Genomic Messages: How the Evolving Science of Genetics Affects Our Health, Families, and Future - George Annas, Sherman Elias (2015)

Chapter 3. Nature, Nurture, and the Microbiome

Everything is environmental until you
convince me that it is genetic.

—Barry Marshall (2014)

Shortly after President Obama announced his 2015 genome initiative to save lives and cure cancer, physician-New York Times essayist Abigail Zuger wrote that her own experience with patients is that the patient’s environment is much more important than the patient’s genetics. She described her admittedly extreme patient, Barbara, as a smart, homeless, alcoholic who suffered from “medical problems as predictable as spokes on a wheel: bad heart, terrible liver, crumbling hips, gummed up lungs, AIDS from a brief foray into injectable drugs.” Always on the verge of changing her life, Barbara nonetheless often missed her medical appointments. Zuger agrees that it may turn out that many of Barbara’s problems are related to her “genetic predispositions,” but suggests that more knowledge about her genome is unlikely to help her much. Zuger suggests that the federal money the president is proposing for more genomic studies could be better spent on her Barbara’s other needs, “like supportive housing with on-site counselors and addiction services.”

Yes, Barbara is an “extreme example.” Nonetheless, she shows starkly that “genes are seldom the whole story behind illness . . .” As Barbara’s story highlights, environment and lifestyle play at least as important a role. Genomics will not solve homelessness, addiction or poverty. Public health will continue to be more important than medicine in actually making the lives and health of populations better because of the importance of our environment on our health. Genomics could, nonetheless, help some of us. This is primarily because we can often control at least some of the environmental factors that influence the expression of our genes. For example, if you are genetically predisposed to being overweight and having high blood pressure, eating a healthier diet and getting regular exercise could reduce your risk of diabetes.

In this chapter, we address the interactions of our genomes and our environment by examining the genetics of cloning, the influence of the uterine environment on the fetus, the influence of the environment and genetics on diabetes, and the interaction of both genetics and the environment with our microbiomes. These topics are all interrelated, and the goal is to demonstrate that our genomes alone do not determine our health; genes interact with each other, and with our environment and microbiomes, in ways that can be influenced by our own actions.

Twins and Genetic Research

Cloning is a method of producing genetically identical animals (twins) born years apart—a technique that can be used to observe gene-environment interactions and effects. The most famous cloned animal and perhaps the most famous animal in the world was Dolly the sheep, a Finn-Dorset ewe (figure 3.1). Dolly was born in the laboratory of Ian Wilmut and Keith Campbell in Scotland in 1996. Almost instantly, she became an international celebrity. Her fame was based on her shocking novelty: she was the first mammal whose genetics was derived almost entirely from a body cell or “somatic cell” (to differentiate it from a “germ cell,” an egg or sperm) removed from an adult—a feat most scientists thought was simply impossible. She was gestated from an embryo produced by fusing a cultured adult somatic cell with an egg from which the nucleus had been removed. Because her nuclear DNA was identical to that of her genetic mother—the ewe from whom the somatic cell had been removed—Dolly was a genetic duplicate, a later-born identical twin. She is usually referred to simply as a clone.

Genetics did more than label Dolly a twin; genetics was also used to identify her mother—the dead ewe that was the source of the somatic cell used to construct the embryo. Dolly’s two other mothers—the egg donor and the ewe that gestated and gave birth to her—were never seriously considered as either exclusive or joint mothers to Dolly, even though they completely determined her environment from fertilization to birth, and the egg donor also supplied mitochondrial DNA.

The international debate Dolly sparked was and is primarily about how important genetics is to personal identity and what impact environmental factors can have on genetically identical animals (or people). Is there, for example, any reason we should not use the cloning technique on humans to try to create babies that are genetically identical to an existing person? George joined Ian Wilmut and others to testify on this subject before a U.S. Senate panel in early 1997. George and Ian (who was the star of the hearing) agreed that human cloning should not be pursued. On the flight to Washington for the hearing, George sat next to political analyst James Carville, who opined (accurately) that human reproductive cloning would not be attractive to the public because it has “no payoff.” Parents want their children to have better lives than they had, not to simply “duplicate” their lives. It is also likely that the later-born “twin” (the clone) would be seen as a copy of a more valuable existing person (the “original”), and that the twin’s value (to herself and others) would be lessened because her future life is seen as dependent upon her genome rather than on anything she herself does.

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3.1  George with Dolly at the National Museum of Scotland, Edinburgh, 2012. Personal photo.

