by Greg Gibson
Some people, it appears, have genes that force them to present their new arthritis-promoting antigens to the immune system. As we have seen previously, these perfectly good and even essential genes are being forced to do something harmful specifically to humans in their modern environment. Aside from a fictional camel named Joe, other animals are not exposed to tobacco smoke. You just don’t see many chimpanzees sitting around the Serengeti dragging on a pack of Marlboros. Those proteins that are presenting the citrulline on the surface of your cells do that for a living, but now they have been duped into delivering the wrong message.
Once more it appears that susceptibility to arthritis seems to be advanced in people who have a particular set of alleles in their Human Leukocyte Antigen genes. Recall that these are the baseball mitt-shaped picture hangers that present bits and pieces of molecules on the outside of our cells where the immune system can see them. To be precise, people with MHC Class II HLA-DRB1 SE are more likely to present the unusual homemade antigens such as citrulline, and hence to experience rheumatoid arthritis. This is just one of the many variable alleles in the HLA complex.
Inevitably, the stored up variation in the MHC can be led to do bad things. Another example is provided by the multiple sclerosis that afflicted the character Jed Bartlet on the television show The West Wing. For millions of Americans he served as surrogate President of the United States in the early 2000s, and the prospect of losing him to MS was as devastating as the glimpses we saw of progressive loss of central brain function that results in pain, depression, loss of coordination, vision, and many other symptoms.
It is likely that Jed carried the DRB1*15 allele as one of his HLA flavors. Had his son-in-law been a medical geneticist rather than a much-ridiculed Drosophila geneticist, perhaps we would have found out. This flavor happens to present fragments of the protein myelin particularly well. Myelin is just one of the hundreds of thousands of fragments that DRB1*15 can present. Normally it does not get the chance to do so because the T-cells do not cross something called the blood brain barrier. But in MS patients, immune invasion into the brain is triggered, perhaps by a bout of flu or high levels of stress, and a process begins that is analogous to that which causes arthritis in the joints.
The difference is that myelin is the substance that insulates the axons of your neurons, allowing signals to be communicated at high speed. Attacking it would be like someone sabotaging all the telephone lines that connected your home to the outside world.
The other really terrible well-known autoimmune disease is lupus. If arthritis is akin to friendly fire, then lupus is outright bullying at the hands of those assigned to protect you. Debilitating waves of attacks on the skin, joints, heart, lungs, blood vessels, liver, kidneys, and even the nervous system can strike at any age, and women are particularly vulnerable. Lupus apparently gets its name from the appearance of wolflike red blotches on the face, but that is as obscure as the disease itself.
Again the MHC region is implicated, but so are a dozen other places in the genome whose roles are yet to be defined. So too are stress, sunlight, and infection, and certain drugs can bring on the symptoms as well. The only good thing that can be said about lupus is that it is relatively rare and not obviously on the rise like so many other diseases.
Imbalance of the Immune System
The wonder with all of these diseases is not so much that they happen, but that severe forms afflict only a few percent of us. As with cancer and diabetes, we’re dealing with an extremely complex genetic system in a species that has done an awful lot of evolving recently, in an environment that is fundamentally foreign with respect to most of our history. The question, “Why are there genes for arthritis?” is as misplaced as asking, “Why are there soldiers who fire on their own?” They don’t mean to; it just happens.
Let’s consider the complexity first. All organisms face a bewildering array of microscopic enemies. Belligerent bacteria, vile viruses, and pesky parasites confront the immune system with different challenges that must be met in cavities as different as the throat, intestines, joints, and sexual organs. It meets these challenges with immediate mechanisms such as coughs and sneezes, and an innate system that does things such as drilling holes in any bacteria that turn up where they should not be. Then it kicks in the so-called adaptive immune response, which has many layers and modalities depending on the specific needs. There is so much to coordinate that it is almost unavoidable that things will go wrong occasionally.
Some may say that this argument is a little bit of a cop-out, because adaptive immunity has been around for more than a hundred million years. Evolution has had plenty of opportunity to solve the riddle of how to distinguish self from foreign, so maybe you would think it would have perfected it. But as far as we know other mammals also get arthritis, degenerative encephalitis, lupus, asthma, eczema, and inflammatory bowel disease—support groups for dog and cat owners can readily be found on the Internet. It is just a downright difficult problem.
Next is the reality that optimal immune function is a constantly moving target. It is a bit of a myth to think that there is a single optimum value for any human trait, be it height or blood glucose levels or level of extraversion. It is definitely a myth to think that there is one optimal way to defend ourselves. This is most clearly seen for the MHC, which is the most variable part of our genomes, deliberately evolved that way to ensure that we can effectively fight off millions of potential pathogens. But it is almost certainly also the case for all the cytokines and other regulators of the immune response. There’s an inbuilt balance of stratagems set to engage now for influenza and then for the common cold, and this is reflected in genetic variability in our genomes.
