The previous chapters of this part of the book emphasize how the vast majority of your cells and genes are microbial, not mammalian, and why that is important for understanding yourself and your well-being. In particular, the fact that more than 99 percent of the genes in your body are from your microbiome and not your chromosomes is one of the more eye-popping findings in this field of inquiry. What does that mean? A product might be 99 percent lactose-free. That is usually good enough for most lactose-sensitive people to avoid problems when consuming the product in moderation. But are genes different than lactose? Do you really think that the 1 percent of mammalian genes exerts more control than the microbial 99 percent? As we will see, the answer is probably not, considering not just the raw numbers but also a variety of interactions hidden from our normal view. The two genomes, mammalian and microbial, work together. Sometimes it can even be challenging to be sure exactly what is a result of microbial activity and what is mammalian. All of these cells and genes have very ancient origins that are somewhat murky, but definitely interdependent and intertwined.
There are two levels of genetic control involving the microbes and the genes on our chromosomes. Let’s call them gene swaps and gene switches. A gene swap is essentially about a gene’s location and who possesses it, where it came from, and where it went after the swap. A gene switch has to do with a gene’s use, whether a gene is on or off like a table lamp. Gene swaps and switches are a fundamental way microbes exercise their power within you, the superorganism.
One of the major recent findings in biology is that genes can be swapped. Who would have thought? The very things that we believed made us exactly who we are and distinguish us from others are actually at a type of swap meet. They can be sold or given away like items at a yard sale.
Researchers studying gene swaps try to determine where a gene originated—was it swapped? It is a little like looking at our current genes and asking what spectrum of ancestry gave rise to all of those genes. I like to think of it as looking at the people in the United States today and asking: Where were the prior homes of all of our ancestors? The US is a melting pot of many populations who over centuries migrated from other areas, countries, and continents to this particular geographic location in North America. Of course, it is still happening. A majority of the ancestors of people now in the US originally lived in different parts of the world and, of course, most of their genes were from elsewhere as well. People can move and relocate. And, it turns out, so can genes. The theme of this chapter might well be location, location, location.
What we identify as microbial or mammalian in origin is perhaps the first question. As explained in a prior chapter, a big biological issue of the latter twentieth century concerned the bacteria-like energy powerhouses called mitochondria, which are located in the cytoplasm, a region of our cells that is outside the nucleus. The present consensus is that mitochondria are a remnant of what were once microbes that our ancestors’ cells somehow captured because the mitochondria were useful and could diversify our energy sources. Diversifying energy sources can be beneficial, and that topic is in the news today on a larger scale as countries seek to develop renewable energy sources to protect the earth. If the mitochondria were originally microbial, then the genes within the mitochondria were originally microbial genes. But even if these outside-the-nucleus, bacteria-looking cell components were originally bacteria, the nucleus in our cells was surely 100 percent mammalian through and through. Our chromosomes would not be compromised by interspecies sharing or transfers. Or would they?
The main way our chromosomes acquire a gene from a different species is through a process called horizontal gene transfer. This is a form of swap where a gene in one species is snatched or grabbed by a different nearby species (like two species inside a superorganism). Often this exchange seems to advantage one species quickly and the other species slowly. It can be somewhat like when a bank provides a lump sum to pay for a borrower’s new house (initial advantage to the borrower), but then the homeowner must pay off the mortgage including interest over decades (longer-term advantage to the bank).
With horizontal transfers, a gene gets moved from one living organism to another during the same generation. Genes as property are exchanged. This horizontal transfer is in contrast to vertical gene transfer, which occurs during reproduction. With vertical transfers, genes are transferred between generations from parent to offspring. In vertical gene transfer for humans, a mother and father transfer chromosomes via the sperm and egg to form the zygote, which grows into the baby. Also, the mother donates her microbiome to the baby at birth as the vertical transfer of microbial genes. Vertical gene transfer has long been recognized and was indeed widely thought to be the only way genes made their way across generations. Horizontal gene transfer is a whole new ball game, at least for science. It requires genes to jump. It may seem like the equivalent of a simple handshake between species, but the actual process is probably a little more mysterious.
In 1950 Cornell-trained geneticist Barbara McClintock showed that genes could be mobile and could indeed jump and change locations, at least along chromosomes within in a cell’s nucleus. It took decades before her revolutionary, Nobel Prize–winning discovery was fully embraced and appreciated. But if genes could do that, could they jump between species?