A contrary argument is that cloning should be categorized as just another method of human reproduction, and infertile couples should be able to employ cloning to have genetically related children (at least if there is no other way for them to have genetically related children). The paradoxical presumption behind this argument seems to be that the only children who count as “your own children” are those with whom you or your spouse have a genetic tie, that the genetic tie is (much) more important than the (environmental) ties of rearing a child. Although genetically identical to her genetic mother, Dolly had different markings on her coat and suffered from different illnesses, including arthritis. She also died young, at six years, from a contagious lung disease she caught from another sheep—proof that genetics alone is not destiny; our destiny is also heavily influenced by our environment.

In 2012, two scientists shared the Nobel Prize in Medicine for their work on reprogramming cells to be used for cloning. Cloning on the cellular level to produce tissues for medical treatment is known as “therapeutic cloning” (more accurately, gene transfer experiments) and is to be contrasted with cloning to make an entire animal, which is asexual “reproductive cloning.” The great advantage of therapeutic cloning to make replacement tissue (instead of using tissue donated from another person) is that any tissue made from a patient’s cells carries the patient’s own genome, and so will not be rejected. In the spring of 2014, two groups of scientists used this technique to produce human embryonic stem cells (from fusing skin cells of two adult men in one case, and cells from an adult female in the other, with an enucleated human egg). The attempts required hundreds of human eggs, making the procedure unsuited for clinical use at this time, but this was a major milestone in gene transfer experimentation.

Experimentation on cells, at least prior to the human embryo stage, is seldom controversial. Animal and human experimentation, however, can raise complex ethical problems. Even though Dolly, for example, was a well-treated celebrity, she was confined to a pen during her short life. Nonetheless, if an important scientific question is being asked and the experiment does not involve inflicting pain or suffering on the animal, experimentation with animals (at least nonprimates), especially genetic experimentation, is generally supported by both the public and scientific communities. The disgraced Korean cloning researcher, the veterinarian Woo Suk Hwang, who fabricated the results of his human cell cloning experiments, announced in 2014 that he had resumed work on dogs and other animals, and has cloned hundreds of dogs. In one experiment he claims to have cloned a dog that has symptoms of Alzheimer disease to see if he can develop an animal model to study this devastating human disorder. We are skeptical of his work, but cloning can produce genetically identical animals that are useful in genetic research. Nonetheless, as Ian Wilmut has stressed, “Cloning does not confer exact replication. The dialogue between the genes and their surroundings . . . controls the development of an organism from a single cell into a sheep—or indeed into a human being or an oak tree.”

The ethics of research on humans, including genetic research, have been articulated primarily in reaction to horrific scandals. One of the worst involved the murder and torture of twins by the Nazi physician Josef Mengele at Auschwitz-Birkenau concentration camps during World War II. Mengele specialized in genetics, working under the supervision of Germany’s leading geneticist, Otmar von Verschuer, and his genetics research at Auschwitz was funded by the German Research Council. Both men had a particular interest in doing genetic studies on twins. Survivors of Auschwitz recall Mengele shouting when the transports arrived, “Zwillinge, zwillinge, zwillinge” (twins, twins, twins). His biographers say that Mengele’s main genetics goal at Auschwitz was to establish, using twins, which attributes (including blue eyes and blond hair) and disabilities are genetically inherited and which are determined by lifestyle and environment. Little, if anything, he did can be labeled science, however, and most of his “studies” were bizarre and unconscionable. Virtually all ended with the simultaneous murder and dissection of the twin pair.

The Nuremberg Code, which among other provisions requires the voluntary, competent, and informed consent of the potential research subject, was fashioned by U.S. judges at the Doctors’ Trial at Nuremberg after the war, where some of the major physician war criminals were tried for murder and torture under the guise of human experimentation. Mengele, the most notorious of the murderous experimenters, escaped to South America after the war and was never apprehended. Needless to say, the Nazi twin experiments and Nazi belief in the racial (genetic) superiority of the Aryans did little to foster public faith in genetic research or to distinguish genetics from eugenics, the selection of desirable human traits to improve the human race, usually by selective breeding.

