AS A RESULT of the efforts of Newton and Maxwell and Darwin and a legion of other scientists and clinicians, we now have the ability to measure a lot about ourselves, not just at the level of organs such as our heart or lungs, not just at the level of the cells that make up the organs and tissues in our bodies, but now at the level of the molecules that make up our cells. These molecules are the most basic determinants of our identities. It is this amazing advance that is fueling the personalized medicine revolution.
Knowledge of yourself at the molecular level is going to have a huge impact on you because you have a fundamental problem. When you were born, you were given a unique body, possibly the most complicated organism on the planet, but you were not given an operator’s manual. To use a car as a metaphor, you were not even given very many instruments to monitor how well your body is functioning, and you weren’t given any information on the best fuel you should feed your body, whether it should be premium or regular, or whether ethanol can be used as an additive. A number of us seem to run quite well on ethanol, also known as alcohol; but others, not so much. You weren’t given any early warning lights to tell you that a life-threatening disease is starting somewhere in your body or that your immune system is going off-kilter, or that some behavior or environmental exposure will lead to arthritis in the future. You have no instrumentation to tell you whether any of those lifestyle changes you make to better your health actually work, and you are usually not quite sure whether the medication you take to fix your aches and pains is doing what it is supposed to do.
In addition to the lack of an operator’s manual, you have another, possibly even more basic, problem. Evolution, which led to the exquisitely designed body you live in, does not care about you. Once you are born, you are on your own. If you have lots of children that survive, your genetic code will survive and prosper, but once you have passed child-bearing age, evolution has no further use for the rest of you at all, and your body gradually breaks down and dies. So not only do you need an operator’s manual, but you also need to understand how you were made in the first place in order to combat this inevitable decline.
Molecularly based, personalized medicine will give you a rather intimidating operator’s manual. It will contain information you may not want to know but really need to be aware of to maintain your health and avoid illness. When used in combination with our ever-improving ability to engineer biological systems, it will provide knowledge that could lead to an ability to fix yourself — your personal repair manual — by manipulating yourself at the cellular and molecular level. It will be by far the most valuable thing you will ever own.
How will we bring your personal operator’s manual into reality? The first step is to make an inventory of the molecules that you are made of. The sum total of all this molecular information can be called the “molecular you.” The second step is to store all this molecular information in digital form. The resulting dataset comprises the “digital you.” The digital version of you will be an impressive amount of data, but not that much use to you unless you can use it to answer your questions about yourself. So the final step on the way to achieving your personal operator’s manual will be to devise computerized methods to query your digital self to get definitive answers to important questions you may have.
What questions will your personal manual be able to answer? As we shall see, when fully operational, it will answer more questions than you might think possible. If you don’t feel well, you will be able to ask it what is wrong with you and what the best treatment may be. You will be able to find out what drug will most effectively treat whatever disorder you have, and whether you will experience harmful side effects. You will get answers concerning what diet may be best for you and what foods you should avoid. You will be able to find out whether the medicine you’re taking or the lifestyle change you’ve made is effective. It will tell you of your risks of diseases, and you’ll get early warnings that a disease is forming in some part of your body well before it becomes life threatening.
The initial versions of your digital self will contain four categories of molecular information, and you can expect more categories to be added over time. First will be your genome: the molecular information that will be measured and stored will be the sequence of your genome, which contains the blueprint of your physical being. Your genome can be taken from almost any cell in your body, as they all contain the same sequence of DNA. Second will be your proteome. Initial measures of your proteome will likely involve determining the levels of 100 or more proteins in your blood, which should be sufficient to get an immediate snapshot of your health. Third will be your metabolome; measurement of 100 or more metabolites in your blood will yield clues as to how your body is dealing with your diet and can also diagnose disease. Finally, we will have to get a measure of your microbiome, or the bacteria and other micro-organisms that live in and on your body. Here, the detection of a few hundred bacteria in your feces will provide vital diagnostic and therapeutic information, particularly for the origin and treatment of immune disorders.
