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Modern Medicine and the Garden of Eden

Published:September 03, 2012DOI:https://doi.org/10.1016/j.amjmed.2012.06.001
      The human genome is a complex, intricate, and changeable biological system with major implications for clinical medicine. We noted earlier that simplistic approaches to interpretation and manipulation of the human genome were unlikely to result in positive clinical outcomes in the near future.
      • Alpert J.S.
      • Chen Q.M.
      Has the genomic revolution failed?.
      Considerably more basic science and clinical research efforts will be required before modern medicine can reach that ideal place, the “Garden of Eden of medical care,” where human disease will be reversed or markedly attenuated by genomic technologies.
      A recent publication in the cardiovascular literature has further underlined our earlier conclusions. Scherrer et al,
      • Scherrer U.
      • Rimoldi S.F.
      • Rexhaj E.
      • et al.
      Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
      working at the Swiss Cardiovascular Center in Bern, Switzerland, reported on systemic and pulmonary vascular function in children and adolescents who had been conceived by assisted reproductive technologies. This remarkable technology, involving in vitro fertilization and initial cell culture of the developing embryo, has been practiced for more than 30 years and currently represents 1% to 4% of births in technically advanced, industrial nations. The authors noted that a number of authorities in this field have been concerned that these “test tube” children might harbor genomic abnormalities that could predispose them to chronic cardiovascular and metabolic disease when they reached adulthood. To explore possible abnormal vascular development and function, Scherrer et al
      • Scherrer U.
      • Rimoldi S.F.
      • Rexhaj E.
      • et al.
      Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
      performed noninvasive vascular tests on 65 putatively healthy children/adolescents who were conceived by assisted reproductive technologies and compared the findings with the same variables from 57 normally conceived individuals of similar age and gender.
      The results were striking:
      • Brachial arterial size was 25% smaller in the cohort conceived by assisted reproductive technologies, although hyperemic arterial blood flow was the same in both groups.
      • Carotid arterial thickness and pulse-wave velocity, measures of vascular stiffness, also were abnormal in the children conceived by assisted reproductive technologies.
      • Finally, pulmonary arterial pressures at altitude (∼10,300 feet above sea level) were 30% higher in the group conceived by assisted reproductive technologies.
      The authors concluded that children conceived by assisted reproductive technologies display generalized vascular dysfunction that was not an inherited characteristic and was likely related to the assisted reproductive technology procedure itself. These authors also explored the possible mechanism for the vascular abnormalities that they observed in humans in a rodent model of assisted reproductive technology and found that changes in the culture medium in which the embryos were initially grown resulted in epigenetic changes in the methylation of the embryonic DNA.
      • Rexhaj E.
      • Bloch J.
      • Jayet P.Y.
      • et al.
      Fetal programming of pulmonary vascular dysfunction in mice; role of epigenetic mechanisms.
      These epigenetic changes were the result of environmental influences and not the result of alterations in the basic DNA code itself.
      Recently, there has been a great deal of interest in the molecular biological community concerning epigenetic mechanisms and their influence on an individual's phenotype. Epigenetic mechanisms are not part of the inherited DNA code. Rather they are the result of environmental influences, for example, constituents in the cell culture medium used during assisted reproductive technology. Epigenetic alterations in DNA function often involve methylation of some of the nucleotides in the DNA. This methylation process alters the expression of the particular gene containing this nucleotide. Methylation of some of the gene's nucleic acid components can turn off or decrease the production of a specific protein and thereby alter the biochemical and physical characteristics of the resultant individual during later life.
      Epigenetics thus help to clarify the long-standing conundrum concerning nature versus nurture. Current scientific thinking supports the idea that an individual's physical structure and makeup are the result of a combination of factors involving nature (the DNA code itself) and nurture (epigenetic influences on the DNA code). The observations of Scherrer et al
      • Scherrer U.
      • Rimoldi S.F.
      • Rexhaj E.
      • et al.
      Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
      support the idea that individuals with DNA coding that should have led to normal vascular function might instead manifest as abnormal vascular function as a result of epigenetic events occurring secondary to scientific manipulation during early embryonic life.
      What are the clinical implications for practicing internists and subspecialists who will eventually come to care for individuals who were conceived by assisted reproductive technologies? One message would seem to be clear already. Apparently, these patients are at increased risk for vascular and possibly metabolic dysfunction that might well predispose them to the development of cardiovascular disease, for example, systemic or pulmonary hypertension and premature arterial atherosclerosis. Only time and further observation of this still young cohort of individuals will tell whether the observations of Scherrer et al
      • Scherrer U.
      • Rimoldi S.F.
      • Rexhaj E.
      • et al.
      Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
      and others do portend an increased tendency to develop circulatory disease during later adult life. In the meantime, however, physicians should add one more piece of information to a patient's history, that is, was the patient conceived by assisted reproductive technologies? If we were caring for such an individual, we would be particularly assiduous in searching for and seeking to correct any atherosclerosis-generating risk factors that were present. Of course, lifestyle recommendations that sought to prevent atherosclerosis also would be part of our conversation with such a patient. We look forward to hearing more about the newly observed entity of assisted reproductive technology–related vascular dysfunction and what clinicians will need to know and do for these individuals. As always, we welcome comments and questions on our blog at http://amjmed.blogspot.com or on our Facebook page.

      References

        • Alpert J.S.
        • Chen Q.M.
        Has the genomic revolution failed?.
        Clin Cardiol. 2012; 35: 178-179
        • Scherrer U.
        • Rimoldi S.F.
        • Rexhaj E.
        • et al.
        Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
        Circulation. 2012; 125: 1890-1896
        • Rexhaj E.
        • Bloch J.
        • Jayet P.Y.
        • et al.
        Fetal programming of pulmonary vascular dysfunction in mice; role of epigenetic mechanisms.
        Am J Physiol Heart Circ Physiol. 2011; 301: H247-H252