The Nazi twin murders and tortures in the guise of experiments had no justification, but legitimate twin studies had long been advocated in genetics research. Francis Galton first described the method of twin studies in 1875 as a way of disentangling the relative environmental and genetic influences on individual traits, behaviors, and disease states. Identical twins (termed monozygotic twins) result from fertilization of a single egg with a single sperm; fraternal twins (termed dizygotic twins) result from fertilization of two eggs by different sperm at the same time. In classical twin studies, comparisons are made for correlations of a disorder (for example, cancer or diabetes) or a quantitative characteristic (such as height or blood pressure) between identical twins and fraternal twins. If both members of a twin pair share a trait, they are concordant; if they don’t share the trait, they are discordant. Because identical twins are (almost) genetically identical, differences between them should be due to environmental effects. Fraternal twins are also a convenient comparison; their environmental differences should be similar to those of identical twins, but their genetic differences are the same as those between siblings in that they share only 50 percent of their DNA.

Using twin studies to help clarify the “nature versus nurture” debate is nonetheless complicated because identical twins never share an identical environment. For example, during pregnancy, blood flow to each twin differs. How much a disease is influenced by genetics compared to environmental factors varies by disease. Perhaps the most impressive twin study to date involved data from 53,666 identical twins from the United States, Sweden, Finland, Denmark, and Norway. Using registry data that included twenty-four diseases, the researchers found that rather than one twin helping to predict the other’s disease risk, the twin had about the same risk for these diseases as the general population. Commenting on the study, professor of genetics at Harvard David Altshuler observed that “even if you know everything about genetics, prediction will remain probabilistic and not deterministic.” He thought this was true because disease is affected not only by genetics but also by behavior, the environment, and random events. One of those random events involves changes in DNA itself.

Until recently it was believed that identical twins had identical DNA throughout their lives. However, new genomic technologies have shown that there are often differences in the DNA of identical twins. These differences include both additional DNA segments (duplications) and lost segments of DNA (deletions) on certain chromosomes, a genetic state called copy number variants, or CNVs. Such variation is a natural occurrence that accumulates with age in everyone. Our genomes experience gains and losses of genetic material over time. Thus, as identical twins age, their somatic (body) cells diverge in CNVs. The extent to which CNVs contribute to human disease is unclear and remains an important area of ongoing research, as discussed in chapter 6.

Studies of identical twins are also shedding light on interactions between genome and environment at the molecular level. Epigenetics refers to a rapidly growing field that investigates heritable alterations in gene expression caused by mechanisms other than changes in the DNA sequence. Environmental factors can modify genes and their actions without changing the nucleotides (the As, Ts, Gs, and Cs) themselves, an issue we now explore in the context of pregnancy.

Genetics and Environment in Pregnancy

Altering the environment can significantly affect genomic expression as early as embryonic life. Sherman saw Erin and Sean during their first pregnancy because Erin had a routine blood test at about sixteen weeks of pregnancy that showed an abnormally elevated level of maternal serum alpha-fetoprotein, or MSAFP. Further testing determined that the fetus had spina bifida, a birth defect in which the bones of the spine (vertebrae) and overlying tissues do not form properly around part of the spinal cord. Their fetus had a sack of fluid containing part of the spinal cord, called a myelomeningocele, bulging through an opening in the back. After detailed counseling about options, Erin and Sean decided to continue the pregnancy. Their child, Sean Jr., required surgery shortly after birth to close the defect. To prevent hydrocephalus (increased cerebrospinal fluid pressure within the brain), a shunt—or drainage tube—was placed in Sean Jr.’s head. At four years of age, Sean Jr. had normal intelligence, urinary incontinence, and required forearm crutches to walk.

Erin and Sean planned to have a second child and consulted Sherman about the risk of having another child with spina bifida and what measures could be taken to prevent it. They were told that the recurrence risk for spina bifida, anencephaly (absence of a major portion of the brain), and related malformations (collectively called neural tube defects, or NTDs) was 2–5 percent. Most NTDs are caused by multiple genes in combination with environmental factors. A key environmental influence in the development of NTDs appears to be diet, most importantly folic acid (a B vitamin) intake. It is recommended that all women who might become pregnant take 400 micrograms of folic acid daily, starting before conception and continuing through the first trimester. For women such as Erin, who have had a previous pregnancy with an NTD, a tenfold higher dose of folic acid supplementation is recommended. This could reduce the risk of having a child with an NTD by about 80 percent.

Three approaches to preventing NTDs have been recommended by the U.S. Public Health Service: improve dietary intake of folate-rich foods (for example, lentils, spinach, or black beans); use dietary supplements containing folic acid (400 mcg per day, unless there is a history of a prior NTD, in which case 4 mg per day is recommended); and fortify foods with folic acid. NTDs have been reduced by an estimated 26 percent in the United States by fortification of foods, but failure to eliminate NTDs suggests that factors other than maternal deficiency in folic acid are involved.

