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From His Dry Lab, Appel Seeks to Apply Proteomics in the Clinic

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AT A GLANCE

Name: Ron D. Appel

Age: 43

Position: Professor at the University of Geneva and Head of Proteome Informatics at the Swiss Institute of Bioinformatics

Prior Experience: Developed Melanie, a suite of programs for analyzing and comparing 2D gel electrophoresis images, as well as other proteomics tools.

Nestled in one corner of a giant concrete building on the campus of the Geneva University Hospital Medical School, the Swiss Institute for Bioinformatics (SIB) doesn’t quite have the commanding presence of some of its counterparts in the private sector. But the institute, like many things Swiss, has built a reputation for creating products of high quality — in this case protein databases and bioinformatics software — and a substantial portion of the credit goes to Ron Appel.

The genesis of Appel’s involvement with SIB dates to 1983, when Appel and his colleague Matthieu Funk jointly decided to pursue PhDs after they finished their master’s degrees in computer science at the University of Geneva. Appel and Funk weren’t interested in pure theory, however. “It was fairly simple: we wanted to use computer science to do something, and computer science could be most useful in medicine,” said Appel last month in his office at SIB. So Appel and Funk began looking for a physician or clinical researcher with an interest in computer science, and settled on Denis Hochstrasser.

Hochstrasser, who went on to co-found GeneProt, was at the time about to start a research group at the Geneva University Hospital Medical School to try to apply 2D electrophoresis to medicine. He took Appel and Funk into his group to write software for digitizing and comparing the gel images, a task attempted by only a few other researchers in the US. The two students didn’t have to start from scratch — through a collaboration with Mark Miller and Arthur Olson at NIH they obtained a set of VMS command-based programs — but Appel helped port them over to UNIX and adapt them to Hochstrasser’s technique for running 2D gels. “We adapted their programs, developed new detection techniques and new algorithms on top of that, and that’s what we know today as Melanie 1,” said Appel.

Over the course of five years — from 1984 to 1989 — Melanie developed into a set of 50 different machine code programs that were “impossible to run by anyone else but the people who developed it,” Appel said. To fix this problem, Appel and his colleagues scrapped the old code in 1990, and set out to write a new suite of object-oriented programs in C++. In 1993, this version, known as Melanie 2, was picked up by Bio-Rad, which continued to distribute updated versions of the software until 2000. At that point, GeneBio, the licensing arm of SIB, took over the exclusive distribution of the software. SIB and GeneBio are currently preparing to release Melanie 4. Tragically, Funk did not live to witness Melanie’s success, having died in 1992 of cancer.

Writing 2D gel software hasn’t been Appel’s only activity in bioinformatics; nor is it the only component of SIB. Starting in 1986, Amos Bairoch, another bioinformaticist at the University of Geneva, began building a database of protein sequences he called Swiss-Prot, and in 1990 Appel began working with Bairoch to connect the database and its associated analysis programs via telnet to universities in Geneva and Lausanne, 37 miles away. At the same time, Appel, along with Hochstrasser, joined up with Robin Offord at the University of Geneva, who contributed his expertise in microsequencing proteins excised from 2D gels, and Keith Rose, a mass spectrometry expert. The result: ExPASY, or Expert Protein Analysis System, the first web searchable database of protein sequences and of identified proteins taken from 2D gel maps.

“Putting this together, we thought we should allow other people to access the data,” said Appel. “I looked around at what kind of system we could use so that we could [make the data available], and in July of 1993 I found out about the world World Wide Web.” Appel spent two weeks writing the html code to make the databases web-accessible with the help of Mosaic, a precursor to Netscape Navigator. It was the 151st website to appear on the web.

Although Appel and his ExPASY collaborators initially relied on word-of-mouth to spread the word about their online protein databases, conference presentations and a paper published in the journal Electrophoresis contributed to a steady increase in web traffic on the site. In December 1994 about 100,000 visitors accessed the ExPASY site; the average number of monthly visitors is now around 6 million.

Today Appel spends his time overseeing his group of 15 staff researchers in their attempts to improve SIB’s algorithms for rapidly searching Swiss-Prot and 2D gel image data, proteomics tools, as well as overlooking a parking lot adorned with carefully crafted graffiti — the future site of SIB’s expansion. Appel and Hochstrasser are also continuing to pursue their dream of developing a tool that they call a “molecular scanner” for using 2D gel electrophoresis in the clinic to help diagnose and understand how to treat patients. Ultimately, this is is what motivates Appel. “The goal was to use all of what we developed in the clinic,” he said. “It’s still a long-term goal.”

— JSM