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DNA: The Things We Carry

Heal

Ninety percent of the cells in what we think of as our body are nonhuman. Our nonhuman components fuel our cells, digest our food, synthesize vitamins, maintain our immune defenses, and may explain our epidemics of asthma and depression as well as why obesity can be contagious. Understanding how we acquired all this nonhuman life with us is important, not only for how we think about ourselves and how we are treated medically but also for our future as a species.

In 2002, Nobel laureate Joshua Lederberg coined the term “superorganism” to describe the ensemble of human and non-human cells that constitute our body. We consist of about 10 trillion cells. They make up our brain, muscles, bones, blood, and major organs. In addition to these 10 trillion human cells, the average healthy person also carries about 100 trillion nonhuman cells in the form of bacteria, fungi, and entire organisms such as mites, lice, and worms. These passengers are alive; many are capable of an independent existence and yet end up living in and with us. That we carry around 10 times more nonhuman than human cells pales beside the fact that there are 100 times more microbial genes within us than human genes. In other words, there are 100 times more genes in our metagenome — the set of all genomes in our body — than in the human genome within our chromosomes.

On top of all this, there is the weird and wonderful world of the “almost alive,” or, perhaps more dramatically, the “living dead” — namely, viruses. Viruses are not strictly life forms as they are incapable of reproducing without using the machinery in the cells that they infect. Many viruses rest intact inside our bodies, ready to reproduce and affect us under a variety of conditions. In addition to these nearly living organisms, we also contain relics and fossils from earlier invaders and passengers. These have become incorporated into our human cells over billions of years of evolutionary history, either in the form of pieces of DNA or, in some cases, as organelles — internal structures within a cell, each completely surrounded by a membrane, each having a specific function.

Engulfing Our Hitchhikers
Lederberg’s vision of how critical the superorganism has become for human life is captured in the following two examples. We carry in the human genome the DNA for endogenous retrovirus (ERV), passed on by our ancestors about 100 million years ago, before the evolution of the placenta. Today, it is activated in large quantities during implantation of the embryo in the mammalian uterus, causing immunosuppression in much the same way as its notorious cousin, HIV. However, ERV has become essential to human survival: by suppressing the mother’s immune system, it allows the embryo to implant in her uterine wall and thrive. Without ERV, the mother’s immune system might attack the embryo as an invader.

Another instance of ancient assimilation of nonhuman material by one of our ancestors is the mitochondrion, which powers nearly all our cells. The mitochondrion was originally a separate bacterium capable of using oxygen to generate an electrochemical gradient across its membrane. One of our single-celled eukaryote ancestors — eukaryotic cells have a distinct nucleus (plants, animals, fungi), unlike prokaryotes (bacteria) — engulfed this bacterium and used it to generate energy. Gradually, the bacterium lost many of its genes and became dependent upon the host cell for survival. At the same time, the host cell became dependent upon its acquired bacterium for energy. The mitochondrion and its host have survived together for more than two billion years, and mitochondria are now present in every single eukaryotic cell.

Our Bacteria DNA
The Human Genome Project, which sequenced all three billion DNA bases in the human genome, revealed that of the 23,000 genes in the human genome, 233 were coded for proteins that are homologous to ones found only in bacteria. This suggests that we acquired roughly 1 percent of our genes from ancestral bacteria.

What happened was that over time, our nonhuman passengers began to shed some of their own genetic complement, which they no longer needed to survive within the human host. In so doing, the organism became smaller and smaller, ultimately fusing with the host in an inextricable way. This process is happening today among the tens of thousands of different species that inhabit our body. As a superorganism, we are ever changing.

Studying our nonhuman complement can teach us a great deal about evolution and how humans are evolving today. Most of us, when we think of evolution, tend to think of small, random changes in DNA that may or may not confer some selective advantage. Those that do confer advantage are retained and become established in the genome. The acquisition of nonself cells to confer new capabilities is a form of evolution that does not rely on random single DNA mutations but rather on the wholesale assimilation of an organism and its subsequent application to the host’s benefit. The acquisition of big chunks of DNA from viruses or a whole organism, such as a bacterium, is akin to a large company acquiring a smaller one, rather than growing itself organically.

Leaps from Cooperative Evolution
Some biologists argue that symbiosis — where two different organisms live attached to each other, or one as a tenant of the other, and contribute to each other’s support — is far more important in the evolution of life and the functioning of organisms and ecologies than the competition-centric views of Darwin. Indeed, they argue that it may be the key driving force in the evolution of life on Earth. Nevertheless, symbiotic cellular cooperation is subject to the same stringent selection pressures as an individual cell, or two separate cells, and if the new combination is not at least as fit as the precursors, that population will soon become extinct. The wholesale acquisition of genetic material is one way an organism can make a leap forward and acquire a number of properties that may not have been able to evolve separately and incrementally, making for an interesting comparison with classical Darwinian evolution in which success is defined as the continuation of the organism’s current existence. In this case, the acquisition of a symbiont leads to the organism’s evolution into something new, and thus, from one perspective, destruction of its original self.

