Genetics in Medicine: A Game of Odds

Each of us begins life as a single cell. The chromosomes within, formed out of long chains of DNA called genes, carry all the information necessary for the formation of a human being. The entire complement of  DNA, including long segments that have no known function, must replicate itself billions of times over the course of development of the baby and the life of the individual who emerges from the womb.  If there were never any errors in the original DNA,  if there were never any errors in replication of DNA, and if genes did not turn on and off in response to environmental factors, aging would not occur and human misery would be confined to infectious diseases and trauma. Now that the human genome has been decoded, can we look forward to a disease free world and to extension of the seemingly fixed lifespan of 110-120 years? Not likely, but the focus on the genetic contribution to disease will change medicine, for better and for worse, in the years to come.

Visible genetics: the family history

Doctors have always taken a family history as part of the initial evaluation of a patient. Physical features, health and ailments that run in families are visible genetic information. Height and body shape, nose shape, bunions, baldness, premature white hair all “run in” families. So do a variety of illnesses. Family history tells the story of genes that have expressed themselves already. Laboratory analysis of an individual’s genes attempts to predict what may happen in the future.

Laboratory genetics

In a few rare illnesses such as cystic fibrosis, sickle cell disease, and some devastating neurological degenerative disorders resulting from errors in very small parts of the genetic code, the genetic information is clear cut – the individual has an abnormal gene, and they have or will eventually show signs of the disease. These diseases, along with problems of chromosome breakage or duplication such as Downs syndrome, are the object of prenatal screening tests.  For the most part, however, genetic results are statistics – the odds that a problem will eventually appear. Potentially damaging treatments applied to healthy people, based only on future odds,  is the “for worse” change that may come with the addition of genetic information in the practice of  everyday medicine.

 The problems with statistical medicine 

Statistical predictions apply to large numbers of people, not to individuals. Not all people who have a gene associated with Alzheimer’s dementia will get the disease, but since more people born with that particular gene will develop Alzheimer’s than those born without it, the gene is said to increase the risk for the Alzheimer’s disease. The prediction of a strongly hereditary trait – one associated with an 85% likelihood that some kind of illness or cancer will appear by a given age – gives the impression that the illness is almost inevitable for every member of the family. But from the standpoint of an individual within the family, the risk is always 50%.  Either they will or will not be affected.

The importance of treatment availability when disease risk is high

What does knowing that there is an increased risk of suffering a given disease do for you? If there is a treatment that prevents the evolution of the disease, and it has no adverse effects, then it would be reasonable to gamble on undergoing treatment based on worry that the disease will appear, rather than waiting to see if one is in the lucky percentage that escapes. Women who undergo removal of their breasts and or ovaries because they have a genetic trait that greatly increases risk for cancer in these organs have made this judgment.  (They also must accept the minuscule risk that breast or ovarian cancer can still occur even after surgical removal of the organs.)

In the case of the devastating brain degeneration known as Huntington’s disease (HD), people usually know they are at risk because one parent has developed the characteristic dementia and movement disorder in midlife. Because of the so called dominant inheritance pattern of HD, half of the offspring of the parent, statistically, will also be affected.  But no one knows which children carry the gene unless testing is done. Now available and definitive, the genetic test for this disease is a double-edged sword. Life is normal for the carriers of the gene until middle age. The knowledge of what is coming might convince the bearer of the gene not to reproduce, but also make living a full and happy life seem out of reach.

The role of genetics in common diseases

What about the prediction of increased susceptibility to more common diseases, such as heart disease and some cancers?  This aspect of genetic testing may help people with their motivation to lose weight, exercise, eat well and get their routine colonoscopies. Genetic analysis of cancers that have already developed is already proving helpful in the design of specific treatments for specific tumors. All tumors of lung or liver or brain are not alike and “one size fits all” treatments, the only type available in the past, will give way to individualized plans and drugs. An individual’s responses to drugs for conditions such as high blood pressure and heart disease, including both desired and to adverse effects, is also based on genetic makeup.  Personalized treatments are already increasing for these problems.

Genetics and aging

Genetic studies are also teasing out at least some of the pathways involved in aging. Will advances someday lead to immortality? Very unlikely, and a bad social idea anyway. But understanding the way the genes gradually fail in their the mission of cellular repair may well lead to better old age. The key will be to use the knowledge early in life. So far it looks like preventing the errors in DNA replication that contribute to the diseases of old age depends on the same old things that your grandmother might have advised – eating modest amounts real food, preferably from fresh sources in all food groups, avoiding sugar and other refined carbohydrates, drinking little alcohol, avoiding sunburn, keeping in motion, sleeping enough, and most importantly,  avoiding the biggest DNA error trigger of all – cigarette smoke.  Of equal importance is recognizing that no matter how much we know and try to prevent, life will eventually wind down. Living one’s individual allotment well and fully is as important as avoiding cancer – and may actually help genes replicate correctly.

(For readers especially interested in how the genetic code works, Francis Collins’s The Language of Life, and Matt Ridley’s Genome: The Autobiography of a Species in 23  Chapters are good starting points.)


