The question of what it is that produces form from the formless has captivated and fascinated people since antiquity.1 Even today, the arrival of a newborn baby confronts us with the marvellous, made all the more so by the fact that birth follows a routine which verges on the casual. It is only natural that human beings should have wondered at the unseen and miraculous forces of reproduction since time immemorial: each and every creation myth is an expression of this wonder.
The earliest attempts to answer the question of the origin of form centred on the egg. From apparently formless eggs come a multitude of different creatures, but the origin of these creatures from within an apparently homogeneous medium, the contents of an egg, were quite mysterious. This mystery has attracted a wealth of mythic and cultural associations. Gods and demons in myths the world over are seen to hatch from eggs. Even modern physicists – of all scientists, the most sensitive to the power of myth – talk of the Universe hatching from a ‘cosmic egg’, when they freely admit that the first instants following the Big Bang are perhaps forever inaccessible to theory or observation.
The first-century Roman scholar Pliny the Elder was entirely seduced by the pervasive mythology of eggs, as he was by every other facet of the natural world, no matter how dangerous the observation (he died from the effects of smoke inhalation while making notes on the same eruption of Mount Vesuvius in 79 CE that buried Pompeii and Herculaneum). Pliny blithely mixed fact and fancy to such a degree that he was described by one later scholar as that ‘voluminous, industrious, unphilosophical, gullible, unsystematic old gossip’. 2 In his Natural History, Pliny gives an account of a magical egg laid by serpents. Every summer, he wrote, it is possible to witness an egg formed from the saliva and sweat of a writhing bundle of snakes. The egg squirts out of the knot like a champagne cork – ‘the serpents when they have thus engendered this egg do cast it up on high into the aire by the force of their hissing, which being observed, there must be one ready to catch and receive it in the fall again’. 3
The catcher must then leave the scene as quickly as possible, preferably on horseback, for fear of pursuit by the angry snakes, who can only be stopped by a body of water. But the egg, if dropped, ‘will swim aloft above the water even against the stream, yea though it were bound and enchased with a plate of gold’.4 The historian of science Joseph Needham, who quoted this passage in his History of Embryology (1934), suggests that whereas the writings of Pliny (in the seventeenth-century translation by one Philemon Holland) are deficient in accuracy, their entertainment value is sufficient compensation.
Aristotle (384-322 BCE) was more clear-headed than Pliny, and can be fairly said to have been the ‘father of biology’. He was one of those people who thinks seriously about things everyone else takes for granted. In this case, Aristotle wondered how and why women gave birth to babies with such assurance and regularity, each child so exquisitely and minutely formed, where nothing had before existed. Where did babies come from? Any expectant parent may wonder at this same everyday miracle, yet it was Aristotle who, as far as we know, first asked about the forces that made babies possible. He essayed a classification of living things, and considered how they came to be the way they were, and, significantly, how organisms acquired their form as they developed.
Given their cultural importance, eggs were a good place to start an investigation into the origin of form. Methods of incubating hens’ eggs had been developed by the Egyptians in antiquity, so the study of eggs posed relatively few practical difficulties: simply open eggs at various stages of incubation and describe the contents. Aristotle, presumably familiar with this ancient but reliable technology, made a distinction between animals which laid eggs and those, such as human beings, which gave birth to live young. He supposed that human babies formed when unshed menstrual blood was sparked into life by the semen, the active male principle. Aristotle’s views accorded with ancient Greek tradition that ascribed all inheritance to the male line: women were simply vessels for nurturing the germ of the male.
As with so many of Aristotle’s pronouncements, it is a measure of the man’s authority that subsequent investigators chose to take his hypothesis as an established truth without exploring it for themselves. However, there is a tale – hopefully apocryphal – of a proposal to put his idea to the test, in which Cleopatra ordered the killing and dissection of female slaves in various stages of pregnancy. Apart from that, Aristotle’s ideas had to wait more than 1,500 years before they were tested. When this finally took place, it was found that not only had Aristotle been quite wrong about menstrual blood, but the dichotomy between laying eggs and bearing live young was false all along. In fact, all animals – whether superficially egg-laying or live-bearing – came from an egg.
