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Of Mice and Men

From John Kopchick’s Mini-Mouse Come Giant Possibilities

At two years and nine months, a normal mouse (right) nears the end of its life expectancy, while John Kopchick’s Laron mouse, only half the size, is likely to live another year.

About 30 years ago, when John Kopchick was a new professor and researcher at Ohio University in Athens, he set out to create a more potent growth hormone, so young patients would need fewer injections to help them grow. “No one likes needles,” he reasoned.

Kopchick never found that more potent molecule, and to this day, those patients still require daily injections. What he and his team did discover was a molecule that inhibited, rather than promoted, growth. It was an unexpected find, but Kopchick knew it was significant.

That compound became the basis of a drug that in the last decade has helped people with a rare condition called acromegaly. Most often associated with the late professional wrestler Andre the Giant and some Guinness record holders for tallest man in the world, acromegaly leads to excess growth and early death if left untreated.

But more recently, the scientific community has begun looking at Kopchick’s drug for something more—its potential as a treatment for cancer and diabetes and as a means for prolonging life. And Kopchick never would have expected that.

With Kopchick, from left, are Savanna Lyda, undergraduate research fellow; Stephen Bell, lab technician; and Reetobrata Basu, postdoctoral fellow

Kopchick’s team at Ohio University’s Edison Biotechnology Institute researches growth hormone and how it affects diabetes, cancer, and aging. With Kopchick, from left, are Savanna Lyda, undergraduate research fellow; Stephen Bell, lab technician; and Reetobrata Basu, postdoctoral fellow. Photo by Keith Boyer

The son of a second-generation coal miner, Kopchick was born in Punxsutawney and moved with his family to Ernest and then to Indiana, where his father got a job in the receiving area of IUP’s Weyandt Hall. When he entered IUP as a history major, Kopchick initially spent little time in his father’s building, but that all changed after a basic biology class.

“How an egg and sperm come together as one cell, and in humans, nine months later, it’s 40 trillion cells with the same genetic material—it’s still a big question,” he said. “So that’s what got me into biology.”

In his new major, Kopchick took part-time jobs in Weyandt washing laboratory glassware, making media for cell cultures, and delivering packages for his dad. Because of similar research interests, he became friendly with many science faculty members en route to earning his BS in 1972 and his MS in ’75. As a master’s student, he did research under the guidance of Richard Hartline, a biochemist in the Chemistry Department. He was also a teaching assistant under Frank Baker and Frank Liegey and would sometimes spend the night in a sleeping bag in Baker’s office to get an early start on laboratory duties.

But come Friday at 4:00, Kopchick and his fellow “lab rats” would shut the books and start the party, which would last until 2:00 a.m. Sunday. “We studied hard, worked hard, and played hard,” he said. “I’ll never regret that, and I’m very proud of that.”

As an undergraduate, Kopchick helped start Chi Alpha Sigma fraternity. He also met the former Char Labay ’73, a special education major from Sagamore, whom he married in 1976. After teaching special-needs students for 15 years, Char Kopchick went on to get a master’s degree from Ohio University, where she is now assistant dean of students for campus involvement.

One afternoon in 1974, Kopchick and some of the other graduate students under Hartline accompanied the professor to a seminar in Morgantown, West Virginia. The lecture, about RNA tumor viruses, intrigued the students so much that after the session, they corralled the speaker, Ralph Arlinghaus of the University of Texas MD Anderson Cancer Center in Houston, and peppered him with questions. That encounter eventually led to Kopchick’s acceptance into the Virology-Biomedical Sciences PhD program at MD Anderson and the Graduate School of Biomedical Sciences, where Arlinghaus would serve as his advisor for more than four years.

Black an white photo of professional wrestler André “the Giant” Roussimoff comparing fists with heavyweight boxer Chuck Wepner in 1976

Acromegaly is often associated with professional wrestler André “the Giant” Roussimoff, right, who compared fists with heavyweight boxer Chuck Wepner in 1976. Roussimoff died in 1993 at age 46. Photo courtesy Marty Lederhandler/Associated Press

Under Arlinghaus, Kopchick studied viruses that cause leukemia and lymphomas—similar to what the world soon would know as human immunodeficiency virus, the cause of AIDS.

After earning his PhD in 1980, Kopchick continued his study of cancer-causing viruses during a postdoctoral fellowship at Roche Institute of Molecular Biology in Nutley, New Jersey. His doctoral and postdoctoral study of molecular aspects of viruses then paid off with a job at pharmaceutical giant Merck in nearby Rahway.

“The biotechnology revolution was just starting, and each pharmaceutical company wanted molecular biologists who knew how to study genes,” he said. “I was just in the right place at the right time.”

