, are years away from doing so.

Once this can be figured out, doctors and patients would have a larger window of time to take steps to stop the cancer before it starts.

In the laboratory of Daniel W. Rosenberg in UConn Health’s Center for Molecular Medicine, concurrent studies — epidemiological, genomic, and molecular — are ongoing and are expected to yield a series of published papers this year and next. One, which describes how the Rosenberg lab uncovered evidence of the origins of colorectal cancer that historically have been poorly understood, was published in the June edition of Molecular Cancer Research, a major scientific journal of the American Association for Cancer Research.

We believe identifying early molecular changes may uncover new targets that could be used for preventing early neoplasia from progressing.

Cancer evolves from what is known as neoplasia — or new, abnormal growth of tissue. Not all neoplasias become malignant tumors, but they are considered an early warning sign of possible cancer.

“Understanding early neoplasia has become such a major focus at the National Cancer Institute — how do we characterize these early changes so we can prevent cancer,” says Rosenberg, HealthNet Inc. Endowed Chair in Cancer Biology and professor of medicine, “and I believe we’re at the forefront of answering this question.”

MD/Ph.D. candidate Allen Mo, first author on the Molecular Cancer Research paper, says colon cancer is thought to be an epithelial disease, meaning that it starts with a mutation in the tissue that lines the surface of the colon (the epithelium), and grows and then invades the underlying support tissue.

“People historically believed these are separate compartments, that there is no interaction between the epithelium and the support tissue until the cells become cancerous and break through the membrane,” Mo says. “We’ve been able to demonstrate that, even at the very early stage, prior to the polyp stage, the supportive tissue is actually influencing how these epithelial initiate cells are evolving.”

That’s important because it provides another potential early intervention point — if scientists can figure out a reliable way to make alterations to the signaling pathways between the two tissue types, perhaps they could influence how the mutated cells progress.

The Devers Data

The work includes collaborators from both within and outside the institution, but central to all of it is Dr. Thomas Devers, a UConn Health gastroenterologist whose volume of consecutive colonoscopies over the past five-and-a-half years has yielded data from 5,000 patients. The resulting demographic database has been powering the engine driving the research that has helped substantiate epidemiological findings, such as how smoking completely cancels the protective properties of aspirin, how consumption of diets rich in Omega-3 fatty acids appear to reduce risk of early neoplasia in the colon, and how walnuts may have protective properties, as described in a study recently published in Cancer Prevention Research.

“Dr. Devers routinely screens patients at a resolution that only a handful of clinicians are doing,” Rosenberg says.

Devers uses a high-definition endoscope with contrast dye-spray that enables him to detect tiny — less than 5 mm — lesions that are scattered throughout the colon.

“Many of the subjects have already returned for follow-up [surveillance] colonoscopy, so we actually have genomic data from three and five years ago that we can use to predict the possibility they may develop advanced adenomas or even cancer,” Rosenberg says. “We’re actually at the point now where we can follow the impact of these early changes over time.”

The work involves the intensive application of bioinformatics, the collection and analysis of complex biochemical and biological information.

What the Earliest Changes Can Reveal

Among the tiny lesions of particular interest are those known as aberrant crypt foci (ACF), which represent the earliest detectable precancerous change in the human colon. ACF tend to be detected less frequently during conventional colonoscopy, occur throughout the colon, and are the source of tissue that the Rosenberg lab uses for many of its analyses.

“We’re one of the only places in the country that actually look for these very early lesions,” says Mo, whose work has been instrumental to a number of ongoing studies in the Rosenberg lab.

“Most people study colon cancer development in the context of polyps as the earliest lesion,” Rosenberg says. “But we’re going one step earlier, with our focus on ACF. ACF present a unique opportunity to study the risk factors that may predispose the development of colon neoplasia, and may help to guide us toward potential interventions that may actually eliminate neoplasia prior to the appearance of polyps.”

Devers says the ACF he’s been finding in one particular area of the colon can be very telling when it comes to predicting future cancer risk.

“Part of our hypothesis is, we’re going to find these tiny lesions on the right side of the colon that have a lot meaning, that are only present in a small percentage of the population compared to the people who have tiny lesions in the rectosigmoid (the lower part of the colon), which everybody has,” Devers says. “And by finding these tiny lesions in the right side of the colon, you may want to screen those people more frequently.”