This challenge to Aristotle came in 1651 with the publication of a book called Exercitationes de generatione animalium (‘On the Generation of Animals’) by the English physician William Harvey (1578–1657). At that time, the question of the origin of form was referred to as the problem of generation. Harvey’s work on generation came at the end of an illustrious and sometimes controversial career. His life started auspiciously. He was born into a well-to-do family at the height of the reign of Queen Elizabeth I. He took his degree at Cambridge in 1597, after which he went to Padua in Italy to study under the famous anatomist Hieronymous Fabricius (1537–1619). Fabricius was interested in the question of generation, and based his theories on detailed studies of eggs and chickens. Finding the reproductive tract of hens to be exceedingly convoluted, Fabricius reasoned that any semen from a cockerel would find it difficult to navigate its way towards the eggs. Even if this were possible, the semen would hardly have been able to influence the egg – which, by the time it has completed its formation inside the hen, already has a thick shell. Fabricius suggested, therefore, that the male principle does not contribute to the chick in any material way, but acts as a kind of wake-up call (just like a cockerel), using the energy and vitality of the male to stir the otherwise quiescent egg into development. Harvey was intrigued by his teacher’s views, which sparked a lifelong interest in the question of generation.
Harvey returned to England in 1602, and soon married a daughter of one of Elizabeth’s physicians. This royal connection, combined with his extraordinary energy and intelligence, led to a busy and profitable career as a physician. One of the perks of his royal association was access to the best seats at the Globe Theatre, in the era of Shakespeare. The world premieres of some of the world’s greatest dramas may have been witnessed by one of the Elizabethan world’s greatest medical scientists. In 1618, Harvey was appointed physician to the court of James I, a post he retained under the rule of James’s successor, Charles I. Ten years later, he rose to academic fame with the publication of his ideas on the circulation of the blood.
Harvey’s life, so blessed thus far, took an ill turn with the outbreak of the English Civil War. After Charles I was defeated at the Battle of Edgehill in 1642 (at which Harvey was present), the court, including Harvey, fled to Oxford, but despite the upheaval Harvey settled back into academic life as the Warden of Merton College. While in Oxford, Harvey met the anatomist Nathaniel Highmore (1613–85), who shared his interest in generation. The two men worked together at various times over the next four years. Highmore was an accomplished exponent of the relatively new science of microscopy, and it has been suggested that Harvey’s ideas were shaped by the revelations afforded by the microscope.
Respite from war was short-lived. Oxford fell to the forces of Oliver Cromwell in 1646. The King fled once again but was eventually defeated, and he was executed in 1649. Life for former courtiers was doubtless uncomfortable; most of Harvey’s private papers were destroyed by Cromwell’s troops. Any other septuagenarian ex-courtier living under a regime which viewed him as a potentially subversive element would have gone into discreet retirement, but Harvey seems to have been spurred into yet greater activity. He still saw patients, worked tirelessly for the College of Physicians (where he founded and endowed a library) and carried on researching. Exercitationes was his swansong, published when he was seventy-three. It is notable that in that same year, 1651, Harvey’s colleague Highmore published The History of Generation, containing the first micrographs published in England. Harvey died in 1657, not quite managing to outlive his nemesis, Cromwell, who died the year after.
Exercitationes was a summary of a lifetime’s work on generation. It was based on Harvey’s work on recently mated does culled from the deer parks of his erstwhile royal patron. Examining the wombs of the dissected animals, Harvey found no fauns coagulating from menstrual blood (as Aristotle had predicted), no trace of semen, nor, indeed, anything that might bear in any way on the question of generation.