Merck’s molecular biologists were spread among many therapeutic areas, which left little room for anything else. “They wanted us to work 100 percent of our time on what they told us to do, and with the other 50 percent, we could do whatever we wanted, and Merck would support it,” Kopchick said. “You get the joke, right? But it wasn’t a joke—they were serious.”

It was in the other 50 percent of his time that Kopchick began studying growth hormone. He was amazed how one molecule could decrease fat and increase muscle and bone mass—two opposite physiological effects. “I knew it had to be important,” he said.

Meantime, Ohio University had recently started its Edison Biotechnology Institute, named for Ohio-born Thomas Edison, and it had a new, patented technology that allowed foreign genes to be inserted into mouse eggs to create transgenic mice. Interested in what Kopchick could do with growth hormone and this new technology, university officials approached him about a faculty position.

The extent of the offer was greater than Kopchick had initially realized. Funded by the state of Ohio’s Eminent Scholar program and the family of Milton and Lawrence Goll, this professorship would support—in perpetuity—Kopchick and three other positions, plus the cost of supplies.

“I was 36 years old, and I came in as a full professor with an endowed position,” he said. “I didn’t know how lucky and how prestigious and how important that whole thing was, because I had no academic experience.”

Soon after joining Ohio University’s Biological Science Department and becoming director of the Growth, Diabetes, and Obesity section of the Edison Biotechnology Institute, Kopchick began his search for a more potent growth hormone that would lead to his groundbreaking discovery.

In its early experiments, Kopchick’s team created mice that were twice the size of normal mice. But because of heart, liver, and kidney problems, they lived only half as long. So he set out to alter the growth hormone molecule to retain the growth but reduce the negative effects.

Making changes to the molecule under Kopchick’s direction, one graduate student, Wen Chen, created a small mouse instead of a giant one. Skeptical, Kopchick had him repeat the experiment several times. “He kept getting small mice, so I had to believe it,” Kopchick said.

They found that changing a single amino acid was responsible for making the molecule suppress growth rather than enhance it. In the body, this new molecule binds to the growth hormone receptor, thus blocking the actual growth hormone from binding to the receptor. Normally, that interaction would stimulate production of insulin-like growth factor 1 (IGF-1) and trigger growth, but Kopchick’s molecule kept that from happening.

John Kopchick and IUP students seated at desks in a classroom in Walsh Hall

John Kopchick returned to campus in March as a speaker for IUP’s Sigma Xi Science Inspires Series. Before his lecture, he discussed research opportunities with students in Walsh Hall. Photo by Keith Boyer

“When I was at Merck, we were taught that anything that inhibits may be of clinical value,” he said. He had also learned the importance of intellectual property and knew that, to get a patent, he needed to find a use for his compound.

Kopchick researched conditions that involve high levels of growth hormone and found acromegaly. A non-hereditary disease that affects about 40,000 people worldwide, acromegaly is caused by a tumor that makes the pituitary gland secrete too much growth hormone. Although it’s often associated with gigantism, people who develop the condition as adults don’t grow any taller but show other signs, such as more muscle, fluid retention, bigger teeth and jaws, and thicker skin.

“Those are the outward signs,” Kopchick said. “The inward signs are its negative effect on the heart, kidneys, and liver. Without treatment, these patients typically die within 10 years of diagnosis.”

Kopchick and Chen obtained a patent for the growth hormone antagonist in 1994. Still, Kopchick knew the compound would need a champion to make it to market, since developing a drug and meeting the requirements of the Food and Drug Administration would cost upward of $100 million.

When he approached pharmaceutical companies about licensing the compound, they turned him down. But by chance, Kopchick learned while working out with former Ohio University assistant football coach Joe Dean that a former player, Rick Hawkins, had gone into the business of developing drugs.

Hawkins and Kopchick formed Sensus, a small company that would produce the drug and conduct preclinical and clinical trials (tests on animals and people, respectively). Because the compound had a short half-life, it needed an additional technology, called pegylation, to make it an effective antagonist.

Sensus produced only enough of the drug for one set of clinical trials; fortunately, it proved effective and safe on its first run. “If the FDA would have said you have to redo this, our investors—who were in it for about $40 million at this point—wouldn’t have put more money in,” Kopchick said. “So, we were lucky.”

a package of the drug somavert

Somavert, a drug based on the compound Kopchick developed, is used to treat acromegaly, a rare condition that causes excess growth. Photo courtesy of John Kopchick

Swedish pharmaceutical company Pharmacia bought Sensus, and in 2003, the FDA approved the drug, pegvisomant for injection, sold under the brand name Somavert. Pfizer, which bought Pharmacia, began marketing the drug two years later.

Since that time, Somavert has generated about $160 million a year in worldwide sales. As the owner institution, Ohio University has received approximately $90 million in royalty income, and Kopchick and his co-inventor Chen, now a professor at Clemson, have also benefited.