An early result was reported in the 1950s, showing this was possible among bacteria, including the one that causes the disease diphtheria, Corynebacterium diphtheriae. In the case of the diphtheria-causing bacterium, genes that were transferred into the diphtheria bacterium by bacterial viruses called bacteriophages controlled how aggressive (or virulent) the bacterium was in producing the disease. Following this, it was shown that the genes providing resistance to antibiotics could be horizontally transferred or swapped between different species of bacteria with the help of the same viruses.
It turns out that our bodies are perfect locations for horizontal gene transfer. In fact, the microbes within our microbiomes are known to use locations such as the gut as a type of swap meet. We only recently discovered that different bacterial species living inside us in the same body location can occasionally exchange genes. But can this type of transfer happen when the recipient is a higher organism: a plant, an animal, or even a human?
The subject of horizontal gene transfer in higher organisms, including humans, has been debated for more than a decade with speculation as to whether a swap or transfer of genes could occur. Horizontal transfer of genes between two plant species, rice and millet, was demonstrated in 2005. Rice is nice, but what about humans? Could genes that originally came from microbes not only end up in human chromosomes but also be transmitted from parent to child during reproduction? In one of the best studies to date, a team of researchers led by Alastair Crisp at the University of Cambridge focused attention on human genes that share remarkable similarities to those of bacteria, archaea, and fungi.
Tens to hundreds of foreign genes of probable microbial origin have been identified in the human mammalian genome, and many of these seem to code for proteins with unique enzyme activities. Because of these functions, these apparent microbial genes appear to provide our cells with chemical-processing capabilities they would otherwise lack. The discovery of microbial genes in our chromosomes raises several questions: Does horizontal gene transfer and genes jumping between species impact Darwin’s view of evolution? Can the “tree of life” depicting species relatedness and the process of evolution continue to exist as a pristine tree, or is it really something different? Maybe it is closer to a pecan tree completely encased in webs of the fall webworm (Hyphantria cunea). How much of it is tree and how much is caterpillar web depends upon one’s perspective.
This microbe-to-human horizontal gene transfer is a relatively new swap discovery, and not everyone is totally convinced horizontal gene transfer is the only explanation for the findings. But the evidence for gene swaps between microbes and other plants and animals is so strong that to exclude humans from this widespread biological process would seem to be a stretch and require us to make the assumption that humans don’t do things biologically the same way as most other animals. Most of the debate now is more about when such transfers occurred and into what combinations of vertebrate species.
A prior swap of genes from microbes to our ancestors’ mammalian chromosomes would mean that some of the approximately 1 percent of human mammalian genes are not really mammalian at all. At least some of those genes sitting on our chromosomes today were swapped into us from microbes. So the more we look, the less of us is actually nonmicrobial and free from microbial influence. If these once microbial genes help us to do useful stuff that we could not do before we grabbed them, that stuff we now can do is of microbial origin, even if the capacity resides in our own chromosomes. Gene swapping and the microbially originated genes sitting within our mammalian cells make the boundary between the mammalian part of us and our microbiome very fuzzy.
It turns out that he who controls the gene switch controls a lot. The idea that your genes determine not only who you are but also your appearance, personality, and health profile had much currency as the Human Genome Project was being completed in the 1990s. You probably heard talk of the crime gene, the gay gene, even the intelligence gene. These features of a person add up to what biologists call a phenotype, which is simply a group of observable traits in an individual. The traits might be something you see, such as eye color, height, and facial structure, or something you don’t see outwardly but can measure, such as heart size, level of thyroid activity, metabolism, or biochemistry. Biologists have known that the inheritance of genes and different forms of genes, called alleles, does not always predict phenotype. This had been chalked up to interactions between genes and some environmental effects. That’s the old biology. We are now realizing that simply having a gene determines very little about how, when, and to what extent you may ever use that gene. The real control is whether a gene gets switched on and when. In most cases, if it just sits there on a chromosome and is unused, it might as well not be there. The control of gene use is called epigenetics, and this control mechanism is a central component of the new biology.
As mentioned in the introduction, humans have an underwhelming number of mammalian genes that, by themselves, are not capable of sustaining human life. That is why our second genome, via the microbiome, is not simply a luxury but a necessary and fundamental part of our being. However, genes are a little like electricity in the modern world. You can do amazing things with it, it likely powers your house or apartment and maybe even your car, but it is only useful once you can plug into it and control it—i.e., turn it on and off.
Wiring your house or apartment for electricity is only a potential for use. It provides a potential for having light and using electrical appliances. However, you need a circuit box with circuit breakers and light switches as well. You also need access to the electricity via outlets. If electricity simply comes to your house but you lack circuit breakers, light switches, and outlets, you are not going to see any benefit from the initial wiring. You have no access; only a potential exists. Genes are the same way. Whether they are mammalian or microbial, or genes from outer space, it makes no difference if they can’t be turned on.