Whenever you have variability, you must also have individuals at the extremes. Most of us sit comfortably in the middle, but the price for this is that some of our friends and family are left exposed. They get combinations of genes that are probably ideal under some conditions of infection but leave them vulnerable in others. Apparently, one of these vulnerabilities is being hypersensitive to allergens that never would do much harm if left alone but look like they will, so end up inducing diseases such as asthma.
This is all exacerbated by the fact that humans occupy such diverse environments, many of which are extremely unusual from an historical perspective. What was good for a caveman is not necessarily good for an Eskimo, and what a Texas cowboy’s immune system sees may not overlap much with the infectious exposure of a Michigan car salesman. As humans spread across the globe they put enormous pressures on their immune system, setting up a genetic imbalance that will be with us for hundreds of generations to come.
On top of which, we keep pushing the insults. Cigarette smoke and household dust mites are probably the two most nasty irritants in our daily environment: Neither has been a pervasive threat for more than a handful of generations. Add in diesel fumes and all sorts of other air pollutants, not to mention the pollens and perfumes of the new world, and you have a toxic mix for our airways to deal with.
Deal with it they must, but they probably do so from a position of weakness induced by the very conditions of life that have isolated us from the worst that nature sends our way. Hygiene itself, in ways we’re only just beginning to understand, may be making it difficult for children to develop the robust and balanced immune systems needed to prevent inflammatory diseases. Deprived of exposure to pathogens that prime the development of adaptive immunity, it is thought that the army of T-cells just sits around getting soft or getting trigger happy. Oversimplified as this notion is, there is surely something to it.
Finally there is the matter that we are a young species, not yet in balance with our new surroundings, nor with our new human persona. At some places in the genome this is easily seen; at others we can as yet just infer that it is the case.
Precisely 524 letters upstream of the stretch of DNA that leads to the start of the IL4 cytokine gene is the first of a run of five Cs. The sequence is identical in all of
the great apes—chimpanzees, bonobos, gorillas, orangutans, and baboons. In fact, it is in a region of the chromosome that is pretty much the same in cats, dogs, and mice as well. However, if you’re from Cameroon or China, the chances are pretty good that both of your copies of the gene read T instead of C at this 524th position. For Ethiopians and New Guineans, either type is equally likely, while folks from Italy or India most likely have Cs.
There are a couple of remarkable things about this state of affairs. One is that it is really unusual for the sequences of our genes to vary so much in a seemingly random manner. There are plenty of places where Africans differ from Asians, or Europeans from Native Americans, but for the most part these differences follow a pattern that traces the history of human migrations over the past 40,000 years. The C/T difference near the IL4 gene stands out because the differences in frequency are much more regional. It provides a classical example of recent selection shaping the human genome.
Another is that people with the T version are able to produce considerably more of the IL4 protein. This is because another protein called NFAT prefers to bind to the sequence with the T, allowing the message of the gene to be read more often than when the ancestral C occupies the spot. This in turn makes such individuals just a bit more likely to be asthmatic and a bit more likely to succumb to leprosy and tuberculosis. These aren’t obviously good things, but they are balanced by a slight reduction in susceptibility to different classes of pathogens for which one arm of the immune system is required, such as nematode infections and retroviruses.
IL4 is a wonderful and visible example of how the genome is in the process of responding to the different demands placed on the immune system as humans have migrated across the planet. A genomic tug of war is going on between a more or less active trigger, and it is likely playing out at several of the other genes implicated in inflammatory disease.
In parallel, the genome is also trying to adjust to the consequences of some of the other profound changes in human physiology that marked the birth of the species. With each new model of Ford or Chevrolet that rolls off the assembly line, subtle changes in the chassis hide subtle engineering feats that make the engine run more smoothly or the air conditioning adjust more quickly. Place the engine of a 1990 model in a brand new Mustang, and you would be pretty disappointed in the performance. Compare the climate control in a Taurus with that in a Camry, and you may get a sense that it can take time for new technologies to catch up with the body itself.
Evolution doesn’t work as quickly as engineering. It is basically conservative, tinkering here and there, gradually improving, but necessarily the different parts change at different rates. Our lungs are pretty much built on the same design as those of other primates, but with some structural differences necessitated by our upright posture and changes in the larynx to accommodate voice. These developmental changes will have required subtle shifts in the genes that model lung development, including as we have seen, proteins such as ADAM33 that give flexibility to the muscles that let us breathe.
A couple of hundred thousand years really isn’t a lot of time to bring these genetic changes to a new equilibrium. The genome is coping, but it can do better. Given time and relative calm, we would expect that new genetic variants should spread through the human gene pool that make the lungs more efficient in the relatively new human body. Instead, we’ve added pollution and allergens that provoke inflammation, asking yet more of the genes, and have pushed them to the limits of their comfort zone.
5. Genetic AIDS
AIDS and the world One percent of all humans will soon be infected, while as many as a quarter of the people already are in some countries.
from HIV to AIDS There is no longer any doubt the virus causes immune deficiency, though coinfection with other pathogens causes the symptoms.
why HIV is so nasty It is an insurgent that attacks the very immune system that is supposed to destroy it and a competent shape-shifter adept at avoiding drugs.
how to resist a virus with your genes The surprisingly large amount of variation among people influences whether they become infected and how much virus they may have.
