4:00 P.M.

October 7, 2004

Lifestyles & Genetics
In Health & Disease

by David Baylink M.D.

Assembly Room, A. K. Smiley Public Library

Summary

(this needs updating after the Oct 04 paper) We have the geography of the world and the geography of people, which we call anatomy.  The geography of people can be further reduced to the geography of the genome, which is a miniaturized blueprint of the molecules of human cells. There is a considerable difference in magnitude between the geography of the world and the geography of the cell. The circumference of the world is roughly 26,000 miles and the circumference of the cell is about 26 ten thousands of an inch.  However, because each tiny cell of the body contains six feet of DNA and because there are five trillion cells in the body, there is enough DNA to wrap around the surface of the Earth 200,000 times. 

The genome revolution, so far, has shown that we are 99.9% alike as humans, even though, when looking at your neighbor, you might wish that were not the case.  Even less comforting is the fact that C. elegans, which is the Earthworm, shares 65% homology with humans.

Where will the genome revolution lead?   Jeremy Rifkin, who is a popular futurist, has raised the consciousness of the significance of the genome revolution. Moreover, he has made both desirable and outrageous  predictions. For example, he suggests that there will be a revolution in agriculture so that we will abandon farms and, instead, produce food in giant bacterial baths by recombinant DNA technology. It is true that genetically engineered bacteria could produce the protein composition of a steak, but what would it taste like?  He also predicts that human/chimpanzee hybrids could be widely used as experimental subjects in medical research and also organ donors.  He also proposes that parents could choose to have their children conceived in test-tubes and gestated in artificial wombs, a technological advance that women may find a lot easier than the current method. He makes many additional predictions that are even more threatening to our individuality.

In conclusion, anything with the enormous potential of genetic engineering, when coupled with computer sciences, could vastly improve the human condition or could be misused to the extent that could produce a devastating threat to what we consider a free society.

Dr. Baylink went on to provide a short PowerPoint presentation of some of his advances in molecular genetics and gene therapy. He concludes that much of what Rifkin has predicted is hype and that the reality of the situation is that the advances that are being, and will be made in the future, will eliminate a considerable amount of human suffering but that this will not happen for several years.

Abbreviated Curriculum Vitae
of David J. Baylink, M.D.

After postdoctoral fellowships at Harvard Medical School and the Postgraduate Medical School of London, Hammersmith Hospital, in 1966 Dr. Baylink moved to the University of Washington in Seattle, Washington, where he subsequently rose to Professor of Medicine in 1977.  In 1981, Dr. Baylink moved to Loma Linda University, where he is currently Distinguished Professor of Medicine and Professor of Biochemistry. At the Jerry L. Pettis Veterans Administration Medical Center he is the Associate Vice-President for Medical Affairs for Research, as well as Director, Musculoskeletal Disease Center. Dr. Baylink belongs to many scientific organizations, including the American Society for Clinical Investigation, the American Association of Physicians, and Alpha Omega Alpha.  He is a member of the editorial board of several scientific journals. He has served on scientific study sections of the Veterans Merit Review System, the National Institutes of Health, the National Aeronautics and Space Administration, and, also, the review bodies of non-federal granting institutions.  Dr. Baylink has received several awards for his work on bone and mineral metabolism, including the Medical Investigator Award, Veterans Administration.  Dr. Baylink has published well over 500 papers in the musculoskeletal field, including molecular genetics, tissue regeneration, and gene therapy.

Dr. Baylink and his wife, Colleen, have three children and six grandchildren.

Lifestyles & Genetics
In Health & Disease

This paper is one of a series of my fortnightly papers that touches on the human genome.

 It is an expansion of a column that I recently wrote in the San Bernardino Sun Newspaper.  I will begin by illustrating the definition of some of the elements of the title of my paper.  Many years ago when I was doing postgraduate work at Harvard University, I heard an incredibly authoritative lecture on Huntington's disease.  After the

Lecture, I must have had a look on my face that said what an awesome lecture since my friend looked at me and said, "I agree, but do you know why he is so knowledgeable on the subject?"  As was his custom, he then answered his own query. " Our lecturer is desperately searching for the Huntington's gene because he has about 10 years before his brain will begin to rot from this fatal brain disease."

We have often heard the expression, nature versus nurture.  Nature refers to genetics and nurture refers to environment.  Huntington's disease is an example of nature, as is eye color, whereas, physical fitness is an example of lifestyle or environment.

We talk about nature versus nurture in an either/or type of language, whereas much of what we have attributed to nature and most of what we have attributed to nurture actually represents gene -- environmental interactions. Technically, what this means is that something in the environment such as calcium intake interacts directly or indirectly with the promoters of certain genes to activate these genes. The promoter of a gene is like accelerator of a car; metaphorically your foot would accelerate calcium utilization.  The situation is slightly more complicated because the promoter of a gene also has breaks which can be turned off or on by environmental cues.  To oversimplify for the sake of clarity, once activated, the calcium dependent genes cause changes that lead to strong bones.  In this case, calcium is the environment and the calcium response genes are the genes for the gene environmental interaction.  Some individuals have calcium response genes that are more beneficial than other individuals and as a result the calcium requirement for strong bones varies from one individual to another.

