Rethinking the Promise of Genomics
I used to be a big believer in the enormous potential of genomics, and each of my two previous books, Fantastic Voyage and TRANSCEND: Nine Steps to Living Well Forever, had chapters devoted to this topic. The relevant chapter in the earlier book, Fantastic Voyage, published in 2004, was titled “The Promise of Genomics.” My co-author in these books, Ray Kurzweil, is widely regarded as one of the world’s foremost inventors and futurists, and he has made predictions for what is likely to occur in the future in the field of genomics . Yet, these days I find that I am feeling far less confident at least for the near term about the near term prospects for this “promise.”
“The Promise of Genomics” chapter in Fantastic Voyage contains a sidebar titled "Life as a Game of Cards” and in my public lectures on the topic, I would often display a slide showing playing cards from the gambling game of blackjack to emphasize this message. “Until quite recently you have been forced to play this card game of life almost completely in the dark, unable to look at the cards you’ve been dealt… almost no one has ever had access to precise information regarding his or her own specific genetic code.” We made the case that knowing one’s genetic makeup — what genes you carry — would allow an individual to make better lifestyle choices so that you can override your “bad genes” and emphasize the expression of “good genes."
In our 2009 book TRANSCEND: Nine Steps to Living Well Forever, we wrote, “Until the Human Genome Project was completed in 2002, you had to play the card game of life without being able to see the cards you’ve been dealt. As any poker player knows, if you don’t know what cards you hold, every bet is a bluff! Try deciding whether to take a hit or double down at the blackjack table without seeing either of your hole cards. You’ll play a much better game if you can see the cards you’re playing.” But I would like to share with you why I have removed that slide from my lectures and why I no longer feel that knowing what genes you carry is of great importance in most cases. For the foreseeable future, other than a few exceptions, I feel that genomics will not be terribly relevant in helping us make rational lifestyle choices.
The theoretical basis leading to “The Promise of Genomics” began in the 1950s when Roger Williams, M.D., introduced the concept of biochemical individuality. This is the idea that every person possesses a specific, unique biochemical blueprint. In Fantastic Voyage, we bemoaned the fact that “uncovering your biochemical individuality had been hit or miss at best, the result of decades of careful trial and error.” We went on to discuss the concept of genetic determinism, the idea that the genes you possess will determine your fate, which was originally advocated by Gregor Mendel, the father of modern genetics. In our own defense, even in 2004, we recognized that genetic determinism was not the answer either and advocated instead the concept of genetic relativism, that one’s genes merely represented tendencies that could be overcome by proper lifestyle choices. However, I now feel we didn’t go nearly far enough in diminishing the importance of the specific genes we carry as individuals.
Currently I have moved much closer to the idea of “genetic irrelevance,” the idea that in the overwhelming majority of cases, our genes are of much less importance in determining our fate and that the environment in which we live and the lifestyle choices we make are of far greater importance.
Please note that I said this is true in the “overwhelming majority of cases,” but it is not true all the time. About one in 20 people is born with an abnormal gene that will create a major problem that can affect life and be quite relevant, either from birth or at some point further down the line. Examples include cystic fibrosis, a genetic disease that can manifest from birth for which we have been doing routine screening for decades and the BRCA-1 and BRCA-2 genes, which dramatically increase a woman’s risk of breast and ovarian cancer later in life. But for nearly 95 percent of us, we come off of the assembly line of birth virtually perfect.
I feel there are three key reasons that genomics will not be the panacea in the near term that we had thought. First of all, the long-held belief that our genes control our lives is wrong. Secondly, epigenetics, which refers to inheritable changes in the genome that result from environmental factors, appear to be of far greater importance than the actual genes themselves; and, thirdly, making sense of the genome is proving to be too complex to provide much relevant clinical information for perhaps at least a decade or more.
Genes are not in Control
It has long been held as dogma that the processes of cellular life are under the control of our genes. We learned in school that genes contain the DNA within the nucleus of the cell that makes messenger RNA (mRNA) which travels out into the cytoplasm to bind with ribosomes which then begin the process of creating the proteins necessary for life. DNA to mRNA to protein is the accepted flow of events and is correct, but the problem is… the process doesn’t begin with the DNA. It is not the genes or the DNA within the genes that decides when it’s time to “turn on” and start making mRNA and protein.