Genetics, Environment, and Diabetes

When Natalie married Craig, she was twenty-two years old, weighed 136 pounds, and was in good general health. Natalie is now forty-three, weighs 247 pounds, and has just been diagnosed as having type 2 diabetes and high blood pressure. Her sixty-four-year-old mother also has type 2 diabetes, weighs 238 pounds, and recently had a stroke that has affected her ability to walk and slurred her speech. Natalie’s doctor told her that she has a “metabolic syndrome,” a designation given to someone who has risk factors that occur together and increase the likelihood of coronary artery disease, stroke, and type 2 diabetes. These risk factors include increased blood pressure, high blood sugar levels, excess fat around the waist, and abnormal blood fat levels.

Four months ago Craig was laid off from his job as a road repair worker. The family’s income is now dependent upon Natalie’s job as a paralegal professional at a small law firm and Craig’s unemployment insurance. Between her job and having to take care of her mother, Craig, and their three children, Natalie does not have time for exercise, and eating a healthier diet is more costly and less convenient than meals at fast food restaurants. She wonders whether her obesity and diabetes are simply her destiny, given her family history. She is concerned about her future health but also the health of her children and their risk of becoming obese and developing diabetes.

Diabetes (diabetes mellitus) is a disease in which there are high levels of a sugar (glucose) in the blood. When food is digested, it is broken down and glucose enters the bloodstream. Insulin, a hormone released from the pancreas, moves glucose from the bloodstream into fat, muscle, and liver, where it is used as a source of fuel. Once inside the cells, glucose is either used immediately for energy or converted to fat or glycogen (a long-term storage form of glucose). People with diabetes have high levels of blood glucose because their pancreas does not make enough insulin, their cells do not respond to insulin normally, or both. In the United States, diabetes is the leading cause of kidney failure, nontraumatic lower-limb amputations, and new cases of blindness among adults; it is a major cause of heart disease and stroke; and it is the seventh leading cause of death. Of course, our environment plays a major role. High-fat diets typical of fast food restaurants—what sociologist George Ritzer called the “McDonaldization” of society—have become the norm in Western nations and are spreading globally. In the United States, more than a third of all adults (36 percent) are obese; about 17 percent (12.5 million) of children and adolescents ages two to nineteen years are obese.

There are three major forms of diabetes: type 1, type 2, and gestational diabetes. Type 1 diabetes (formerly called juvenile-onset diabetes) can occur at any age but most commonly develops in children, teenagers, and young adults, and accounts for about 10 percent of diabetics. It results from the permanent destruction of most of the insulin-producing cells, called beta cells, in the pancreas (most often due to an autoimmune disorder in which the immune system mistakenly attacks and destroys the beta cells). Type 2 diabetes (formerly called adult-onset diabetes) makes up the majority of diabetes cases. Although the pancreas produces insulin, sometimes at higher levels than normal, the tissues of the body do not respond appropriately to insulin—called insulin resistance. Reduced physical activity, poor diet, and excess weight, particularly around the waist, are all associated risk factors. Among U.S. residents sixty-five and older, almost 11 million individuals, or about 30 percent, have this disease. Gestational diabetes is defined as high blood sugar that begins or is first recognized during pregnancy. It affects 2–10 percent of all pregnant women.

Natalie has type 2 diabetes, obesity, and associated health problems. Considering how common and costly diabetes is, it remains remarkably poorly understood. Can new knowledge about type 2 diabetes at the genomic level help us better understand the underlying causes of this disease and lead to “actionable” therapeutic and preventive strategies?

There are some rare single-gene disorders associated with diabetes for which improved diagnosis and treatments have been developed. Maturity-onset diabetes of the young (MODY) accounts for about 2 percent of all cases of diabetes and is caused by mutation in one of several genes. Mutations in a gene called HNF1A are the most common cause. Testing for HNFA1 mutations is important not only for correct diagnosis but also to identify other family members who are mutation carriers. In the vast majority of individuals with type 2 diabetes, however, there is no mutation in a single gene responsible for the disease. Researchers have undertaken genomewide association studies(GWAS) to understand what genes affect diabetes. GWAS compare common genetic DNA variants among large numbers of individuals who have a condition (for example, diabetes) and those who do not have the condition to determine whether an association exists between specific variants and the condition. Although a valuable research tool, GWAS have not had much practical impact on clinical management. This is because the genetic variants that have been detected are associated with the disease, but they do not cause it.

