Menu

UW–Madison Smart Restart: For information about fall semester instruction and campus operations, please visit smartrestart.wisc.edu. For COVID-19 news updates, see covid19.wisc.edu.

Fall 2020

Feature

Assistant scientist Sangita Murali works with a blood specimen from a patient with cystic fibrosis at the Huichuan Lai Lab in the Nutritional Sciences Building. Photo by Michael P. King

 

Medical student Alice Huang was dutifully taking notes during a lecture at the Mayo Clinic Alix School of Medicine when she snapped to attention. There on the projection screen, next to the title of a cystic fibrosis study, appeared a familiar name.

“That’s my mom!” she gasped to the student beside her. Alice’s mother happens to be Huichuan Lai MS’90, PhD’94, a renowned cystic fibrosis researcher and professor of nutritional sciences at CALS.

A couple of years later, Huichuan Lai’s younger daughter, Leslie Huang, a genetic counseling student, had her turn to beam with pride when her mother’s influential research turned up in her cystic fibrosis training at Mount Sinai in New York. Of all the ways to measure research impact, perhaps the most surreal is learning that your work is being taught to your children in professional training programs across the country.

“That’s when you know your work is being not just viewed but used to educate the next generation,” says Lai, who also has affiliated appointments in the pediatrics and population health sciences departments in the UW School of Medicine and Public Health.

After more than a quarter of a century studying cystic fibrosis (CF) and leading the largest prospective, longitudinal birth cohort study of the condition, Lai has made an undeniable impact on the field. Her work has illuminated the role of nutrition in the disease and its progression, changing the standard of care.

There is still no cure for CF, which afflicts more than 70,000 people worldwide. The complex hereditary disease, which makes it difficult for patients to breathe and absorb nutrients, can lead to deadly malnutrition, infections, diabetes, liver disease, and other complications. And while life expectancy has improved in recent decades, many patients with CF still die before their mid-30s. But earlier screening, new treatments, and research like Lai’s are making it easier to manage the disease and improve patients’ quality of life.

“Working in the field of cystic fibrosis is very rewarding,” says Lai, whose work is supported by the National Institutes of Health (NIH), the Cystic Fibrosis Foundation, and the Legacy of Angels Foundation. “One reason is that the Cystic Fibrosis Foundation bridges research and clinical practice, and they take the research findings and broadcast them to the community. With diabetes or other diseases, it might take years for new findings to make it into clinics. In CF, it can be within months. It’s very, very fast, and they work very hard to reduce the barrier between research and clinical practice.”

From Student to Professor at UW

It was the University of Wisconsin–Madison that sparked Lai’s interest in CF research. After she earned her undergraduate degree in health and nutrition at Taipei Medical College in Taiwan, Lai debated between Rutgers University and UW–Madison for graduate school. Her father, who had lived briefly in New York, lobbied for Rutgers.

Huichuan Lai, professor of nutritional sciences, walks through her neighborhood to deliver a blood specimen, recently analyzed in her lab, to the nearby UW Hospital and Clinics in Madison, Wis. Photo by Michael P. King

But then Lai’s phone rang. It was Denise Ney, Billings-Bascom Professor of Nutritional Sciences, with some questions about Lai’s application. The personal connection made UW even more appealing, and Ney would later become Lai’s Ph.D. mentor.

Lai didn’t stop with her Ph.D. She decided to become a registered dietitian (RD) — not because she intended to practice as an RD, but because she wanted to deepen her understanding of the clinical world. “That would allow me to meet clinicians and perhaps get involved in clinical nutrition research,” explains Lai, who later earned a master’s degree in biostatistics as well.

During her one-year internship for the RD program, she spent a rotation at the UW Pediatric Pulmonary Center. There she met Philip Farrell, the former dean of the UW School of Medicine and Public Health and a neonatologist and pediatric pulmonologist who has spent his career studying CF.

At the time, Farrell was conducting the largest pediatric research study since the polio vaccine field trials of the 1950s — a clinical trial that evaluated the potential benefits of newborn screening for CF, particularly in preventing malnutrition. It was thanks to Farrell’s work that Wisconsin (and eventually the rest of the country) started screening all newborns for CF.

Lai spent her postdoctoral fellowship in Farrell’s lab and continues to collaborate with him today. “We now always joke that I was on his grant before, and now he’s on my grant,” she says. “It’s a very fruitful collaboration.”

Toward Precision Nutrition

Before newborn screening, children with CF were diagnosed at an average age of 9 months — a point when many babies’ nutrition and growth had already suffered, and most mothers had stopped breastfeeding. But by 2011, most babies were diagnosed within the first two months of life, which made it possible to investigate an important question: What’s the best food for those babies? “It is the very first question that all CF physicians face in the clinic the first time they see a family with a newly diagnosed infant,” Lai says. “Moms will ask: ‘Can I continue to breastfeed?’ And physicians had no answer.”