  In the grand scheme of biology, for an organism to function throughout its lifespan, it must be adaptable, adaptable to the availability of nutrients, adaptable to changes in temperature, adaptable to changes in the need for the amount of physical strength and so on.  Gene -- environmental interactions are critical cogs in the big wheel of adaptation.

In the plant kingdom, an example of gene -- environmental interaction is my avocado tree that it is extremely bent in order to circumvent the shade of nearby trees so that it can harvest the energizing rays from the sun.  Returning to the animal kingdom, an example of adaptation is eating more when the weather is cold in order to store energy for the winter months when food supplies are diminished.  In this regard, some of you may have noticed that your appetite seems to be much greater in the cold winter months than in the hot summer months.

There is also a downside of gene -- environmental interactions.  Accordingly, I will list just a few of the diseases that are the consequence of the interaction of our environment with our genome. These include, cancer, depression, obesity, high blood pressure, alcoholism, asthma, and Alzheimer's disease.  Most of us have a preponderance of good genes but some of us have an excess number of bad genes.  Tails is disease and heads is longevity in the coin toss of how genomes interact with the environment.

Many of us in the fortnightly club are interested in the topic of longevity, for fairly obvious reasons.  How long we live is an interaction between our genome and our lifestyle.  In terms of lifestyle, we can live longer by reducing our caloric intake, but for most of us that is a pill that we would not choose to swallow.  I will touch on longevity again a little later in my presentation.

Environmental emotional stress can cause depression in some individuals but not others, depending upon their genetic makeup.  In a very elegant study, researchers found that differences in the length of a gene, responsible for transporting an important brain chemical messenger, can cause differences in the level of emotional well being.  Persons with a long version of this gene, which is normal, were less likely to suffer depression under the same stressful encounters as people who had the shorter, abnormal gene.  Just having the shorter version of a gene was insufficient to cause depression:  Anxiety superimposed upon the genetic variation was required for depression to manifest itself.

Gene environmental interactions are very important to scientific inquiry.  For ordinary people such interactions are even more important because in many instances, it is possible to favorably alter the environment and thereby, prevent an adverse gene environmental interaction.  For example, an individual with the shorter gene genotype might be placed on a medicine to curb anxiety in order to prevent depression.  Ordinarily this patient would be placed on an antidepressant medication, which might not be effective in that particular patient.  This example illustrates how knowledge of individual genotypes can improve the quality of life.

The cause of some if not most, cancers is gene -- environmental interaction.  For example, an individual might be born with a mutation that could increase the risk for colon cancer.  However, this mutation by itself is insufficient to cause colon cancer.  If this mutation is combined with mutations induced by certain environmental conditions such as obesity or alcoholism, then there are sufficient alterations of the genome to lead to an unregulated and continuous proliferation of colon cells, which is the hallmark of the cancerous process.  In effect, the cells, because of their accumulated mutations, now ignore the normal stop signs that appear on the road to healthy organ maintenance.

Obesity is one of the causes of cancer and also many other chronic diseases and itself is a product of gene environmental interactions.  Identical twin studies show that obesity is due in part to genetics.  But while genetics probably has not changed that much in the last two decades, the incidence of obesity has markedly increased in the last two decades, to epidemic proportions, emphasizing the importance of the environment in our current obesity epidemic.  Those who study obesity have concluded that in the last decade, major growth has occurred in television and electronic stores and rather stagnant growth in sports and bicycle shops.  Major growth has also occurred in fast food restaurants.

With respect to caloric intake and body weight, a recent study, published in the Journal of the American Medical Association, showed that one can of soda per day could lead to a 15 lb. weight gain in 1 year.   This amount of soda contains 40 to 50 g of sugar. 

The topic of obesity and diet brings to mind a very important new discipline called nutrigenomics, which is a study of the variable effect within a population of subjects of dietary elements on the body’s metabolism.  This is a challenging topic that can now be addressed because of the recent mapping of the human genome.   An illustration as to why nutrigenomics is so important is as follows: two individuals with high cholesterol switch to a low saturated fat diet, one shows a marked decrease in blood LDL cholesterol and the other shows only a modest change in this blood parameter.  For some reason, the diet is more effective for one than the other individual.  The goal of nutrigenomics is to know enough about the genome of each individual subject such that dietary intake can be optimized for each subject.   Can you imagine everyone on a jumbo jet requesting an individualized meal to satisfy their genomes?  Undoubtedly, nutritional requirements for genomes will fall into subclasses, with each subclass requiring a unique set of nutritional options.  Hopefully the number of subclasses will be manageable.

One of the predicted budget busters for the next two decades is Alzheimer's disease, which is on the rise in part because the average age of our population is increasing.  Alzheimer's disease is another example of gene environmental interaction.   Atherosclerosis of the blood vessels in the brain, which is itself a disease due to genetic environmental interactions, is a risk factor for Alzheimer's disease.  In contrast, subjects who remained mentally active are at lower risk for Alzheimer's disease, again emphasizing how important adaptive mechanisms are for normal human function in disease prevention.

