It Takes a Genome: How a Clash Between Our Genes and Modern Life is Making Us Sick

by Greg Gibson

  Speaking of triggers, two of the more prevalent forms of disease are postnatal depression and seasonal affective disorder (SAD). The baby blues, consisting of sleeplessness, irritability, headaches, and impaired concentration, apparently affect more than three-quarters of new parents and last a day or two (actually, for different reasons, a decade or two). But some combination of an anxious and naturally melancholy personality, the stress of parenthood, perhaps exacerbated by an unsupportive marriage, stressful job, substance abuse, hormonal swings, and flat out chance, leads to at least five percent of mothers (and some fathers) entering an episode of clinical depression. Untreated, postnatal psychosis can result in infanticide, a generally unthinkable crime that challenges our sense of personal responsibility, and which society is patently unsure how to approach.

  SAD by contrast is perhaps the best-named disease on the planet, although if the Icelandic term skammdegisthunglyndi rolled off the tongue a little better it could catch on as well. It means short-day-heavy-mood, and communities with a high prevalence know exactly what to do about it: bathe in the light of a sunlamp for half an hour every morning. My Seattle colleagues swear by it. Given a choice it seems simpler to live by a sunny beach. Citizens of the cloudy people’s republic of Ann Arbor regularly prefer to imbibe the target of sunlight, melatonin, and fittingly wander around battling jet lag symptoms half the year.

  Bipolar disease is also conveniently categorized in two types, I and II, which are differentiated by the severity of the manic phase. Mania refers to a period of elevated mood lasting for at least two weeks. The full-blown type I form is often associated with a racing mind as if the brain is working too fast. Sleep is disrupted, the person may be irritable or may be unable to pay attention, and delusions of grandeur are frequent, giving way to psychosis, namely a loss of contact with reality. Less than one percent of people suffer in this way, but an equivalent number if not more may experience the lesser form, hypomania.

  Hypomania on the face of it does not sound so bad. Many of us would gladly experience the creative surges that accompany the state, allowing people to write poetry, compose music, have unusually original ideas, and overcome social inhibitions for a time. It sounds a lot like staying at a Holiday Inn Express overnight. I wonder whether that experience also blunts a person’s emotions and makes a person laugh uncontrollably.

  Typically, manic and depressive phases last a month or two and alternate every other year, but there is enormous variability. Some cycle much more rapidly, several times a year, and some experience both conditions simultaneously, which you can imagine makes for a volatile state of mind. Some have much stronger manic phases, while some have more prevalent depression. Particularly in children, diagnosis is complicated by coincidence with other psychological conditions including attention deficit hyperactivity disorder and schizophrenia.

  One final feature that all modes of depression seem to have in common is that left untreated, the episodes tend to get more intense and more frequent as life proceeds. A first episode of major depression almost always indicates a lifetime of battles, with control, rather than cure, the therapeutic objective. A depressive’s mind wanders along the edge of the cliff, prone to missteps that leave it clinging to sanity until rescued by a helping hand that can never quite drag it to the plane of normality.

  The Pharmacology of Despair

  Serotonin is e-mail for the brain. This one little chemical seems to be the key to the lousy mental state of a billion people whose neurons just can’t communicate efficiently. One way or another it is the target of just about every antidepressant drug on the market, and quite likely of psychotherapy as well. Google “serotonin” with “depression,” and you will find hundreds of thousands of hits. Search with the same two words on the academic search engine PubMed, and you will be led to more than 12,000 scholarly articles. This is a pretty good indication that the two are linked, but also that we really don’t understand how.

  It is all so very complicated. Serotonin does many different things with many different partners, and many different things do some of the things that serotonin does. Among those 12,000 articles you will find references to inducement of vomiting, the age at which we first have sex, sudden infant death syndrome, and aggressive lobsters. They will tell you that humans have seven different types of receptors encoded by 14 genes, and impart more exquisite detail concerning the biochemistry and pharmacology than even an expert can possibly assimilate. Look more deeply and you will discover that at some level most mood-altering drugs converge on serotonin: ecstasy and crystal meth, LSD and all manner of psychedelic snuffs, Ritalin and Fen-Phen, pituri and betel nuts, and indirectly even caffeine and nicotine.

  So while low levels of serotonin activity are certainly causal in depression, simply bathing the brain in the chemical is not necessarily a particularly good idea. Actually, it is not that simple, either, since ingested serotonin cannot find its way into the brain. You can try eating foods rich in its precursor, tryptophan, which is said to help, but in my experience those who have diets rich in cottage cheese, wheat germ, and soy aren’t necessarily happier than the rest of us. (Actually, poultry, fish, eggs, avocados, and other beans are also good sources.) The preferred method of serotonin enhancement is via a host of drugs.

  To see how these work, let’s return to the e-mail for the brain analogy. We’re not talking about the content of the e-mail here, just the fact that it is a major means of communication. It facilitates talk between neurons, while the content of the messages is a function of which neurons are being connected when and how. Serotonin is not an information-carrying molecule, it is just a chemical that connects one neuron to another, encouraging the electrical signals to continue along their way. Many other chemicals have a similar role, and we can think of them as regular mail, telephones, and text messaging, but why interference of serotonin in particular leads to depression is simply not clear.

