Farmers help fund UW research on whey protein
MADISON ‒ Sometimes one discovery in science leads to another serendipitous discovery. The work of Dr. Denise Ney, Professor of Nutritional Sciences at the University of Wisconsin-Madison is such a case – and it has been made possible by a number of grants from dairy organizations, including funding from dairy farmers’ checkoff.
Several years ago, Ney and a team of colleagues set to work finding and developing whey products that could help people who suffer from a genetic condition called PKU. The inherited disorder doesn’t allow sufferers to process phenylalanine ‒ an amino acid which is found in most foods that contain protein.
A few years ago she and her team – boosted with funding from Wisconsin dairy farmers – were instrumental in utilizing something called glycomacropeptide (GMP) isolated from sweet cheese whey to create a diet for PKU sufferers that was more palatable.
The traditional “amino acid” foods that were developed for the PKU community were described as “smelling bad and tasting worse.”
People with PKU are discovered at birth through required newborn screenings. If babies with PKU are not fed a special diet they are at risk of developing intellectual disabilities, seizures and other serious health problems. One in 50 people carry one copy of the gene that leads to PKU; in Wisconsin four to six babies are born each year with the disorder. (Both the mother and the father must contribute one copy of the gene for their baby to have PKU.)
“The good news is that with treatment – a medical diet which is low in phenylalanine – these people can have pretty normal lives,” said Ney, who shared her findings at the 2023 Dairy Symposium. Without the special diet though, dangerous levels of phenylalanine build up in the body because PKU sufferers cannot metabolize that particular amino acid.
Creating a new diet
The problem in formulating that special diet is that most naturally occurring proteins contain phenylalanine – and avoiding it means that it’s difficult for people with PKU to get enough protein in their diet.
Before Ney and her UW team stepped in with their whey protein, the medical PKU diet was created with synthetic protein substitutes made from amino acids that those patients can metabolize. Because of the taste, smell and texture of the necessary diet, it has traditionally been difficult for people to adhere to this diet throughout their lives.
Back in the 1950s when this genetic mechanism was discovered, scientists went into mental institutions and found up to 20 percent of the patients tested positive for PKU. If those people had had the right diet, their mental disabilities could likely have been prevented, she said.
The Wisconsin connection with this inherited disorder is a strong one. Dr. Harry Waisman, a pediatrician at the UW-Madison in the 1960s treated PKU sufferers in Madison and testified before Congress, urging lawmakers to require the testing of newborns for PKU. The Waisman Center at the UW-Madison is named for him.
In 2003, Ney started to get questions from dietitians at the Waisman Center about improving the diet of their PKU patients. Research began to come together when Professor of Food Science Mark Etzel, PhD, came up with the idea of the GMP whey protein.
“It is the third most abundant protein in whey and Mark knew it didn’t contain any phenylalanine,” she said. “In fact, GMP is the only naturally occurring protein that in pure form is free of phenylalanine.” A grant was secured from the dairy industry to investigate further.
Their initial project zeroed in on a method of getting GMP out of cheese whey and that process was then patented by the Wisconsin Alumni Research Foundation (WARF) the entity which takes care of all the intellectual property generated on the campus.
Ney credits Waisman Center dietitian Sally Gleason, MS, RDN for rallying interest in the PKU community which led to the formation of a task force to develop the GMP diet. “It was just an idea and we needed some research,” says Ney.
In 2005, a National Institute of Health (NIH) grant allowed Ney to do a study of 11 people with PKU who were admitted to the hospital for the study. She also studied mice known to develop PKU because they have the same mutation that causes human PKU. She showed that these mice could grow on a GMP diet.
Research solves 'terrible problem'
Results of those experiments were favorable and led Ney to work on food development for PKU patients with food scientist Kathy Nelson at the Center for Dairy Research on the UW campus. Nelson came up with a number of foods that met the needs of the PKU community. Very quickly the whey-based PKU diet was licensed to a medical foods company which developed a number of GMP medical foods for the PKU community.
“I don’t think this project could have gone forward if it weren’t for the Center for Dairy Research. They told me it’s their mission to find new markets for milk. They were so nice and so enthusiastic about this novel project,” says Ney.
“I wanted to do research in nutrition that made a difference in people’s lives and this research solves a terrible problem for people with this disorder,” she told us.
Ney also credits the process of patenting and development through WARF. “At that time I didn’t realize the entrepreneurial part. A patent is the quickest way to get a discovery to the people it can help. I think I was very fortunate to be in Wisconsin when this idea came up.
“I’m pretty sure this couldn’t have happened anywhere else. We had all the pieces here on this campus – the Waisman Center, the medical school, the hospital with a clinical research unit, a professor who understood the applied nutritional biochemistry, food scientists and the Center for Dairy Research. How many places in the world have all of that and a culture that supports working across departmental lines to solve a problem?” she added.
Discovery on weight loss
While she and her colleagues were at work on finding a new way to supply nutritious food to those with PKU, Ney found something else. If further research can be done, it might lead to an even more widespread use of this whey protein in the general population.
A large study of mice that are known to develop PKU and control mice that don’t get the disorder, led to the discovery that even the control mice fed the GMP diet had bigger, stronger bones and more lean body mass compared to mice fed a normal casein diet. “In other words, a GMP diet in mice burns fat and builds bone and muscle and this effect was always more prominent in the females,” she said.