In an experiment performed 60 years ago, nuclei were removed from amoeba and protein synthesis measured afterwards. After the nuclei were taken out, the amoeba did not die and protein synthesis did not stop. In fact, cells can live very nicely for relatively long periods of time without nuclei or nuclear DNA. Most cells have all the organelles and functioning proteins needed to sustain life for a period of time without a nucleus. If a cell is able to live without a nucleus or any genes, how can we say that genes control life? After some time, a gene free cell will eventually run out of needed proteins, and without the DNA blueprints contained within the nucleus it will die. Therefore, it would seem that we can say that genes and DNA-directed synthesis of new proteins is needed to sustain cellular life. But if a cell can live without a nucleus, we cannot say that genes control life.
So if genes aren’t in control, what is? If you look at each of the cellular building blocks, the proteins, carbohydrates, fats, phospholipids, or the cellular organelles, the mitochondria, Golgi apparati, lysosomes, peroxisomes or ribosomes, none of them seems to fit the bill either. They all play a role, but none seems in control. After some thought, it appears that the only possible answer is that the environment outside of the cell is in control of what happens.
The surface of the cell, the cell membrane, serves as the interface between the inside of the cell and the outside world. Scattered throughout the phospholipid bilayer surface of each cell membrane are tens of thousands of protein receptors. It is the function of these receptors to sense environmental changes occurring outside of the cell. There are receptors for complex molecular signals such as hormones and neurotransmitters, receptors for simple compounds such as calcium and glucose and even receptors that sense energetic signals such as heat or light. Coupled with these receptor proteins are effector proteins that carry the environmental information detected by the receptor proteins to the inside of the cell. The information is carried through the cytoplasm of the cell to the nucleus.
The cell membrane contains the receptors that sense that some type of environmental change has occurred. Signaling molecules then carry this information to the genes in the nucleus. The genetic material within the nucleus is about half DNA and half protein. At any given time some of the genes are being expressed – we say they are “turned on,” while others are “turned off.” What this really means is that the histone protein, which under normal conditions covers the gene, has moved away so that the underlying DNA is exposed and can be expressed (“ turned on”). The signaling molecule binds to the histone proteins and tells them to move out of the way and uncover the underlying DNA so that the gene can be expressed. The DNA is then free to do its job of creating a copy of messenger RNA, which can then travel out into the cytoplasm to create new proteins.
The genes contain the genetic blueprints that determine what proteins should be made, but the genes do not decide whether they should be expressed or not. The trigger, the event that initiates this chain of events, is the environmental change which occurred. Without an environmental stimulus, there is no reason for anything to happen. Cellular activity is clearly dependent on and the result of changes to the environment of the cell. The genes have nothing to do with the decision-making process and simply do what they are told by outside environmental factors. It is not our genes, but the environment, which is in control.
Epigenetics vs. Genetics
In Greek epi- means “above,” “over”, “on” or “besides.” So, epigenetics refers to the way in which environmental factors from the outside change the expression of genes without changing the genes themselves and how these changes are then carried down to subsequent generations. We can see this at the level of the cell and at the level of an organism as a whole.
Cellular epigenetics is seen very readily in autologous (a patient’s own) stem cells. Many centers collect abdominal fat and isolate the rich harvest of mesenchymal stem cells contained within. These stem cells can be used for numerous functions. Some common purposes include injecting these mesenchymal stem cells into damaged joints or tendons to treat orthopedic problems such as arthritis or tendinitis or into areas of the heart to treat damage from a recent heart attack. Freshly isolated from adipose tissue, mesenchymal stem cells have the ability to become cartilage, bone, fat, nerve or muscle cells. Which route the mesenchymal stem cells will take is largely determined by the niche or the environment in which they are placed.
If the stem cells find themselves in an arthritic joint, signaling molecules in the local environment will tell them that damaged cartilage is present and epigenetic factors will direct the stem cells to become chondrocytes or cartilage-building cells and they will immediately begin the process of rebuilding cartilage. They will no longer have the potential to make bone, fat, nerve or muscle; only cartilage. And, what is most important, when each of these cells reproduces, their daughters and granddaughters will also be chondrocytes and only make cartilage as well. The environment directs changes to the genetic expression of the cells which are then passed down to subsequent generations. Similarly, if mesenchymal stem cells are injected into a region of cardiac muscle recently damaged by a heart attack, the stem cells will differentiate under the influence of signaling factors in their local environment to become cardiac muscle cells and they will begin the process of rebuilding the damaged region of heart muscle. And, similarly, subsequent generations of cells will become only cardiac myocytes and only build heart muscle. Many centers in Europe and Asia now routinely treat heart attack patients in precisely this fashion.