  In any case, if you are using dial-up or have an unreliable Internet service provider, then your e-mail is slow, and these days most of us can’t function properly without it. This is basically like not making enough serotonin, so drugs such as SAMe and 5HTP have been introduced because they fiddle with the enzymes that convert tryptophan into serotonin. For some reason, they are not yet particularly popular, even though clinically they can be effective and seem to have limited side effects.

  Then, perhaps you are still using one of the old e-mail servers such as Pine or Eudora, in which case you can function but probably are not utilizing e-mail as effectively as you might. This would be the situation if one or more of the receptors for serotonin were not functioning properly, but unfortunately the pharmacology is too complex, and fixing this has not proven to be a fruitful approach to treatment.

  The most fixable problem with depression seems to be that our natural servers delete e-mails at a rapid rate, sometimes so quickly that the message doesn’t get through. This can be alleviated by preventing the decay of serotonin, or by preventing it from being reabsorbed by the neuron that was using it to send a message in the first place. Monoamine oxidase inhibitors (MAOIs) were the original antidepressants. They work by inhibiting the enzyme that degrades serotonin in the gaps between neurons. However, they also act on several other essential chemicals, so have a variety of nasty side effects, and can cause potentially fatal interactions with other drugs and foods.

  They have generally been replaced by tricyclic antidepressants or by selective serotonin reuptake inhibitors (SSRIs). Prozac is the best known, but Zoloft and Paxil are heavily advertised, and there are at least a dozen others. Wellbutrin, preferred by many in part because it has less of an effect on weight gain and libido, inhibits reuptake of another signaling chemical, dopamine, but may act by indirectly stimulating serotonin release.

  Each of these drugs has advantages and disadvantages, and it turns out that there is enormous variation in how people respond. Consequently, it can take months to years for clinical psychologists to find the combination a
nd dosage that is right for any particular patient. Most settle on a cocktail that balances the improvement of mood with acceptable side effects, and once they have done so are advised to stick with the drugs for the rest of their life.

  Of course, the major problem that plagues e-mail is spam. It is thus surprising that there is precious little written about the possibility that too much messaging can clog up the serotonin system. Manic phases are largely attributable to an excess of serotonin, as are hallucinogenic highs, but that is not the same thing as too much junk signal getting in the way of normal communications. The idea that depression arises not so much from a deficit of serotonin, but rather from the buildup of resistance to it (much as diabetes arises from resistance to insulin), is just starting to gain traction. It is a controversial hypothesis, but an attractive one with respect to understanding the evolution of sadness, as we shall see at the end of the chapter.

  Something that is not at all controversial is the role of stress in promoting depression. Psychological stressors such as losing a family member, experiencing prolonged financial hardship, or coping with mental abuse are regarded by many as kindling for depression. They are the sparks that light the fire.

  One of the major responses to stress is the activation of cortisol. Cortisol is also the hormone that gets us out of bed in the morning and does many other things such as suppressing the immune system (making us susceptible to infection in the days after a prolonged period of tension) and contributing to obesity by mobilizing blood glucose. Conventional wisdom is that cortisol levels shoot up in depressed patients and contribute to the mood change, either directly or by feeding back to serotonin. Not surprisingly, the pharmaceutical industry is hot on the trail of cortisol inhibitors.

  In the meantime, we have Relacore, America’s number 1 belly fat pill. According to the manufacturer’s Web site, excess tummy fat is not a woman’s fault, but rather arises from the harmful combination of everyday stress, overeating, and excess cortisol. The recommended solution is to take this natural mood enhancer and antistress pill that makes you feel better and lose the belly fat by inhibiting serotonin’s natural antagonist. Like so many of the advertisements for antidepressants that show melancholy people taking the drug and soon thereafter hiking with the family through mountain meadows, playing fetch with the dog, and generally enjoying life, you have to wonder whether there aren’t more effective ways of combating the hormones that keep us down—such as going for a hike or playing with the dog.

  Or attending psychotherapy sessions. Data suggests that just taking antidepressants works only for about half the population. Similarly, talking with an expert is effective for no more than half of us. But combining the two seems to work well, helping probably at least three-quarters of the clinically depressed population to manage their disease.

  Misbehaving Serotonin

  Depression is one of the most genetic illnesses there is; yet paradoxically no one has yet found a gene for depression. Certainly not in the sense of “if you have this mutation, you will be bipolar,” but also not even conclusively in the sense of “if you have this variant, you’re strongly predisposed.” There are some suggestions, as we’re about to see, but they’re at best of the “maybe, sometimes, depends on the circumstances” type—which actually makes them interesting.

  Even though bipolar disorder afflicts only a few percent of the population, identical twins have about a 70 percent concordance rate. That’s maybe a fiftyfold increase in susceptibility by sharing all your genes (and the womb and upbringing) with your twin. Even nonidentical twins have a 1 in 4 chance of bipolar disorder if their twin is afflicted, also heavily implicating the genome. It is similar for major unipolar depression, though perhaps with a slightly reduced genetic component.

