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It's hard to imagine how the international gene mapping consortium would have ever been a success without James Sikela. His development of single-pass cDNA sequencing was the main sequencing method used by the consortium that produced the first comprehensive human gene map. In the early 1990s, Sikela, a professor in the department of pharmacology and the human medical genetics program at the University of Colorado Health Sciences Center was already working on single-pass sequencing of human cDNAs. In 1991, the fledgling Human Genome Project sponsored his lab to produce human ESTs in order to identify thousands of human genes.

His was the first lab to make available to the public large mouse EST datasets. Sikela's work with ESTs has also made a considerable dent in the battle against Alzheimer's disease. Human ESTs generated by his lab were used in a study that identified PSN2, a gene believed to play a central part in the onset of the disease. He was also the first to apply array CGH genome-wide across human and primate genomes in a study conducted with Jon Pollack at Stanford University. Their work resulted in the genome-wide identification of more than 1,000 ape and human genes that displayed lineage-specific changes in copy number. These alterations may account for the majority of lineage-specific changes over the last 15 million years that have occurred in human and great ape evolution.

Currently, Sikela's research involves applying genomic approaches to the discovery of genes involved in alcoholism and drug abuse, as well as the identification of genes important to hominoid evolution, including those that are specific to the human lineage.

Custom approach

In addition to these contributions, Sikela has given much to the many graduate students and postdocs that have passed through his lab. And while it is often the case that PIs will lead based upon their own experience, Sikela takes a more attentive approach. "What I try to do is tailor-make the program to suit the person," he says. "Some people come in very insecure about their abilities, and then other people are really ready to go and we just turn them loose. … We try to modify how things are structured so that it really maximizes the challenge of the person and fits the person who is coming into the lab."

He maintains an open-door policy around the office and the lab to ensure that his students have access to him to see how research is really done. "Part of it is to expose them to how science works: we have lab meetings all the time, a lot of hall meetings where you just run into somebody and they come by," he says. "I didn't have a really big lab all these years — it's been a modest size — so the door was always open and I'd be happy to talk with students any time."

As with many other mentors in genomics, Sikela's key qualities include an unbridled enthusiasm for science and, beyond that, the desire to undertake challenges and stick one's neck out. "We're very fortunate we can ask these large questions and have a chance of actually getting an answer, and I think that it's fun to show students that that's possible," Sikela says. "We've actually tried to ask some pretty big questions. We tried to get methods to work that no one had tried and in a few cases they did work, so it's been fun to take risks."

Former graduate student Erik MacLaren remembers Sikela as supportive but not overbearing. "I felt like he was a very encouraging mentor, a pretty hands-off kind of supervisor," says MacLaren, now a research associate at the Sanger Institute. "He wasn't tapping you on the shoulder every day asking you what the results were." MacLaren helped Sikela establish the cross-species array CGH program in his lab. This project resulted in the first genome-wide and first gene-based study of copy number gain and loss in human and great ape evolution.

MacLaren says that his time with Sikela definitely instilled in him an appreciation for the human genome that helped inform his career today. "I think the main thing was just to try to take advantage of the genome itself because that sequence was all completed while I was there, and his idea was always to take the best advantage of the human genome," says MacLaren. "That's what I took with me to the Sanger Institute: I wanted to get into neuroscience but wanted some place that wasn't just a one-gene lab — it was something with a whole genome perspective."

'Through the downs'

As with many young graduate students, Sikela went through his own period of struggle. As the first member of his family to ever go to college, the investigator says he was plagued with doubts about his abilities to pursue scientific research successfully, but his advisor, Bill Hahn, convinced him otherwise. "I had actually been through a fairly rough time about having doubts about science and my ability, and Bill gave me a chance and got me through this doubting period," says Sikela. "So I certainly tried to learn from him that people go through ups and downs, and sometimes the role of the PI is to get them through the downs to where they're doing things and are confident in their abilities."

But as someone whose job is in part to usher young researchers onto the path of their own research careers, Sikela says that strength of character and an appreciation for those you work with, more than just academic chops, is what really counts in the end. "The idea that who you meet every day is important. Be aware of whom you are with in the present, and value that time," he says. "The relationships you develop are all important, so have integrity and consideration for the people that you work with."

Naming Names
A number of students have spent time learning in Jim Sikela's lab. Here's where a few of them have landed:

Kari Buck
Developed and applied assays for the measurement of expression levels of genes related to alcohol action. Buck is now an associate professor in behavioral neuroscience at Oregon Health Sciences University and is also director of the Molecular Genotyping Laboratory at the Portland Alcohol Research Center.

Rebecca Berry
This former graduate student helped establish that single-pass sequencing into the 3' UTR of random cDNAs could be used for the generation of gene-based STSs, which in turn could be used to rapidly map human genes to specific chromosomal regions. This method was later scaled up and used to make the most comprehensive human gene maps. Berry is currently director of cytogenetics at Esoterix Oncology in Austin, Texas.

Marissa Ehringer
Spearheaded the Sikela lab's comparative sequencing of genes located in mouse alcohol-related QTLs. She is currently an assistant professor at the Institute for Behavioral Genetics, where she works on identifying genetic causes of alcohol and tobacco dependence, as well as other forms of substance abuse.

Akbar Khan
Currently a researcher with the US Army's Edgewood Chemical Biological Center, Khan helped Sikela develop the lab's methods for single-pass automated sequencing of randomly chosen human cDNAs, before they were called ESTs.

Magdalena Popesco
Popesco was first author on a recent Sikela lab paper that demonstrated domains that are extremely amplified in the human lineage and may be important to evolutionarily unique capacities of the human brain — findings that received considerable media attention worldwide. She is currently a postdoc in the lab and will be finishing up this summer.

Arto Orpana
This former Sikela postdo helped develop a novel approach to facilitate rapid full-length sequencing of human cDNAs. He is currently the director of molecular genetics at Helsinki University Central Hospital.