Pioneering geneticist Merlin G. Butler, M.D., Ph.D., keeps pushing the boundaries of science
August 10, 2020
By Leilana McKindra
Merlin G. Butler, M.D., Ph.D., professor in the Department of Psychiatry and Behavioral Sciences at the University of Kansas Medical Center, is a self-described medical detective.
It's a less formal way of framing his incredibly complex work as a medical geneticist. That work involves examining a physical, mental or even behavioral problem and trying to pinpoint a genetic cause. His evidence field, the human genome, is massive - the average adult contains 200 trillion meters of DNA, or the equivalent of 55,000 trips to the moon and back - and the answer could be any one of 10,000 known genetic syndromes. Or, perhaps it's a new or emerging condition that hasn't been identified yet.
The good news is Butler is a Sherlock Holmes-level master at finding the illusive needle in a daunting genetic haystack, and he's spent his entire career expanding our understanding of genetics. Perhaps what stands out most is both the sheer volume and significance of his contributions, which include groundbreaking research into Prader-Willi syndrome, a genetic disorder that occurs in one out of every 15,000 births in the United States.
Though retirement has begun to beckon, Butler keeps a brisk pace. He still finds great meaning in his work and, well, there's more work to be done, especially as advances such as pharmacogenetics, the study of how people respond to different treatments based on their genetics, open up new fronts for exploration.
"In medicine, the concept is to identify a problem or disease, then develop a medication and write a prescription; this does not work in genetics as there is no drug that can fix broken DNA found in every cell. How do you fix a spelling error or gene mutation in 100 trillion cells in the body?" he asked. "Now the technology to identify small DNA or gene changes exists and mice or fish models are available to study genes causing human diseases. In the next 5 years or so, we may be able to fix the genetic damage in humans to lessen the impact of common and rare human genetic diseases. Our work has just begun, and we are opening up the very tip of the iceberg."
A genetics pioneer
If genetics is teetering on the edge of any major breakthroughs, then Butler has helped nudge the field to this precipice. With more than 500 published research articles and multiple textbooks to his name, his fingerprints are everywhere.
Over the course of nearly four decades, Butler has helped unravel some important genetic mysteries, many of which have propelled him into the pages of weighty research journals such as the New England Journal of Medicine and mainstream media outlets like The New York Times. For example, he was involved in early research on birth defects that led states and counties nationwide to modify the language used in warnings now attached to products such as cigarettes and hot tubs due to environmental exposures.
Butler's expertise is wide-ranging, though Prader-Willi, the most common genetic cause of life-threatening childhood obesity, has been a career-long research interest and clinical focus. In the early 1980s, he was the first to report the genetic cause of this syndrome, a chromosome 15 deletion, was donated by the father only. Later in the same decade, he teamed up with investigators from Harvard University using advanced DNA technology and determined about one-third of Prader-Willi cases were the result of maternal disomy 15, when a mother passes two copies of chromosome 15 to her child with Prader-Willi syndrome instead of one copy.
Before that barrier-breaking discovery, the disease was thought only to occur due to a deletion of a section of chromosome 15 from the father. In fact, the team was rebuffed when it initially tried to report its findings to one scientific journal and was forced to replicate its work because the phenomenon of having both copies of a chromosome from only one parent was thought impossible. Ultimately, the results lead to a new concept of genetic understanding and testing of theories based on those studies on how Prader-Willi syndrome could be transmitted, via a process called genomic imprinting, which implies that differences exist in gene activity depending on which parent contributed the chromosome. Prader-Willi syndrome became the first example of errors in genomic imprinting in humans and now imprinted genes are known to contribute to more than 100 different conditions and even malignancy.
Today, both maternal disomy and genomic imprinting are better understood, but at the time of discovery, the science was so revolutionary the team had to develop the terminology for it.
Butler also demonstrated that exposure to environmental hazards such as hydrocarbons could cause birth defects, primarily Prader-Willi, but others as well. Over the years, he has helped identify subtypes of the disease, which has led to more targeted treatment and care.
"He's been able to take this rare, very poorly understood disease and move it right into the front and center of science so now medicine can help treat it, which is remarkable," said Albert Poje, Ph.D., an associate professor of psychology in the Department of Psychiatry and Behavioral Sciences at KU Medical Center. "But, even if we were talking about something on a less grand scale, the fact that he discovered a new way genes are transmitted is remarkable. They said the same thing about Einstein when he discovered newer principles of physics. At the time, people said there's no way that can be true. It broke out of contemporary thought. Dr. Butler has done the same thing in the area of genetics."
Poje is among the legion of researchers Butler has mentored, trained and collaborated with throughout his career. The duo has worked on multiple research projects related to Prader-Willi and one of its prevailing characteristics called hyperphagia, the abnormal drive to eat. Specifically, Poje has studied the psychological aspects of the behavior and examined the effects of using transcranial direct-current stimulation to the brain to modify the behavior.