  If you’re thinking that the genes that mediate serotonin signaling might be good places to look for an involvement in depression, you’re not alone. The serotonin transporter gene, variously known as 5HTT, hSerT, or SLC6A4, has been a particularly popular object of genetic studies for three reasons. First, SerT is the protein that Prozac, Zoloft, and company act on. Second, many of the studies do actually detect some tantalizing link between variation and mood. Third, a couple of unusual features of the gene affect how much it is used.

  Basically, humans have a short and a long form at the front of the gene, and another section of variable length in the middle of it. The one that has been linked to depression is the first one, known, for good reasons that need not concern us, as the 5HTTLPR. About half of us have one copy of each allele, while one-quarter of us have two copies of the long form, and similarly one-quarter have two short forms. It turns out that people with the short form make less of the protein, which almost certainly affects the amount of serotonin that lingers in the little gaps between neurons.

  SSRI antidepressants function by preventing 5HTT from transporting serotonin out of these gaps, so it stands to reason that the 5HTTLPR should affect the onset of depression. Well, sometimes it does, and sometimes it doesn’t, and after pooling the results of dozens of studies together, maybe the short form increases your chances of having depression somewhat, but no more than 20 percent. It is a surprisingly small risk factor, and also surprising in that the less active form provides the risk—unless continued elevation of the chemical over time leads to serotonin resistance.

  The story does not end there, though. There are a couple of interesting subplots. Because major depression so often leads to suicide, people have asked whether this polymorphism might be involved in the tendency to commit suicide. Believe it or not, suicide also has a large genetic component to it. Several studies have suggested that the short form has a highly significant impact on the incidence of violent suicide, but not of nonviolent suicide. It came as a surprise to me to learn that there is a difference, and the authors of the papers assume this is self-evident. Presumably gunshots, hanging, and jumping off a cliff are violent methods. The speculation is that 5HTTLPR is having an independent effect on the tendency to aggression and self-mutilation, which combined with depression, pushes someone toward violent attempts on their own life.

  Dunedin is a city of just more than 100,000 people situated close to the tip of the south island of the beautiful country of New Zealand. It faces out into the great Southern Ocean, next stop Antarctica, and bears the brunt of its cool, damp winds that bring clouds, drizzle, and the sort of conditions that make a person sad. It seems an unlikely place to carry out a groundbreaking study of the genetics of depression, but nevertheless that was the case back in July 2003.

  The research team followed almost 1,000 Dunediners from birth through young adulthood. They recorded the number of stressful life events each person had to cope with between the ages of 21 and 26: One-third of them were charmed; one half had one or two episodes of financial, health, relationship, or similar stressors; and the remainder were not so lucky. Around 17 percent experienced some measure of depression in their 26th year, and 3 percent reported either attempting suicide or thinking about it a lot. The startling finding in this study was that neither stress nor genotype alone had much of an effect on measures of depression, but the combination mattered a lot. Experiencing three or more stressors and having at least one copy of the short 5HTTLPR more than doubled the probability of depression symptoms, of clinical major depression, and of suicide thoughts. Additionally, adults with the short form were found to be far more likely to suffer episodes of major depression if they had been maltreated as children.

  This was a landmark study because it confirmed with hard data the long-held suspicion that the interaction between a person’s genetic makeup and their environment is what really matters. A dozen groups around the world have since had some success in replicating the finding, though it must be said that not all of them succeed. That is not really surprising, given the complexity of both the biology and of study design. Interestingly, the same group a little earlier had found a similar interaction between a gene that encodes the enzyme that degrades seroton
in, monoamine oxidase, and the experience of parental abuse as children. Again, the type of allele or upbringing alone had little effect, but the combination of genetic and environmental risk factors increased the incidence of acts of violence and other antisocial tendencies committed by the teenagers and young adult men. These types of studies are notoriously controversial and the specific conclusions should be taken with a grain of salt, but they point in a direction that many believe must be true, namely that what genes do is very much a function of everything else going on with the person they find themselves in.

  Faint Genetic Signals

  All this searching for the key to depression underneath the lamplight of serotonin is fine, but we need to remember that it takes a genome. When the book on the genetics of sadness is finally written, it will surely also include entries on the enzymes that synthesize the chemical and on the receptors that take up the signal. It is increasingly apparent, though, that it must include dozens if not hundreds of other chapters that can barely be sketched in outline yet.

  The search continues using more traditional approaches. Linkage mapping in pairs of affected twins has turned up a dozen possibilities. This is where researchers look for parts of the genome shared by non-identical twins who both have the disease. As a matter of logic, siblings always share about a half of their genes, but if the same region of a chromosome is shared in a sizeable fraction of hundreds of twins, it suggests that there is a gene thereabouts. One strong possibility is a gene called PREP, not because depression is a preppie disease, but rather because it encodes prolyl endopeptidase, an enzyme that processes a class of mood-altering hormones in the brain.