Fish eyes: modeling genetic mutations behind ocular disease

7 November 2016

Using zebrafish as a model, Dr Yuk Fai Leung studies the gene networks behind ocular diseases. Finding the genetic root of ocular diseases allows for more accurate and effective treatment, and Leung explores both Western and Traditional Chinese medicine.

Leung is Associate Professor in the Department of Biological Sciences at Purdue University, in West Lafayette, Indiana.

He completed his undergraduate and Master’s degrees in Biochemistry at Hong Kong University of Science and Technology (HKUST) but did not anticipate a career as an academic scientist when he took his first a job as a Research Assistant. It was while working at the Department of Ophthalmology and Visual Sciences, at the Chinese University of Hong Kong (CUHK) located at the Hong Kong Eye Hospital in Kowloon, that his boss suggested a part-time PhD.

“I enjoyed ophthalmology. Like most Hongkongers, I was adaptable and thought it was a very worthwhile field of research,” he says.

Genetic underpinnings

The basis of his PhD research was gene networks and he was able to take many blood samples from patients suffering from various ocular diseases at the hospital. Many human ocular diseases such as cataracts, glaucoma, diabetic retinopathy, and age-related macular degeneration remain poorly controlled due to lack of proper understanding of the pathogenesis and the corresponding lack of effective therapies.

“Certain numbers of these diseases have genetic components and we try to understand the genetics underpinning those diseases,” says Leung.

“If we find gene mutations, it allows us to understand the problem better before we try to fix it,” he adds using the analogy of a domino, to explain how a mutation will not just topple the first domino but will ripple through the other dominoes and spread to other genes in the network.

“We need to study all the genes affected in the network,” he says. In fact, Leung learned so much during his time at CUHK that he set up one of the most popular genome websites in the world, which became recognised by leading research universities like Harvard and Stanford.

Microarrays for comparing patterns of gene expression became a hot topic and Leung’s website grouped a collection of annotated links so that students could better understand the basics of gene chips and experts could access a range of products for making and scanning microarrays, new laboratory protocols, and rosters of people using microarray technology.

The Zebrafish

A Croucher Fellowship awarded in 2002 allowed him to pursue post-doctoral research at Harvard University into disease-causing gene networks for retinal degeneration.

“This was my aim with the post-doc research; to progress my work using the zebrafish model,” he says.

As an animal model organism, the zebrafish not only addresses the need to closely mirror human eye pathology but can, in many respects, reflect the human situation better than rodent models.

“The fish is a unique creature for disease study; eye disease in particular,” says Leung, pointing out that at less than 1 inch long, you can keep a lot in a small area.

Young zebrafish at five days old

“This was one of the reasons I wanted to pick on this research model. I thought they would be ideal for research in Hong Kong where space is at such a premium,” he says, but after Harvard the zebrafish led him not to Hong Kong but Purdue University in Indiana where his knowledge of gene networks is combined with the need to screen compounds in pre-clinical testing of drugs to combat ocular degeneration.

“If I could measure every gene, I could fully understand the disease and fix it. This approach still complements my work with drug screening. They are two sides of the same coin,” he says.

Although much has been learned about the molecular basis for the group of inherited eye diseases including retinitis pigmentosa and age-related macular degeneration, they remain incurable. The zebrafish retinal-degeneration models seeks to expedite new drugs and understand the genetic characteristics of the disease.

“If we screen the drug when we don’t fully understand the disease, we are not operating at our full capability. Are the drugs hitting specific targets in the gene network?” he asks.

Zebrafish can lay a lot of embryos within a very small footprint in a multi-well container so Leung’s team can put drugs in the different wells and examine the fish’s vision motor response. It is a proven method for detecting early-onset photoreceptor disorders and offers an effective drug screening process which prioritises compounds potentially beneficial to the treatment of human disease.

“We simply switch the lights on and off and observe how the fish detect the light and how they respond to it,” he says making the process sound very simple.

Traditional medicine

This research undertaken at Purdue University is linked to Leung’s undergraduate studies at HKUST, when he looked at Traditional Chinese Medicine (TCM) compounds and their impact on ocular disease.

“I wanted to go back to my roots and use our zebrafish platform to analyse compounds that are used in TCM to treat ocular disease,” says Leung, who describes this as his “research vision.”

His team has a list of the TCM compounds it wants to test and obtained its first TCM compound from Dr Robert Ko, Leung’s former Professor at HKUST.

Leung believes that the goal of medicine should be to shift the body’s equilibrium back to the normal state, so the cell can function normally.

“This is interesting about TCM because it does not seek a magic bullet but thinks of the human body as a network and tries to restore this normal state. I want to use scientific thinking to formalise the benefits of TCM,” he says.

Dr Yuk Fai Leung is an Associate Professor in the Department of Biological Sciences at Purdue University. He received his B.Sc. and M.Phil. in Biochemistry at the Hong Kong University of Science and Technology and Ph.D. in Ophthalmology at the Chinese University of Hong Kong. In 2002,  Leung began his postdoctoral research at Harvard University with the support of the Croucher  Foundation.

To view Leung’s personal Croucher profile, please click here.