To understand the type of information the digital version of you will provide, and the insight it will give into how to fix whatever is wrong with you, you need to understand a bit about the biology of your body, the processes that go on inside you that make you the fascinating organism that you are. Let’s start with your cells — those little bits of you that Leeuwenhoek was the first to observe. You have a lot of cells in your body, approximately 30,000 billion of them, and each of those cells is on average 10 micrometers, or 10 millionths of a meter in diameter. To understand how small a micrometer is, the thickness of the lines forming the letters you’re looking at as you read this book is about 100 micrometers. That means ten cells could fit into a line wide enough to be part of a letter big enough for you to read. But the journey towards smallness doesn’t end there. Each cell in your body contains a lot of even smaller bits and pieces. Some of these are a thousand times smaller than a cell.
To describe how big these components are, we have to use the nanometer as a measure. There are a thousand nanometers in a micrometer. Luckily, we don’t have to go any smaller than that or we’d have to use quantum mechanics to understand ourselves. Each cell contains a nucleus that is approximately 100 nanometers in diameter. And the nucleus contains your genome, your deoxyribonucleic acid, or DNA — the genetic material that codes for the proteins that make the cells that make up your body — wrapped up in twenty-three pairs of bundles called chromosomes. DNA is made of four molecules — guanine (G), cytosine (C), adenine (A), and thymine (T) — known as “bases,” which are joined together in long strands. Each of these strands is associated with another “complementary” strand to make up the iconic double-helix structure that Watson and Crick first identified. The complementary strand has a sequence of bases that is complementary to the sequence on the first strand: all the Gs are opposite (paired with) Cs, and all the As are paired with Ts. And vice-versa.
Approximately 99.9 percent of the 3 billion base pairs in your genome are the same as in any other member of the human race. All your differences — the features that make you unique — are encoded by only 0.1 percent of your DNA. But 0.1 percent of your genome corresponds to 3 million base pairs, so there is the potential for a lot of genetic differences. Included in these differences are some sixty brand new mutations — changes in the sequence of bases in your DNA — that have never existed in any person ever before. You really are a mutant. All these genetic differences determine not only differences in eye and hair color between you and anybody else, but also whether you have a higher risk of lung cancer or a lower risk of Alzheimer’s disease or a greater chance of a heart attack. The ways that you differ genetically from everybody else also allow the forces of natural selection to work. If you prosper and have lots of children that survive, your genetic code will be conserved and passed down to future generations.
In our exploration of your biology and how molecular-level information such as the sequence of your genome can be incredibly useful, let’s start from the beginning, from when your mother and father had (hopefully) a mind-blowing sexual encounter that led to one of your father’s sperm cells getting together with one of your mother’s eggs to produce a fertilized egg — otherwise known as a totipotent stem cell — from which all the other cells in your body have been made. The sum total of all the DNA in this totipotent stem cell, half of which came from your mother and half from your father, is your genome. The sequence of your genome is fixed: it doesn’t change in your lifetime. This DNA supplied all the information needed for the totipotent stem cell to divide time and time again to ultimately form your heart, arms, legs, and every other part of your body. If we could understand all the instructions encoded in your genome, we could predict a lot of things about you: what you would look like at various ages, what reasoning abilities you were going to have — and what diseases you might be susceptible to. Your genome codes for how tall you are, what color eyes you have, how well coordinated you are, the color of your skin — all the physical characteristics you have — whereas your environment has determined what languages you’ve learned, what religion you might or might not believe in, and which football team is clearly the best in the world as far as you’re concerned.
The proteins that your genome codes for enable you to think or move or see or smell. If you had a lethal dose of radiation, which would destroy your DNA, you would not die immediately, but you would be a dead man — or woman — walking. That’s because you wouldn’t be able to make new proteins to replace old ones as they are degraded; all the proteins in your body are turned over on a regular basis. The sequence of bases in your DNA code for proteins using twenty amino acids that can be put together in any order. It takes a sequence of three bases to code for a particular amino acid, so if a protein is composed of 1,000 amino acids, it requires a gene consisting of a stretch of 3,000 bases of DNA to code for it. In order to make the protein that the gene codes for, the sequence of bases on the gene in the genome is first copied into another stretch of nucleic acids called ribonucleic acid (RNA; which is very similar to DNA) that then contains the code for just this one gene. This “messenger” RNA (mRNA) is then translated into a protein.