From conception and throughout fetal development, environmental influences can affect and even permanently modify genes that predispose people to adult diseases. This applies not only to type 2 diabetes but to other conditions, including obesity, coronary artery disease, and even conditions such as osteoporosis, cancer, and psychiatric illnesses. More than twenty years ago, a group of epidemiologists in Southampton, England, led by David Barker observed that the smaller a baby was at birth the higher the likelihood that he or she would die of coronary artery disease as an adult. This was followed by their findings that malnutrition of the fetus during pregnancy leads to the development of cardiovascular disease as an adult. These observations were popularized as the “Barker Hypothesis,” or fetal origin of adult disease. Later it was shown that low birth weight was associated with development of type 2 diabetes as well. How does this happen?

Even relatively mild changes in the intrauterine environment (for instance, diet, inflammation, toxins, and infections) can cause the fetus to be “programmed” to produce different physical or biochemical characteristics that can persist throughout a person’s life span. One tragic example occurred during the Dutch famine in World War II and is dramatically described by Amsterdam researchers:

To support the Allied offensive, the Dutch government in exile called for a strike of the Dutch railways. As a reprisal, the Germans banned all food transport [causing a famine in The Netherlands]. . . . At the height of the famine from December 1944 to April 1945, the official daily rations varied between 400 and 800 calories. . . .

Throughout the winter of 1944–1945 the population had to live without light, without gas, without heat, laundries ceased operating, soap for personal use was unobtainable, and adequate clothing and shoes were lacking in most families. In hospitals, there was serious overcrowding as well as lack of medicines. Above all, hunger dominated all misery [emphasis added].

In follow-up studies, infants whose mothers had severe caloric restrictions in mid or late pregnancy were underweight, while those infants whose mothers endured the famine in early pregnancy had normal birth weights. Adults whose mothers were exposed to undernutrition during pregnancy developed health problems in later life, particularly reduced glucose tolerance indicating type 2 diabetes and blood lipid profiles characteristic of coronary heart disease. The effects of the undernutrition thus depended on its timing during pregnancy. The investigators concluded that maternal malnutrition during pregnancy affects the health of the child in later life. This fetal programming evolved as an adaptive response; in times of food shortage, metabolic adaptations that increase energy storage may be beneficial.

Clinical studies have shown that metabolic imprinting (the epigenetic programming of metabolism during prenatal life) caused by obesity and a diabetic intrauterine environment can be transmitted across generations. This helps explain the increase in obesity, gestational diabetes, and type 2 diabetes seen over the past several decades. For example, the children of Pima Indian women with diabetes have larger infants at birth and at five years of age. Maternal diabetes was also the strongest single risk factor for type 2 diabetes among Pima Indian youth, accounting for 40 percent of diabetes in that population. There is a direct relationship between maternal weight prior to pregnancy, weight gain during pregnancy, and large babies who develop type 2 diabetes in later life. This is a vicious cycle in which “diabetes begets diabetes”: heavier mothers give birth to heavier daughters, who are at increased risk to be obese and develop type 2 diabetes during their reproductive years.

The dangers of fetal exposure have been the subject of increasingly hysterical media attention, which you should not take too seriously. An article in the Chicago Tribune, “Your Health Partly Wired in the Womb,” reported that “possible threats to the fetus” include urban air pollution, which might cause alterations in chromosome structure; bisphenol A (a chemical present in many plastic bottles), which could change the way the fetus responds to estrogens, leading to subsequent advanced puberty; and even a mild case of the flu in the pregnant woman, which could predispose male offspring to heart disease after age sixty. Fetal exposure to the maternal stress hormone cortisol has been implicated in causing an epigenetic effect that “slows growth in most organs.” In other words, if a pregnant woman constantly worries about the seemingly endless number of environmental exposures that could possibly harm her fetus, the worry itself could injure her fetus. Of course, pregnant women can’t live in a bubble throughout pregnancy, so common sense should prevail: avoid recognized substances, such as alcohol, tobacco, and drugs, that can put your fetus at increased risk for birth defects, eat nutritious foods, exercise, reduce stress, and practice moderation.

