Somewhere along his evolutionary timeline, Richard Dawkins turned from a priest to a preacher. The difference is subtle; indeed, in many parts of the world, perhaps non-existent. But to those of the same faith it is discernable. The priest is calm, at one with his surroundings. The unsure flock to him while he, claimed by inertia and zen in equal measure, stays put. The preacher, on the other hand, seeks the unbelievers constantly, for he is racked by their supposed ignorance. He pities them and he wants to show them the light. He proselytises, he pounces, he perseveres, and he is unstoppable. The Origin of Species is his holy book and he waits for the day when impressionable torsos go to and fro on it.

This is not to condemn the preacher. Far from it. For too long, science has had only priests, apathetic to the world around them even as it changes for the worse. Dawkins has been a welcome change. Once a practising scientist – a very good one at that – he now devotes all his waking hours to preaching science. If religion is the opium of the masses, atheism is Dawkins’ hashtag. His twitter timeline is not so much a kitchen spat as it is a war zone, and when the smoke clears, one can spot him swinging the thurible with joyous aplomb. Occasionally, though, it swings a little too sharply and hits him in the face.

 

 

The reaction that followed these seemingly innocuous tweets would have made the Ayatollah blush. True, “It would be immoral” and “Abort it” are the kind of cold-as-steel phrases one expects from a morbid theologian-turned-gynaecologist and not one who calls himself quaintly “English biologist and writer”. But Dawkins preaches ideas, and ideas can hurt, especially those that go against religious orthodoxy and the doctrine of right and wrong, ordained and forbidden. Worse, he has done away with bubble-wrap. Emotion peeled away from fact makes it heartless. And true.

Down Syndrome, or DS, is a genetic disorder that afflicts 1 in 600 American babies. It is not inherited and in only 1per cent of the cases is it passed on. Even though John Langdon Down had described in detail – albeit under a despicable title – the syndrome as far back as 1866, it took another hundred years for scientists to discover the cause – Trisomy, i.e. the presence in the nucleus of a human cell; an extra copy of a chromosome, in this case chromosome 21. Unfortunately, as with many other ground-breaking discoveries, there ensued quickly a fight over its ownership, with undercurrents of some relevance here.

In 1956, barely three years after Watson & Crick – with a little help from Rosalind Franklin – had mesmerised the world with their double-helix, Swedish scientists discovered that humans possessed 46 chromosomes in every cell. Thousands of miles away, the finding inspired a young American woman by the name of Marthe Gautier to examine chromosomes under a microscope. In 1958, she struck gold. A cell sample from a DS patient, discovered Marthe, contained an extra chromosome. But her microscope was too low-power for her to study the phenomenon in detail. That’s when she accepted an offer of collaboration from a French scientist Jérôme Lejeune. Six months later Lejeune published the work citing himself as the main author. Yet another Rosalind retreated to the shadows. Meanwhile, Lejeune, a devout Catholic and an anti-abortionist, worked tirelessly to campaign against prenatal DS screening until his death in 1994. A friend of the Pope, his beatification is currently under consideration.

DS is debilitating for those who suffer it, causing learning and memory deficit, cognitive impairment, reduced muscle strength, speech impairment, a much-increased risk of congenital heart disease and leukaemia, dysmorphic features, an early onset of Alzheimer’s, and numerous immunological deficiencies. Studies have also suggested that, because of an extra copy of a gene called DYRK1A that is present in the DS-causing region of chromosome 21, DS individuals have a thicker neural retina leading ultimately to abnormal retinal function. With increasing maternal age, the chances of a foetus carrying the extra copy of chromosome 21 rise dramatically – 1 in 800 for a 30-year-old, to 1 in 100 for a 40-year-old mother – making it prudent for mothers to undergo a battery of prenatal tests. DS screening has been around since the 1970s, starting from the first grainy ultrasound images to detection of alpha-fetoprotein in foetal blood as well as cerebrospinal fluid. Other invasive procedures like Amniocentesis and Chorionic Villus Sampling are techniques that increase the risk of foetal injury and miscarriage as they entail removal of amniotic fluid or placental tissue. Given these constraints, agreeing to a DS test was a decision not to be taken in a hurry.