The process of forming a protein from a gene is called gene expression. Gene expression and how well the protein produced will work depend on many factors. For instance, gene expression depends on which variant of a gene you’ve inherited from your parents. These variants can be dominant or recessive, and you need only one copy of a dominant variant — for example, the one that codes for wet earwax — for that trait to be expressed. In contrast, you need two copies of a recessive variant — the one that codes for dry earwax, say, to see that trait expressed.
Lots of things can go wrong with gene expression. If one of the DNA bases in the gene that is expressed is wrong or is omitted, the resulting protein will have a different amino-acid composition and may be defective, leading to genetic diseases such as familial hypercholesterolemia, Huntington’s disease, or sickle-cell anemia. The story surrounding the severe form of familial hypercholesterolemia, in which two recessive variants are present, is a great example of how a genetic analysis can lead to basic understanding of a disease and the development of appropriate medicines. Individuals afflicted with severe familial hypercholesterolemia inherit defective genes from both parents that code for a protein called low-density lipoprotein receptor (LDL-R). The cells of these people are unable to accumulate low-density lipoproteins (LDL, commonly referred to as “bad” cholesterol), which transport cholesterol from your liver to peripheral tissues such as muscle and heart. As a result, LDL levels in the blood build to extremely high levels, resulting in cholesterol deposits forming atherosclerotic plaques within the arteries, which then restrict blood flow and cause heart attacks. For people with familial hypercholesterolemia, these heart attacks can occur early in life — during the teenage or young adult years. In families suffering from this condition, there are tales of fathers play-wrestling with their teenage sons, and both father and son dropping dead of heart attacks as a result of the sudden exertion.
In the 1970s, after high cholesterol levels in the blood were identified as the cause of atherosclerosis and high rates of heart attacks, researchers immediately focused on finding ways to inhibit the production of cholesterol in the body to reduce atherosclerosis, which was then the major cause of death in the Western world. This research resulted in the discovery of statins, which interfere with the production of cholesterol in the body. Despite the side effects that statins can have for some people, they have been instrumental in reducing the incidence of heart disease in the Western world to the extent that cancer is now the dominant killer.
Aside from differences in DNA sequence, there are other ways in which protein production can be affected. One common way in which you may differ from the person next to you is in the number of copies of a particular gene you have in your genome. These genetic differences, known as copy number variants (CNVs), can cause changes in the number of proteins made. If you have more copies of a gene that makes proteins that metabolize certain drugs, you will have a different response to those drugs than a “normal” person might. This idiosyncrasy will be revealed when your genome is sequenced. CNVs have also played an important role in evolution. Chimpanzees, for example, make only two copies of a protein known as amylase, which is present in saliva and plays a role in digesting starches, such as those found in potatoes and wheat. Humans, however, can have as many as fifteen copies of amylase — presumably an adaptation that assisted in our transition to a diet that included starchy foods.
A protein that has the wrong amino-acid composition, whether as a result of a faulty gene or errors in either transcription from the genome or translation of the mRNA, probably won’t fold into a functional shape. In addition, misfolded proteins are typically not water soluble. An example is the denatured proteins that form the skin on the surface of boiled milk. Misfolded, insoluble proteins in your body can build up as harmful deposits called amyloid plaques and are associated with more than twenty serious human diseases, particularly neurological diseases such as Alzheimer’s, Parkinson’s, and Huntington’s. Amyloid plaques also play a role in prion diseases such as mad cow disease or its inherited human variant, Creutzfeldt-Jakob disease. Once you know which protein is present in the amyloid plaques, you can then design therapies to specifically inhibit production of the protein being deposited, or ways to dissolve the plaque itself.
Only about 2 percent of your genome consists of the 20,000 genes that code for the proteins that make up your body. For a time, it was thought that the “noncoding” regions represented genetic material acquired during human evolution that was no longer needed. Some called these regions “junk DNA.”1 Whoever came up with that phrase should have known better. Evolutionary forces certainly do not favor wasting energy, and it takes a lot of energy to make the enormous amounts of DNA present in the genome in each cell in your body. It turns out that at least some of the noncoding DNA in your genome codes for RNA sequences that do not make proteins but instead regulate gene expression by a process called RNA interference, or RNAi. The RNAi sequences, called microRNA (miRNA) do this by binding to specific mRNA molecules that have a complementary sequence to them. This process causes the mRNA to be degraded and prevents it from making a protein.