We are very fortunate that, just as switches in a house can be installed by an electrician in keeping with code, our genomes come with both access and switches. The only difference is that the switches are not toggles to be physically flipped. Instead, they are chemical switches. And there are several different kinds of chemical switches. Understanding and better utilizing these chemicals is part of the new biology and the future of human medicine.
Being able to control when a gene is turned on, how much of a gene’s product can be made, and when during development the gene is on or off can be the difference between life and death, health and disease. Consider the production of hemoglobin, the oxygen-carrying protein in blood. Without adequate oxygen, your cells and tissues would die. It turns out you have different types of hemoglobin, and they are tailored precisely for different life stages and the oxygen needs of your tissues during those specific life stages. The production of embryonic versus fetal versus adult hemoglobin is under the control of epigenetic gene switches. The switches are flipped at precisely the right developmental stages for everything to work. It turns out that one of the small molecular metabolites of gut bacteria, sodium butyrate, can control these gene switches and affect hemoglobin expression. It and related chemicals are being tested for possible use in treating hemoglobin-related diseases such as sickle-cell anemia and beta-thalassemia. In those diseases, tissues often do not receive enough oxygen. Sodium butyrate can boost the amount of a high-oxygen-carrying form of hemoglobin in the blood. Clearly the microbiome has a biological role in the control of gene switches.
I am not alone in thinking about epigenetic control of gene usage as a type of switch. Recently, Dr. Dietmar Spengler and colleagues at the Max Planck Institute for Psychiatry in Germany described how chemical switches for gene usage are critical for healthy neurological development. They also described what can go wrong with the programming of these switches. They used the analogy that these switches are a part of writing your very own personal book of life.
I like to think about the programming of the switches for our development much as you might program the lights in your house while you go on a week’s vacation. In the old days you might have set this up using timers plugged into electrical outlets. Today, they could be computer-driven and connected in “smart houses.” If you had only one chance at the programming and it would last the entire week of your vacation, you would need to get the programming right so that lights in different locations in the house and yard would come on when they should and go off when they should for maximum security. If you got the timing wrong, it wouldn’t work out well, and lights could turn on during daylight and turn off at night. This is what can happen with gene switches in your body—with far worse consequences.
You can also think about these switches across different periods of life. A good analogy is that of railroad switches that determine the track taken by a train. For example, the longest rail line in the world, at approximately 5,772 miles, is the Trans-Siberian Railway. It connects Moscow through the Ural Mountains with the Russian Far East, the port city of Vladivostok, and the Sea of Japan. Shortly after arriving at Lake Baikal in the east Siberian town of Ulan-Ude there are track switches. The main track follows a route (the Trans-Mongolian Route) that leads through Mongolia (Ulaanbaatar) and into China, eventually reaching Beijing. A later switch point in eastern Siberia is about sixty miles past Chita, where a line switches off and runs directly southeast to China, leading to Beijing but skirting around Mongolia. These switches send trains to different regions.
Complex biological functions are under a certain level of gene switch/epigenetic control. These include such critical human functions as the formation of and maintenance of memories, the effectiveness of your immune response, the levels of specific hormones in your body and your responses to those hormones, and the levels and quality of sperm production.
The point is that these switches matter so much because they can be programmed. The programming begins in early life but can also occur during the lives of our parents and grandparents. In effect, they connect us both to our past and to our probable future. And of course, in some cases, the microbes in our microbiome can tell our mammalian genes whether they should be on or off both in the moment in real time and also later in our life and even in our grandchildren’s lives.
These switches, also called epigenetic marks, have their own memory. The memories of these gene switches are just as important as any of the mammalian and mitochondrial genes we have inherited. These epigenetic “memories” can span generations.
One of the most remarkable rebound stories in the history of biology, if not all of science, has been the changing fates of biologist and naturalist Jean-Baptiste Lamarck. Before Darwin there was Lamarck, whose theory of evolution said that environmental adaptation was driving generational changes and eventually inherited traits. Essentially, giraffes’ necks are long because adult giraffes stretch their necks when reaching for leaves high in the trees. These long necks acquired in maturity can be passed along to their progeny. This was at odds, to say the least, with Darwin’s approach.
