by Greg Gibson
Two major places in the MHC seem to provide some protection. Unimaginatively, as usual for human geneticists, one is called HCP5. It encodes a rogue copy of the enzyme that turns RNA into DNA in other retroviruses. There are signs that the whole gene is a new arrival in the genome, since it is found only in some primates. Worse, the protective allele is once again almost absent from Africans, and Asians as well. Only five percent of Caucasians have it, but for those who do, like CCR5 Δ32, it is something of a genetic condom.
Not far away is a much more common variant found in about half of all people that also affects the amount of virus in the blood. This allele appears to affect the utilization of a portion of the MHC that was not previously thought to play a role in recognizing any viruses, let alone HIV. Together with HCP5, it explains as much as 15 percent of the variation among patients in how much virus they have in their blood. Presumably, if all of us had the alleles that are currently low frequency, then there would be a lot less AIDS.
Quite a way further down the chromosome is yet another variable site, this time in the ZNRD1 gene that actually lengthens the time interval between infection and onset of disease. ZNRD1 is what we like to call a housekeeping gene: It has a crucial yet somewhat dull job in every single cell. That job is to make components of protein factories. It is bizarre that this variant influences AIDS susceptibility, analogous to changing a minor component of all the local power relay stations around the country and then observing that we’re now protected against a particular brand of terrorists. Perhaps I should wait until the result has been confirmed and studied more before trying to explain it any further.
The point is, though, that if genetic factors influence how much virus a person has in his blood, or how long a person can survive with the virus, there ought to be ways for scientists to work out how to manipulate the genes. Doctors might also be able to use the patient’s genotype to guide when they ought to start administering the expensive drugs while minimizing the time that the virus has to evolve resistance. Without a doubt, education and sound public policy are the keys to dealing with HIV globally, but it is likely that new generations of drugs will play their role as well.
HIV Imbalance
The youth of HIV as a human virus may be the greatest source of its threat to our species. Astonishingly, simian forms of the virus, SIV, are widespread in chimpanzees and some other apes, where they cause minimal morbidity. Similarly, the closely related feline immunodeficiency virus, FIV, is common and relatively benign in wild cats such as cheetahs. For some reason, canines are free of such viruses (one is tempted to say, on no grounds other than the pure prejudice of a dog-lover, because of their intelligence).
Tellingly, SIV and FIV both become deadly agents of immune disease the minute they cross into a nonexposed sibling species. Domestic cats that become infected soon succumb to AIDS-like symptoms, indicating that they do not have the antiviral defense mechanisms that have evolved over millions of years in their wild relatives. Macaques are the preferred animal model for AIDS studies because, like humans, they have not carried SIV during their sojourn as a species, and it causes them to become sick. Wait another few thousand generations and it seems likely that we too will evolve responses that allow us to live with the virus as a normal part of our biology, much as most humans coexist with CMV and probably many other viruses.
Current thinking is that HIV jumped from primates to humans on two separate occasions early in the last century. There are actually two different lineages of the virus. HIV-1 is the more pernicious form and is the common one outside Africa. It was probably contracted through an open cut in a person who was butchering an SIV-infected chimpanzee, and quickly evolved into the human form. HIV-2 may have arisen more recently from a sooty mangabey, since its sequence looks most like the form of SIV found in that species of monkey.
For a while, a conspiracy theory was doing the rounds, asserting that HIV crossed into humans during the preparation of polio vaccines from monkey kidney cells in the Belgian Congo in the early 1950s. The first documented case of a patient with the virus comes from around that time, in Africa, but this is likely just a coincidence. For one thing, the molecular clock method tells us that the virus was almost certainly in humans several decades before then; for another, an old vial of the original vaccine has no trace of it, and it turns out that only macaque kidney cells were used in making the vaccine, but macaques don’t naturally have SIV.
The bottom line, in any case, is that AIDS is a very young human disease whose primary cause is a virus that is only now in its third or fourth generation of human exposure. Yet there is a wide range of genetic variation for how people respond, some of it reflecting our general history of disease, some of it possibly of little or no functional importance until now. The situation is little different from the other major common diseases that this book is concerned with, namely cancer, diabetes, asthma, depression, and dementia, but for the fact that the environmental exposure is to a virus rather than carcinogens, carbohydrates, pollutants, psychological stress, and unusually old age.
At first blush, it may seem strange there is any variation in our genomes for how we would respond to a new pathogen. One view of evolution supposes that species are so exquisitely finely honed, that they do not carry around any variation not needed for some purpose. Defending oneself against a virus that did not exist in all but a handful of people until 20 years ago would not seem to be much of a purpose. Proponents of this view would prefer that the variation had arisen after the threat appeared, as an adaptive response, waiting to spread through the gene pool. But there has patently not been sufficient time.
A different view has it that in fact the situation is the opposite, namely that the genome is full of variation of so little consequence that natural selection cannot be bothered with it. This is particularly apt for a species such as ours that has just come through a rapid evolutionary spurt and is equilibrating to all manner of new situations. On this view, it is to be expected that some of this variation all of a sudden assumes functional significance in the new environment. HCP5 could be an example of this effect, a mutation that has had little consequence since it popped into the chromosome, but which now confers protection against HIV.