That’s because there were no clinical standards for CF nutrition before Lai’s study. “In clinical practice, we typically wait and watch until growth falters,” she says. “But if you wait until growth falters, it’s basically too late.” And so the FIRST (Feeding Infants Right . . . from the STart) study was born.

Assistant scientist Sangita Murali prepares a blood specimen for analysis at the Huichuan Lai Lab. As part of the ongoing
FIRST study, Lai’s lab staff process and measure nutrient levels in breast milk, blood, and fecal samples. Photo by Michael P. King

Breast milk, which has immune-boosting properties, is usually considered the optimal nutrition for healthy babies. But the picture is more complicated for babies with CF, who have increased nutritional needs. Those infants have trouble absorbing breast milk’s essential fatty acids, which are vital for growth. Breast milk is also low in sodium, which can lead to electrolyte imbalance because babies with CF lose so much sodium through their sweat. In severe cases, babies can die because of low blood sodium levels, a condition called hyponatremic dehydration.

But before Lai could even begin recruiting her own research cohort, she needed data. “It wasn’t easy to launch this study,” she notes. She began by conducting a retrospective study using a 10-year cohort (1994-2003) generated from Wisconsin’s CF newborn screening program that was implemented after Farrell’s cohort (1985-1994) demonstrated unequivocal nutritional benefits of early diagnosis through newborn screening. She looked at differences in growth and lung infection rates in babies who were exclusively breastfed versus those who were fed formula.

That gave her enough data to design a longitudinal observational study, which earned NIH funding, for a new birth cohort (2012-17) that continues a decade later. While it’s not a randomized clinical trial, the observations of nearly 200 families who have chosen to breastfeed, use formula, or do a combination of both have led to interesting insights.

Lai had to wait until her youngest subject turned 2 in December 2019 to complete the data analysis from the primary end point of 2 years of age, and she plans to share her results at the North American Cystic Fibrosis Conference in October 2020. But her preliminary data show that babies who were exclusively breastfed for the first six months did not grow as well during their first year as babies who were exclusively formula-fed or who received a combination of the two. Lai found that babies who were exclusively breastfed were also deficient in iron, essential fatty acids, and vitamin D.

The impact on infection rates is less clear: She found no difference between the babies who were exclusively breastfed and those who were exclusively formula-fed, but babies who had both feeding types had higher rates of infection in the first year of life. “So that’s a puzzle,” she notes.

Because of poor growth, two-thirds of infants with CF are prescribed fortified, calorie-dense formula by six months of age, “and then they start to catch up,” Lai says. So Lai wondered whether she could predict which babies will need fortified feedings and which won’t. Babies typically grow rapidly during their first month of life, but Lai found that babies who lose more weight shortly after birth tend to have more severe CF symptoms. She believes those babies are the ones who would benefit most from earlier fortified feedings.

“Nutritional status and pulmonary status are so closely related,” she explains. “The better the nutritional status, the better the lung status.”

A Dedicated Team

To recruit patients, Lai’s lab works with pediatric CF centers in Madison, Milwaukee, Chicago, Indianapolis, Boston, and Salt Lake City. Recruitment is challenging because families must enroll within a baby’s first two months of life, and the study requires ongoing questionnaires, food diaries, and blood and fecal samples as a child grows.

While a high attrition rate is common for such studies, more than 90% of Lai’s patients have stuck with it. “We understand the burden of data collection on families, but we have a lot of families who are so dedicated,” says Lai, who keeps a photo collage of smiling kids and parents from the FIRST cohort on her computer.

FIRST study participant Veronica Brockwell undergoes a “multiple-breath washout” test, which measures her lung function, at American Family Children’s Hospital. Photo by Danielle Sander

Those families spur her relentless search for answers. For at least a decade, she regularly clocked 80-hour workweeks. “The complexity of a longitudinal study like this is that I can’t wait because these kids are growing,” she explains.

Now she’s down to 50 to 60 hours a week, but she’s just as motivated as ever. “She’ll often come down to the lab, and it’s usually to pilot some new idea or some new thought, and it’s like, when do you sleep?” says Taiya Bach Streiffer BS’05, a clinical RD who also serves as a research dietitian in Lai’s lab. “She’s always got something up her sleeve. She’s very dedicated to the research.”

The same could be said of Lai’s staff. It takes a lot of work to manage such a large national cohort: meeting with local families to go over the study; consulting with participating centers across the nation; updating a database that grows with every child’s weight check-in; and processing and measuring nutrient levels in breast milk, blood, and fecal samples. They also use chest CT scans to assess lung function and whole-genome sequencing to determine whether genetic differences could play a role in how patients respond to certain CF drugs.

