Depression

Lesson 8: The Science of Depression

The Genes and New Treatment Possibilities

Speaking of genes: The day of genetic blood screening appears right around the corner. For instance, if a particular gene says you will respond to Paxil, your doctor will say let's try Paxil.

At the National Depressive and Manic Depresive Conference in Boston in 2000, Dr Charles Nemeroff of Emory University talked about "antisense technology." Basically, RNA acts as a messenger that is involved in creating disease-causing proteins. Traditional drugs are made to interact with these proteins. By contrast, antisense drugs are designed to inhibit the production of these proteins by wrapping itself around the messenger RNA.

This is possible because the two strands of DNA partly uncoil, with the "sense" strand separating itself from the "antisense" strand. Under normal circumstances, the antisense strand transcribes enzymes which assemble messenger RNA, which leads to the production of proteins. Antisense drugs are complementary strands of small segments of messenger RNA. Once you know the sequence of messenger RNA, antisense binds to it, gets in the way, and "stops it dead." Scientists are already hard at work applying it to cystic fibrosis, as we know the gene responsible.

Antisense technology, Dr Charles Nemeroff informs us, is the "ultimate magic bullet." But for that to happen, these drugs would have to cross the blood-brain barrier, and we don't know yet if that is possible. Moreover, recent attempts with the technology on other diseases have been failures due to enzymes doing what enzymes do best.

Gary Stix, an editor at Scientific American, reports that, "scientists have encountered great difficulty in delivering genes where they are needed in the body and triggering their activation in cells."

Instead of genes, Stix argues, it's the proteins, stupid, and here life gets a lot more complicated. We may have sequenced the human genome, but no one has come up with a map of amino acids, the building blocks of proteins. We now know there are about 30,000 genes in the human genome, but there may be as many as a million proteins dispersed along 100 billion human cells, and even if we produced a picture of all of them at work, there exists yet another layer of the onion represented by a million constantly changing connections among our brain cells for each of the three billion units of DNA.

Writing in the Journal of the American Medical Association, W Maxwell Cowan MD of the Howard Hughes Medical Institute and Nobel laureate Eric Kandell MD of Columbia University note that neurology is a relatively new animal, with only 600 members in the Society of Neuroscience in 1968. Today, that figure is 25,000. These days, neurologists track down individual neurons and connect the dots to other neurons, and with sophisticated imaging techniques they can view whole regions of the brain in crisis or recovery.

According to the authors, the future is just about now, with molecular genetics and molecular cell biology leading the way. Schizophrenia and bipolar seem to be grabbing most of the headlines, with researchers tracking down suspect genes. Raymond DePaulo MD, the new chair of Johns Hopkins Psychiatry and Human Behavior and author of numerous articles on mood genes, recently told a gathering at NAMI's 2001 conference there is probably not a single gene that causes bipolar. More likely, we are dealing with several genes, each gene having a modest effect, which means flushing them out will not be simple.

Nevertheless, "when we find the first one, things will move very quickly."

Dr DePaulo argues that eventually our knowledge of genes will be used to illuminate the pathology of mental illness and find targets for rational treatment, something equivalent to giving insulin for diabetics - it's not a cure but it's smart.

These days, we define mental illness by a cluster of symptoms. Tomorrow, our treating physicians, armed with definitive readouts of our genetic and molecular markers, may simply tell us we suffer from a few chromosomal anomalies affecting some activity in the brain, and send us on our merry way with the perfect remedy. Since my chromosomal anomalies may look nothing like yours, saying we have the same illness could be as accurate as confusing the flu with a common cold.

Today, pharmacology works on the "one drug fits all" principle, with the paradoxical effect of fitting very few. In another decade or two, we will have drugs tailor-made to a person's genetic specifications. If we can believe what the scientists are telling us, routine gene-scans will successfully predict patients' responses to any given number of biochemical interactions. The hit-and-miss technique of trying medication after medication - often with heartbreaking results - will be a thing of the past.

But not so fast, says science writer John Horgan. In his book, "The Undiscovered Mind," he writes:

"Researchers forever seem to be on the brink of uncovering the key to aggression, depression, addiction, schizophrenia, even consciousness itself. The problem is they never get there. A century's worth of investigations has not produced a paradigm powerful enough to push Freud off his pedestal."

Medical science has at least a decade to prove Horgan wrong.

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