That led to the idea that people wouldn’t need to alter their whole diet like PKU patients do, but could possibly take a GMP supplement and still get the benefits, she said. The working theory as to how this mechanism works in the body is that the pre-biotic properties of the GMP affect the microbiome – the flora and fauna in the human gut – which in turn results in stronger bones and weight loss.
Burning fat, building bone
Her most recent research focuses on how GMP could potentially help burn fat and build bone, especially in overweight post-menopausal women. In that group, she explained, weight loss is usually accompanied by a loss a bone density. Her recent research also shows that GMP may work in women by promoting satiety, the feeling of being full, and by helping the colon’s microbiota by reducing inflammation.
Though the research has focused on women, Ney said that in the studies on mice, male animals also were found to build bone and lose weight. “It works in them too,” she said.
After the effect on mice was noted, a subsequent study with obese post-menopausal women was designed to assess how a GMP supplement – rather than a wholesale change of diet – would affect weight loss. There were 13 women in the study which involved visiting the Clinical Research Unit at the UW hospital five times for tests.
The study looked at how GMP affected the “feel-full” or satiety hormones in the women, their insulin, glucose and glucagon levels (it was thought that GMP would support hormonal control of glucose levels) and the composition of their gut microbiota. The latter was determined through fecal samples from the women.
First of all, the study determined that most of the women (12 of 13) enjoyed the GMP supplement, which was delivered through a milkshake-like drink. No one dropped out of the study and they reported that their gastro-intestinal comfort was good with the treatment and they preferred taking the shake twice daily (rather than three times.)
Ney says they found the GMP shake to be easy to prepare. It involved mixing GMP milk powder in water and provided 130 calories and 25 grams of protein.
Soy shakes were used as a baseline or control in the women. The research showed that they felt fuller on the GMP product compared to the soy. On days when the study subjects took the GMP supplement, their caloric intake from other foods went down, she noted.
From this study, Ney and her colleagues have concluded that a GMP nutritional supplement has potential for treating obesity. The GMP increased satiety hormone levels, improved the stability of glucose levels by reducing glucagon and increasing the insulin-to-glucagon ratio. It altered the gut microbiome. They would like to see further investigation of the anti-obesity effects of GMP supplements.
As a component of whey, GMP fits with what the food industry calls “Generally Recognized as Safe” or GRAS criterion and as a food ingredient it would not need any special or lengthy approval process from the Food and Drug Administration.
Ney recently presented the findings of her latest research on using GMP to promote weight loss to a technical symposium of the American Dairy Products Institute. She said the group was very interested in it because it shows potential for using a dairy product to help people lose weight.
Agropur is a leader in whey fragmentation and helped her with the GMP for her work. The Wisconsin Alumni Research Foundation holds the patents on GMP for women’s health.
One thing she noted is that GMP is abundant in whey. “It’s the third most abundant ingredient in whey. It’s not like a rare earth element. But the process to extract it is expensive,” she said. The process involves ion exchange – placing particles under an electric charge to separate them from the rest of the whey. For the weight-loss supplement, she said the purity of the product would not have to be as high as it is for the PKU product.
Waiting for development
Ney said that the GMP for women’s health project was carried forward by a grant from the Wisconsin-funded Dairy Innovation Hub but that it now needs a company to develop the product for general use by consumers.
“I think there’s enough evidence to interest a commercial partner in this,” she said. She feels confident that it should be possible to secure a grant to do a larger human trial.
The results of her recent study on women’s health and GMP has been peer-reviewed and approved for publication by the “Journal of Nutrition”. “In my world,” she said, “no one believes you unless you’re peer reviewed by a reputable journal.” That journal article on her research will be published shortly and is now available online for free.
For Ney, who has been at the UW for 37 years and plans to retire soon, the PKU diet and the potential development of the GMP for women’s health as a commercial product are important achievements. “It feels wonderful and reaffirming that the research I was doing was important. I knew it was all along.”
When it comes to the PKU diet, she notes that the standard of care for those patients has been changed internationally because of her work. “Everybody won – the PKU patients, WARF received royalties and three PhDs worked on this project and now they have key roles working to improve treatments for those with rare diseases,” she said.
One collaborator on the PKU study that led to the second discovery was Eric Yen, an associate professor who worked with the mice and noticed that the mice being fed GMP were burning fat. Another collaborator was Karen Hansen, MD, a bone specialist who helped analyze the effect the GMP had on bone density and was co-principal investigator for the women’s health study.
Ney was also very appreciative of the help her research project received from the Dairy Innovation Hub. “The Hub made this possible. I really want to give them credit. This wouldn’t have happened without the Dairy Innovation Hub,” she said.
As Ney tries to wind up her career with another significant achievement, she is struck by the fact that so much of her research has been helped along by dairy farmers and dairy research institutions. “My first grant was from the Wisconsin Milk Marketing Board (the state dairy promotion council that is now called Dairy Farmers of Wisconsin) and my last grant is from the dairy industry too.
“That feels good to me,” she said.
To read Ney's research online visit https://bit.ly/3OyNho3