Genome drafts cloud future of gene-to-drug paradigm

Street Smarts. By Scott Gottlieb, MD, amednews contributor. March 19, 2001.

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If there's one criticism that's been lodged against genomics as a tool for drug discovery, it's that information derived from the sequencing of the human genome provides only a static picture of senescence and disease.

In the real world, genes are involved in a dynamic process, constantly interacting with the environment. Even if the element of disease is introduced into a person's genetic code, it's not certain that he or she will ultimately succumb to a particular illness.

The occurrence of a disease may depend on how much of a particular gene product is made, or the type of post-translational modifications that occur. The idea that scientists will eventually draw direct lines between certain genes and the expression of disease vastly underestimates the complexities inherent in biological systems.

One thing made clear from last month's publication of the papers containing the first drafts of the human genome is that it's going to be a lot harder to uncover "disease-causing" genes.

The last common ancestor of mice and men probably lived 100 million years ago, yet according to Celera Genomics Group, the firm's scientists have found only 300 genes that people have and mice do not. Celera is a division of Norwalk, Conn.-based Applera Corp.

The human genome is far more similar to that of a fruit fly, or even an earthworm, than most would feel comfortable believing. The real difference, it seems, rests not with our sequences of nucleotides but with how genes are turned on and off.

What does this mean for all the companies who made their trade in gene discovery? These companies once postulated that every disease and every major biological process would be coded for at its own discrete location on the human DNA. The recent findings about the simplicity of our own genome turn these old notions upside down.

The fact that we have far fewer genes than once believed means that every disease, and every process, is unlikely to have its own spot on our genome. Another intriguing finding is that almost half of the human genome leads a life of its own, quite unrelated to the needs of human existence. This is the so-called "junk DNA."

Drugmakers had hoped that when they discovered a gene linked to a certain disease, they would be able to use that knowledge to devise a new drug. Now we're learning that the gene that causes a disease is actually irrelevant as a drug target. Instead, the key is in understanding the whole biological chain of events that occurs when diseases strike, and then selecting the best place in that chain to intervene.

The rise of proteomics

In all likelihood, we'll discover diseases are coded for by a variety of different genes whose products end up looking vastly different than their chromosomal origins. So identifying which diseases particular genes are responsible for, and finding ways to modify them, is like trying to predict which college a person will attend by examining their fetal stem cells.

To those ends, emphasis is being placed on understanding how and when genome-encoded events occur and what relationship non-genome-encoded events have to certain physiological states. On Wall Street, this is becoming known as proteomics because it focuses on the protein products of the genome and their interactions rather than on DNA sequence.

Proteomic companies use genes, but only to get at the machinery that is responsible for disease. Instead of focusing on the gene that might be related to a particular disease, these companies focus on the products generated by genes. It is proteins that are responsible for the incidence of the disease. The gene is important only in so far as it helps scientists identify the proper targets for new drugs.

It should come as no surprise that many biotechnology companies that made their primary trade in gene discovery have been quietly shifting their focus to uncovering the mechanisms that cause disease. They're using their gene discoveries and their novel sequencing techniques to identify relevant protein targets, but they don't expect the genetic code to provide more than clues.

Companies making this transition include some of the biggest names in the gene discovery trade. Rockville, Md.-based Human Genome Sciences makes sequence data available to a few pharmaceutical partners; however, now it also has three molecules in clinical trials.

Salt Lake City-based Myriad Genetics, made famous for its discovery of the so-called breast cancer genes (BRCA1 and BRCA2), recently went so far as to start a new subsidiary dedicated solely to the discovery of proteins that are manufactured by the genes Myriad has discovered.

Myriad's scientists have devised a method for rapidly discovering which proteins interact with others. As a result, they're now constructing networks of proteins and using them to find new proteins that may be promising drug targets in some diseases.

These companies encompass what has become known as the gene-to-drug paradigm, in which the genome is scoured for novel protein drug targets or protein biopharmaceuticals. This burgeoning field is not without its own set of technical challenges, but given what we've accomplished with the sequencing of the human genome, there's no reason to believe that these barriers won't be easily surmounted.

While stock prices are rising across the board, the differences between various biotechnology companies may matter little to short-term investors. However, the prospects of genomics companies will alter rapidly over the next decade.

Proteomic companies are poised to create a wealth of investment opportunities in biotechnology and eventually revolutionize the practice of medicine, shifting it from today's late diagnosis and symptom-based therapies to earlier diagnosis and disease pathway-based therapies in the new millennium.

Dr. Gottlieb is a resident in internal medicine at Mount Sinai in New York and a former analyst for the Wall Street firm Alex. Brown & Sons.