This draws a round of hearty laughter from the audience. The venue is the Depression and Bipolar Support Alliance Conference in Boston in 2000, and the speaker is Charles Nemeroff MD, PhD of Emory University.

"How gullible was I," he acknowledges. The liver, he goes on to say, has the same composition no matter which way you slice it, while the brain's various parts are as different from each other as the liver is from the kidneys.

"Ninety percent of what we know about the brain," he tells us, "we've discovered in the last ten years."

One can hear some oohs and ahs from the audience, as well as sense a collective feeling of recognition. Of course, five hundred people are thinking at once, this explains everything, doesn't it?

Meanwhile, this new knowledge is on its way to finding new applications. For instance, PET scans may be able to tell doctors which drugs to prescribe, say an SSRI such as Paxil vs a novel agent such as Remeron. My notes say something about serotonin transporter sites, which some of you no doubt have written your masters thesis on.

Then there is the chemical dance of the reuptake process, which leads to the number one cause of SSRI noncompliance - sexual dysfunction. Why not, Dr Nemeroff asks, combine an SSRI with a "blocker" to block the side effect?

Searching for Depression and Bipolar Genes

The most exciting stuff is saved for last - the possibility of finding the genes responsible for depression and bipolar disorder and coming up with effective treatments. Ninety-six to 97 percent of human genes are identified in the chimpanzee, a species which does not suffer from bipolar or depression. So by process of subtraction we should come up with candidate genes fairly soon.

In another seminar, Robert Lenox MD of the University of Pennsylvania reels off the locations of the likely bipolar genes - chromosome 18, chromosome 12, chromosome 4, chromosome 22 ...

In 2000, John Kelsoe MD of the University of California at San Diego informed this writer:

"We have identified a gene on chromosome 22 which we believe plays a role in the susceptibility to both bipolar disorder and schizophrenia."

Before you let your hallelujah ring through the rafters, it pays to recall the false alarm that was raised in 1987 after a study of Amish families supposedly yielded the culprit near the tip of the short arm of chromosome 11. The researchers were forced to concede defeat two years later.

What's so different this time? For one, Dr Kelsoe and his team have the complete human genome at their disposal. Over the last several years, they have scanned the entire genome in a set of families with bipolar, attempting to identify a chromosomal region consistently associated with the illness.

The approach is called linkage analysis, and it led to "very strong evidence" for the presence of a gene on chromosome 22, identified by two peaks. This region has already been implicated in many studies of schizophrenia.

With the publishing of the entire genome, the team discovered that one of the peaks - at 22q12.1 - corresponded to the location of GRK3, whose normal role is to regulate the response and level of sensitivity to several neurotransmitters, including dopamine. It has long been argued that a supersensitivity to dopamine may play a role in bipolar and schizophrenia.

In four human subjects, reduced GRK3 expression corresponded with bipolar I, while the other two subjects not showing a GRK3 decrease had bipolar II.

In parallel with these studies, Dr Kelsoe and collaborator Alexander Niculescu MD, PhD were experimenting with amphetamine administration to rats as an animal model of mania. In Dr Kelsoe's words:

"We examined the role of 8,000 genes in the response to amphetamine and found that the gene with the biggest response to amphetamine mapped in man to that exact region on chromosome 22 that we identified in our clinical
family studies. Since then we have examined this gene in detail and found what we believe are several abnormalities that prevent it from working properly in a portion of people with bipolar disorder."

Together this set of data implicated the gene both through function and chromosomal position.

Collaborator Thomas Barrett MD, PhD then sequenced much of the gene to find six sequential variants - single-nucleotide polymorphisms (SNPs or "snips") - in the promoter of the gene, that region of the gene that switches the gene on or off. Dr Barrett then tested 153 families for association to these mutations and found that one of these, P-5, occurs three times more frequently in affected individuals. These findings were replicated at the University of Toronto with a separate set of 237 families, and in 2003 the researchers published their findings in Molecular Psychiatry.

Thus a picture begins to emerge, albeit still a hypothetical one: A P-5 mutation causing GRK3 to fail, resulting in the brains’ receptors’ inability to desensitize to dopamine, ending in a situation akin to, in Dr Kelsoe’s words, "being born on cocaine."

Now to the wider scheme of things: The study found that the GRK3 variant occurred in only three percent of bipolar families. Since single-gene disorders are a rarity, it probably isn’t the only gene responsible for illness in this population. For the other 97 percent of those with bipolar, multiple genes are believed to be the rule, as well, leaving researchers with the daunting task of teasing out candidates from some 16,500 genes believed to be expressed in the brain.

But Dr Kelsoe and his team have also identified five other suspect genes, grouped into "psychogenes" (that lead to mania or psychosis), and "psychosis-suppressor" genes (of which GRK3 is an example). The other psychosis suppressor is SULT1A1, found on chromosome 16, which inactivates dopamine and other compounds. A defect in this gene may lead to impaired clearing of dopamine from the synapse, with a resulting amphetamine-like effect.

The psychogenes include: IGF-I, on chromosome 12, which stimulates an enzyme in the biosynthesis of dopamine; DBP, on chromosome 19, which is involved in stimulant sensitization and circadian rhythms: FDFT1, on chromosome 8, which synthesizes cholesterol, which in turn has downstream effects on mood; and MALS-1, on chromosome 12, which helps regulate neurotransmitter receptors.

If Dr Kelsoe and company are on the right track, then the future is likely to bring more sophisticated diagnostic tests, together with more effective drugs.

Antisense Technology

Meanwhile, back at the DBSA Conference, Dr Nemeroff is talking 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 Nemeroff informs us, is the "ultimate magic bullet."

Ultimate, magic, and bullet, I highlight in my notepad, feeling a bit too jaded to take the speaker at his word. There is, after all, a blood-brain barrier these new drugs would have to cross, and we don't know yet if that is possible. Moreover, recent attempts have been failures due to enzymes doing what enzymes do best.

Then again, you never know. Perhaps the day will come - ten, fifteen, twenty years from now - when I leave the pharmacy with one of these new prescriptions. Then I will remember where I was when I first heard about this bright new promise. And so will the five hundred other people who shared a weekend in Boston.

And perhaps so will you, reading this article.

(See also Gene Quest.)

Click here for more on Dr Kelsoe's BP gene research and how to volunteer for a study.

For three free online issues of McMan's Depression and Bipolar Weekly, email me and put "Sample" in the heading and your email address in the body.

Updated Aug 10, 2003

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John Kelsoe: "We have identified a gene ..."