These mesenchymal stem cells, like all the cells in the body, contain the entire spectrum of human genes. In addition to becoming cartilage, bone, fat, nerve or muscle cells, they also have the genes to become brain or kidney or fingernail or lens of the eye, but what they actually become is determined by their environment. The genes have no say in the matter. The environment says it all. It now appears that, in the majority of cases, once again, environmental or epigenetic factors play a far bigger role than the genes themselves.
Too Much Information … or Too Little
My co-author Ray Kurzweil has promulgated “The Law of Accelerating Returns,” which holds that in the world of technology, knowledge is not only growing at an exponential rate, rather the rate at which the rate of change is accelerating is itself also accelerating; in other words, technology advances at a double exponential rate, exponential growth of exponential growth.
We like to point to The Human Genome Project as a perfect example of “The Law of Accelerating Returns.” Back when the first human genes were fully sequenced in the early 1980s, the number of base pairs that had been sequenced was around 106 and DNA sequencing costs were measured in the tens of thousands of dollars. By 2008, six years after the human genome project had been completed, base pairs were up to 1011 (a 100,000-fold increase) and sequencing costs had dropped to 1/1000th of a penny (a billion-fold decrease in price).
We felt that the exponential growth in exponential growth of genetic data would open a new world of diagnostic and therapeutic applications. Pharmaceutical companies were convinced that human genome data would herald the advent of personalized medicine. There appear to be laboratory test kits that will be available in the near future to help physicians determine in advance from their genetic profile whether a patient is likely to develop muscle pain or other side effects from cholesterol-lowering statin drugs or bleeding problems from blood thinners. But these tests are only now finally coming to market 10 years after the sequencing of the human genome was completed.
It is true that prices for access to genomics information have fallen dramatically. Complete genome sequencing of all 3 billion base pairs in the human genome went on sale in 2007 for $350,000, and fell to $99,000 in 2008, $20,000 in 2009 and is between $5,000 – $10,000 in 2010. Even so, very few individuals avail themselves of this option. It’s still too expensive and no one knows how to make much sense of so much information. More popular are single nucleotide polymorphism (SNP pronounced “snip”) tests in which, depending on the test kit, somewhere between dozens and thousands of common, specific mutations are tested.
I was among the first to jump on the genomics bandwagon and was among the first physicians in the country to have SNP testing done on myself and to offer it to my patients. I have, in fact, had parts of my genome sequenced by four separate genomics companies. (I like to beta test new procedures on myself before offering them to my patients.) But what have I actually learned from this testing and what am I doing differently as a result?
For instance, I know that I possess two copies of the 677 C à T mutation on my MTHFR (methylenetetrahydrafolate) reductase gene, which helps control homocysteine metabolism. This means that at the 677th nucleotide location, cytosine, the nucleotide that is supposed to be there is replaced by thymidine. The MTHFR enzyme is intimately involved in methionine metabolism and people who have this genetic mutation (particularly individuals such as myself who have two copies of this mutation) are predisposed to developing elevated levels of homocysteine, a toxic byproduct of methionine metabolism. Yet, I have checked my homocysteine levels on multiple occasions over many years and my levels are exceptionally low, among the lowest of any patient I have checked in my clinic. Clearly, either my lifestyle has been able to overcome this genetic risk factor or I possess other genes that have mitigated the 677 C à T mutated gene. In sum, this genomics information didn’t lead to any behavior change. Once again, it would appear that the environment — my lifestyle — far outweighs my genetics.
Several relatives in my family have developed (and died from) colon cancer. Colon cancer risk for the population at large is 6%. For me, it’s 7%. I have a family history of prostate cancer. The average risk for a man is 17%; my risk is 20%. The genomics testing didn’t really provide much information above and beyond what I already knew from my family history.
It was reassuring to learn that I am at lower than average risk of: rheumatoid arthritis, glaucoma, diffuse stomach cancer, sarcoidosis, Crohn’s disease, Graves’ disease, multiple sclerosis, celiac disease, lupus, deep vein thrombosis, restless leg syndrome, melanoma, obesity, psoriasis and type II diabetes. I am at slightly increased risk of brain aneurysm (me 0.8%, average 0.64%), abdominal aneurysm (3.9% versus 3.1%), and atrial fibrillation (33% versus 26%). I will get regular abdominal aortic aneurysm ultrasound screening and electrocardiograms, but I would do this anyway as part of the health evaluations we do at my longevity center. I don’t know of any noninvasive test for brain aneurysms.