Why Cancer Happens

    According to Greek mythology, Cancer was the crab that the goddess Juno immortalized in the night sky after the lowly creature sacrificed himself in a fabled battle between Hercules and the nine-headed Hydra.  Since Juno was stingy with the number of stars she allotted to the crab’s constellation, the amateur astronomer often looks in vain for a body with claws. Nevertheless, first century physicians, searching for picturesque language to describe their patients’ ailments, found in the crab constellation a name for hard masses covered with tortuous veins – particularly those that seemed to burrow deeply into the body.  And so we came to know cancer, the disease that inspires today’s most sophisticated research in cell biology, by a name that has no scientific meaning whatsoever.

The biggest risk factor: age

Cancer is a problem of birth, growth and death of cells, and occurs because our bodies are in a constant state of renovation, from development as tiny embryos until death many decades later. At first we grow and change shape. Then shape becomes fixed but body maintenance requires cell replacement on a regular, repetitive timetable. The master plans laying out instructions for regular destruction and reconstruction of cells lie in the DNA coiled into chromosomes.  Just as job-site blueprints get smudged, torn and stained, DNA accumulates damage over time. External agents such solar, cosmic and X- radiation, toxic chemicals, some hormone use, and some viruses add to the innate wear and tear.  In some people DNA code errors are built in from birth, handed down from one generation to the next.  Errors in the blueprint lead to the imperfect cells which give rise to cancer.

Errors in cell reproduction are visible everywhere. We call them signs of aging. Crinkles around the eyes, sagging skin, “liver” spots, bunions and so on – all are external, visible reminders that internally, similar changes are underway. It is no coincidence that tobacco smoking, single-handedly responsible for most cancer deaths, also produces conspicuous, premature aging.  The most remarkable thing about cancer is that it occurs so infrequently despite billions of cycles of error-producing cell reproduction in each person.  Fortunately for us, DNA also contains numerous safeguards for getting rid of error-ridden rogue cells before they get out of control.

What makes a cancer diagnosis

While cancer cells are identified under microscopes by changes in their appearance, looks alone do not make a cancer diagnosis. Until abnormal cells acquire the ability to grow unchecked, and to travel to other parts of the body (to metastasize), they are precancerous.  In many cases, pre-cancerous cells never make the transition to cancer, but we are unable to predict with 100% accuracy which ones will and which ones won’t.  A large number of breast abnormalities detected on mammograms will not go on to run wild, but few women will comfortably forgo treatment without 100% accurate prediction of the growth potential of their abnormal cells.

Difficulties in prediction

In addition to the breast, the prostate gland in men and the colon in both sexes are the sites of cell growth abnormalities that can, but do not always, result in cancer. Prostates enlarge with age and develop nodules of cell growth called adenomas. Colons develop polyps – enlargements of the lining protruding into the colon on flat or narrow stalks, with or without adenomas on their surfaces. Intuitively, it seems as if detecting these abnormalities and removing them before they have a chance to become cancerous is a good idea. This thinking drives the screening studies aimed at early treatment of cancer. But many of these common cancers are very slow and indolent in their growth and epidemiologic studies do not bear out the intuitive bias.  Unless a patient is young at the onset of a slow growing cancer, treatment does not necessarily lengthen life. Routine prostate cancer screening has fallen out of fashion because, while removing a cancerous prostate may prevent death from prostate cancer, treated patients do not outlive untreated ones.  Decisions about treatment have to be weighed carefully, with attention paid to age and the potential for harm and diminished quality of life that can go along with cancer treatment.

While all cancers begin slowly, some escape the body’s control mechanisms more easily and become aggressive and difficult to treat.  Primary brain, liver, pancreatic and ovarian cancer fall in this category. Toxic external factors that alter DNA may render cancer cells more resistant to the body’s methods of keeping slower growing cancers in check. Lung cancer from smoking, blood cancers secondary to radiation and some viruses, ovarian cancers stimulated by hormone use, and asbestos-induced lung tumors  gallop along compared to the slow movers like prostate and colon cancer.


Currently cancer treatment consists of removing cancers surgically and/or intervening with drugs or radiation to kill the abnormal cells. Both approaches leave something to be desired. Surgery removes a tumor already developed, but not the underlying biology that produced the tumor. Chemotherapy that seems effective at first is often followed by a relapse in which the cancer is less responsive – not surprising since the cells surviving the first rounds of treatment are resistant to the drug’s actions. Radiation induces cell damage in all exposed tissues and accounts for cancer development years later in people who have survived the first bout.

The new paradigm for thinking of cancer is as an age and genetics related derangement of cell growth that is also influenced by environmental factors.  Effective, tolerable treatments require understanding of the individual biology of each person’s cancer.  As the interior of living cells give up their secrets to researchers, we are beginning to see some real successes with drugs such as Gleevec (used for chronic myelogenous leukemia) – drugs aimed at specific pathways in the life of microscopic cancer cells – and also with immunotherapy in melanoma.  Perhaps we will eventually  be able to retire the image of the crab to his home in the sky.


Factors in cancer development

Under your control

Not under your control

Avoiding tobacco  Your genetic makeup
Using sunscreen The passage of time
Maintaining normal weight Cosmic radiation
Choosing high quality foods, low in sugar Accidental radiation exposure
Eating and exercising enough to avoid constipation (avoiding slow transit of waste through the colon) Exposure to carcinogenic agents not currently recognized as carcinogenic


Minimizing post menopausal hormone use Bad luck
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