Harvey could have regarded the absence of semen as vindicating the views of his old mentor, Fabricius – that semen does not play a direct role in generation. But there was something else amiss. Fabricius had studied the reproductive tract of hens, which – even without semen – are visibly busy with the creation of eggs, plainly visible to the naked eye. The reproductive tracts of deer made as stark a contrast as might be imagined. In contrast to the insides of hens, the reproductive tracts of does, even recently mated ones, were barren and bare. Not only could no semen be found, but there was no sign of anything else that might betray the origin of new lives.
Inasmuch as Harvey found no trace of embryos being formed out of blood, Aristotle’s centuries-old view was plainly wrong – but Harvey could offer nothing that might stand in its place. He confessed himself stumped, and a brave and honest confession it must have been, given his distinguished past. But he was as honest an observer as Aristotle had been, and believed the evidence of his own eyes, even though he could not account for this evidence. His contemporaries (including the gamekeepers who tended the deer in the royal parks) swore by Aristotle’s ideas and insisted that Harvey must be mistaken.
Still puzzled, Harvey embarked on a further series of investigations of the reproductive tracts of does that had been mated days or weeks before, long after the influence of semen must have worn off (if semen had had any effect at all). He discovered, within the wombs of the deer, formless, water-filled sacs that were not present in unmated deer, but whose exact origin was a mystery – presumably the consequences of phenomena too small to see. It is now thought that the sacs observed by Harvey were the very early embryos of deer, implanted into the uterus wall and each surrounded by a translucent membrane, or amnion, but within which no distinct form could easily be discerned. Significantly, although Harvey was unable to establish a direct, causal link between the fact of mating and the origin of these objects, he made the bold, intuitive leap that these featureless sacs were in fact eggs, in every way equivalent to the externally laid eggs of hens. Aristotle’s inferred fundamental difference between egg-laying and live-bearing creatures was, therefore, spurious. Harvey came up with the concept of the egg, or ovum, as an example of a primordium, a more general concept that encompassed the eggs of hens as well as the fluid-filled sacs inside dissected does. Both were destined to grow into adults, nourished by the mother – whether directly, in the uterus, or remotely, by the yolk of a new-laid egg.
It is important to remember that Harvey, looking at the eggs of hens or the early embryos of deer, could have made no distinction between them inasmuch as he would have regarded both as primordial – members of the same category. This is in marked contrast to what we now think of as eggs and embryos, which are quite different. Eggs are single cells whose activities are determined by the genome of one individual, the mother. Embryos are more complex objects, usually made of many cells, whose state is determined by the fusion of two genomes, each parent having made its contribution. Harvey could have known nothing of this: in his time, there was no distinction between single and multicellular organisms, because cells were not yet recognized as the fundamental building blocks of organic life that we understand today.5 Fertilization – the fusion of egg and sperm – was also not understood. In the 1650s, sperm had yet to be discovered. In any case, Harvey had learned from his mentor, Fabricius, that semen played an indirect role in the process of generation, spurring the egg into life by a process generally termed fecundation, without direct contact between egg and sperm.
Although Harvey could not distinguish between ova and embryos – regarding both as the same kind of object – the fact that he was seeing not the actual ova of deer but early embryos probably in the germinal-disc stage, not long after implantation, does not detract from the importance of his insight that all life came from the egg. The title pages of the first two editions of Exercitationes showed the enthroned Zeus holding an egg at the point of hatching, an egg from which a parade of beasts is about to emerge. The egg is inscribed Ex Ovo, Omnia – Everything Comes from the Egg.6
Harvey’s insight, remarkable though it was, fell short of a full account of generation. He had shown that everything came from the egg, but he could not account for how form emerged, or where it all came from. Harvey speculated that the egg or primordium is truly formless, and that the embryo develops gradually from homogeneous matter by a process he called epigenesis. However, this says no more than that form arises out of nothing by some unspecified mechanism. As a name, epigenesis is a wild-west storefront with nothing behind it. At best, it is an observation of what happens – that is, form emerging from nothing – not an explanation of why it does so. In coining the term, Harvey essentially sidestepped the issue of generation. Harvey was celebrated as an anatomist and physician of great skill and judgement, but despite his efforts the question of the origin of form remained open.
