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June 2010

Visionary

From Estonia to Eye Genetics Research

Interview with Rando Allikmets, Ph.D.

By Allyson T. Collins, M.S.
NEI Science Writer/Editor

Rando Allikmets, Ph.D.
Rando Allikmets, Ph.D.
Director, Molecular Genetics Laboratory
Department of Ophthalmology
Columbia University Medical Center

As a fifth-grader in the early 1970s in Estonia, Rando Allikmets, Ph.D., knew he wanted to be a biologist; he had already spent years studying birds. By the time he graduated from high school, however, he thought molecular biology would be a more practical career. He eventually earned a Ph.D. in Moscow, where his research involved constructing genetic libraries of different organisms. He even used his own DNA to develop a human gene library.

Today, Allikmets is a National Eye Institute (NEI) supported researcher and director of the Molecular Genetics Laboratory in the Department of Ophthalmology at Columbia University Medical Center. In a recent interview, he discussed his research transition from cancer to vision, and his focus on the genetics of blinding eye diseases.

What drew you to a research career in the United States?

In 1989, a scientist from the National Cancer Institute at the National Institutes of Health, Dr. Michael Dean, visited a lab where I was working in Estonia. He was interested in my research, and two years later invited me to join his lab in Maryland. I was tasked with cloning genes that belonged to a superfamily known as ABC transporters, which are proteins that help transport a variety of molecules across cell membranes. A superfamily is made up of genes that are similar to each other because they all have similar DNA sequences. My mission was to clone all of the human ABC transporter genes. I discovered more than 30, one of which was a gene called ABCA4.

Why was that a significant discovery?

In 1997, we found that the ABCA4 gene was responsible for Stargardt disease, an inherited form of macular degeneration. This is a recessive genetic condition, so people must inherit the gene mutation from both their mother and father. The disease causes progressive vision loss and blindness, often starting in childhood. Some advanced stages of age-related macular degeneration (AMD) look similar to Stargardt disease, and we also found evidence to suggest that ABCA4 was associated with AMD. These findings caused a lot of controversy. In scientific meetings, researchers told me point-blank that I was wrong. Even my friends advised me to get out of eye genetic research, but I don't mind controversy. I stayed and transitioned to an eye geneticist, starting my own lab at Columbia University. I really liked how this gene discovery changed and charged the field.

ABCA4 gene
Expression of the human ABCA4 gene (in red) in the light-sensitive photoreceptor cells of a mouse model of Stargardt disease. Transfer of the human gene to the mouse eye corrected the disease in treated mice. (Kong et al., Gene Therapy, 19:1311-1320, 2008)

How do you determine that a particular gene is responsible for a disease?

One of the best-known methods is linkage analysis. We collect blood samples from families that have the disease and analyze their genomes to detect regions where they have the same genes. If we have large enough families or many families, we can define a location on a chromosome where all of the affected people share that DNA segment. Therefore, the gene for the disease must be in that region. We then begin to screen the genes there to pinpoint the one that is involved in the disease. When we mapped the ABCA4 gene, we realized that it was in a region that was already defined for Stargardt disease. However, it's not always this simple. Sometimes we study a region for many years and still can't find the disease-causing mutation.

What is the research focus of your lab at Columbia?

Our first and foremost goal has been to identify AMD genes. In Stargardt, we knew the gene was ABCA4, but we know that AMD is a complex disease, meaning that a combination of many genes and the environment cause the condition. Our lab has received funding from the NEI since the beginning. We started from zero and have now collected blood samples and clinical information from more than 3,000 AMD patients and people without the condition. We have used this vast resource to screen for candidate genes that could be related to AMD.

What other AMD genes have you and your collaborators found?

In 2005, I was involved in the discovery of the role of complement factor H (CFH) gene in AMD and in 2006, the discovery of complement factor B. The complement system is involved in our innate immunity--our built-in defense from infections and other external harm. The discovery of the involvement of complement genes in AMD has been a breakthrough in AMD genetic research. We now know more than half of the genetics that underlie AMD, and it could be as high as 75 percent. AMD is the poster-child of complex disease genetics research. It is the best-defined complex disease, more than other well-known complex diseases such as cancer or Parkinson's disease.

"AMD is the poster-child of complex disease genetics research," Allikmets says. "It is the best-defined complex disease, more than other well-known complex diseases such as cancer or Parkinson's disease."

If scientists have discovered that many genes, can they predict a person's AMD risk?

Prediction in an individual is much more difficult than figuring out the factors that cause AMD. This is not a plus or minus situation where you either have the gene or you don't. At this stage, it is very difficult to come up with a good formula that tells you definitely whether or not you will get AMD. The best we can do is to estimate disease risk. We know the main causal genes, but we don't know much about other modifiers such as the environment, including diet and smoking. Their impact on the disease is currently very difficult to estimate, but we are working on it.

What do you hope will come of your genetic discoveries?

Finding genes that cause a disease is the first step to dealing with the disease. From there, we can work on properly diagnosing it, understanding what happens in the eye, and treating it. If my work with ABCA4 translates to gene therapy or other treatment for Stargardt disease, that will be the proudest accomplishment of my career.

For more information about Allikmets' lab, visit http://www.cumc.columbia.edu/dept/eye/research/fac_allikmets.html.

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Department of Health and Human Services NIH, the National Institutes of Health USA.gov