The breakthrough, when it came, surprised physicians and scientists alike. In 1997 scientists discovered bits of foetal DNA circulating in maternal blood. Crucially, they were able to not only isolate the foetal DNA but also sequence it. The foetal DNA test, or Non-Invasive Prenatal Genetic Testing (NIPT), as it has come to be known since, has revolutionised prenatal DS screening. Because the foetal cells begin circulating in the mother’s blood at a relatively early stage, the test can be performed when the foetus is just 10 weeks old, much earlier than the legally prescribed limit for carrying out an abortion – 24 weeks in most countries that allow it. Two large-scale 2011 and 2012 studies published in the British Medical Journal and the American Journal of Obstetrics & Gynaecology, found sequencing of foetal DNA in maternal plasma to be an effective non-invasive alternative to the earlier DS screening methods. A comprehensive 2014 trial involving 1,914 women reached the same conclusion: NIPT was far superior to the currently used DS screening procedures.

NIPT works by detecting a higher proportion of foetal chromosome 21 DNA in the maternal plasma, with the “noise” of maternal chromosome 21 overcome by an advancement so revolutionary one could be forgiven for thinking it is the doing of extra-terrestrials. As it is, no other scientific field – except perhaps Computing – can boast of leap-frogging innovations year-on-year like what Molecular Biology & Medicine can; but this was massive, and fittingly it was baptised so.

Massively Parallel Sequencing, or MPS, is what one might call a space-age extension of the simple yet profound ideas of Sanger (Nobel Laureate, 1958 and 1980) and Mullis (Nobel Laureate, 1993). Single-stranded DNA molecules are attached to a glass surface, and their sequence read through a crafty piece of dye-chemistry – every letter that is read registers as a “blink” when a laser is shone upon it. This animation describes the process in notable detail. Using MPS, the human genome – that took thousands of scientists a decade to sequence – can be read from start to finish in a matter of hours. Hours. MPS is the future of Molecular Biology that has come calling in the present.

Meanwhile, other advancements amaze of their own accord. While earlier trisomy was identified by determining the number of DNA molecules belonging to different chromosomal regions in maternal plasma, a new technique now allows one to detect chromosome variation based solely on DNA fragment size, marking out foetal trisomy 21 with an incredible 100 per cent sensitivity and specificity. Yet another technique bases trisomy detection on “semiconductor sequencing”, reducing the time and cost of screening appreciably.

The choice for pregnant mothers is clear: a drop of your blood can help detect DS as early as in the first trimester.

“For what it’s worth, my own choice would be to abort the Down foetus and, assuming you want a baby at all, try again. Given a free choice of having an early abortion or deliberately bringing a Down child into the world, I think the moral and sensible choice would be to abort. And, indeed, that is what the great majority of women, in America and especially in Europe, actually do. I personally would go further and say that, if your morality is based, as mine is, on a desire to increase the sum of happiness and reduce suffering, the decision to deliberately give birth to a Down baby, when you have the choice to abort it early in the pregnancy, might actually be immoral from the point of view of the child’s own welfare.”

– Richard Dawkins in An Apology for Letting Slip the Dogs of Twitter War.

From here on it gets difficult. While one cannot help but agree with Dawkins, is there, one wonders, another side to his argument? Let us assume for a moment that the suffering in question was not DS but AIDS. What would Dawkins suggest – to abort an HIV positive foetus because it was immoral not to do so? After all, leaving aside the fact that both afflictions are presently incurable, the social stigma attached to an HIV positive child – especially in India – is more if not comparable to one suffered by a DS child. An HIV positive child, apart from being bullied and harassed and cruelly ostracised by the society, has to pop in everyday a cocktail of retroviral and other drugs just to stay alive, to “reduce suffering”, to “increase the sum of happiness”. An abortion would have put an end to this torment. And yet the child smiles, he survives, he thrives, he lives, for in his eyes shines hope that one day science would find a cure for his suffering.

Faith is not always religious in nature. It forms the bedrock of scientific discovery, the spur that begets the spark.

They are hope and faith, the Pillars of Hercules through which the daring must pass.