“One of the biggest surprises for me was what a community effort CF research is,” notes Danielle Sander, another RD and research coordinator in Lai’s lab. “It’s not just the researchers and the families that we work with, which are of course the most important, but it’s also health care providers and the other registered dietitians and the respiratory therapists and the CT technologists. We coordinate with a lot of other people to make CF clinical research happen.”

Three undergraduate students also work in the lab, including two freshmen. “It’s a great opportunity for undergrads,” says Sangita Murali, an assistant scientist with the FIRST study. “They learn about the study and about the disease, and they learn how these big studies are handled. It’s a great mentoring experience for them.”

Questions Beget Questions

The first phase of the study focused on nutrition, growth, and lung disease outcomes over a baby’s first two years of life. Phase II extended the study to follow the children until age 6 and expanded to include more sensitive outcome measures, such as lung clearance index and chest CT.

And new research questions have emerged along the way. For example: Are there microbiome differences in children with CF, and could their mix of gut bacteria affect the relationship between breastfeeding and growth and immunity? To find answers, Lai added a gut microbiome substudy to compare children with CF with their siblings without the disease and found distinct differences in the bacterial mix between the two.

For another substudy, she examined how probiotics changed the microbiome profile and the effect on gastrointestinal symptoms and antibiotic therapy. She continues to study the effect of repeated antibiotic therapies on gut microbiome because children with CF have more infections that require antibiotics.

The CF field has also evolved over the life of the FIRST study. There are now four drugs, known as CFTR modulator therapies, which target the gene involved with the disease. Since 2012, the percentage of patients who are eligible for those therapies has grown from 5% to 90%, Lai notes.

CF symptoms stem from a malfunction in a protein that controls the movement of chloride throughout the body. When chloride gets trapped in cells, it leads to the production of sticky mucus that can hinder gastrointestinal and lung functions and trap bacteria, causing malnutrition and recurring respiratory infections. CFTR modulator therapies can lower a child’s abnormally high sweat chloride levels, reduce pancreatic insufficiency (low digestive enzymes), and preserve their respiratory functions. After treatment, patients may be able to reduce the dosage of pancreatic enzyme supplements that are needed to increase digestion and nutrient absorption.

The FIRST study will continue until at least 2025, but with new aims. “We want to study the postmodulator era — do those kids have better growth and disease outcomes?” Lai says. Treatment effectiveness varies, so she wants to see if there are patterns in the children who respond better to treatment. “The advantage of our study is that we have all that life history,” she explains. “I think this will be the most completely studied pediatric cohort in the history of CF.”

And it’s possible that Lai’s team will continue to follow these children into adolescence. “Phase III would be fascinating because they’re entering puberty, and that’s when many start to go into decline and when some start to develop CF-related diabetes,” Lai notes. There are many more questions to explore, “and a lot of the CF clinicians want to find out the answers,” she says.

Research for Better Lives

Lai is delighted that her work has gone beyond peer-reviewed journals to influence clinical practice. “I am most proud of bringing people from different disciplines together — dietitians and nutritionists, biostatisticians, and traditional medical clinicians,” she says. “I have elevated the status of dietitians and nutritionists in CF care because my research points out the importance of nutritional management, and you can only achieve good nutritional management if you have expert clinical dietitians and nutritionists on your team. And I have actually changed how providers monitor nutritional status. Now BMI [body mass index] and weight-for-length at the 50th percentile is universally used as a benchmark in the care of CF patients, and that was all because of my studies.”

Five-year-old Easton Kibbel, a participant in the FIRST study, has seen improvements in digestion and lung function since starting a new medication for treating cystic fibrosis in 2017. Photo courtesy of Dana Kibbel

Then there are the families at the heart of her work. Parents will email Lai after discovering her research online or come up to her at conferences to tell her how much her work has meant to them. “Your findings answered my question about why this is happening to my baby,” one mom told her.

Among the grateful families are the Kibbels of Waupun, Wisconsin. This is the first time the family has participated in a research study, but they didn’t hesitate to sign up after their son, Easton, was diagnosed with CF in 2014.

Thankfully, 5-year-old Easton is doing well, especially since he started one of the newer CF medications in 2017. “He’s super healthy. He’s pancreatic sufficient [produces enough digestive enzymes], so that makes it easier,” says Easton’s mom, Dana Kibbel. “His pulmonary function has significantly increased, and it’s a progressive disease, so for that number to increase every time we go to the clinic is pretty amazing.”

The Kibbels’ oldest son, Cooper, who does not have CF, participated in the sibling study. “He thinks it’s cool to be involved, too,” Kibbel says. And most recently, their newborn, Krew, was also diagnosed with CF, giving them yet another reason to support research like Lai’s.

“How far they’ve come with CF research doesn’t come from researching normal kids — it’s because these CF patients and families are stepping forward and wanting to be part of this,” Kibbel says. “So we decided that this is what we want to do for the future of CF.”

This article was posted in Fall 2020, Features, Health and Wellness, Named professorships and tagged , , , , , , , , , , , .