Biopsies and data from about 300 patient research volunteers have been the basis of several studies, including a collaboration with scientists at the Van Andel Institute in Grand Rapids, Mich., and The City of Hope in Duarte, Calif.

“We’ve done a complete genome-wide analysis of the epigenetic changes present within these tiny lesions, something that has never been done before,” Rosenberg says. “We’re uncovering all these interesting changes that occur to a person’s epigenetic profile years before they may develop a more advanced neoplasia. Much of this transformative epigenetic work was been performed by Matthew Hanley, a fifth-year graduate fellow in my lab. The question is, why we are interested in this ‘predictive’ profile? We believe identifying early molecular changes may uncover new targets that could be used for preventing early neoplasia from progressing.”

Often Hidden, Likely Telling

Another finding: some people seem to have a higher likelihood of forming what are known as sessile serrated adenomas (SSA) in the upper part of their colon. SSA, which also tend to be harder to detect, carry a strong likelihood of progressing, and may contribute to 20 to 30 percent of colorectal cancers.

“We believe that missed right colon cancers, or interval colon cancers, are related to these serrated adenomas,” Devers says.

SSA are larger than ACF but are also very difficult to catch during colonoscopy because of their flat shape and their tendency to be camouflaged in mucus along the colon wall. It takes a high-definition scope and experience — Devers has both — to find them.

“We’re able to actually identify thepeople who form this lesion, then go back to the epidemiological database and develop risk profiles as to which people are more likely to form that type of lesion,” Rosenberg says.

On the molecular level, Rosenberg’s lab routinely uses laser capture microdissection, which enables scientists to select and retrieve small groups of cells from a single biopsy. From there, they can apply genomic technologies to particular cells and screen for cancer-related mutations and genome-wide alterations. This technique was used in the research behind the Molecular Cancer Research paper.

“Early neoplasia has become a very hot area, and because of Dr. Devers, here we probably have accumulated the largest repository of human early neoplastic lesions anywhere in the world,” Rosenberg says. “With this amazing resource, we can now begin to define many of the key changes that are happening at this very early stage. It’s never been done before.”

Tell-Tale Heart

‘Heart-In-A-Dish’ Sheds Light on Heart Disease Genetics

By Nicole Davis for The Jackson Laboratory for Genomic Medicine
Photography by Peter Morenus

Dr. Travis Hinson holds petri dishes containing beating heart tissue

Dr. J. Travis Hinson is seen holding petri dishes that contain heart cells. Hinson, a joint faculty appointment at UConn Health and The Jackson Laboratory for Genomic Medicine, has pioneered a system to study the genetics of heart failure by recreating beating heart tissue using patients’ stem cells. Photo: Peter Morenus


When a patient shows symptoms of cancer, a biopsy is taken. Scientists study the tissue, examining it under a microscope to determine exactly what’s going on.

But the same can’t be done for heart disease, the leading cause of death among Americans. Until now.

Dr. J. Travis Hinson, a physician-scientist who joined the faculties of UConn Health and The Jackson Laboratory for Genomic Medicine (JAX) in January, uses a novel system he pioneered to study heart tissue.

Hinson engineers heart-like structures with cells containing specific genetic mutations in order to study the genetics of cardiomyopathies, the diseases of the heart muscle that can lead to heart failure and, ultimately, death.

“We basically try to rebuild a little piece of a patient’s heart in a dish,” says Hinson, who developed the technique during his postdoctoral fellowship.
He combines cardiac muscle cells with support cells, such as fibroblasts, and other key factors, including extracellular matrix proteins. Although these tiny, three-dimensional structures do not pump blood, they do contract rhythmically, and their beating strength can be studied.

Making a Difference

Hinson is applauded for his ability to move seamlessly between research, clinical practice, and teaching — the three prongs of an academic medical center’s mission. He’s able to do so, perhaps, because his own career began at the intersection of multiple scientific specialties.

As a University of Pennsylvania undergraduate, Hinson interned at DuPont in New Jersey to explore interests in chemistry and engineering. But he soon realized his passion for science needed a real-word focus. “I wanted to do science that made a difference in people’s health,” he says.

The same summer, he volunteered in the emergency department of a local hospital. Impressed by a cardiologist’s calm and collected manner in a crisis, and gaining interest in the heart, Hinson changed his career trajectory from engineering to medical school.