"The first thing you notice is he has huge volumes of knowledge about the subject. It's really kind of like drinking from a firehose. You realize this is somebody who has devoted his life to the study of a particular subject," Poje said. "I see Dr. Butler as a role model in that he is brilliant, he's hard-working and he's been so successful. He's also really true to the creed of a scientist and physician in that he wants to give back, see the field move forward and see humanity move forward, and there's a kindness to him. It's really awe-inspiring in that way."
Another colleague and frequent collaborator, Ann Manzardo, Ph.D., an associate professor in the Department of Psychiatry and Behavioral Sciences at KU Medical Center, credits Butler with helping to sharpen her productivity and efficiency as a scientist. She has been actively passing those lessons on to others.
"If you look back, there's such a small handful of people who were instrumental early in the field of genetics. He was involved in a lot of those discoveries," she said. "The main thing I've taken from him is how to be a more productive scientist and to not take no for an answer. It's having the confidence, and he has a lot of confidence in himself and passion for what he's doing."
That's a special human
That confidence and passion spills over into his care of his patients and their families, many of whom wait up to a year or longer for a consult. Referrals and inquiries come from all over the nation, including Mayo Clinic.
Lauren Lucht, Executive Director, Mental and Behavioral Health, The University of Kansas Health System, is confident Butler has built close relationships with and made a real difference in the lives of practically every family in Kansas, and the region, who has a child with Prader-Willi.
"The gene [for Prader-Willi] would not have been identified as early as it was without him. Finding the gene might have been enough for a lot of geneticists, but he's not stopping," she said. "He wants to find a way to make their lives better, not just make a diagnosis. That separates him from just a researcher to a researcher with a passion to solve a problem, not just identify a problem, and that's a special human."
Ahead of the times
Butler has been on this path since he was a child growing up on a ranch in the Sand Hills of rural Nebraska and attending class in a one-room country schoolhouse as one of five to seven students.
"Once a month the teacher would take us all to town to the library. I checked out a book on the discovery of insulin. I read that book and I still remember making a pledge to myself to become a medical researcher one day," he said. "I was in the fourth grade. I guess I was ahead of the times."
His quest led him to Chadron State College, where he became just the second person in his family to attend college. His initial plan to focus on biology was altered when his faculty mentor, Dr. Jack Rary, introduced him to genetics and its importance in human disorders and diseases.
"One of the first tests on the genetics of a course in biology during my freshman year under him, I received an 80%. I'd never gotten an 80% before in my life. I was like ‘what's going on?'" he said. "I decided I was going to master genetics, and I guess that was the triggering point."
Butler earned his medical degree at the University of Nebraska then completed his doctorate and a four-year postdoctoral training and fellowship in medical genetics at Indiana University. After rising to the rank of tenured associate professor at Vanderbilt University, he transitioned to Children's Mercy as section chief of medical genetics and molecular medicine. He also was a professor of pediatrics at the University of Missouri-Kansas City School of Medicine.
An innovative model
Butler joined the KU Medical Center faculty in 2008 as a professor in the departments of Psychiatry and Behavioral Sciences and Pediatrics. Medical geneticists are more commonly embedded in pediatrics or internal medicine departments, not psychiatry, because in the past, most prominent major genetic disorders were noted in childhood. But now there is greater awareness of genetics' role in different types of cancers, several major psychiatric disorders and intellectual ability. In adding Butler, William F. Gabrielli, Jr., M.D., Ph.D., chair of the Department of Psychiatry and Behavioral Sciences at KU Medical Center, took a novel approach to filling the department's need for a behavioral geneticist.
"Dr. Butler has helped us build out of nothing, essentially, a genetics presence," Gabrielli said. "We have an opportunity to grow upon that."
As Butler has built a sterling international reputation, countless achievements and distinctions accent his remarkable body of work. A founding fellow in the American College of Medical Genetics and chair of the scientific board of the Prader-Willi Syndrome Association (USA), he's served on several medical advisory board for various diseases and genetic journals and the National Institutes of Health sections.
In 2016, he was honored with the University of Kansas Chancellor's Club Research Award, which recognizes exceptional achievements that have had significant and long-term impact on a research field. Butler also earned the Distinguished Alumni Award from Indiana University and the Distinguished Service Award from Chadron State, which also named a scholarship and an applied chemistry research lab in his and his wife's honor in 2019.
"It's true he has the kind of drive that makes him good at what he does. He lives and breathes his work," Gabrielli said. "What sets someone apart in academic medicine is that they are unique. They have a combination of skills and special thinking in terms of standing out among the crowd. Dr. Butler has done that."