The biggest shock to me was my increased risk of heart attack (52% for me versus 42% in general). This was particularly surprising in that, as far as I know, no one in my family has ever had a heart attack or has died of heart disease. Cancer, not heart disease, has been the Grim Reaper’s preferred tool for harvesting previous generations of my ancestors.
There is one gene test, however, that I feel is definitely worth doing. The most important thing I found out from my genomics testing is that I am among the 26% of the population that carries a copy of the Apo E4 gene. Apo E carries fat in the bloodstream and has been associated with increased risk of cardiovascular disease and Alzheimer’s. There are three varieties of Apo E – E2, E3 and E4 and each person carries two copies, one from each parent. E3 is the default or neutral type and 55 percent of the population is genotype E3 E3. Apo E2 reduces risk of Alzheimer’s and has been associated with increased longevity. Approximately one in five people carries at least one copy of Apo E2. Apo E4, on the other hand, increases risk of Alzheimer’s. Individuals who are E3 E4 (the second most common genotype, which I also have) and carry one copy of E4 have an increased risk of Alzheimer’s disease, 20 – 27% rather than 9 percent for E3 E3.
What good has it done me to find out I have this Apo E4 gene? For one thing, it’s not all bad news. People with a copy of Apo E4 are at substantially lower risk of developing macular degeneration — my risk is 1.3% versus 3.1% for the population at large. Interestingly, my grandfather lived to be nearly 105 and also had macular degeneration, characteristics associated with Apo E2 not E4. He might’ve had one or two copies of Apo E2, but all I know is that I didn’t inherit one of these genes from him if he did. Then again there’s always the possibility he actually had a copy of Apo E4 like me and lived past 100 anyway (which is what I’m hoping to do) because environmental lifestyle factors trump genetics nearly every time. But we’ll never know for sure since genomic testing was not available while he was still alive.
My Apo E status provided me with actionable information and I often recommend that my patience have Apo E testing. However, there are many people who prefer not to have it done. I know that it’s depressing to learn that you have a gene that triples your risk of Alzheimer’s disease, as it does in my case (or if you have two copies of Apo E4, the increases is sixfold), but if you find out you have this genetic predisposition, there are things you can do. For instance, I take low doses of lithium salt and huperzine A, two safe nutrients for which there is some evidence of effect against Alzheimer’s and promotion of brain health. I engage in other behaviors to lower Alzheimer’s risk. I exercise my brain regularly and am always studying and learning something new. I took up crossword puzzles last year and am now hooked. I try to get plenty of rest, control my stress level and get adequate amounts of physical exercise, other behaviors associated with decreased risk of Alzheimer’s.
There is evidence for some seemingly contradictory behaviors as well. A 2010 report suggests cell phone radiation can break up Alzheimer’s plaque – at least in mice. As a result, often when I use my cell phone I hold it directly against my head rather than utilizing my Bluetooth. Previous to this discovery, I would almost always use my Bluetooth, which reduces radiation exposure to the brain and which we advocate in our books. By holding up the cell phone against my head I may be increasing my risk of brain cancer somewhat, but I know that I have a one in four chance of developing Alzheimer’s, so I feel that the potential benefit is worth the risk.
Other actions may be advisable, beyond taking supplements and excercising. A 2006 article from the Scripps Research Institute suggests that delta-9-tetrahydrocannabinol (THC), the active ingredient of cannabis or marijuana, blocks acetylcholinesterase, the enzyme associated with the formation of Alzheimer’s plaque. THC blocked this enzyme five times better than Aricept and 14 times better than Cognex, pharmaceutical drugs used to treat Alzheimer’s disease.
Genomics testing still has enormous potential merit, but it appears that many of the much heralded breakthroughs lie years in the future. Single nucleotide polymorphism (SNP) testing provides interesting information, but often not a great deal more than what can be obtained by taking a good family history. Whole genome sequencing is still a case of “too much information” and will require a large database and sophisticated numbers crunching to provide clinically relevant, actionable suggestions. Above all, we need to realize that no matter whatever genes we hold — good and bad — the environment in which we live, largely determined by the lifestyle choices that we make, minute by minute, day by day, year by year, is far more powerful in determining the weave and weft of the tapestry that is our life.
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