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Trailblazing Her Way from Ireland to Germany to Protein Arrays

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AT A GLANCE

Name: Dolores Cahill

Age: 35

Position: Group leader, protein technologies group, Max Planck Institute for Molecular Genetics, Berlin

Director, proteomics core, Institute of Biopharmaceutical Sciences, Royal College of Surgeons, Dublin

Prior Experience:

Postdoc, Technische Universität, Munich

At age 35, Dolores Cahill manages two proteomics groups in two different European countries and is working to bring her protein chip technology to market through a German startup. No wonder she is one of the few women who has made a name for herself in proteomics.

Like many of her peers who went to college at a time when genes, not proteins, were considered the hottest area in biology, Cahill — a native of Ireland — received her undergraduate degree in genetics, from Trinity College in Dublin in 1989. But it did not take her long to realize that it is not DNA but proteins that do the real work in the body, and as a graduate student she joined Richard O’Kennedy’s lab at Dublin City University to study immunology, making monoclonal antibodies against tumor-associated antigens in the brain. After receiving her PhD in 1993, she and her husband, whom she met during her graduate studies, both moved to Munich for postdocs. “I wanted to leave Ireland, and I could speak German,” she remembered, having spent four summers in Germany as a teenager. In Munich, Cahill spent two years in Adelbert Bacher’s group at the Technische Universität studying two proteins, GTP cyclohydrolase I and sepiapterin reductase. But by the end of her post-doc, after having spent seven years studying just a handful of proteins, Cahill realized that there must be a more systematic way. “Looking at individual proteins wasn’t the way to go,” she said.

Good fortune struck again when she and her husband both found positions in Hans Lehrach’s department at the Max Planck Institute for Molecular Genetics in Berlin, where she started out as a postdoc in 1996 and soon moved up to group leader of the protein technologies group in 1998. It was at this point that Cahill — together with her colleague Gerald Walter and Konrad B ssow, a graduate student — began to develop the idea of high-density protein arrays.

But first Cahill had to obtain the proteins to place on the arrays. So she and her colleagues have been creating high-quality cDNA libraries from different sources, having finished so far a human brain library and working on mouse T-cells and Arabidopsis thaliana meristem libraries. By devising a semi-automated system for subcloning, E. coli expression and screening, Cahill managed to obtain a set of 10,000 highly characterized human brain protein expression clones, ready for the production of tagged proteins, in an automated fashion, for arrays or other applications. In addition, Cahill has modified the clones in a way that allows her to shuttle the cDNA into other vectors, for example for mammalian expression or yeast-two-hybrid studies. Obtaining these clone libraries took several years, Cahill said, and involved automating both molecular biology and protein expression.

At the moment, one technician — paired up with one robot — can produce small amounts of about 2,500 proteins in three weeks, Cahill said. In theory, this is enough for thousands of chips. While the first arrays were simple PVDF membranes and had a large format of 22 by 22 centimeters, the current chips carry 2,500 proteins in duplicate on a coated glass microscope slide. What’s unique about Cahill’s approach is that the proteins are denatured, making them suitable for antibody specificity testing or for assaying autoimmune disease patient sera for autoantibodies in order to find new diagnostic markers, but not for studying protein-protein interactions. The reason not many other researchers have chosen to make similar arrays, she said, is that “it’s not so easy … protein expression is difficult.”

Sensing that her technology might have commercial potential, Cahill joined Dortmund, Germany-based Protagen as a co-owner in 2000. The startup, founded originally as a proteomics fee-for-service company in 1997 by Helmut Meyer, a professor at Bochum University, and two of his students, is currently reinventing itself as a drug discovery company, looking for venture capital as well as partners to market and distribute Cahill’s protein arrays. “We are in discussion with a number of partners but we haven’t closed a deal,” Cahill said. Protagen, which has 18 employees to date and recently moved from Bochum into larger premises in Dortmund, is currently funded through company collaborations and various grants from the German government. It has licensed the protein chip technology from the Max Planck Institute, and two of Cahill’s 12 lab members are ready to switch over to Protagen once a partner has been found. The first commercial chip, Cahill said, will probably contain 2,000 different proteins from her human brain library and will be marketed for determining the specificity of antibodies and for profiling the antibody repertoire in human serum.

Although Cahill seems firmly established in Germany, she hasn’t let go of her ties to Ireland. In 2000, she agreed to serve as director of the proteomics core at the Institute of Biopharmaceutical Sciences at the Royal College of Surgeons in Dublin, which was founded with government funding in 2000. In this capacity, she set up the institute’s mass spec facility and is still actively involved in running it. “When I left Ireland, there wasn’t really that much funding to do research, but now Ireland’s economy has done really well,” she said. The department of pharmacology, where the institute is located, can easily access patient samples and focuses on platelet research — a system highly suitable for proteomics, Cahill said, because of its almost unlimited availability. Not surprisingly, Cahill’s Berlin and Dublin groups are collaborating to produce a platelet protein array.

By now, Cahill has gotten used to being the only woman at many conferences and grant meetings, she said, but this has clearly not prevented her from pursuing her aims in science. Her first priority in the next few years will be to bring her protein chips to market with Protagen and to prove their usefulness, especially for medical purposes. One of her projects is to help develop a new meningitis vaccine, based on screens with sera from protected individuals on meningitis protein chips. “If the protein arrays could have … some real medical applications, it would help people, then I would be happy,” she said. “That’s, I think, really why I am doing it.”

— JK

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