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From Detection to Drugs

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  • Title: Research Scientist, University of California, San Francisco
  • Education: PhD, University of California, San Francisco, 2003
  • Recommended by: Charles Buck

Giselle Knudsen wants to find a better way to detect proteins in cells. To this end, she is developing Raman spectroscopy, a detection method based on how the sample scatters light from a laser, for the life sciences, particularly proteomics and cancer drug target development. "It's extremely sensitive. It's going to enable us to quantify very small ratios of two different protein species at very low concentrations," she says.

Knudsen, who originally trained as an enzymologist, made the switch to proteomics when she realized that looking at proteins in a vial doesn't necessarily reflect how those proteins behave in a cell. "I realized that we can do reductionist biology only so long. We have to start looking at what things actually do in the real cell," Knudsen says. Along with her postdoc advisor, Jo Davisson at Purdue University, who also trained in enzymology, Knudsen is adapting to a world where "enzymologists are becoming proteomics experts and they are interested in classical pharmacology — but they don't call it that anymore."

First, Knudsen is focused on working on Raman spectroscopy, which she says is more sensitive than fluorescence-based detection methods and is competitive with other detection methods used in biology. "I can measure the spectrum of these two species in the same measurement. That means that I reduce the noise, the background, so I can get very accurate and precise numbers," she says.

Once the technique is refined, Knudsen plans to apply it to studying the diversity of protein isoforms found in cells, especially cancer cells. "We're realizing in proteomics that it's not just one enzyme that's inside of a cell, it's actually probably 10 or 15 different forms of the same enzyme. Each of those 10 or 15 different forms have different, unique functions," she says. "In cancer biology, for example, we want to be able to target just one of those 15." By targeting that one protein, she says scientists will be better able to define that protein as a drug target and thus reduce the number of side effects or nonspecific effects seen when that drug is used in patients.

Publications of note

Knudsen's work on Raman spectroscopy was recently published in Bioconjugate Chemistry. In it, Knudsen and her colleagues were able to use their Raman spectroscopy-based technique to accurately and precisely quantify human GMP synthetase. In the single-point determination mode, synthetase with mass ranging from 1 µg to 1 ng could be measured with between a one and six percent error and as an imaging application with a relative standard deviation of 16 percent.

Looking ahead

Knudsen hopes that Raman spectrometry will be applicable in a clinical setting. "The only reason I am working on this methodology is because I really want to use it. The next step is, once I get people to accept the method, I really want to start solving problems. It's going to have to get much more clinical, I think," she says.

And the Nobel goes to …

Knudsen doesn't approach her work thinking about Nobel prizes — she looks at it as wanting to change the way people do experiments, particularly how they measure molecules, to be more accurate. "If I can be recognized in the future for doing biomolecular detection, that would be great," she says. "But I see myself as being very spread among different fields, so I don't know if that's going to work for me."

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