By John Russell
November 15, 2002 | Atlantic City, N.J. – Amid the gloomy quiet at last month’s World Genomic Symposium and Exposition (attendance was so light, there was more buzz at the dry cleaning convention two halls down in the Atlantic City Convention Center) William A. Haseltine, the controversial CEO of Human Genome Sciences (HGS), delivered a stern opening keynote presentation, arguing that Wall Street, Big Pharma, and most of the public had missed the point of the genomics revolution.
Genomics’ role is to deliver validated targets, not drugs, said Haseltine, and the roughly 150 to 200 targets it has yielded so far are proof of its success. The problem is the slowness with which most pharmaceutical companies get those targets into to clinical trials. “Something has gone dramatically wrong, not with the genomics part of drug discovery but with the bread-and-butter chemical discovery part,” he said.
Haseltine chided the Human Genome Project for its misguided emphasis on sequencing the genome rather than on cataloging expressed genes. He declared he never believed pharmacogenetics would lead to personalized medicine. Lastly, he promoted a vision of drug discovery based on expression genomics using libraries of RNA transcripts (in cDNA form), which, coincidently, HGS has in abundance.
Haseltine has beaten this drum before, though perhaps less loudly. HGS was founded to exploit expressed genes, and it currently has five drugs (proteins and antibodies) in clinical trials. The company has cataloged expressed genes from more than 1,000 tissue types. Nevertheless, its drug development program has hit speed bumps (see HGS Battles the Pipeline Blues, June 2002 Bio-IT World, page 10).
Haseltine took pains to distinguish between “genetic genomics” and “expression genomics.” Genetic genomics, he said, focuses on differences within the genome, such as SNPs (single nucleotide polymorphisms). Expression genomics, on the other hand, is focused on similarities and treats the genome as a set of interchangeable parts. Both approaches have scientific merit but vastly differing commercial prospects, he said.
The assumption that understanding how genotype variances produce phenotypic changes will lead directly to disease treatments, cures or prevention, “is a philosophical leap, which is, in general, not the case,” he said.
Haseltine gave a bleak prognosis for personalized medicine. “Until such time as we have effective gene therapy, or effective tools to change our genetic inheritance, you will not have personalized medicine based on genotype. The consequence is that those companies that premise themselves on genotype as a basis for pharmaceutical development are going to have severe difficulties.”
Expression genomics, he argued, is a more direct, predictable route for drug development. Rather than search the sequenced genome with specialized software to identify genes of interest, researchers pluck RNA messages directly from tissues, and convert them into stable cDNA libraries.
Researchers can then express and test proteins in other tissues for useful pharmacological activity. That’s how HGS discovered B-Lymphocyte Stimulator (BlyS), a promising drug candidate in clinical trials for treatment of immuno-suppressed patients and certain tumors.
“I would argue that there has been a serious, long-term miscalculation on the part of the Human Genome Project as to what is most valuable for medicine and for the pharmaceutical community,” said Haseltine.
HGS took roughly two years to move its first BlyS candidate to clinical trial. “Just look at the number of new drug applications filed this year, both NDA (new drug applications) and drugs for approval. There’s been a dramatic fall-off. Every year for the last three years it’s been dropping, until this year it’s half of what it was last year,” he said.
Big Pharma, he said, simply isn’t serious about tackling protein drug development, and is missing an opportunity just as the train manufacturers never understood their undoing by the automobile.
Haseltine’s preaching has long rattled many observers. The larger issue is whether he’s right. Was the emphasis on sequencing the genome a mistake? Is personalized medicine an unrealistic chimera for the foreseeable future? Is Big Pharma stuck with a small-molecule mindset that prevents it from successful protein drug development? Haseltine says so.
The next goal, he said, should be to provide researchers with a complete set of genes in their RNA format. This will help accelerate medical discovery, he said.
“I cannot overstate how important having a complete set of expressed human gene sequences is as a starting point for medicine. Unfortunately, mostly as a result of policy decision by the Human Genome Project, that power is not in the hands of most academics. It is restricted to certain biotechnology and pharmaceutical companies because the emphasis was on genetic genomics,” he said.
One of those companies just happens to be HGS.