What about Natalie? Unfortunately, genomic studies have thus far added little that can be used in clinical management to our understanding of cases of type 2 diabetes and obesity like Natalie’s. A person’s individual risk for type 2 diabetes or obesity reflects a “barcode” combination of susceptibility and protective genetic variants, which are influenced to a greater or lesser extent by “relevant” environmental exposures, primarily diet and exercise. But this is not all. In addition to complex gene-gene and gene-environment interactions, our health is also directly affected by the trillions of microbes that live in our bodies and make up our microbiome.

Your Microbiome

Your body is made up of about 10 trillion cells and is the home of 100 trillion microbes that live both within and on the surface of our bodies, including thousands of species of bacteria, yeasts, parasites, viruses, and others. Microbiome is the term for the totality of microbes, including their genomes, their gene products (such as proteins), and their unique interactions in a particular environment, or habitat, such as the gut, mouth, skin, or vagina. Human health and diseases are greatly influenced by the diversity of our microbiome, especially bacteria. We can’t live without them.

The human microbiome contains at least 20 million unique genes (humans have about 22,000 protein-coding genes). From a cellular point of view, humans are more bacteria than they are human—bacteria outnumber human cells ten to one. However, because microorganisms are small, they make up only about 1–3 percent of the body’s mass; a two-hundred-pound adult has two to six pounds of bacteria. Many of these organisms have not been cultured, identified, or otherwise characterized because their growth is dependent upon a microenvironment that has not been reproduced in the laboratory. However, new DNA-sequencing technologies and sophisticated computer bioinformatics now allow these microbes to be studied in great detail because we can distinguish between the DNA of humans and the DNA of microbes, so that only the bacterial genome is analyzed.

Bacteria that are absent are sometimes as important as the bacteria that are present. For example, Streptococcus mutans (S. mutans) is known to cause tooth decay by converting sugar to acid. Therefore, tooth decay can be considered an infectious disease. A synthetic antimicrobial, C16G2, has been shown to have robust killing efficacy against S. mutans, and even a single application of a mouth rinse containing C16G2 has been associated with reduced plaque, lactic acid production, enamel demineralization, and tooth decay.

Another example of the absence of a bacterium that caused disease is a sixty-one-year-old woman whom we will call Alice. She was referred to Alexander Khortus, a gastroenterologist at the University of Minnesota. Alice had suffered eight months of crippling diarrhea, which started shortly after she had been treated with antibiotics following back surgery that was complicated by pneumonia. Her diarrhea had become so severe that she had to wear diapers all the time. She had lost almost sixty pounds and needed to use a wheelchair. After several hospitalizations and numerous courses of antibiotics for a life-threatening bowel infection involving an organism called Clostridium difficile (C. difficile), treatment options were running out.

Khoruts decided that Alice needed a novel new treatment—a fecal transplant (transferring fecal matter from one patient to another). The donor was to be Alice’s husband of forty-four years. Using colonoscopy, a stool sample from her husband that had been put through a blender and diluted was injected into Alice’s colon (fecal transplants are now done by processing the fecal material and putting it into tablet form for consumption). In addition, colonoscopies were performed a week prior to the transplant and two weeks afterward. Khoruts and his associates were able to show that the disease-causing C. difficile in Alice’s colon had been replaced by the normal gut bacteria Bacteroides from her husband. On the second day after the procedure, Alice had her first solid bowel movement. At her six-month follow-up, she reported once-daily formed stools. In a subsequent randomized trial of patients with recurrent infections and multiple episodes of diarrhea, the combination of antibiotics and fecal transplant was so successful (cures were achieved in fifteen of sixteen patients within two treatments) that the study was stopped early. An editorial accompanying the study concluded that “FMT [fecal microbiota transplantation] is now in the mainstream of modern, evidence-based medical practice.” Science writer Ed Young has described the procedure as “spectacularly successful, far more than conventional antibiotics.” Young also noted that the great advantage to finding health problems rooted in the microbiome is that unlike the human genome, we may be able to alter our microbiomes “through probiotics, fecal transplants or other means.”

The gastrointestinal tract harbors a complex assemblage of microbial organisms that are essential for food digestion, absorption of nutrients, and development and regulation of the immune system. Bacteria stimulate the lymph tissues in the intestines to produce antibodies against pathogens. The immune system recognizes and fights harmful bacteria but does not react to helpful species of bacteria or a person’s own tissues (if the immune system does attack the person’s own tissues, it can lead to autoimmune diseases such as rheumatoid arthritis, lupus, inflammatory bowel disease, and type 1 diabetes). This tolerance develops in infancy and is called the “old friends” hypothesis.

