We wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA). This structure has novel features which are of considerable biological interest." – Watson and Crick’s substantially understated opening sentences to their article in "Nature" in 1953, announcing the revolutionary discovery of the double helix structure of DNA.

Let’s play spot the pattern.

"Association of a Triallelic Serotonin Transporter Gene Promoter Region (5-HTTLPR) Polymorphism With Stressful Life Events and Severity of Depression," reads one article, soon to be made into a major motion picture starring Johnny Depp.

"Association of the Dysbindin Gene With Bipolar Affective Disorder, reads another destined for a People’s Choice award.

And the one we’ve all been waiting for: "Gender-Specific Effects of the Catechol-O-Methyltransferase Val^108/158Met Polymorphism on Cognitive Function in Children."

Took the words right out of my mouth.

Before we start connecting the dots, we need to rewind the clock back 20 years to two articles in the Feb 26, 1987 "Nature":

"The use of DNA markers has shown that manic-depressive illness can be caused by a single gene," proclaimed a news piece in the same journal that published Watson and Crick’s groundbreaking discovery 34 years earlier. That was the trailer. The main feature came in the form of a research article which purported to have found such a gene. According to the study’s authors, an analysis of gene variants in a population of Old Order Amish "has made it possible to localize a dominant gene conferring a strong predisposition to manic depressive disease to the tip of the short arm of chromosome 11."

Wow! THE bipolar gene! Honey, round up all my lithium and start flushing! We’re going on a cruise!

Two years later, the same researchers acknowledged that they had badly miscalculated. Turned out this dominant gene was something of a 98-pound weakling.

Oops.

Nevertheless, the study served as a model for linkage studies to follow. Its lead author, Janice Egeland PhD of the University of Miami, has devoted her life to studying bipolar in Amish populations, and her research continues to shed invaluable light upon our illness, particularly in how symptoms first manifest in children.

In the meantime, the gene quest widened to genes (plural) quest. Depression and bipolar were way too complex to support the notion of a single gene, the new thinking went. There were likely to be ten or twenty or even dozens of gene variants lurking out there, each one making a small contribution. The trick was to match phenotype (symptoms) with genotype (genetic identity).

More recently, the hunt has broadened from phenotype to include endophenotype, namely poking around upstream or downstream of mood, such as for genes that regulate sleep or arousal or cognition or routine cell maintenance.

Are we getting any closer to fingering suspects? Read on …

Turning in Their Homework

A sampling of studies published in late 2006-early 2007 illustrate some of the principles behind gene research and how this research is changing how we think about our illnesses:

A Cambridge University and other centers survey of a large healthy population of children found that the boys with a variation in the COMT gene scored less well on intelligence tests than those without the variation. The variation may account for a 10 point deficit in verbal IQ in boys. The variation affects the enzyme that breaks down dopamine in the prefrontal cortex. The gene has long been in the police line-up for schizophrenia and is also being investigated for bipolar.

Dysbindin is another gene that researchers have been linking to schizophrenia due to a variation that appears to affect concentration. An Institute of Psychiatry (London) and other centers "power analysis" of earlier data suggests that "the human dysbindin gene may play a role in the susceptibility to bipolar affective disorder" and that the illness may overlap with schizophrenia.

The serotonin transporter gene may the most intensely scrutinized gene today. A 2002 landmark study involving brain scans on subjects performing mental tasks found that a certain variation resulted in increased amygdala activity, a part of the brain that governs fear, while a 2003 study on a New Zealand population found the same variation was associated with high rates of stress-induced depression. Together, these studies (and others) were cited by the journal Science as the second-biggest scientific breakthrough of the year (the big bang finished first).

Serotonin transporter gene studies are now coming in thick and fast. A recent Columbia University study supports the depression findings of the 2003 study while a Dutch study suggests that neuroticism (low emotional stability) may be the true effect of the variation rather than depression. Meanwhile, a recent Yale/NIMH study found that depressed patients in remission with the variation had greater activity in the subgenual anterior cortex (a region associated with emotional control), the hippocampus (which plays a role in memory), as well as the amygdala.

BDNF also featured in the same set of breakthrough studies singled out by the journal "Science." The protein encourages the growth of new neurons in the hippocampus and appears to be part of an involved chemical process that allows antidepressants to work. A 2002 study on family groups implicated a variation in the BDNF gene in bipolar disorder, with more studies flooding in. A recent University of Toronto study on families now more precisely targets rapid-cyclers.

Meanwhile, back in Serotonin Land (over the synapse and through the woods to the 2A receptor), an Oxford/Yale study of brain scans found that a genetic variation resulted in higher receptor-binding in the cortex of recovered depressed patients, which corresponded with higher dysfunctional attitudes.

And last but not least, a Johns Hopkins study among family groups found that chronicity in depression may be inherited. (Another way of putting it is that other people with depression may not inherit chronicity.)

Spotting the Pattern

Now to the broad picture. What these studies and others seem to be telling us is that our illness appears to be influenced by a host of genes that regulate a range of functions in the brain, including those not seemingly related to mood. In short there is no "bipolar" gene or "depression" gene – just genes that tell proteins what to do.

One or two or ten or a hundred of your genes may have variations that set you up for a mood episode, but your depression or bipolar may be an entirely different genetic animal than someone else’s depression or bipolar. Even if they are an exact match, there’s the whole matter of interactions with the rest of what your 25,000 genes are telling your proteins to do. No wonder one pill doesn’t fit all.

