An Interview with Gregory Hageman, PhD
By William Sweet
A journey that started under the sea, initial studies into eyesight of aquatic creatures, has surfaced as a startling series of revelations that offer new hope for people with Age-related Macular Degeneration (AMD).“The knowledge we have gained over the past few years, as it relates to our understanding of the genetics and biology of AMD, has been nothing short of incredible,” said Gregory Hageman, professor of ophthalmology and visual sciences at the University of Iowa’s Carver College of Medicine.
Now in the midst of a $14.6 million National Institute of Health study of genetics and the immune system, Hageman first started out in research that required wearing fins rather than a lab coat.
“After graduating from the University of Southern California in 1983, I directed research at the marine biology station on Catalina Island off the coast of California for about six years. One area of research interest was the study of eye spots on bryozoans, tiny sea creatures that live in colonies, similar to that of coral.”
But life got between Dr. Hageman and the bryozoans.
“I married, and my wife tried to live out there, but it’s a pretty isolated place. And part of the truth was I needed to come back to reality. I became interested in the eye spots in those critters, and I told myself I thought the eye was a pretty neat system.”
This fascination, combined with an opportunity to join a group at the University of Southern California’s department of ophthalmology, resulted in what has becomea 20-year journey exploring vision loss. Knowing many people afflicted with AMD was also a significant factor in Dr. Hageman’s decision to focus specifically on this disease.
In 2005, researchers on Hageman’s team at the University of Iowa, collaborating with Columbia University and the National Cancer Institute, made headlines whenthey linked two genes, dubbed Complement Factor H and Complement Factor B, with the predisposition to develop AMD.
To explain how they reached this conclusion, Dr. Hageman relied on generous gifts of donor eyes to his research program. He reasoned that a better understanding of drusen – abnormal deposits that develop in the maculas of individuals with AMD — might lead to the identification of biological pathways and genes associated with AMD.
“People that don’t have the disease don’t have the deposits,” he said. Starting in 1988, “we went after the idea that if we could identify what these deposits were made from or where they came from, then that would tell us something about the pathways that were associated with the disease.”
About 15 years ago Dr. Hageman and his colleagues discovered that the drusen were full of proteins from the complement system, which is part of the immune system.
Activation of the complement system “creates some pretty ugly proteins that are meant to destroy bacteria, abnormal cells and things like that,” Dr. Hageman said. “But in a number of diseases, such as Alzheimer’s and multiple sclerosis, where that system is not controlled appropriately, it actually does as much damage to healthy cells and tissue in one’s own body as it does to bacteria and other organisms that it’s designed to kill. It was the observation that the complement was active in the back of the eye in individuals with AMD that really led us to find the first AMD-associated gene.”
Complement Factor H, or simply CFH, is a protein that controls the complement cascade. Variations in the CFH gene were discovered to associate very strongly and very significantly with the predilection for developing AMD. It was found in greater than 50 percent of a study group of people with the disease. “We’ve never seen this kind of a genetic association with any disease,” Hageman said.
“Basically, you can imagine a situation in which Factor H doesn’t shut off when it needs to shut off, leading to a lot of damage to healthy cells and tissues. In the case of AMD, the damage is to your macula, resulting in its destruction and ensuing loss of vision,” he said.
Subsequently, Dr. Hageman and his colleagues found a link between AMD and another complement gene, Complement Factor B. Others found an association with a third component called C3, another member of the complement system.
According to Dr. Hageman, the early theories proposed by him and his collaborators about drusen and the complement system were not readily accepted by their colleagues over the years because scientists are conservative by nature.
“It was a long, long laborious piece of work. Fifteen years ago, ten years ago, people thought we were well off base. There were many times that I considered leaving the field because of the unwillingness of colleagues to accept the concept that the complement system plays a major role in the disease process.”
“At the end of the day, however, I look back and realize that it’s been a wonderfully exciting time, and it’s been great to be a part of such an important discovery. I think from a scientific and layman’s perspective, we have a strong understanding of the genetics of this disease.”
With the identification of associations of disease risk with Complement Factors H and B, the atmosphere has changed surrounding drusen and the immune system. Does this mean a genetic test could be available?
“I think we now have sufficient knowledge to develop realistic and predictive genetic tests,” Dr. Hageman said.
He casts a similarly sunny forecast for treatment of AMD. “It is clear that the complement system is playing a major role in AMD and I don’t think many would disagree at this point in time. Importantly for patients who are afflicted with this terrible condition, there’s a lot of current activity in the development of therapeutic agents that will regulate the complement system appropriately. Every major pharmaceutical company is pulling out their various complement inhibitors.” He notes that firms such as Potentia and Alexion are just two names apparently entering the fray. “These activities should ultimately lead to prevention and/or delay the progression of the disease.”
According to Dr. Hageman, there are drugs that have been developed in the past for other diseases and people are pulling many of these off the shelf. Dr. Hageman notes that these candidate drugs will have to be tested in appropriate clinical trials over the next few years.
“I certainly don’t want to give the impression it will take forever before new therapies are available, but the regulatory pathway is long and complicated and it will take a number of years to develop, test for safety and show the efficacy of these new drugs. Another important step will be to integrate genetic testing with therapies,” he said.
The search for new therapies resulted in Hageman’s latest project, a start-up company called Optherion, Inc., which will be developing potential diagnostics and therapeutics.
Inhibiting the system over long periods of time may not be the best approach, as it would deter both the bad and the good factors. Dr. Hageman’s team has identified forms of Factor H that are strongly protective. If you carry those protective genes, they actually do a very good job of preventing you from developing macular degeneration.
Optherion’s strategy is to take advantage of this concept and deliver a functional, protective protein. By putting the good protein in a person’s body and having it expressed all the time, the individual will hopefully never develop the disease.
Hageman helped to found Optherion, in addition to his work in Iowa, in an attempt to keep up with the fast-paced developments.
“The field is excitingly out of control. It is difficult to keep track of all that is happening,” he said. “This, however, is good news for AMD patients.”
“If I had this disease, I would be excited by all of the current activities. Things will move very quickly, and I think that’s the most important thing. This work is certainly the most important thing I’ve done in my life. To think that maybe in a few years we will have something preventative or at least therapeutic is tremendously rewarding.”
“The most important thing we can do now for all those who are afflicted will be to educate them about the complement system and the advancements in our understanding of the disease. Continued focus on the complement system will surely result in the development of therapies that will halt, delay and/or prevent the development and progression of this devastating condition!”