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His Kingdom for an Eye

  • Title: Assistant Professor, Baylor College of Medicine
  • Education: PhD, Baylor College of Medicine, 1999
  • Recommended by: Richard Gibbs

Learning how eyes develop, even the complex ommatidia of fruit flies’ compound eyes, eventually gives insight into how other visual systems develop. At Baylor College of Medicine, Rui Chen is trying to decipher the genetic networks that control retinal development. Since he is studying eyes from a developmental perspective, Chen is also interested in early-onset human eye diseases, particularly Leber’s congenital amaurosis, a disease that affects newborns.

Drawing on his background in both classical genetics and computational biology, Chen is integrating different research methods to understand how visual system development is regulated. First, Chen trained as a classical geneticist, doing gene knockout studies to look at phenotypes and gene function, but grew dissatisfied. “You knock out genes and you look at phenotype, but you don’t really see the full picture necessarily,” he says. As a postdoc, he moved to Richard Gibbs’ genome-level focused lab. “You look at it globally instead of just local,” says Chen.

By mixing classical genetics with gene expression profiles, transcription factor binding assays, and computational approaches, Chen hopes to be able to predict a gene’s downstream targets and how the different pathways of gene networks function together. To get to that point, Chen is compiling a list of candidate genes that might be involved in eye development. “What I think it is really helpful in the next … year or so is, we are starting to use next-generation sequencing technology, the enrichment method, we pull out a lot of exons that seem possible and then we just sequence them all. I think that should be going pretty fast from this point on,” says Chen.

There are still challenges to overcome, particularly with the classical genetics aspects of Chen’s work. “No matter how good we are right now, there are a lot of genes that we are looking at that we are knocking out and there’s no phenotype,” he says. Chen is hopeful that the new next-generation sequencers will help them solve those phenotypes.

Looking ahead

In the next few years, Chen hopes that researchers will start to appreciate how dynamic the pathways involved in eye development are. Right now, he says, people are still unsure how the major pathways interact and that researchers should try to at least semi-quantify the process. He also says that human diseases, such as age-related macular degeneration, could benefit from large, genome-wide studies to parse out which alleles are involved in its development.

Publications of note

“My favorite paper is always the one that has been published,” laughs Chen. In a 2006 paper in Genome Research, Chen reported a strategy to identify the downstream targets of a transcription factor. He and his colleagues combined computational biology, genomics, and classical genetics to narrow down genes that might be downstream of Eyeless, a retinal determination protein in Drosophila. They constructed a position weight matrix of the Eyeless protein to predict, in silico, potential binding sites in fruit flies. At the same time, they performed microarray analyses of wild-type flies, flies ectopically expressing Eyeless, and flies from a mutant background to identify genes induced by Eyeless. Combining the information from both threads of experiments, Chen discovered three new genes — eyes absent, shifted, and Optix — that are novel targets of Eyeless.

And the Nobel goes to…

“I would say I would love to be able to take a cell, any cell, and turn it into an eye,” says Chen.

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