An even stronger version of this theory posits that, in fact, the genome has evolved to suppress the effects of some genetic variation. If you own a pool you might consider the pH tests you’re supposed to run every few days, where the test solution is green for the first dozen drops you add from tube M007, and then suddenly turns red on the thirteenth drop. What is happening is that the extra little bit of perturbation pushes the chemical system past a threshold, and it switches phase.
Genetic systems are similar. They are so exposed to differences in the environment that they have evolved buffering mechanisms that minimize the effects of hundreds of subtle mutations that are in the gene pool. These subtle mutations drift around not bothering anyone until some major change in the environment pushes them outside the buffering zone, and now they influence the course of disease: Sometimes they may promote it; sometimes they protect us from it. In this respect, HIV is just a microcosm of the same types of processes that affect many other complex human diseases.
6. Generating depression
creative depression It is amazing how many world leaders and entertainers have suffered from the disease.
an epidemic of mood swings Depression is on the rise, afflicting well more than 1 in 10 people at some point in their life.
bipolar and monopolar disorders Each, with differing degrees of severity, are much more than prolonged sadness.
the pharmacology of despair Serotonin and cortisol are a neurotransmitter and a hormone that jointly regulate mood.
misbehaving serotonin Genetic variation in the serotonin transporter is associated with some measures of depression and suicide, particularly if life is stressful.
faint genetic signals It seems likely that hundreds if not thousands of genetic variants contribute
to mood disorders.
schizophrenia and other mental disturbances Many other types of mental problems are equally as genetically complicated.
the genetic tightrope of the mind Cultural and genetic change have affected the brain perhaps more than any other organ.
a kindling theory in the modern world Depression gets worse with time as mood becomes less stable and more sensitive.
Creative Depression
When the “Piano Man” sings about men at the bar sharing a drink they call loneliness being better than drinking alone, the melancholy is somehow erased by something uplifting in the melody. Few people are aware that the lyrics of another of Billy Joel’s anguished songs, “Tomorrow Is Today,” were penned as a suicide note. For most of us, complete loss of the will to live is incomprehensible, yet more and more people experience the profound and debilitating sadness of clinical depression. What’s going on and what might our genes have to do with it?
It is astonishing to consider how many creative artists have fought or fight the demons of sadness. When Saturday Night Live’s Chris Farley committed suicide, it came as a complete shock to the American public, but he is just one of a half dozen well-known comedians who have at least attempted to take their own lives. Contemporary funnymen Drew Carey and Jim Carrey express their infectious senses of humor in different ways, but for each, the public persona belies private swings of darkness. The bullet in Kurt Cobain’s temple left little doubt that he was unable to find his personal Nirvana here on earth. Even a whole genre is named after the blues. And can it really be true that Harrison Ford, the actor behind the swashbuckling heroes Han Solo and Indiana Jones, got his start in acting in part because his inability to overcome depression-induced sleeplessness had him thrown out of high school?
Nor are intellectual and world leaders immune to the debilitating shadow of sorrow. Two of the towering figures of the nineteenth and twentieth centuries, Abraham Lincoln and Winston Churchill, both suffered from melancholy and depression. Some have argued that Churchill drew inspiration to overcome adversity and the forces of evil from his battles with what he called his “black dog.” Few can argue that the illness can be a well of tremendous creativity: Witness the talents of such profound writers as Tolstoy, Goethe, and Kafka; consider the lives of Tennessee Williams and Ernest Hemingway.
This male-biased menagerie misses a crucial point, which is that women are in fact far more prone than men to mood disorders. If you read accounts on the Web, you quickly notice that depression in women is often attributed to situational cues. Lady Diana, Princess of Wales, battled bulimia in the glare of the enormous pressure of popularity while trapped in a loveless marriage. Brooke Shields and Marie Osmond are the poster women for postpartum depression. Amy Tan and Anne Rice are said to project the tragedy in their lives.
The reality though is that the disability has organic roots and casts a shadow that must be managed and confronted on a lifelong basis for tens of millions of typical adults, the majority of them women. As Sheryl Crow puts it in “Soak Up the Sun,” she’s “gonna tell everyone to lighten up (because she’s) got no one to blame for every time I’m feelin’ lame.” There is no point in blaming the genes either, but as we shall see, these are part of the equation, once more because we’re still finding our way as an evolving species.
An Epidemic of Mood Swings
At any given time, somewhere in the vicinity of four percent of women between the ages of 25 and 45, and two percent of men, are clinically depressed. These are conservative estimates. They mean that without a doubt someone in your neighborhood or workplace is struggling mightily to face each day with characteristic cheer. Multiply them by five to obtain the number of people experiencing the blues, and double again to arrive at a lifetime estimate of the fraction of the population that experiences at least one somewhat debilitating episode of depression.