In normal pregnancy, the fetus develops in the sterile environment of the uterus. At birth and rapidly thereafter, the infant is colonized with bacteria from its surrounding environment. When the baby is born through the vaginal canal, its first contact is with bacteria from the mother’s vagina and anus, predominantly Lactobacillus. Lactobacillus is usually found not in the vagina but rather in the gut, where it produces enzymes that digest milk, but as pregnancy progresses toward term, Lactobacillus becomes prominent in the vagina. During a normal term delivery, the infant is covered with Lactobacillus as it goes through the vaginal canal, thereby preparing the infant to digest breast milk.

Approximately one in three babies in the United States are born by cesarean delivery. Cesarean babies are first exposed to and colonized by bacteria found on the mother’s skin, predominantly Staphylococcus. These differences in exposure can be significant. For example, most cases of virulent and often fatal methicillin-resistant Staphylococcus aureus (MRSA) infections in infants follow cesarean deliveries. There is also accumulating evidence that these differences in intestinal bacteria play an important role in the development of the infant’s immune system. Microbes in the intestines may be involved in the so-called “hygiene hypothesis,” wherein lack of exposure to a variety of microorganisms during early life may result in the development of diseases such as asthma, type 1 diabetes, celiac disease, and food allergies, which appear more often in children who were born via cesarean delivery compared to vaginal delivery.

A more dramatic example of how things go seriously awry is when the intestines fail to discriminate between friendly and hostile bacteria; inflammation sets in that can progress to a condition called necrotizing enterocolitis (NEC), or death of the intestines. NEC is among the most common and devastating diseases in newborns. The estimated death rate from this condition is 20 percent. The excessive inflammation initiated in the highly immunoreactive intestine in NEC extends to other organs, including the brain, kidneys, lungs, liver, and heart.

Almost all infants born prematurely are treated with broad-spectrum antibiotics, which decrease the diversity of the intestinal bacteria and increase “less desirable” bacteria, thus facilitating the development of NEC. Recent studies suggest that giving these infants probiotics (live microorganisms, such as lactic acid bacteria and certain yeasts that confer health benefits) could help prevent NEC. Probiotics should be distinguished from prebiotics, which are nondigestible food ingredients, such as soluble fibers and oligosaccharides found in breast milk. Like probiotics, prebiotics have a beneficial effect on intestinal bacterial microbes and have been shown to help prevent NEC in premature infants.

In developed countries, the average child has received ten to twenty courses of antibiotics by the time the child is eighteen years old. Antibiotic treatment can prevent or cure serious diseases and may be lifesaving, but overuse of antibiotics carries substantial risks to our health. Sometimes our friendly bacterial flora never fully recovers after treatment with antibiotics. Some of these friendly bacteria provide important benefits. For example, the Bacteroidesspecies that live in the colon are needed to synthesize vitamin K, which is required for blood coagulation and also helps resist invading organisms.

The role of microorganisms is not always straightforward. Helicobacter pylori (H. pylori), a corkscrew-shaped bacterium, for example, is found in half the stomachs in the world. This is astounding because gastric (stomach) fluid is composed mostly of hydrochloric acid with acidity of a pH between 1.5 and 3.5. H. pylori is associated with increased risk of gastritis (inflammation of the lining of the stomach), peptic ulcers, and stomach cancer. However, children without this bacterium are more likely to develop asthma, hay fever, and skin allergies. Eradication of H. pylori from people’s stomachs has also been linked with an increase in gastroesophageal reflux disease (GERD) and esophageal cancer.

The story of how H. pylori was discovered as the major cause of peptic ulcers seems like the plot of a mad scientist movie. Until the 1980s medical dogma held that gastritis, stomach ulcers, and duodenal ulcers were caused by overproduction of gastric acid resulting from chronic stress. As one article put it in 1967, “The mothers of ulcer patients tended to have psychogenic symptoms, and to be striving, obsessional, and dominant in the home; fathers tended to be steady, unassertive, and passive.” The dictum was “no acid, no ulcers,” which led to treatments to neutralize acid, such as bland diets and antacids. In 1981, Barry Marshall, an Australian internist, began working with a pathologist, Robin Warren, at the Royal Perth Hospital. Taking biopsies from ulcer patients, they discovered that the gut was overrun by a newly identified bacterium, Campylorbacter pyloridis, later called H. pylori. This was an astonishing observation because it meant that ulcers were an infectious disease that could be treated with antibiotics.