HIV imbalance AIDS is a young disease and there has been insufficient time to build a genetic defense.
AIDS and the World
If you travel to sub-Saharan Africa or much of Southeast Asia, you will quickly find that our Western medical preoccupation with genetic disease is displaced by the manifest misery of infectious disease. Malaria sends a person through waves of debilitating fever, tuberculosis literally takes their breath away, and sleeping sickness and nematode infestation drain the lifeblood. That’s not even considering by far the most prevalent pathogens on the planet: viruses. Gastrointestinal rotaviruses pose the chronic threat of diarrhea and dehydration for babies and children, occasional outbreaks of Ebola remind us that nature will eat us alive given half a chance, and even the common influenza virus leaves its scar on the world each fall. Perhaps the most pernicious of all, though, is the most recent arrival: Human Immunodeficiency Virus, or HIV.
Within a decade, one percent of all humans will be HIV positive. That’s 60 million infections if you’re counting, pretty much all within a 30-year period. Homosexuality can’t account for this; nor can intravenous drug use, not even close. These were just the sentinel behaviors that triggered the world’s attention back in the early 1980s. Far more accountable, at least on the global stage, is unprotected heterosexual intercourse, particularly that associated with sexual violence and prostitution. Now that more than ten percent of young adults are infected in countries such as Botswana and South Africa, the new threat is mother to child transmission, either during childbirth or via breast-feeding. Talk of losing a generation in the most destitute developing countries is no more scare mongering than talk of global warming. The threat is as real as the millions of orphan children who will soon inherit the villages and shantytowns of southern Africa.
Much of the tragedy of AIDS, like many other diseases, is that it is preventable, but for human frailty. Conservative Christians are 100 percent correct in their claim that abstinence is the most assured way to prevent transmission of the virus, but their notion that it is achieved simply by placing trust in Jesus is as porous as used condoms, and about as effective. Al Gore in his The Assault on Reason talks of a rock-paper-scissors circle of faith, fear, and reason, in which faith trumps fear, fear trumps reason, and reason trumps faith. Here is a case where good intentions essentially throw the cycle into reverse, but with fear replaced by sexual desire. Add drugs to the mix, and the situation is nearly hopeless; even in the United States, crystal meth is breaking down the bonds of self-control that brought the spread of AIDS to a standstill a decade ago.
Life expectancy in southern Africa has dropped by ten years due to AIDS, in some countries hovering in the mid-forties. Leaders in government and the arts are being lost just as nations take tentative steps toward democracy. A powerful statement of this can be seen in the form of a permanent exhibit of dozens of exquisite stone sculptures that line the walk to the first terminal at Atlanta-Hartsfield Airport: Please step off the moving walkway and amble by them next time you have the chance. Meanwhile, the fabric of society is stretched to the limits as grandmothers resume the parenting roles of caregiver and provider for maybe a quarter of all families.
There is some hopeful news in that the prevalence of HIV infection is dropping in central Africa. Cynics bemoan that this may merely reflect high mortality rates of those first infected before anyone knew anything about the spread and control of the virus. Yet there is a crucial difference between countries such as Uganda where rates are at least steady and those such as South Africa where they continue to rise. That is awareness—awareness built by very public educational ABC programs promoting Abstinence, Being faithful (to a single partner), and using Condoms. Official policies that deny there is a problem or if there is one that it is due to an infectious agent, that promote herbal remedies in place of antiretrov
iral drugs, and that silence Western-oriented physicians aren’t nearly so effective.
Highly Active Anti-Retroviral Therapy, or HAART, at $15,000 a year is an expensive but ultimately affordable lifesaver for half a million Americans. It is a cocktail of three or four drugs aimed at different aspects of viral biology. Hit with one drug at a time, the virus can easily evolve resistance, but hit with a combination it has little chance. For most people it extends life by a decade or more, and if mercurial basketball player Magic Johnson is any indication, in some cases it may even work to cure the disease indefinitely. In the developing world, generic local manufacturers have stepped in to provide the drugs for just $500 a year, but where incomes peak at $2 a day, even this is unbearable.
Drug treatment is wonderful for those who can get it, but it is not the solution that prevention will ultimately have to provide. Informed public policy, education, and chemical interventions with viral transmission are needed as well. The latter is where genetics makes its contribution.
From HIV to AIDS
I would hazard a guess that most Americans have never met a person suffering from AIDS. Perhaps they have heard about an old college friend after the fact, or know of a distant relative, but the closest they have come to the disease is through Tom Hanks’s character, Andrew Beckett, in the movie Philadelphia: Remember the stoic conversations with his mother about T-cell counts, the harrowing operatic aria, the intolerance and fear mirrored in reactions to the purplish blotches of Kaposi’s sarcoma, and the dramatic final courtroom collapse? Yet we never really learn exactly how the disease takes his life.