The success has allowed Kopchick to do some great things in academics. He and his wife, Char, made a $2-million gift to Ohio University for the training of molecular biology graduate students. More recently, they gave $10.5 million to UT’s MD Anderson Cancer Center and Graduate School of Biomedical Sciences to fund fellowships for graduate and medical students and a research symposium—the same kinds of opportunities that helped him on his career path. The gift will also enable an IUP undergraduate to do a summer internship at MD Anderson.

A recipient of IUP’s Distinguished Alumni Award and an honorary doctorate, Kopchick has also played a key role on the IUP College of Natural Sciences and Mathematics advisory board, which has helped the college plan new and expanded academic programs and its forthcoming science building.

John Kopchick, Mat Buchman, Kevin Funk, and Alison Brittain standing with a display of mice in a laboratory

In three decades at Ohio University, Kopchick has involved hundreds of students in his growth hormone research. With him, from left, are Mat Buchman, Kevin Funk, and Alison Brittain. Photo by Keith Boyer

In spite of international awards, publications, and speaking engagements, Kopchick said the most rewarding part has been the drug’s effect on acromegaly patients. Ninety percent of patients treated with Somavert have seen improvement in their signs and symptoms. And Kopchick has received letters, e-mails, phone calls, and visits from some very appreciative patients.

“It doesn’t get any better than this,” he said. “I still get chills when patients come to my office and thank me for discovering a drug that makes them better.”

During pegvisomant’s 14-year journey to market—which Kopchick described as remarkably short—the Edison institute moved to a new home, Konneker Research Laboratories, on a part of Ohio University campus known as the Ridges. There, Kopchick’s research continued. The team found that pegvisomant had additional benefits beyond the treatment of acromegaly: It alleviated kidney problems in mice with Type 1 diabetes. Researchers elsewhere noted that it also slowed the growth of some forms of cancer.

Given those results, Kopchick wondered what the effect on diabetes and cancer would be if he could block all of the trillions of growth hormone receptors in the body—something even large amounts of the antagonist would have difficulty doing.

In the laboratory, he and graduate student Yihua Zhou disrupted the growth hormone receptor gene and inserted those cells into a mouse embryo. In 1997, the growth hormone receptor knockout mouse was born.

Half the size of a normal mouse, this mouse has nearly double the body fat—about 50 percent. Yet, it has a very low incidence of cancer and diabetes, a condition for which obesity is a risk factor. The dwarf mouse also has an average life span of three to three-and-a-half years—a full year longer than that of a normal mouse—and some have reached the age of five, making the “Laron mouse” the longest-lived mouse in the world.

Kopchick named the mouse after Zvi Laron, a 90-year-old pediatric endocrinologist in Israel who was the first to identify people with a type of dwarfism caused by a hereditary defect in the growth hormone receptor gene. Essentially, Kopchick created the same mutation in his mice. And like the mice, people with Laron syndrome are very short, have high body fat, and have almost no cases of diabetes or cancer.

Laron and Kopchick collaborated on a 2010 book, Laron Syndrome: From Man to Mouse, and each has used the other’s research to further his own findings. “There’s a really nice synergy, and we’re very good friends,” Kopchick said.

John Kopchick, his wife, Char, brother Bill, mother Kathryn, and sister-in-law Cindy pose together at a mexixan restaurant

John Kopchick and his wife, Char, in back, frequently return to Indiana to visit friends and family, including his brother Bill, mother Kathryn, and sister-in-law Cindy. Kopchick’s father, Peter, died in 1996. The family celebrated Kathryn Kopchick’s 92nd birthday in February at a Mexican restaurant in Wheeling. Photo courtesy John Kopchick

Their research was also included in a 2012 French documentary, Secrets of a Long Life, and has been part of an international discussion in the scientific community about the capability and ethics of using drugs and dietary interventions to prolong human life. Because it inhibits growth hormone and the production of IGF-1, Kopchick’s pegvisomant is believed to hold potential for slowing the aging process.

The drug’s future in the fight against cancer also remains to be seen.

“I don’t think it will ever be used to cure cancer, but if it slows it down, it could work in combination with chemotherapeutics—medications that kill cancer cells,” Kopchick said. “Still, human clinical trials need to be done, and we’re hoping that some pharmaceutical company will do that.”

While Kopchick gives some lectures for graduate students and for students in the Heritage College of Osteopathic Medicine, the focus of his teaching at Ohio University has been to involve hundreds of students—PhD, medical, master’s, and undergraduate—in his research on growth hormone and the antagonist.

Most recently, that research has involved the study of compounds from common and exotic plants—which one day may include cannabis—to see if they’ll yield new therapeutics for cancer, diabetes, and other conditions.

“I hope we find another compound that inhibits growth hormone action,” Kopchick said, “so we have another—perhaps even better—antagonist.” He added with a wink and a smile, “Who knows?”