There have been significant advances in genomics technology, but not enough to warrant the claims of some companies out to catalog human proteins. Or so say some proteomics forces, such as Ian Humphery-Smith, who argues that proteomics companies are promising more than they can deliver.
Humphery-Smith, a protein chemist at the University of Utrecht and the organizer of the Human Proteome Organization, spoke about these dilemmas at a June proteomics conference in Philadelphia. DNA microarrays will soon offer near-total coverage of the human genome on one chip, but current 2D gel and mass spectrometry technologies only allow researchers to catalog about five percent of the human proteome, he notes. At present were at five percent and weve got 95 percent that are defying current technologies, he says. When [proteomics companies] have done 15 percent of 400,000 [proteins], or 15 percent of all the genes activity, then Ill take back that criticism.
People have been overselling, putting their heads in the sand to steer away from the question, he continues. Theyre more [than] happy to show you what they can do, but the task we have to do now is the human proteome, and we must scale up and think about getting the job done.
Humphery-Smith says the key to getting at low-abundance proteins in cells is to design affinity agents, or molecules that capture certain classes of proteins, to screen out high-abundance proteins before attempting to analyze those that remain with mass spectrometry or other separation techniques.
If you have antibodies or other ligands [to act as affinity agents], you have the potential to enrich your signal to do good mass spec, he says. But we cant do PCR and we cant hybridize [proteins] so we must have a ligand-affinity enrichment of signal.
Ultimately, Humphery-Smith says, protein micro- array technology is the most likely to discover therapeutically important proteins because it will allow researchers to precisely study how the proteins in cells change with disease. Weve got to compete with Affymetrix and others, he says, until weve got a reporter matrix that can look at your proteome in six organs, before and after dinner, seven days of the week, with three drugs.
John S. MacNeil