We now know that there are several life style measures that will help prevent Alzheimer's disease. I will provide three: 1) normalize blood pressure, cholesterol, blood sugar and body weight.  2) exercise mentally as well as physically.   3) Apply 21st-century nutritional advances. For example, antioxidants and other nutrients such as vitamin C and E that have been shown to decrease the risk of Alzheimer's disease.  Also, there is some evidence that omega-3 fatty acids have a preventative effect on Alzheimer's progression.   A risk factor for Alzheimer's disease  is a high serum homocysteine, which can be reduced by diets that are high in fruits and vegetables, containing B vitamins, particularly folic acid, vitamin B12 and vitamin B6.

The same type of gene interaction seen with nutrients is also seen with drugs.  The most commonly prescribed drugs in the US are statin drugs which are used to reduce blood cholesterol.  Although the statin drugs are effective in most patients, recent evidence suggests that there are some patients with gene sequence variations that make them poor responders to statin drugs.   This is another example of variable gene environmental interaction.  Pharmacogenomics is analogous to nutrigenomics. The goal of pharmacogenomics is to optimize medications for all individuals despite their variable genomes.  Presumably many patients with the same clinical manifestations will be divided into subclasses in which each subclass will receive its own unique set of drugs.  It is likely that many chronic diseases, including coronary artery disease and osteoporosis, will eventually be divided into subclasses based on pharmacogenomic principles of therapy.

Now I would like to return to the topic of longevity.  The August 30, 2004 issue of Time Magazine devoted several pages to an article titled, "how to live to be 100".  Three major conclusions were drawn from current knowledge.  1. About 30% of how long we live is genetically determined.  2. If you want to live longer and be healthier you can do so by eating less, much less.  Incidentally, Okinawanin's eat only about 80% of the food they need for complete satisfaction.  Scientists are now attempting to discover metabolic pathways that might lead to discovery of drugs, which could accomplish the same effect on longevity without modest starvation.  3. Scientists have been following the Okinwinan centenarians since 1976.  The centenarians have a lower incidence of Alzheimer's disease other forms of senility than their US and European counterparts do.  However when Okinawanins move permanently off the island, their life spans decrease and their rates of cancer and heart attacks accelerate.  Although lifestyle is an important feature of longevity, it is noteworthy that brothers of centenarians are 17 times more likely to live to be 100 than other Okinawinans without 100-year-old brothers.  Finally, one of the interesting environmental findings of these human century trees is that they eat twice as much soy as any other population in the world.

We are all aware that environmental pollution can have adverse effects on lung function.  Additionally, scientists have linked environmental pollution, and other tiny particles produced by combustion, to heart attacks, asthma and lung cancer, a major environmental health problem, which is being addressed by the US environmental protection agency.  These findings are not particularly surprising.  What is surprising is that when laboratory animals are exposed to environmental pollution, they develop inheritable mutations.  Accordingly, mice were housed in cages at a site near a highway and two steel mills in Ontario Canada for 10 weeks.  Some mice breathed the polluted air whereas others breathed air passed through a fine filter.  The mice born to males that breathed unfiltered air had up to 2.8 times more mutations in their genomes than did mice with fathers that breathed unfiltered air or clean air at a rural site.  Apparently, these inhaled toxicants reached the blood stream from the lung and were transported to the testes where they reacted with stem cells to produce DNA damage.  The lesson here would seem to be that, if we want to preserve our miraculous genetic makeup, we need to take care of what we expose our lungs, our intestines and our skin to.

In 1997, Decode Genetics, Inc., a genomics biotechnology company, based in Iceland, proposed to the Icelandic Ministry of Health that a centralized database on health care in Iceland be established for gaining new knowledge and insight about common diseases and to serve as a model system for individualized health care practice in a nation.  The bill was passed by the Icelandic parliament by approximately 75% of the vote.  In return for the population's participation in this genetic study, Decode promises to provide any drugs and diagnostics, developed through the use of the database, free to all people in Iceland during that patent protection period.   Decode now has a market capitalization of approximately $450 million.  Iceland has approximately 294,000 people.  It is ideal for a genetic study because the population is genetically homogeneous.  In the five years that Decode has been in operation, genes have been discovered that are involved in the following diseases: tremor, stroke, hypertension, asthma, Parkinson's disease, schizophrenia, anxiety, osteoarthritis, multiple sclerosis, osteoporosis and heart attacks.

Hopefully in the future, genetic information can be used to prevent chronic diseases worldwide.  This would be particularly true for those genes that have gene environmental interactions.  We cannot at this time, systemically modify the structure of a gene, but we can still modify gene environmental interactions because we have some control over our environment.  Once we better understand our own genetic blueprint, we will know how to best manipulate our environment.  We will find environmental ways to deprive the adverse genes and to foster the favorable genes.