What most caught the imagination of Harvey’s contemporaries was his insistence on the egg as a fundamental unit of life. The next generation of anatomists began to think that the form of the embryo was not created from nothing, but was present in the egg all along, just waiting for that vital seminal spark to prompt it to grow to visibility. This idea (known as preformation – see below) had been hovering in the wings of thought since antiquity, and many scholars had touched on it as a possible explanation of the origin of form. One scientist enthused by these ideas was the distinguished anatomist and microscopist Marcello Malpighi (1628–94).
The one facet of Malpighi’s character that transcended all others was his determination. He was born a farmer’s son near Bologna in Italy, and had to shoulder the burden of caring for his siblings after the family was orphaned when he was twenty-one. This did not stop him from graduating in medicine at the University of Bologna four years later. Although his academic career took him all over Italy, Malpighi returned to Bologna in 1666, where he was to stay for most of the rest of his life, concentrating on his anatomical studies.
It was here that Malpighi embarked on a one-man voyage into the microcosmos, making many spectacular discoveries in the then very new science of microscopical anatomy. He observed blood cells, establishing the fine connections between arteries and veins and thus completing Harvey’s pioneering work on the circulation of the blood; he established that the lungs had a fine structure of tubes and cavities, and were not simply formless spongy masses; and he established the anatomy of the spleen and the kidney. Generations of biology students, even those studying today, can remember having to draw the network of vessels in the kidney now known as the Malpighian tubules. But Malpighi was wrenched away from both the microscope and Bologna in 1691, when, at the age of sixty-three, he was summoned to Rome to be physician to Pope Innocent XII. Malpighi died in his post three years later (the Pope, however, lasted until 1700, perhaps as a testament to Malpighian ministrations).
Malpighi’s long love affair with his microscope did not make him a hermit. He was a keen correspondent with other scientists in Europe, including those at the Royal Society in London. Now the leading scientific body in Britain, the Royal Society was then a fledgeling institution, for all that its early fellows numbered such luminaries as Robert Hooke and the chemist Robert Boyle.
In common with many microscopists of his day, Malpighi had made a detailed study of the development of the chick in a quest for the origin of form. An adept microscopist, he was perhaps more capable than most of teasing out the very smallest structures, on the limits of resolution, that could yield clues about how form originated. Did embryos really coalesce from nothing, as Harvey had suggested, or did they emerge from preformed germs that might yet be discerned by the keen-eyed investigator? Malpighi published his findings in 1673, as Dissertatio epistolica de formatione pulli in ovo – ‘The Formation of the Chicken in the Egg’. Although he described the development of the chick embryo in unprecedented detail, the very earliest stages of generation eluded even him. Given the questions about the role of semen raised by Harvey and Fabricius before him, Malpighi wondered whether the form of the chick might be discerned in unfertilized eggs. He could make out no signs of life in unfertilized eggs, but thought there might be germs of an embryo in eggs that had been fertilized but left unincubated. Working on the very edge of the unseen, Malpighi – good scientist that he was – admitted that he could not rule out the possibility that the germ of the chick might not reside in the egg before fertilization. In other words, he considered seriously the idea that the form of the chick might not have been created anew in each egg by a process of epigenesis as envisaged by Harvey, but might, in each case, represent the instantiation of some eternal pattern residing in eggs, continuous between the generations.
Similar thoughts had occurred to a researcher working in the Netherlands, Jan Swammerdam (1637–80), who had turned his microscope on many things and was, like Malpighi, interested in the silkworm, an animal of great commercial importance to the textile industry. Swammerdam’s party-piece was to dissect a silkworm chrysalis, revealing the rudiments of the adult moth to the astonished guests. Today this might not astonish us, but in those days the chrysalis of an insect was regarded as no different in concept from the egg of a chicken. In the context of the time, any knowledgeable person would naturally conclude that the rudiments of the adult moth were in the chrysalis all the time, simply waiting for their opportunity to expand to the level of visibility and, finally, emerge. Swammerdam speculated that if they were examined closely enough, eggs (in the sense of ‘primordia’) would be found to contain the minutely detailed, preformed parts of the animals destined to hatch from them. If semen had any role, it was merely as an indirect influence, as Fabricius had supposed. Swammerdam suggested that semen might prompt the emergence of preformed parts in the egg by emitting some impalpable essence or spirit, which he named the aura seminalis.
