It has now been over a decade since the final full sequence of over 20,500 genes was mapped by the multi-national Human Genome Project. It is still surreal to fathom the enormity, and the seeming anti-climactic finality of this achievement. For the numerous scientists who collaborated on this project, their final aspiration was not simply the conquest of a biological puzzle per se but was rather in translating this newly compiled information into health for individuals and across populations.
The full realization of a personalized, “genomic medicine” is still very much an ongoing venture. Dr. Sharon Moalem's third book, titled Inheritance, seeks to imprint the relevance of genetic research on rare conditions to everyday life. As a practising physician and clinical researcher, Dr. Moalem's writing style is bereft of jargon, filled with anecdotes, and presumes little to no prior knowledge on the subject.
Citing the reality of over 6000 rare genetic disorders, Dr. Moalem sets up the advice of the British physician James Paget as his guide. Paget, writing in the British medical journal The Lancet, in 1882, wrote that “[n]ot one of them [rare diseases] is without meaning...[n]ot one that might not become the beginning of excellent knowledge, if we could answer the questions – why is it rare? Or being rare, why did it in this instance happen?”
The reason rare genetic disorders occur so infrequently is that complex, multicellular animals operate under the principle of “biological totalitarianism.” This is the mechanism that, when functioning as it should, “promotes cellular obedience at all costs, an obedience enforced by receptors on the surface of any potentially misbehaving cells.” Yet the paradox is that our DNA – our hereditary material and biological instruction manual – is susceptible to change through individual actions, and stimuli from the environment. The remarkable fact is that even a a very small change in genetic code has a significant transformation in its expression. Dr. Moalem recounts the story of a young boy in Lahore, Pakistan who had a small mutation in the SCN9A gene leading to his accidental death as he jumped off a roof on a dare, as he was completely devoid of feeling any pain.
There are various points in the book where the reader is encouraged to have their exome (partial) or whole genome sequenced as it has become relatively cheaper to do so. While this is true – in 2000, $10 million could barely sequence 1 person while the same amount, accounting for inflation, can sequence up to 400 people – there is still stubborn bottlenecks due to the complexities involved in computing and interpreting this genetic data. The practicality of access continues to be restricted due to these barriers, and are far more in abeyance in developing countries for the same reasons, amplified.
Dysmorphology is using careful observation of the physical appearance of the patient to deduce the probability of different genetic disorders. While this harkens discomfiting thoughts of a phrenologists' fingers tracing the contours of one's skull, Dr. Moalem outlines how noting certain features of the patient's face can yield useful medical clues aplenty. In fact, just last month, Dr. Moalem and his team won a hackathon event at MIT for developing a smartphone app that can help identify “predispositions to certain diseases based on facial structure.”
The possession of such intimate knowledge raises a slew of other issues. At a time when truly private spheres continue to diminish in a world of prevalent social media and connectivity, privacy concerns are inescapable. Dr. Moalem raises the thorny issue of “genetic discrimination” where someone could be turned down disability or life insurance based on their profile. Perhaps even the prospect of a romantic relationship becomes contingent on genetic capability; the possibilities for exclusion abound. The practise of gender-selective abortion is prevalent in China, and this is inadvertently abetted by the ultrasound technology that enables parents to identify the sex of the foetus. The case of Ethan, who does not even have the a trace of a Y chromosome, who was still born male is a caveat against eugenics of this kind. The personal ebullience of Dr. Moalem shines through in the passages where he praises the courage and patience of his patients with rare conditions, sincerely expressing how much they have to teach us, not just in biology, but in being human.
Availability of genetic data need not always be so irredeemably filled with pitfalls. Parents Amy Garland and Paul Crummey were placed under surveillance in the UK under suspicion of abuse when their infant son had numerous broken bones. It was only much later that the source was diagnosed as a symptom of osteogenesis imperfecta or OI, a genetic disorder which impairs the quality of collagen that constitutes healthy bones. The acknowledgement of the physiological fixity of transgender traits – whether they be kathoeys in Thailand or hijras in the Indian Subcontinent – have helped usher in increased social tolerance in very conservative societies.
Personalized genomic medicine seems like a panacea to rigid rules, and holds the promise of maximal individual care. In this way, genetic abnormalities can nullify many behaviours that are deemed harmless and even recommended. Having Hereditary Fructose Intolerance means that most fruits and vegetables could be toxic. A mutation of the CYP1A2 gene could make caffeine consumption dangerously raise blood pressure. Genetic variation on the MTHFR gene could mean that mothers would need much more than the recommended dose of folic acid to prevent neural tube defects in their babies, while also contending with the elevated levels of folic acid masking a deficiency in Vitamin B12. An interesting conundrum to explore would be whether an overly individualized approach to medicine could erode any authoritative clinical directive? Evidence exists that cigarettes' causation of lung cancer varies along the probability scale based on personal genetic make-up. Would tobacco or junk food companies now be exempt from blame if they can shift it to someone's genes rather than their unhealthy product?
While much of the prose is straightforward and plain, Dr. Moalem occasionally slips into sublimity:
Like shadows behind a rice-paper screen, we do occasionally catch glimpses of our inner workings. We feel our pulse race when we're excited. We notice a but scab over, then slowly disappear altogether. Through it all we are oblivious to the hundreds if not thousands of genes being continually expressed and repressed to make it all happen seamlessly until the inevitable happens.
The inevitable, mortality, happens to us all. Much of the advances gained, and the many more still to come that alleviate pain as illustrated by Dr. Moalem, are no doubt welcome. Yet in all the manic fear and control exhibited in seeking to be a “previvor” (a preventative survivor) there is a great unease in facing death and suffering. Perhaps not all of us can wrestle and attain the grace attained by Tolstoy's Ivan Illyich. But it would be a greater tragedy to not try at all.