The finding was dismissed by mainstream gastroenterologists. In Marshall’s words, “I knew that they were mostly making their living doing endoscopies on ulcer patients. So I’m going to show you guys. A few years from now you’ll be saying, ‘Hey! Where did all those endoscopies go?’” The breakthrough came in 1982. Marshall and a volunteer drank a broth containing the suspected bacteria, then underwent endoscopies showing that they had both developed gastritis and had biopsies from which H. pylori was reisolated. The connection between H. pylori and ulcers was subsequently confirmed by large epidemiological studies. For their discovery, Marshall and Warren were awarded the Nobel Prize for Medicine in 2005. In an interview ten years later, Marshall opined that other serious diseases may turn out to have an infectious cause, saying, “As far as I am concerned, everything is environmental until you convince me that it is genetic.” This may seem extreme, but it underlines the power of environment, including our microbiome, to affect our health, and that is why we opened the chapter with it.

The most common clinical conditions currently studied in the context of the microbiome are obesity and type 2 diabetes. As we have discussed, obesity and type 2 diabetes are caused by a combination of genetic susceptibility and environmental and lifestyle factors. Compared to lean individuals, the bacterial composition in the intestines of obese individuals extracts more energy (calories) from their diet, increases storage of fat, and leads to insulin resistance. For example, eradicating H. pylori with antibiotics disrupts the stomach’s steady production of a hormone called ghrelin, which is released into the bloodstream and in essence tells the brain to keep eating. Farmers have long known that continuous subtherapeutic doses of antibiotics cause animals to gain weight with less feed. Returning the gut to a healthy bacterial state, possibly with fecal transplants or the use of pre- or probiotics, has been suggested as a pathway to reduce obesity and improve insulin sensitivity in type 2 diabetes.

Another area of the body where there is an unexpected diversity of bacteria is on the skin, our first line of defense against illness and injury. The most diversity is seen on the forearm and the least diversity behind the ear. The bacterial composition of our underarms is different from the bacteria that live between our toes, which explains why they smell different. Bacteria on our skin have many beneficial effects, including converting oils into moisturizers that keep our skin supple and prevent cracking. Of course, we know that not all bacteria on our skin are good for us; some bacteria cause infection, hence hand washing is important.

In a New Yorker article, Michael Specter recounts how Andrew Goldberg, an ear, nose and throat specialist at the University of California, San Francisco, cared for a patient (whom we’ll call Colin) with a chronic infection in his left ear. Doctors had tried numerous treatments, including several types of antibiotics and antifungal drops, without success. One day Colin walked into the clinic with a smile on his face, saying that he hadn’t felt so good in years. Goldberg examined his ear and confirmed that it looked great. Colin said, “Do you want to know what I did? . . . I took some wax from my good ear and put it into my bad ear, and in a few days I was fine.” Years later Goldberg came to understand that normally earwax contains many bacterial species, and that antibiotics might have adversely changed the bacterial composition in Colin’s bad ear. By reestablishing the normal ear bacteria by an “earwax transplant,” Colin cured himself.

For the past century, doctors have waged “war” against bacteria with antibiotics. But our view of microbes is changing rapidly. As Julie Segre, a senior investigator at the National Human Genome Research Institute, put it, “I would like to lose the language of warfare. . . . It does a disservice to all bacteria that have co-evolved with us and are maintaining the health of our bodies.” The new health model is “medical ecology,” and at least some physicians are beginning to see themselves as “microbial wildlife managers.”

In this chapter we have seen that, as Dolly’s creator, Ian Wilmut, put it more than a decade ago, there is more to life than genes. “Genes operate in constant dialogue with their surroundings” a dialogue that begins at conception and continues after birth and throughout life. Today, he would have to add our microbiome to the mix, as we are learning more and more about our microbiome’s importance to our daily health. The balance and interaction of our genes and the environment determine if and how genes will be expressed. We are dealing not with a “nature versus nurture” world but with a “nature and nurture” world. This interaction affects almost every aspect of our lives, but perhaps most importantly to our physicians, it affects the way we are likely to react to specific drugs. In the next chapter, we turn to what is widely considered the most promising clinical application of the evolving field of genomics: pharmacogenomics.

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WHEN THINKING ABOUT NATURE VERSUS
NURTURE, CONSIDER THESE THOUGHTS

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It is not nature versus nurture, but nature
and nurture (and our microbiome).

Our environment plays a powerful role in
determining our health and the health of
our children and our grandchildren.

A fast-growing area of genomic studies involves the
human microbiome and its effect on our health.