More Bugs, More Immunity
There are only four places in the human body that are normally sterile: blood, urine, brain, and lungs. These sites can be infected, however, resulting in septicemia, cystitis, meningitis, and pneumonia, to name just a few possibilities. The remainder of our bodies teem with life. Perhaps not surprisingly, more than 1,000 different kinds of beneficial bacteria — about three pounds worth — live in our GI tract. These “bugs” make life possible by synthesizing vitamins such as folic acid, vitamin K, and biotin, as well as fermenting complex indigestible carbohydrates and digesting milk. But even our dry, aerobic forearm skin supports 182 different species of bacteria, like Staphylococcus, Streptococcus, and Corneybacterium which metabolize sweat and other viscous secretions (causing body odor) but also form a barrier to and compete for nutrients with dangerous pathogens that could enter the body through our skin. Skin bacteria even secrete antibiotics to drive off their noxious cousins. If it were not for these symbiotic bugs, we would all be dead. In fact, the more different kinds of symbiotic bugs we carry, the healthier we are and the more adaptable we are to changing environmental conditions and food supplies.

But before we become too enamored of our bacteria, it’s important to remember those which bring us much grief. Dental caries are caused by Streptococcus mutans and Lactobacilli, among others, leading not only to the formation of plaque but also to gingivitis, which can cause tooth loss and jawbone atrophy. As recently as 1993, the bacterium Helicobacter pylori was shown to be the cause of ulcers in our GI system and of some forms of gastric cancer. Keep in mind that although these are examples of bacteria that live happily in us all the time — as opposed to infecting us sporadically — the vast majority of our bacteria are neutral or beneficial.

Why Obesity Is Contagious
The very efficiency of our benign, symbiotic bacteria can also cause problems under some circumstances, particularly those we enjoy in prosperous, technologically advanced societies. Unlike our ancestors, we associate excess body weight with a poor general life prognosis. Investigations by Jeffrey Gordon and Ruth Ley at Washington University in St. Louis found that the intestinal flora of genetically obese mice contain bacteria that derive more nutrients from their obese host’s diet than do the bacteria found in their lean littermates. This also turns out to be true for humans. Gordon and Ley studied 12 obese people who dieted for a year. As they lost weight, the bacterial composition of their GI tracts changed. Gordon and Ley then found that colonizing germ-free mice with the bacteria from the obese animals caused a greater increase in total body fat than did colonization with bacteria from their lean littermates. These data raise the possibility that obesity may be transmissible — not just genetically but also socially — to close friends and family members with whom we exchange bacteria. Indeed, a recent study of over 12,000 people by Fowler and Christakis, reported in the New England Journal of Medicine, showed that a person’s chances of becoming obese went up 57 percent if a friend was obese, 40 percent if a sibling, and 37 percent if a spouse. In the closest friendships, the risk almost tripled.

Can Bugs Beat Depression?
Research with bacteria is beginning to reveal surprising benefits. For example, in 2005, Dr. Mary O’Brien and her colleagues at the Royal Marsden Hospital in London conducted a clinical trial in patients suffering from intractable small-cell lung cancer. She injected her patients with fragmented Mycobacterium vaccae, a bacterium found in soil. O’Brien’s rationale was that injecting patients with bacterial fragments might stimulate their immune system to detect and destroy the cancer cells. O’Brien and her team were unsuccessful in slowing the cancer, but they made another, important discovery. Their patients’ vitality, sense of well-being, and cognitive function all improved, and they experienced a decrease in pain sensitivity.

Four years later, Christopher Lowry and his colleagues at the University of Bristol went on to test what might have caused the mood-elevating effects of M. vaccae. They injected the bacteria fragments into the brains of mice and discovered that the fragments activated immune cells, which released chemicals called cytokines. These chemicals, in turn, acted on receptors of sensory nerves and increased serotonin in the forebrain. The antidepressant effect in mice was not just biochemical — the mice swam longer in a behavioral “despair” test used to predict the efficacy of antidepressants — but it also offered the possibility of treating clinical depression with bacterial fragments that are, in effect, a vaccine. Lowry’s data with M. vaccae may also help explain the beneficial effects of gardening, in which we wrestle mano a mano with mycobacteria in the wild.

The Perils of Clean Living
Ironically, though the word “hygiene” comes from the Greek word for “health,” better health is often not the consequence of our recent obsession with “germs” and their eradication from every facet of our lives. Well-publicized studies by Martin Blasner at New York University have shown that only 10 percent of children today carry H. pylori, and that its absence may be linked to asthma. There is also growing evidence that without low, chronic exposure to foreign materials, the immune system can turn on itself, leading to an increase in autoimmune diseases such as inflammatory bowel, type I diabetes, rheumatoid arthritis, and multiple sclerosis. Increased frequency of Caesarian births may also weaken the immune system because infants are not exposed to bacteria that would be acquired as the child passes through the vaginal canal.

An appreciation for — and a detailed understanding of — our metabiome in terms of its species and genomes, as well as its function and plasticity, will require a blend of Western, molecular, and deterministic medicine, as well as a more holistic view of the entire organism — or in this case, superorganism. The patient is not just his or her enlarged liver. These new ways of thinking about the human “us,” our nonhuman partners, and the combination of “them” and “us” may be the next important frontier in health and medicine.

Ian Williams holds a degree in Biochemistry from the University of Bristol (1972), a D. Phil. from the University of Oxford (1975) and an MFA from -Bennington College (2009). He left corporate life in 2004 to become a full time writer. He has published a book Riding in Africa, which recounts his adventures horse back riding in Africa over a twelve year period. Ian is a keen sculler, stonewall builder and writer.


This entry is tagged with:
MedicineDnaCellsImmunityEvolutionDepressionHealth

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