As far as we know, this disease recognizes no ethnic or socioeconomic boundaries, though of course it is almost impossible to know. Many countries refuse to recognize the existence of mental illness, let alone assemble accessible mental health records. One thing we do know is that in the developed world, it is the leading source of lost life potential. It is expected to become the second leading source of disability worldwide, behind heart disease, in the next decade.
For this reason, depression is sometimes said to be epidemic, implying that it is more prevalent now than ever before, and maybe that it is spreading in an infectious manner. If there is an infectious agent, it is almost certainly cultural, not microbial or viral. Whether depression is truly on the increase is difficult to know. Some authors maintain that the prevalence is underestimated by as much as fifty percent, due to the stigma attached to mental health and the ends that people will go to in order to hide their socially unacceptable anguish. Others maintain that it is overdiagnosed to at least the same degree, because people who are just dealing normally with growing up or with trials in their lives are being incorrectly tagged as depressive.
Those who have never battled the disease often suppose that it is just an extreme form of sadness, but anyone who has so much as brushed against a prolonged episode of depression is more likely to recognize the deeply organic nature of the disease. Every person’s experience is unique, but in the midst of the inability to sleep or to care or to just perform daily routines is the awareness that it is all so very wrong. You know that your behavior is self-destructive, that it is hurting friends and family, and that there is no rationally defensible reason for you to be so self-obsessed and sad. Yet you are absolutely powerless to purge the negative feelings. You can almost feel the bad chemicals swimming around your mind, imposing their will on your mood as surely as alcohol swamps your conscious well-being in a very different way.
For a chilling description of what a mental breakdown due to depression is really like, try Andrew Solomon’s The Noonday Demon. Subtitled An Atlas of Depression, this is a superb account of the disease from the perspective of dozens of different patients, full of sanity and realism. It opens with a telling description of the author’s own battle with the demons, from childhood anxiety attacks to the incapacitating depths of despair in the months after publishing his first novel. What a frail thing is the human mind, what a wonderful thing its capacity for compassion and understanding.
Bipolar and Monopolar Disorders
Psychologists commonly recognize four subclasses of the illness. A basic distinction is made between unipolar and bipolar affective disorders, and within each of these there are at least two categories of severity. Since polarity by definition refers to orientation with respect to two opposites, the term unipolar makes about as much sense as a magnet without North or South, or the sound of one hand clapping. It is used to distinguish patients who experience only the lows of depression from those who alternate low with high episodes, the term bipolar supposedly carrying fewer stigmas than manic depression.
The least disruptive form of depression is a pattern of constant lack of interest in activities and inability to enjoy life that lasts for at least two years. The technical term is dysthymia, which is surely preferable to minor depression, because there is very little minor about it. Dysthymic individuals have problems sleeping, have persistently low energy levels, often either lose their appetite or have troubles with overeating, and may constantly fight feelings of helplessness and of poor self-image. The fatigue keeps them in bed for hours and hours into the day, yet it can also keep them awake long into the night. Doing things that come ever so naturally, such as making a cup of coffee, getting dressed, making a phone call, going for a walk, or even tucking the kids into bed become monstrous chores.
The way to navigate each day is to make each minute or hour a succession of mileage posts that are passed successfully, finding pleasure in the mundane and routine. At times the pressure may become so great that a person is effectively paralyzed, if not physically for minutes or hours, then socially for days or weeks at a time. It is a heavy burden to place on a ca
reer in this fast-paced world. It is a ghastly strain to impose on a marriage or relationship that started with such joy and promise. It is a debilitating tension on the psyche that sits constantly poised on the edge of complete breakdown. It is no way to lead a happy life, but it is the reality for 1 in 20 people today.
Major depressive disorder is worse. It is characterized by recurring episodes of pronounced inability to function in anything approaching what might be called a normal manner. It is worse than melancholy, deeper than grief, more than an exacerbation of the symptoms just described. Atypical episodes, which are actually more common, may include overeating and oversleeping, but can give way to leaden paralysis and heightened sensitivity. Normally calm people find themselves reacting with irrational irritability to slights such as being bumped into in the street or jumped in front of in a queue. These episodes of inability to react with positive feelings to anything last from two weeks to a month or two. Now days, chemical intervention is almost always prescribed.
Typical melancholic major depression involves loss of pleasure and a state of depression unlike anything most of us ever experience, a tendency toward anorexia, and such a slowing of thought processes that people are simply incapable of much more than lying around. Solomon describes being so low that he could not even contemplate suicide, the danger period for that and self-mutilation being during the recovery phase. In severe states, patients require nursing help with eating and essential bodily function.
Yet it can get worse, with the descent into psychotic depression. Symptoms include hallucination, aggression, feelings of intense hopelessness and frustration, loss of the sense of self, and possibly delusional or extreme paranoid behavior. I cannot imagine what it is like to live with the constant awareness that such a state may be just around the corner awaiting some trigger, tragic or prosaic, but always unpredictable, knowing too that the drugs that are effective in stabilizing the condition may not be able to hold back the tide of a psychotic episode.