The Obstacle Course to Being

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Today, I got news that a close friend is in the early days of what might be a difficult pregnancy. The opening remarks of the book “Unweaving the Rainbow: Science, Delusion and the Appetite for Wonder” by Richard Dawkins came to mind. Dawkins marvels at how statistic-numbingly lucky each one of us is to have survived the odds of a sperm and an ovum fusing and giving rise to a living cell. How we are a nanoscopically small number of the total combinations that are possible for the human genome. But as a developmental biologist, for me, this is just the starting point of the great obstacle course. The hurdles that the embryo will clear in the mother’s womb to make it to the light and sunshine, the warmth and fragrance, the colours and music of this, our second home.

We see numerous reminders of each step that falters, in the birth defects that abound our world (according to statistics, 3-6% of infants born). A less than perfect infant brings anguish for the mother and potential disability for the baby. For civilizations, societies, religions, and the superstitious a baby with a birth defect can have many connotations; a symbol of the wrath of God, an indication of uncertain morality in parents, an evil incarnate, a sign of bad times ahead. And the prescriptions to prevent these also come in many flavours; don’t look at the eclipse, don’t face ugly people, don’t eat mango, don’t think ill thoughts, etc., etc. Even in mythology we meet with mothers who were not careful enough and paid the price for it; Ambika, who closed her eyes, and Ambalika, who turned pale upon seeing Vyasa in their bedchamber, the results were Dhritarashtra, born blind and Pandu, born pale.

In colonial Europe, many such mutant foetuses became curios in museum jars or if they survived, became celebrities. It was a world that had suddenly discovered and was entranced by the sheer variety in the human species; to the extend that even the ‘normal’ ‘native’ from the colony was an object of marvel to a people used to standard ‘white’. Armand Marie Leroi, in his book “Mutants, On Genetic Variety and the Human Body”, beautifully traces back the history of some of these famous human ‘monsters’ of the western world and tries to weave our understanding of development and genetics into the past, to identify the syndromes that might have affected these individuals.

Our current understanding of embryonic development has come a long way from the myths and imaginations of our ancestors. As with all other matters of the natural world, Aristotle had a theory on this matter. He observed the different stages of the chicken egg through time and concluded that the animal comes into being in a succession of steps from unformed material and that the force guiding this development is the soul, that enters the egg immediately after conception. But even before naturalists could follow this trail, there came on the scene, the preformationists. They postulated that the egg or sperm come packaged with a small animal or human (homunculus) inside it and that each homunculus has hundreds of homunculus in its own sperm, ad infinitum. Thus, if you extrapolate far back enough the whole of humanity was packed in the groins of Adam.

Most embryonic studies, as can be imagined, relied heavily on model organisms and the opinions and conclusions of scientists could be quite diametrically opposite depending on whether they were looking at insects or amphibians or birds or mammals. Embryos (perhaps fully formed) could be encased in multiple layers of sheaths that are apparently shed in succession as in an insect larva, pupa and adult. New organisms could grow out of parts of the old, as in an amphibian or planaria. Embryos may look like membranous structures with well-populated blood vessels if you open a chicken embryo few days into development.

Model organisms remained the mainstay, but the microscopes improved and Europe went through a rush of scientific enlightenment. Inspired by the question of how much each cell in the embryo knows about becoming an animal, Hans Spemann performed an experiment; a similar one has been described in the ever-imaginative Mahabharata where Gandhari cut up her unformed embryo into 101 pieces to unleash an army of Kauravas on the Indian subcontinent. What Spemann, the master of microsurgery did was a much more refined and precise experiment; he separated the cells of a 2-cell stage newt egg with a sophisticated surgical instrument, a baby hair. He found, to his surprise, two completely formed embryos. This said that each cell had the complete information to make an embryo. What was this information, was it the soul? Could soul be split into two? Shortly afterwards, in 1924 Spemann and his Ph.D. student Hilde Mangold (who was lost to a kitchen explosion even before her paper came out), published a paper. It showed that a small portion of the embryo, which we now call the Spemann-Mangold organizer, can organize the rest of the cells to form an embryo, head and tail, heart and lung, eyes and anus, the full complement. In 1929, Walter Vogt dyed a few cells in a developing Xenopus embryo and traced their fate. This kind of fate mapping of cells, finally showed us conclusively that cells, as they divide, take on different roles in the embryo. That the cells in the embryo are not dumb spectators of a tennis match, but rather a well-choreographed dance troupe that moves in unison to a subsonic music of mysterious nature.

The quest for the soul of the embryos was intensifying. The time was ripe. Molecular biology was at the threshold. The molecular and genetics revolution ushered into embryology by Thomas Hunt Morgan, Conrad Waddington, Salome Gluecksohn-Schoenheimer and others created what we now call developmental genetics. Developmental biology became all about genes, genes that are necessary, genes that are sufficient, genes that are modifiers, genes that are master regulators and so on. In the midst of all this, it is heartening to hear that there are genes I can live without; very recent efforts at whole genome sequencing of more than 2000 individuals in Iceland have discovered a number of genes that are ‘non-essential’ for development.

Today we can watch the dance of cells and hear the music of molecules live in an embryo; even a human embryo can share a smile with its father through the ultrasound screen. But with this also comes our increasing awareness of ‘non-genic’ factors that can influence the foetus and its wellbeing. Let alone the alcohol and drugs that the mother consumes even the nutrition that the father consumed or the lack of nutrition its grandfather experienced may all have an effect on the organism’s development and physiology. As we become better at identifying the obstacles in the journey of an embryo from the single cell to a free-living organism, perhaps we are also becoming ever more uncertain of the control we have over these obstacles.

A friend once told me, that after all the grand dreams and high hopes that you have for your baby, when it is finally born all you care about is that it does have the right number of appendages and sensory organs. Perhaps this is where the biologist and the parent in me meet. To steal Feynman’s thoughts: for me, the scientific knowledge of how an embryo develops and in how many ways it could all go wrong, makes the birth of a baby even more of a miracle than the layman. A baby that has skipped and scaled and sidestepped all the obstacles thrown in its course to make it here, to blink unseeingly at me and to grab my extended finger, is meaning enough for what I do.

by Chetana Sachidanandan, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi

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