MicroRNAs play extensive roles in regulating gene expression in your body, particularly during generation of your organs in embryo, as well as during tissue regeneration and aging. MicroRNAs also play important roles in the growth of cancer cells, and the detection of specific miRNAs in your blood can be diagnostic for the presence of cancer in your body.
All of your cells contain the same genomic DNA, so how do all of the specialized cell types in your body arise? This phenomena is the subject of epigenetics, which concerns how gene expression is regulated so that in specialized cells, only part of the DNA in your genome is translated into proteins. The whole process of differentiation — cells dividing time and time again to form the different organs that you’re made of — relies on a highly orchestrated process of genes turning on and off until the subset of proteins that a cell makes are appropriate to its function. For example, muscle cells make lots of long string-like proteins called actin and myosin. Signals transmitted from your brain can cause these proteins to contract, giving rise to muscle movement. In your eyes, large amounts of a protein called rhodopsin are made. Rhodopsin changes its structure when it absorbs light of certain frequencies, and eye cells use this change in structure to transmit a signal to the brain so that you can see. Cell differentiation occurs in a precise fashion. You certainly don’t want teeth to form in your muscles or an eyeball to form in your liver.
There are two main ways that a cell can modulate gene expression via epigenetics. There is an on-off switch called methylation, which involves chemically modifying genomic DNA to prevent a gene from being expressed. Alternatively, gene expression can be regulated by controlling how tightly the DNA containing the gene is wound up in the chromosome it is associated with.
Scientists are increasingly able to reverse the differentiation process of a cell to cause it to revert to the stem cells from which the tissue was made.2 This finding has huge implications for personalized therapeutics and arises from research that has been progressing steadily for more than forty years. In the 1960s, scientists discovered that when the nucleus of a frog skin cell was injected into a frog egg cell whose nucleus had been removed, the recipient egg could produce a normal tadpole. This result means that all the epigenetic controls on the fully differentiated, non-embryonic skin-cell genomic DNA were removed when placed in the environment of the frog egg, indicating that the chemical modifications of the DNA and how tightly it was coiled are reversible. What was also novel and scary was that the new tadpole matured into a new frog that was genetically identical to the frog from which the donor nucleus was derived.3 This process is called cloning, a graphic example of what was once science fiction coming to life.
Approximately twenty species, ranging from mouse to mule, to horse, to water buffalo, have now been cloned. The first mammal to be cloned was Dolly the sheep.4 She was cloned in 1996 using cells taken from a donor sheep’s udder. As with the frog in the example above, the nucleus was removed from the donor cells and placed in a sheep egg cell from which the nucleus had been removed. The reconstituted egg cell was then placed in the uterus of a host sheep, and Dolly was delivered approximately five months later. She was named Dolly after Dolly Parton because she’d been cloned from udder cells. Who says scientists don’t have a sense of humor?
There is little doubt that any human, including you, could be cloned using technology now available. But from a personalized medicine point of view — ethical questions aside — what use would this be to you? It would take years for your clone to be big enough to provide donor organs such as a replacement heart. Apart from the fact that you may not be able to wait that long, by that time your clone may not be too amenable to giving his or her body parts away. It is here that stem cells come to the rescue, at least potentially. You began as a totipotent stem cell that divided to form other cells that, in turn, eventually formed all the other differentiated cells that make up your skin, heart, brain, and so on. All these tissues are renewed regularly: your skin is replaced every two or three weeks, your blood every four months, your skeleton every ten years, and your heart every twenty years. This renewal is orchestrated by “adult” stem cells — that is, cells that are capable of dividing to renew the tissues in which they reside.
So now we have a somewhat less ethically challenged potential solution to renewing failing organs. If you want to renew your heart cells, you need to stimulate, or replace, the adult stem cells that make heart tissue. The same is true for your kidney or any other cells or organs in your body. As a result, stem cells are the subject of intense research, and new findings come daily. Scientists are now working on ways of making stem cells from any tissue by reversing the epigenetic process that leads to the fully differentiated cells, thereby producing “induced pluripotent stem cells (IPSCs).” These IPSCs can then be led back down the differentiation pathway to produce any tissue you may want. For example, skin cells can potentially be reprogrammed to become heart cells. From a personalized medicine standpoint, if, say, you want to see what effect drugs to treat atrial fibrillation will have on your heart as opposed to anyone else’s, you should, in the not too distant future, be able to scrape a few cells off the inside of your cheek and get them reprogrammed into cardiac cells that are genetically identical to the ones in your heart. You could then treat them with drugs and drug combinations to determine which ones will work best for you and have the least chance of causing adverse drug reactions.
