What is Medical Genetics?

AHMAD NISAR – The field of genetics, although relatively new, has transformed the practice of medicine. While biologists and biochemists had long hypothesized that there must exist a “gene-protein” relationship to explain the consistent transmission of phenotypes of a given cell (or individual) to its progeny, it was only the discovery of the molecular structure of DNA that burst open myriad possibilities of manipulating the very code of life. The study and practice of eugenics, for example, was a misguided attempt to quantify and potentially control the inheritance of traits deemed advantageous to civilization — and although it was thoroughly debunked within the first half of the 20^th century, it facilitated a thorough re-examination of the competing influence of either genetic or environmental factors on the expression of human phenotypes, especially those that involve disease. As our understanding has grown, so has our willingness to use our knowledge to predict and potentially resolve heritable diseases. It is known that various cancers rely on the upregulation of proto-oncogenes to enhance proliferation, while simultaneously downregulating ‘tumor suppressor’ genes; for example, studying the structure and movement of chromosomes have revealed mechanisms like meiotic recombination, dosage compensation, and cis-regulatory elements that can easily be disrupted to cause life-altering congenital conditions. Medical geneticists specifically aim to refine and apply this knowledge to screen, counsel, and treat patients with heritable conditions. 

As researchers have developed multifaceted technologies to amplify, sequence, and manipulate nucleic acid content and the proteins that genes code for, medical geneticists can rely on various tools for genetic testing. For example, inborn errors of metabolism can be screened with biochemical assays for faulty metabolic intermediates, while common oncogenic variants (such as BRCA1/2 mutants) can be detected by amplifying target sequences from blood or saliva samples via PCR and through the use of Illumina or Sanger sequencing to examine every nucleotide in the sequence for the deleterious mutations. 

What is done with this information? Physicians with a medical genetics certification can evaluate genetic data and proceed by administering preemptive therapeutic interventions (such as performing masectomies on those with hyper-proliferative variants of breast cancer-associated oncogenes) or heightened observation of at-risk patients, with administration of constructive diet and exercise programs to mitigate a disease before it starts. Although geneticists are currently limited in excising faulty genes at their source, especially in complex and dynamic systems like in vivo bodies, it is not unforeseeable to imagine potent gene therapies being used to replace, augment, or substitute deleterious gene variants with artificially constructed genes transfected into somatic or germline cells via viral or nano-particle vessels. In fact, the COVID-19 mRNA vaccines developed by Pfizer and BioNTech transfect cells with nucleic acids (mRNA) required to stimulate the endogenous production of coronavirus-mimetic antigens and guide the body’s immune system to combat COVID infection before such infection actually arises. 

The field of pharmacogenomics is another exciting avenue of development. Many critical pharmaceutical agents like anti-depressants, analgesics, beta-blockers and antipsychotics are metabolized by heme-bround proteins known as cytochromes, such as the well-known ‘cytochrome-c’ involved in mitochondrial respiration. Variation in cytochrome genetic sequences can affect the efficiency or speed of drug metabolism, resulting in ‘Poor’, ‘Intermediate’, ‘Normal’ and ‘Rapid’ Metabolizer phenotypes that are distributed in various frequencies across the broader human population. Using pharmacogenetic screening, physicians can determine which drugs to avoid or prescribe to patients with certain cytochrome phenotypes. For example, the cytochrome CYP2C19 is involved in the metabolism of a variety of potent antidepressants. If a patient is found to be a poor or rapid metabolizer for CYP2C19, physicians can instead prescribe drugs specifically metabolized by another major cytochrome — CYP2D6 — assuming the patient has the ‘normal metabolizer’ phenotype for this alternate protein. 

However, controversy has developed around the practice of genetic screening being used to ‘select against’ congenital disorders before birth. In Iceland, universal prenatal screening for Trisomy-21 has caused the near-eradication of Down’s Syndrome-affected children by 80-85% relative to previous figures, raising questions about whether genetic screening could arbitrarily select for or against traits with no normative medical value and be misused for cosmetic purposes to the detriment of those who are socioeconomically disadvantaged. 

Copy Editor: Aditi Madhusudan