Hinson and his colleagues can isolate skin or blood cells directly from cardiomyopathy patients and coax them to form heart muscle cells, making it possible to study the biological effects of patients’ own mutations.

Hinson joined the laboratory of Dr. Robert J. Levy, a pediatric cardiologist and researcher at The Children’s Hospital of Philadelphia, working to harness gene therapy techniques to make artificial heart valves and other cardiovascular devices more durable. Through this early foray into biomedical research, Hinson deepened his interest in biomedical science and gained an appreciation of the work of a physician-scientist.

In Dr. Christine Seidman’s lab at Harvard Medical School, Hinson chose to lead a project on Björnstad syndrome, a rare, inherited syndrome characterized by hearing loss and twisted, brittle hair. At the time, little was known about the molecular causes of the disorder, although the genetic culprits were thought to reside within a large swath of chromosome 2. Using genetic mapping techniques and DNA sequencing, Hinson homed in on the precise mutations.

In addition to casting light on disease biology, he glimpsed the power of genomic information. “I was fascinated by the potential for understanding new genes that cause human diseases, and how important that was to society,” Hinson says.

Matters of the Heart

Throughout his medical training, Hinson noticed there were some significant stumbling blocks to gathering a deep knowledge of heart disease, particularly cardiomyopathies.

Cardiac muscle has essentially two paths toward dysfunction and ultimate failure. It can either dilate — become abnormally large and distended — or it can thicken. Both routes severely impair how well the heart performs as a pump. These conditions, known as dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), can stem from pre-existing disorders of the heart, such as a previous heart attack or long-standing hypertension, or from DNA mutations.

Fueled by advances in genomics over the last two decades, more than 40 genes have been identified that underlie cardiomyopathy. But unlike diseases such as cystic fibrosis or sickle cell anemia, where it is fairly common for affected individuals from different families to carry the exact same genetic typo, it is exceedingly rare for unrelated patients with cardiomyopathy to share the same mutation. With such a complex genetic architecture, figuring out how the different genes and gene mutations contribute to heart disease has been an enormous challenge.


Dr. Travis Hinson speaks with others in his lab

Above: Dr. J. Travis Hinson gives a tour of his laboratory. Photo: Peter Morenus


Because of this formidable hurdle, drug discovery for the cardiomyopathies has languished. “There really has not been a paradigm-shifting drug developed for heart failure in the last 20 years,” says Hinson. Moreover, the few treatments that do exist are primarily aimed at controlling patients’ symptoms, not slowing or halting their disease.

Hinson aims to improve this picture. With his “heart-in-a-dish” technique, he and his team are now unraveling the effects of genetic mutations on cardiac biology.

The system harnesses multiple recent advances in both stem cell and genome editing technologies. With these capabilities, Hinson and his colleagues can isolate skin or blood cells directly from cardiomyopathy patients and coax them to form heart muscle cells, making it possible to study the biological effects of patients’ own mutations. Moreover, he can correct those mutations, or create additional ones, to further probe how genetic differences influence heart biology.

Part of the allure of Hinson’s approach is that it can be readily applied to study other forms of heart disease. It can also be leveraged for drug discovery, providing a platform to screen and test compounds with therapeutic potential in a wide range of cardiovascular diseases.

In addition to his research lab based at JAX, Hinson continues to practice cardiology at UConn Health. He helps run a specialized clinic focused on genetic forms of heart disease, as well as arrhythmias, connective tissue disorders, and other conditions.

“We have an exciting opportunity to provide clinical services in cardiac genetics in the corridor between New York and Boston,” he says. That means state-of-the-art genetic testing, including gene panels and genome sequencing, as well as genetic counseling for both patients and family members to help inform disease diagnosis and guide treatment. Although there are only a handful of treatments now available, Hinson believes this clinic will be uniquely poised to take advantage of a new generation of personalized treatments that are precisely tailored to patients’ specific gene mutations.

“Travis really is a quintessential physician-scientist,” says Dr. Bruce Liang, dean of UConn School of Medicine and director of the Pat and Jim Calhoun Cardiology Center at UConn Health.

“He has a remarkable ability to link basic science with important clinical problems, and his work holds a great deal of promise for developing new treatments for patients with cardiomyopathy. I wish there were two or three Travis Hinsons.”


Hinson’s beating heart tissue. Provided by Dr. Travis Hinson