The future of stem cells as therapeutics is remarkable, given their potential ability to renew any part of your body. One issue is that as you age, the number of adult stem cells in your tissues decreases and their ability to differentiate into functional cells declines. Thus, even though your skin replaces itself every two weeks or so, the new skin produced is not quite as good as the old skin, leading to the thinner, wrinkled skin that older people don’t like very much. If we could find a way of stimulating production of adult stem cells in your body, or reprogram them so that they differentiate more accurately, then they could replace your skin with younger skin, your heart with a younger heart, and your bones with younger bones.
While this may seem impossible, do not underestimate the power of the technologies that Newton and Darwin unleashed on the world. Already there are indications that stem cells can be reprogrammed in the tissues where they are found. In an experiment that has connotations of Dracula, researchers at the Harvard Stem Cell Institute connected the circulation of a young mouse to that of an old mouse whose heart was showing signs of hypertrophy, or enlargement, which comes with age and is a precursor to heart failure.5 Within four weeks of sharing the younger mouse’s blood supply, the heart of the older mouse started to become smaller and “younger.” A protein, GDF11, which is found in large amounts in young mice but which declines with age, was identified as a possible signal. Sure enough, injection of this protein into older mice produced the same signs of reversed aging in the heart.
So, where are we as we delve down into the molecular you? So far, we have covered how your genome leads to your proteome and the ways that the cell you started from can give rise to all the other cells in your body. But there’s a lot more to you than that. There’s the old saying “You are what you eat,” and in a literal sense, that’s true. The proteins, carbohydrates, fats, minerals, and vitamins that you eat all go into making you what you are. A large proportion are either incorporated into proteins in your body or used for energy to power your body. The way that the proteins, carbohydrates, and fats that you eat are used or “metabolized” gives rise to an enormous number of molecules in your body. These molecules are commonly referred to as metabolites.
Consider what happens to proteins, such as those in meat, cheese, or eggs, after you’ve chewed and swallowed them. They travel to your stomach, where they are bathed in strong acid and are partially decomposed into their constituent amino acids, and then they move into your intestines, where the breakdown is completed. The amino acids that made up the proteins are then transported across the lining of your intestines to enter the bloodstream, where they are taken up by the cells in your body and made into proteins required for cell function. All these amino acids and amino-acid fragments in your blood are metabolites, and the sum total of all the metabolites in your body is your metabolome. If you have defects in your ability to metabolize certain foods, or if you suffer from metabolic diseases such as diabetes, those conditions will be reflected in your metabolome.
You are probably beginning to think, “My God, does this process never end? Do I have to know about every molecule and cell in my body?” Luckily, not really. But if you want to know what data your individualized operator’s manual will use to tell you things you really need to know, and also how that information will suggest ways to fix any problems you have, you should stick with the program for just a little longer. There’s one more category of things that you’re composed of that just has to be included in the molecular description of you: your microbiome — all the bugs that live in and on your body.
Your body is a symbiosis of your human cells with hundreds of trillions of other organisms (microbes) that live inside you and on you. For every one of your cells containing your DNA, you also have ten bacterial cells, and they, along with yeasts, viruses, and parasites, make up your microbiome, which contributes to your state of health in ways we are just beginning to understand. There are more than 10,000 species of bacteria in your body, and these populations differ substantially between individuals. There’s a good chance that there are species of bacteria and fungi living inside your ear or in your colon that have not been characterized yet, because many of these organisms have not been grown outside your body. The particular environment in your body that allows them to thrive can be difficult to reproduce.