These findings and others are forcing us to look at our illnesses in different ways, particularly with studies indicating shared genes in schizophrenia and bipolar, not to mention underlying malfunctions that can possibly set off a whole host of possible ills or destructive behaviors.

On one hand, depression and bipolar appear to be amorphous phenomena that defy arbitrary diagnostic boundaries. On the other, we see evidence of micro-illnesses within illnesses. Sometimes, researchers have a far better chance of striking oil when they test for common variations in healthy populations. Other times, particularly with rare variations, it may be more productive for researchers to turn their attention to certain subgroups of affected populations, such as those who rapid-cycle.

Think of the process as taking apart a watch on one work station and putting it back together on another. The object is to learn what makes our illnesses tick. While we’re on the topic, what exactly is depression or bipolar, anyway?

Whichever way the research is heading, these studies and many more are already telling us that the DSM is a document awaiting the same fate as ancient runic inscriptions buried beneath the pedestal of the statue of Ozymandias. In essence, the DSM is offering "bad hair day disease" and "feeling real crazy today disease" as stand-ins for precise biological explanations, but that is bound to change. One or possibly two more editions carved in runes, then it’s a whole new ball game.

And to think as recently as twenty years ago, we thought a single gene could explain practically everything.

Back to the Future

Hold onto your hats. The single gene theory is back. Back in 2001, I happened to run into Amar Klar PhD at the Fourth International Conference on Bipolar Disorder, hosted by the Western Psychiatric Institute in Pittsburgh. Dr Klar is the head of the Developmental Genetics Section at the National Cancer Institute and worked under James Watson at the Cold Spring Harbor laboratory.

Dr Klar was not at the conference as an invited speaker. Instead, as he related to me, he was chatting up the bipolar experts there for feedback on what seemed a very bizarre theory of his. I hardly understood a word of it, but it had something to do with the psychosis in bipolar and schizophrenia being caused by a single gene and that all this was tied into a yet-to-be discovered gene that governed left and right-handedness.

Crazy, man, crazy. Not surprisingly, Dr Klar reported to me he wasn’t exactly winning over converts. Nevertheless, I filed his theory in my head. Dr Klar was obviously digging far below the surface. Even if he were way off-base, could not one genetic malfunction have multiple effects that crossed illness boundaries?

A PubMed search reveals that Dr Klar had published a paper on the topic in a schizophrenia journal in 1999, plus succeeding papers in the genetic journals over the years. Sporadic psychiatric support is evidenced in some of his collaborators in other papers he has published.

In Jan 2007, the single gene theory received a major boost in an article in the American Journal of Psychiatry. The article’s author, Timothy Crow MD, PhD of Oxford University has been pushing his version of the theory for at least as long as Dr Klar. Perhaps this explains why the article conspicuously makes no reference to his apparent rival’s work. Oh well …

According to Dr Crow, the findings to date that purport to link certain genes to bipolar or schizophrenia are unconvincing, and for psychosis in particular "there is no obvious criterion for distinguishing signal from noise."

Dr Crow’s argument for a single psychosis gene is that the structural changes in the brain are fairly consistent, indicating the handiwork of one culprit rather than "a number of unrelated genes varying independently in different populations." Moreover, the incidence of psychosis is constant, even in separated populations supposedly influenced by different genes. Finally gene studies have failed to tease out different genes for different types of psychosis.

Skip this part if you’re one of the majority of Americans who don’t believe in evolution: According to one theory, brains in humans became asymmetrical when man developed the capability for language between 100,000 and 150,000 years ago, an event predated by a crucial genetic "translocation" in our primate ancestors six million years before. With the upgrade from symmetrical to asymmetrical, further genetic rearrangement occurred.

Here’s where handedness comes in. Our symmetrical primate cousins do not express a preference for either hand. Meanwhile, right-handed humans favor the left side of the brain where language resides. Psychosis somehow results when the genetic coding for handedness gets bungled. According to Dr Crow, psychosis can be seen as a disturbance of language, "as deviations in the transition from thought to speech production or from perceived speech to meaning."

So where is the hard evidence of this magic and mysterious single gene? Dr Crow theorizes the causation may be "epigenetic" rather than strictly genetic.

Epigenetics is a new branch of genetics that attempts to explain why identical twins aren’t exactly identical and other anomalies. Recently, scientists found that so-called "junk DNA" in fact interacts with other genetic material. Researchers such as Arturas Petronis MD, PhD of the University of Toronto theorize that dynamic epigenetic fluctuations may account for why bipolar is cyclic in nature and why it tends to surface during periods of major life transitions.

Think of chaos theory for the time being, one unidentified gene acting with an apparent random force producing an improbable result.

But is it possible? All this crazy talk about handedness and language and psychosis and just one gene? The short answer is we’re talking about unexplored universes, and that we are embarking on an exciting new era of discovery. Who is to say that the road from here to the future can’t take us through 1987?

Parting Thought

"We have a treasure trove of new genes to explore, including many that may prove more important than the few neurotransmitters and intracellular signaling molecules that have been studied so intensively these past 50 years."

Thomas Insel MD and Francis Collins MD, PhD, directors of the NIMH and Human Genome Project, respectively, writing in a special issue of the American Journal of Psychiatry (April, 2003) that commemorated the fiftieth anniversary of the discovery of the double helix structure.

For 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.

May 9, 2007

Newsletter

Your online source for issues that matter to you.

For free samples, email me and put "Sample" in the heading and your email address in the body.

Find out more.

Bookstore

Shop for depression and bipolar books online here.