Orthopaedic Surgery/Genetics< Orthopaedic Surgery
Here in the first decade of the 21st century we are 6.5 billion humans. Every second we add another 4.4, every minute 261,and if I keep ahead of the readers capacity to calculate that is 15,679 persons born each hour, and 137,350,692 born every year.
Meanwhile 56,556,474 persons die each year world wide, so indeed we are growing our gene pool, and today our numbers amount to 6% of the persons who have ever lived that number being 106.5 billion.
Evolving in East Africa early protohumans migrated from east africa first to south asia and australia. Secondary migrations occurred to central asia, dispersing then to europe and the americas. We owe our knowledge of these events to the tracing of gene mutations in the y chromosome and the mitochondrial DNA of females. There is some controversy as would be expected and climatic events have played a role in the genesis of these migrations,with intervening calamity leading to periodic destruction of most of our numbers in the early millenia of our existence as a species we were left in scattered pockets numbering perhaps no more than 50,000 individuals world wide. Subsequently we have evolved from these pockets and as a result there is heterogeneity in our genetic makeup.
Orthopedic manifestations of our genetic heritage include risk factors for a number of disease processes which are genetically based. A list of hundreds of orthopedic conditions due to single gene mutations (mendelian diseases) is available from the NLM website. These are mutations of genes coding for transcription factors, growth factor receptors and matrix macromolecules, to name a few examples. Beyond this we are not genetically identical as the human genome contains an estimated 10 million cases of single nucleotide polymorphism (SNP's).
Variable patterns of gene expression rather than variation in the genetic composition itself has the greater impact on the phenotypic heterogeneity. The pattern of gene expression is to some degree programmed as in growth and development, however it is also readily influenced by exogenous factors, thus the distinction between a condition which is genetically based and one that is not may be more a matter of degree than of absolute category. Increasingly we recognize the influence of our environment on genetic expression on a day to day basis such that each day we are subtly changed by our experience of the world. In the brain a short term memory, based on the strength of a synaptic connection, may be fleeting but with reinforcement a transition occurs into long term memory by means of a change in gene expression within a particular set of cells in the brain likewise our musculoskeletal systems retain memories of our experiences, and these memories ar embodied in an altered pattern of genetic expression within the cells of our musculoskeletal aparatus.
Our economic and environmental circumstance is perhaps a better target for our efforts to improve our orthopedic well being than is our immutable genetic inheritance. We can't choose our parents after all, and for the time being can do little to manipulate our gene expression at will. With the advent of erythropoietin, and BMP 2 and 7 we find the addition of genetically engineered products with which we can augment our native biological responses. It has taken 30 years to reach the point where the first clinical applications of genetic engineering have been brought to bear and the growth of these applications is liable to follow an exponential curve in parallel with the growth in computing capability. Increasingly the analysis of the human genome, transciptome and proteome will converge with the science of informatics; the science of analysing large volumes of data to identify meaningful patterns (Kurzweil, R 2005).
For the present it makes sense then to focus the majority of our efforts on improving our well being by impoving our diet, managing our exercise habits, coordinating our health care delivery, keeping environmental toxins in check, and avoiding killing each other all in the process of enhancing the economic potential for all in a stress free way that does not undermine our right to the pursuit of happiness. For that lucky minority who have all of these factors going for them, we can consider genes and gene expression with the goal of directly influencing the process to meet our goals. While this may seem to hold the promise of highly personalized care for the most economically advantaged, the broader potential is for revolutionary advances which hold limitless possibilities for freeing our species from any of our major afflictions including many which affect our musculo-skeletal well being.
With the completion of the human genome project comes the recognition that humans have far fewer genes than once thought. With this realization comes the understanding that the genome is more flexible and more complicated than once imagined. Instead of having 100,000 genes it turns out we have 25,000 genes. The actual number of our genes puts us on par with some simple plants and worms so if the number of genes was the measure of sophistication of an organism then we should feel none too proud. It seems however that our genome has evolved to make more efficient use of our genes and to employ variation in the spicing to enable more than one protein type to be produced by any given gene. Knowing the code it seems leaves us with the more difficult process of understanding how gene expression is regulated, in development and in our adaptations to lifes vicissitudes.
It is estimated that it takes up to 50,000 years for a given adapation to become widely prevalent in the population. So we can consider that we are walking around in bodies that are well adapted to the life of a hunter gather living 50,000 years ago. Of course some lucky members of the population will be quite well adapted to a relatively sedentary and longer life whereas most will find many aspects of modern existence as odds with their aparent constitutions. While inactive physically we are subjected to quite a barrage of stimulation, and stress in the form of information and time management and automated forms of travel. Emotional connection to the community and to the rest of nature is diminished as we become more surrounded by technologies of convenience the workings of which we dimly understand.
When considering genetic disease it is important to begin with the distinction between genetic alteration in a somatic cell, which then results in a disease process, and our genetic make-up acquired from our parents which may encode a susceptibility or even be the direct cause of a disease as a result of an abnormal type or quantity of the particular gene product of function.
The first case is best exemplified by the problem of cancer. Cancer is already recognized of course as not one but many diseases, but this insight is now being carried to the molecular level whereby it is recognized that there are perhaps a dozen or so kinds of lung cancer, and not simply the three or four categories we thought of a generation ago. It will soon be possible to specify the particular set of genetic anomalies that have produced the cancer in a given individual and by so doing know which particular kinds of therapy are best used.
The knowledge of a genetic predisposition to a familial disease can include cancer whereby genetic testing may reveal a calculatable lifetime risk of acquiring ovarian of breast cancer of perhaps 85%. This knowledge in the face of the notoriously difficult task of early detection may currently lead to a decision to consider prophylactic removal of the ovaries or breasts.
As such information comes online we must anticipate an impact on our health care system. Fortunately the costs gaining genetic information are coming down, and certainly the efficiencies gained by early recognition and preventative treatment will pay for themselves. As individuals we will have to come to terms with this new form of self knowledge and its impications, and as a society consider the greater implication this may have in areas such as privacy and health insurance availability and cost.