Bacteria in your microbiome can have a very direct effect on your health. For example, your microbiome possesses most of the gene processing power in your body and can metabolize certain prescription drugs. Thus the makeup of your microbiome can influence the effect drugs have on you. Your microbiome can affect your health in other interesting ways: for example, a New Yorker article in 2012 described a man in Pittsburgh who had been suffering for years from a chronic infection in his left ear.6 His doctors had tried everything, including several types of antibiotics, as well as antifungal drops. Then one day he turned up in the clinic with his ear completely cured of any infection. It turned out that he had taken some of the wax out of his good ear and put it into his bad ear. A few days later, he was fine. Presumably, the bacteria in his good ear had replaced the bacteria that were causing the chronic infection in his bad ear.
A recent review in Nature has pointed out the importance of mammals passing through their mother’s vagina, which is colonized by an enormous number of types of bacteria.7 Babies born by Cesarean section do not necessarily pick up these bacteria and may have an incomplete microbiome, which in turn can influence how the baby’s immune system develops. In 2012, approximately 30 percent of all children born in North America were born by C-section, and the incidence of allergies and asthma is far higher among those children than it is for vaginal-birth babies.
And it doesn’t stop there. It has been some time since it was discovered that the bacterium called Helicobacter pylori plays a causative role in the formation of stomach ulcers, leading to the treatment of stomach ulcers by using antibiotics. But why is H. pylori there in the first place, and does it play any positive role? The answer would appear to be yes: there is strong evidence that destroying H. pylori can alter metabolism in ways that increase the risk of obesity. In people whose stomachs are infected with H. pylori, appetite-stimulating hormones are much less detectable after a meal. But in people whose stomachs are not infected, the levels of the hormone remain high, so the message to stop eating doesn’t make it to the brain.8 Research has shown that mice fed antibiotics at dosages similar to those used to treat children with ear infections gained considerable weight compared to mice that did not receive the antibiotic.9 This, perhaps, is not surprising: most antibiotics consumed in North America are used as dietary supplements to promote faster growth in poultry, cows, and pigs.
We have had a preoccupation with killing bugs since Louis Pasteur showed that infections and illnesses could be caused by microscopic germs entering the body and since Alexander Fleming developed the wonder drug penicillin, which revolutionized our treatment of infectious disease by killing infectious bacteria. However, we may be overdoing it. Perturbing your microbiome by taking antibiotics is not without its dangers. As many as 40 percent of children treated with a broad-spectrum antibiotic will develop a condition called pediatric antibiotic-associated diarrhea due to the havoc that these drugs cause in the bacteria colonizing the intestines.10 About 10 percent of people carry a dangerous bacterium called Clostridium difficile. The bacterium is normally held in check by other residents of the gut. But when those companion bacteria are destroyed by antibiotics, C. difficile can erupt, causing severe diarrhea and deadly inflammation in the colon. The infection causes hundreds of thousands of illnesses and 14,000 deaths in America each year. Nearly every C. difficile infection occurs as a result of antibiotic treatment.11
Conversely, restoring your microbiome to a healthy state by using some rather unusual approaches can dramatically improve your health. For example, fecal transplants replace “bad” bacteria in the gut — those that are associated with diseases such as inflammatory bowel disease — with “good” bacteria taken from healthy donors. The donor’s fecal material is placed in the patient’s intestines, usually during a colonoscopy. Results from initial clinical trials have been remarkable. In one study to treat inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, sixty patients who were treated using a fecal transplant achieved a 95 percent cure rate. Other trials have reported success rates of more than 80 percent.12 This is important: nearly a million Americans suffer from inflammatory bowel disease with major effects on their quality of life. Luckily, it is fairly easy to persuade donors for fecal transplants to provide the necessary material, although the recipients may feel less enthusiastic.
The microbiome in your stomach and intestines break down food that your own proteins can’t, and in the process, they create vital molecules such as vitamin B and vitamin K. And healthy microbiota in the gut and on the skin, not to mention in the ears, eyes, and respiratory and reproductive systems, can be allies against infections by harmful bacteria. Striking the right microbial balance is key: for example, the vagina is home to yeasts and bacteria that usually keep each other in check. A subtle change to the vaginal environment can cause one population to flourish over another, resulting in a yeast infection.
So the molecular version of you has to include your personal microbiome. You will have to get over any squeamishness you may have about the bugs that live symbiotically with you; they are a vital part of your being. You are a tightly coordinated system consisting of billions of micromachines and nanomachines, all of which have to run smoothly individually and act together to produce the living, breathing you.