Lamarck was born Jean-Baptiste-Pierre-Antoine de Monet, chevalier de Lamarck, in 1744 and grew up in a large family in northern France. He distinguished himself as a military officer until an injury forced his retirement. After that he began studying medicine and botany and produced a well-received book on the plants of France in 1778. He was appointed as a natural science professor but in an area viewed as comparatively lowly at the time, the study of invertebrates: i.e., insects and worms. It was through his work on the diversity of lower animal life forms that Lamarck began to form his views on adaptation. He believed that environmental influence on organisms could produce long-term effects as the organism underwent changes in the use of its cells, tissues, and organs. And so he reached his conclusion that, when the interactions spanned significant time, these changes could be inherited and observed across generations.
Lamarck had exceptionally broad scholarly pursuits and writings. His interests spanned medical science and botany and even extended into physics. Nevertheless, he died in poverty and obscurity. Only in the past few decades, as scientists have begun to discover the significance and impact of epigenetics, have Lamarck’s theories been reexamined. A few previously dismissed ideas have gained new relevance. And those ideas are now at the forefront of how we’re considering human health protection and how we’ll treat disease in the coming decades.
The idea of inherited changes through environmental adaptation does not seem as absurd as it once did. In the twentieth century, when science focused on inherited genes, including a rediscovery of Mendel’s work with peas, Lamarck and his ideas were ridiculed if they were paid any attention at all. He had become a poster boy for wrongheaded biological thinking by the time I was in school.
Yet as we have come to see over the last decade or so, what Lamarck described, environmentally driven adaptation, is precisely how epigenetic regulation of gene expression appears to work. He did not have the tools we have, but his perspective is profoundly valuable today. It is a good lesson in how scientific consensus can blinker us to new ideas and breakthroughs in our understanding.
To stay healthy we need to stick to the epigenetic program. If genes we need to switch on for a certain piece of our development fail to switch on or switch on at the wrong stage of our life, it usually causes disease. The resulting diseases that show up are most often of the noncommunicable type.
This process of establishing the pattern of gene activation while you are a baby is often referred to as developmental programming. It is much like programming a computer to do a virus check once a week in the middle of the night when you don’t need to use your computer. Much of my own career has been devoted to questions of how, when, and where programming for your developing immune system occurs. The genes on your chromosomes can be programmed based on early-life environmental exposure, including maternal and childhood diet, exposure to hazardous chemicals and certain drugs, or the presence or absence of key microbes. Each physiological system of your body undergoes this type of developmental programming. For some physiological systems and organs, full adult-level maturation happens earlier in life than in others. For example, the brain and lungs are among the last to reach full maturity as you age.
Developmental programming of later-life disease was first discovered about 1990 by UK researcher David Barker as he studied the developmental basis of heart disease. Barker noticed that if mothers had a limited supply of food, their offspring’s growth curve changed, and the children were more likely to develop metabolic problems, including heart disease. His theories on developmental programming of heart disease became known as the Barker hypothesis.
Through additional investigation conducted by scientists such as Philippe Grandjean of the University of Southern Denmark and the Harvard School of Public Health, Cheryl Walker of the Texas A&M Health Science Center, and Jerry Heindel of the US National Institute of Environmental Health Sciences (NIEHS), we now know that additional NCDs also follow the same pattern of early-life developmental programming of gene activation, usage, and risk of later-life disease.
The new biology covering the developmental programming of human health has become so extensive that brand-new scientific societies and research journals committed to this topic have popped up during the past decade.
The ramifications of gene switching have utterly befuddled the great biological debate of the twentieth century: nature versus nurture (genetics versus environment). As suspected for years now, the two can no longer be usefully separated. That paradigm is simply outdated. The environment so controls the programming of which genes you use that what you are from cradle to grave reflects in large part your combined ancestral and early-life nurturing and experiences (e.g., chemical, physical, and psychological stressors). This was eloquently described at the molecular level by David Crews (the University of Texas at Austin) and colleagues. The researchers described how continued focus on nature versus nurture (part of the old biology) is a problem because the “hoary concept of evaluating traits according to nature versus nurture continues to persist despite repeated demonstrations that it retards, rather than advances, our understanding of biological processes.” We need to move beyond this to advance our biological understanding of humans as a complex, yet fully integrated, superorganism. The food your ancestors ate (or didn’t eat), the air they breathed, and the water they drank all affected their on-off genetic switches.
These gene switches are now playing out in you across your life span. Your gene switches appear to have a memory of what your recent ancestors encountered in terms of stress, food, chemicals, and drugs. Of course this can make it challenging to know whether an environmental effect we see in our lives now is due to a present-generation environmental exposure or something that our parents encountered that still controls our on-off switches.
Evidence for this epigenetic memory, also called transgenerational environmental epigenetics, exists not only in lab animals, through the work of researchers such as Michael Skinner (Washington State University) and Andrea Gore (the University of Texas at Austin) on endocrine-disrupting chemicals in mice, but also in direct human experiences.
