This interview is with Dr James Willey, Editor in Chief of Gene Regulation and Systems Biology and Professor of Medicine and Pathology at the University of Toledo Medical Center, Toledo.

Tom: What would you say is the primary focus of your research effort (and how do you refer to your 'sub-area')?

Dr Willey: The study of human inter-individual variation in gene regulatory pathways related to complex genetic disease risk. More specifically:

1. Development of methods to identify individuals that have inherited sufficient alteration in regulation of a sufficient number of key genes to result in a detectable increase in disease risk.

2. Application of these methods to identify the 10-15% of the population that is at highest risk if they smoke cigarettes.

Tom: What do you consider to be the most significant developments arising from research in your area?

Dr Willey: The recognition that genome wide association studies (GWAS) of interindividual variation in SNP allelotype are insufficient alone to identify individuals with particular complex genetic disease determinants. Rather:

1. SNP analysis must be combined with phenotype analysis (e.g. transcript abundance analysis).

2. Focus on SNP analysis of genes with high prior likelihood of association with phenotype markedly increases chance for success in determining association. Otherwise, when one compounds the number of SNPS assessed (now greater than 1,000,000) x the number of potential models to explain the phenotype, the number of models becomes cosmological.

3. The role of rare SNPs may be much more important than initially recognized and this raises the priority of sequencing key gene areas, rather than simply performing SNP analysis and relying on hapblock estimates to locate disease determining SNPs.

4. High frequency of recombination in CpG islands, which are common in promoters of important genes, leads to high recombination which renders haplotype block estimates inaccurate.

Tom: What do you consider to be the most significant open questions and research challenges in your area?

Dr Willey: Improvement in ability to compare transcript abundance data across experiments and laboratories. Up to this point, the basic analytical tools widely in use simply don't have the performance characteristics necessary to enable data comparison. For this reason, gene ontology efforts have been severely impaired. The software structure is there, but the suitable raw data are not.

Tom: Tell us about your collaborative research. Who else do you directly work with and what are the aims of your collaboration?

Dr Willey:

1. Food and Drug Administration (FDA): Through the MicroArray Quality Control Consortium. The purpose of this effort is to improve ability to compare data across labs and experiments to facilitate drug discovery and development.

2. National Institutes of Standards and Technology (NIST): External RNA Control Consortium. This is a cooperative effort to develop standards that will facilitate development of transcript abundance measurement methods that generate data that may be compared across labs and experiments.

3. Gene Express, Inc.. This is a company that I co-founded and that licenses standardized and quality controlled transcript abundance measurement technology developed in my NIH-funded laboratory. It also licenses new diagnostic tests developed in my laboratory for further development into commercial products.

4. Biotrove, Inc. and University of Rochester. I am Co-PI, along with Tom Morrison of Biotrove, Inc. and Tony Godfrey of the University of Rochester on a recently awarded NCI grant to support development of the Standardized Nanoarray PCR Platform (SNAP). The press release is posted at the Biotrove website).

Tom: Is balancing all these activities challenging? How do you deal with it and what tools do you find useful in doing so?

Dr Willey: Yes. Surround myself with highest quality colleagues. Stay informed regarding latest developments in my field. Think ahead, anticipate demands on my time.

Tom: What do you consider to be the most significant developments or advancements to have occurred in your field of research?

Dr Willey:

1. Recognition that any meaningful understanding of phenotype depends on analysis of regulation and function of many genes.

2. Development of tools and knowledge to assess the function and regulation of many genes and integrate the data.

Tom: When did you decide to be primarily involved in the field that you are now in?

Dr Willey: Early 1990's. Even at this early point in the Human Genome Project, there was sequence information on a sufficient number of genes to begin the process of evaluating expression of many genes simultaneously.

Tom: What resources do you find indispensible for your research work?

Dr Willey: NCBI databases, inexpensive sequencing and oligonucleotide synthesis services, NIH funding, electronic publishing.

Tom: What do you think about the development of open access publishing and open access development? How has it changed your perspective on research or development practices?

Essential component of what I do today. Markedly increases the efficiency of information transfer. Electronic submission, review, and publishing are all important.

Tom: What books do you think should be required reading for researchers working in your area?

Dr Willey: At this point, text books have a difficult time keeping up. Researchers almost need to jump on treadmill that is already moving at high speed.

Tom: What books are current on your reading list?

Dr Willey:

1. A Guinea Pig's History of Biology, Jim Endersby (Amazon.com)

2. Darwin, The Life of a Tormented Evolutionist, Adrian Desmond and James Moore (Amazon.com)

Tom: Do you teach any courses? Is so, which ones?

Dr Willey: Genetic Predisposition to Lung cancer lectures in the graduate school course entitled "Systems Pathophysiology II: Cancer Biology".

Tom: Which historical research figures do you think have most influenced you in how you think about research? Why are they significant?

Dr Willey:

1. Socrates: Always question conventional wisdom.

2. Aristotle: Develop hypotheses consistent with high quality empiric data, rather than developing empiric data to support high quality hypotheses.

3. Darwin: For obvious reasons

Tom: Which meetings do you attend on a regular basis?

Dr Willey:

1. American Association for Cancer Research

2. NIH sponsored meetings: NCI IMAT, NIH study sections to review grants.

Tom: Have you developed any research tools or books that you would like us to know about?

Dr Willey: Will keep you posted, expect developments over the next couple of years.

Tom: If you could change three things about how research in your area is conducted, used, perceived, or resourced, what would they be?

Dr Willey:

1. Researchers need to inquire with greater rigor regarding the performance characteristics of the transcript abundance, protein measurement methods they purchase and/or use.

2. Researchers need to focus more on the ability to compare data across labs and experiments.

My thanks to Dr Willey.

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