If the thought of fecal transplants and borrowed earwax to rescue your microbiome seems a little weird or possibly abhorrent to you, you’re not the only one. It points to a possible problem in Western society: in our quest for cleanliness, we may have gone overboard. Many immunological and autoimmune disorders are much less common in the third world than they are in the Western world. Almost 10 percent of youth in North America suffer from asthma, but in rural Africa it is much less prevalent. This situation may be related to a need to keep your immune system healthy by challenging it appropriately.
Realizing how complicated your immune system is and getting a little dirty may be an important component of your personalized medicine protocol. For example, certain immune cells contain components called toll-like receptors (TLRs) that help to fend off infectious agents. There are more than ten TLRs present in immune cells in the skin and other places susceptible to infection, and TLRs are quite specific with regard to the type of bug that they are programmed to react to and destroy. TLR3, TLR8, and TLR9 recognize RNA from viruses. Most others are specific for proteins found in bacteria. What is clear is that inappropriate activation of these receptors leads to autoimmune problems. Artificial activation of TLR4, for example, which is programmed to respond to certain bacterial infections, gives rise to asthmatic symptoms.
Given the fact that your immune system has evolved to protect you against bacterial and other infections, and that you contain such an enormous population of bacteria and other microbes, it should come as no surprise that your microbiome can have major effects on the function of your immune system. Your microbiome and immune system are clearly barely tolerant of each other, yet they are dependent on each other. Scientists recently demonstrated that the immune systems in genetically identical, same-sex mice responded quite differently to the same stimuli. This effect was eventually traced to different microbiome compositions in the individual mice. So disorders of your immune system, which range from asthma to arthritis, to inflammatory bowel disease, can potentially originate from, or be exacerbated by, an imbalanced microbiome.
The very presence of organisms that the immune system was evolved to fight may be necessary for proper immune function. The lack of stimulation of our immune system in early life and the development of immunological problems later on has led to the “hygiene hypothesis”: that clean upbringings, relatively free of parasites and infectious agents, do not lead to development of a healthy immune system and can cause it instead to become hyperactive. A hyperactive immune system is not what you want: it can result in everything from allergies to disorders in which your immune system attacks your own tissues, such as occurs in multiple sclerosis or lupus.
Keeping your immune system occupied in fighting the battles it was designed to fight might just reduce the chances of it becoming oversensitive and starting to reject parts of you. People who are infected with hookworms seem to suffer fewer autoimmune-related diseases, including asthma and hay fever. This observation has led to a fairly radical treatment for autoimmune disorders known as Helminthic therapy. This sounds innocuous enough until you realize that it involves infecting yourself with parasitic worms that your immune system evolved to fight many eons ago. Helminthic therapy has been proposed as a treatment for a variety of autoimmune diseases: inflammatory bowel disease, multiple sclerosis (a nasty autoimmune disease affecting 300,000 North Americans, in which the body attacks the insulation surrounding its own neurons), asthma, dermatitis, and food allergies.13
Although maintaining your microbiome in a healthy state and in balance with your immune system appears to be a good idea, there is certainly good reason not to go all the way with getting dirty again. The health gains made by the development and use of antibiotics and vaccines are enormous. However, eating a little dirt, avoiding antibiotics when you can, and getting a few infections, especially when you’re young, may not be a bad thing either. While we are still a long way from a detailed understanding of the relationship between your microbiome and your health, the outline is becoming clear. We have evolved an immune system to deal with bugs and parasites of all sorts, resulting in a curious symbiosis and a delicate balance. If your microbiome is perturbed, you will be too.
The catch phrase for an old detective TV series called Dragnet was “Just the facts, ma’am, just the facts”; and in this chapter, we have covered a lot of facts regarding the things that make up the molecular you. And your genome, your proteome, your metabolome, and your microbiome are just the start. There are other “omes” that have not been mentioned and more yet to be discovered. Hidden in this treasure trove of molecular information are facts that provide the clues vital to the detective work of finding out what is right or wrong with you; whether you are in the early stages of disease and whether the therapy you are undergoing is working. So now we have to find ways of measuring all these molecules to get a description of you at a molecular level, put it into digital form, and then figure out what it means. That’s the topic of the next chapter.