Yes, Down Syndrome, like AIDS, is presently incurable. But then so also are many cancers and genetic diseases. And lest we forget, AIDS – with a mortality rate of greater than 90 per cent barely two decades ago – was considered a death sentence. Today, because of jaw-dropping advancements in molecular biology and medicine, HIV-positive patients have life-spans similar to those who are uninfected. HIV is no longer a death sentence, and with continuing scientific discoveries – both in the fields of medicine and biology – it would not be wrong to suggest that a cure for AIDS is on the horizon. Where, then, would Dawkins rather draw the line? Which foetus, when marked out as carrying a disease or a genetic disorder, is to be saved and which aborted? The dilemma is not for the mother; the dilemma is for Dawkins himself. Allow me to explain.

In the year 2000, an international team of scientists stunned the world by reporting the complete genomic sequence of human chromosome 21. Their identification of around 200 chromosome 21 genes – as also the discovery of a Down Syndrome Critical Region (DSCR) – set the stage for some breath-taking scientific adventures. The race to find a cure for DS had well and truly begun.

In 2006, scientists from two independent laboratories discovered a set of gene regulatory factors called NFATs. Their link to DS became clear when it emerged that mice lacking NFATs display skull and jawbone abnormalities. Soon, it was found that two genes, DSCR1 and DYRK1A – both present in the Down Syndrome Critical Region – regulate NFAT functioning leading ultimately to developmental abnormalities. Furthermore, increasing levels of DYRK1A – a normal occurrence in DS because of an extra copy of chromosome 21 – resulted in cognitive and muscular defects. In a related study, scientists studying the Ts65Dn mouse model – that mimics DS symptoms by virtue of these mice carrying three copies of mouse chromosome 16 (wherein roughly half the genes are homologous to their counterparts on human chromosome 21) – found that triplication of the Usp16 gene severely affected cellular self-renewal pathways. The results explained the common occurrence of Progeria or accelerated ageing seen in DS individuals.

In another remarkable experiment, carried out on a set of identical twins where one cell type contained an extra copy of chromosome 21 while the other did not, scientists discovered that trisomy disrupts global gene regulation, with the increase and decrease in gene expression alternating across large chromosomal segments. Specific genes like HMGN1 present in the Down Syndrome Critical Region were implied as responsible for this global gene regulation event.

But the most dazzling achievement till date in the field of DS research, one that sets a benchmark for all future studies, has been the transplantation of the complete human chromosome 21 in mice. The mice, called Tc1, possess 92 per cent of human chromosome 21 and display several DS characteristics, like spatial learning and memory defects as well as heart ailments. Scientists now have an ideal animal model to study trisomy and DS and the results are already encouraging. There is exciting news on the drug front, too. Recently, DS mice were shown to be cured of neurological disorders through administration of small molecules like EGCG that potently inhibit DYRK1A. EGCG, or epigallocatechin gallate, is a major component of green tea. Chemists are now mining natural product libraries so as to discover the next blockbuster – a drug that can cure DS.

Where chemists tread, biologists can’t be far behind. In 2013, in an experiment straight out of an Asimov novel, scientists were able to “silence” the whole of chromosome 21 in DS stem cells by inserting a roadblock DNA fragment called XIST into the Down Syndrome Critical Region. The chromosomal silencing led to an immediate reversal of many DS characteristics, notably neural abnormalities.

The glass is more than half full. New technologies like CRISPR – that have already begun to yield astonishing results (discussed in detail by the author here) – coupled with the extraordinary chromosome silencing experiment described above herald a new era in drug and gene therapy discovery.

When Cystic Fibrosis can be cured in the laboratory, when entire chromosomes can be silenced in living cells, when small molecules can successfully reverse debilitating characteristics of DS, why, then, one might ask, this absence of faith in science, why the need to vex oneself with questions of morality? Well, probably because the philosophical concepts of morality and immorality trouble us as much as they guide us; we are not human beings without them. It is the moral or the immoral, the good or the evil, the selfish or the altruistic in us that dictates the choices we make. That has been and remains the way of the world. Que Sera, Sera: for a selfish gene to choose what is moral.

But if one chooses instead to hold on to a sliver of hope and a semblance of faith, and, no matter what, brace against the winds and steer through those mighty Pillars of Hercules, perhaps what awaits us on the other side is a future where carrying a disease no longer poses a moral dilemma. A future that is ours to see.

This article first appeared in newslaundry on Sep. 10, 2014.