Two prime examples of epigenetic memory in humans involve the Dutch famine of 1944–45 (also called the Hongerwinter, or hunger winter) and the Great Chinese Famine of 1958–61. Apart from the deaths caused by immediate starvation, there were effects in the descendants of those who survived. Ironically, neither of these famines was caused by weather changes affecting crop production and subsequent food availability. They were a direct result of human action: politics and war. The Dutch famine occurred near the end of World War II because the Nazis blocked shipments into the occupied part of the Netherlands. It continued until the Allied forces did food drops in early 1945 prior to the liberation of the area.
While tens of thousands died of starvation, the generational epigenetic effects that lingered were a scientific surprise. The Dutch Famine Birth Cohort Study has provided an opportunity to evaluate the effects of this war-induced famine. Babies developing in utero during the Dutch famine were found to have what are called epigenetic marks for genes involved in metabolism. There is evidence suggesting that the packaging of the DNA in the babies’ chromosomes was altered by the environmental conditions of the famine. This, in turn, affected the expression, or switching on of those genes, and the babies’ metabolism later in life. For example, babies exposed in utero to the famine conditions were more susceptible to the development of type 2 diabetes as adults. The risk of developing diabetes was directly related to the severity of the famine the developing babies experienced. Those whose mothers suffered more severe malnutrition had the greatest risk of developing diabetes as adults. There is even evidence that it carried on to the next generation. Remarkably, the children of fathers who were exposed while in utero during the winter of 1944–45 were heavier and more obese than the general population.
Most scholars agree that the Great Chinese Famine of 1958–61, which led to approximately thirty million deaths, was a man-made catastrophe caused by massive changes in agricultural and other policies during Mao Zedong’s Great Leap Forward. It is considered to be the largest famine in human history based on the number of people affected. While it produced similar results to the Dutch famine, Mao’s redirection of food to cities and the complete lack of food in rural areas allowed for some interesting comparisons of long-term effects among large numbers of people within the same country. A significant number of studies have been conducted on the offspring of famine survivors within the past decade.
Because the Great Chinese Famine is more recent than the Dutch famine, more information is available on the epigenetics and health of the children of the Chinese survivors than on those of their grandchildren and great-grandchildren. However, the developmental programming effects on the health of the Chinese offspring are clear and quite sobering. Among the noncommunicable diseases and conditions at elevated occurrence in the Chinese descendants of the hardest-hit areas of the famine are metabolic syndrome, schizophrenia, and anemia.
These two examples suggest what has been reported in mice and rats—that the effects of nurture on DNA packaging and a gene’s on-off switch as programmed in early life can affect later-life risk of noncommunicable diseases. Additionally, at least some of these thrown gene switches may be preserved and transmitted to subsequent generations that were never exposed to the actual environmental conditions.
If epigenetics, the control of your on-off gene switches, is one of the more remarkable biological discoveries of recent decades, there is still the question of how the microbiome fits into the picture. This is where it gets really interesting. In a previous chapter, I discussed the primary role of the microbiome as your gatekeeper. It serves as a type of protective bubble for you that filters all of your environment and determines what actually reaches your human mammalian cells. It does this for what you eat, breathe, and come into contact with, whether food, environmental chemicals, or drugs. If the environmental exposures of your cells control your gene switches and your microbiome filters your environmental exposures, then guess what exerts a massive effect on your gene switches? Your microbiome. In a sense, your microbes—and which specific bacteria, viruses, and fungi you have in your gut, reproductive tract, and airways and on your skin—have a significant effect on the gene-switch-throwing chemicals that your cells and the mammalian genes in your chromosomes see.
A recent discovery on the gene switches puts the microbiome not just in a passive role as environmental filter but also in the active role of master controller for the switches. It turns out that many of the metabolites released by our microbes can flip the switches in many of our mammalian genes. The microbiome is a major player in establishing our developmental programming, in part through control of the gene switches. Having a complete and healthy microbiome in early life is critical for the healthy programming of the genes in our developing physiological systems.
This is a warning call about the long-term effects of microbiome depletion. If microbiome-related epigenetic marks are transmitted across generations, the full range of effects, including those on subsequent generations, could be harder to correct than by simply taking a probiotic pill.
The first part of this book introduced a new way of thinking about biology in general and human biology in particular. This new biology will revolutionize medicine, human health protection, and opportunities for improved self-care. The philosophical implications are beyond me, but they are nothing less than thinking of yourself as a tropical rain forest or a coral reef. That is at least somewhat existentially unnerving.
To your health!