The work of Swammerdam, Malpighi and others energized a French theologian-turned-philosopher, Nicolas Malebranche (1638–1715). In 1674 he published De la recherche de la vérité, a treatise on the nature of knowledge, generally known in English as On the Search for Truth. This work was as vast and comprehensive as one would expect from a disciple of Rene Descartes, and only a small part of it concerned generation. Its influence, however, was enormous because it collected the scattered observations of microscopists and drew from them a general theory that came to be called preformation. According to preformation, the rudiments of every creature had been created by God at the beginning of time, and were simply waiting for their predestined cue to emerge. All the generations of Man would therefore have been found in the ovaries of Eve. Preformation was to remain the predominant theory of generation for the next century.
At first glance this idea seems quite fantastic, but in the seventeenth century it made much sense. The advocates of preformation – and there were many – were accomplished and in many cases brilliant scientists. ‘It is impossible to believe’, wrote Elizabeth Gasking in Investigations into Generation (1967), ‘that men of this calibre should have all been deluded into accepting a theory such as this, unless they felt there were some very good reasons for doing so.’7 One obvious objection to preformation is smallness. To suppose that all the generations of Man were wrapped up inside the egg of our ultimate foremother is to propose the existence of structures of near-infinitesimal dimensions, a concept that strains credulity. And yet, the theology, the philosophy and – most importantly – the experimental science of the seventeenth century saw in preformation explanations of many disparate phenomena in the compass of a single scheme. This, then as now, is the mark of a sound scientific theory.
First, the number of generations between ourselves and Eve was, in the seventeenth century, not regarded as infinite or undefined. If the world had been created a matter of a few thousand years ago, as attested in the Bible, and women gave birth at an average age of twenty years, then fewer than three hundred generations could have preceded the publication of Malebranche’s Search for Truth.
A theological argument – and the one that most motivated Malebranche – concerns the existence of the marvellously intricate worlds of life that had been suddenly brought into view by the microscope, and whose existence had hitherto been entirely unexpected. To Malebranche, and many others, the impact of this discovery was evidence enough for the power and goodness of God, who had conceived the entire world in such detail so that we might discover it.
Perhaps the most important consideration was philosophical. After recovering from the revelatory shock of the existence of the microcosmos, scholars suggested that there was no good reason to posit any lower limit on size. The theory of atoms, let alone that of cells, still lay in the future, and when the first microscopists turned their lenses on nature, they opened up a whole new world of detail in which substances, apparently featureless to the naked eye, were in fact full of structures and complete living forms of great delicacy. What then, the preformationists asked, would prevent an amoeba-sized scientist, equipped with a suitable microscope, from discovering yet more wonders on an even smaller scale? Today, physicists speculate on the nature of matter at such an inhumanly small scale that the fabric of reality itself becomes granular, and wonder if even smaller structures might exist. The justification for these ideas is entirely theoretical, and there is as yet no hope of verifying them by experiment. Much the same could be said of preformation in the seventeenth century: to object to the existence of something because it is far, far smaller than anything in your experience is hardly a scientific criticism.
Malpighi looked at blood and found it to be made of particles we would nowadays recognize as cells. He studied the seemingly formless tissues of lung and spleen and found in them a wealth of detail. Swammerdam revealed the complexity of the silkworm just before it emerged from the chrysalis. And then a microscopist in the Netherlands turned his microscope on semen, that fluid whose role in generation seemed so ambiguous. The results would come as something of a shock – semen was full of tiny, writhing worms.