Unravelling the Double Helix

by Gareth Williams

  Mendel was a double victim of bad timing – ahead of the crowd, but also eclipsed by a cataclysm that had come a few years too early. The cataclysm was Darwin’s The Origin of Species, which had blazed on to the scientific firmament in 1859. Darwinism, set in the impossibly leisurely time frame of evolution, quickly dominated thinking about heredity and biological variation. Darwin’s work had been discussed at the Brünn Natural History Society’s meeting on 11 January 1865. Mendel’s first talk about peas, just a month later, may well have seemed parochial by comparison.

  His greater misfortune was to be up against minds that were not yet prepared for what he had to say. For nearly two decades, there was no visible sign that anyone had spotted the importance of his work. The pea experiments were mentioned in passing in Encyclopaedia Britannica (1885) and L.H. Baillie’s Plant Breeding (1892), but both missed the point. Up to the end of the nineteenth century, just one scientist realised that this was new and exciting. This was Ivan Schmalhausen, a twenty-five-year-old Russian botanist who praised Mendel’s experiments in a footnote to his thesis on the plant hybrids of north-western Russia (1874). Schmalhausen then moved to Switzerland and became distracted by fossilised seeds; the first recognition that Mendel had discovered something big lay unseen on a library shelf in St Petersburg.

  Soon after the turn of the new century, however, an extraordinary thing happened. More accurately, three extraordinary things happened. Mendel’s findings were confirmed by three botanists, each claiming to have worked independently and in complete ignorance of what Mendel had done. Unfortunately, this was not the fulfilment that Mendel would have wished for. Jealousy, bitchiness and other dark forces that thrive in the minds of scientists quickly took over. Things turned nasty, and there were even accusations that the good abbot had forged his results. By the time the fuss had died down and Mendel’s time really did come, he had been dead for over thirty years.

  Playing catch-up

  The interval between Mendel’s death and his resurrection was a critical period of scientific climate change, because chromosomes were beginning to make sense. They were not mentioned at all in Studies of Plant Hybridisation, but were brought into sharp and credible focus when Mendel’s work was rediscovered. This was because the behaviour of chromosomes when sperm and eggs were formed, and when they united to form an embryo, provided an exact physical counterpart to the abstract ‘elements’ which Mendel had conjured out of the thin air of combinatorial mathematics to explain how traits were passed on in peas.

  The first pieces of the puzzle were in place when C.W. Eichling visited Mendel in 1878. Oskar Hertwig, a former pupil of Ernst Haeckel, had abandoned Germany for the warmth of the French Riviera to study the fertilisation of sea-urchin eggs. This was easily done by milking sperm and eggs from sea-urchins’ gonads* and mixing these ingredients in a drop of sea-water on a microscope slide. Hertwig watched the sperm penetrating the egg, then their two nuclei fusing to form the single nucleus of the first cell of the new embryo. By proving that fertilisation brought together nuclear material from both the mother and father, Hertwig shot down the popular assumption that the egg contained everything necessary to create new life and was merely switched on by the impact of the sperm.

  The next breakthrough was published during Mendel’s last few months. Edouard Van Beneden, Professor of Zoology in Liège, built his reputation on intestinal worms; he was following his father, who had worked out the species-hopping life-cycle of the tapeworm. Van Beneden had delved into the ‘wonderful material’ of the horse threadworm, with its relatively massive spermatozoa and thousands of eggs packed into the female genital tract. He discovered what happened after fertilisation by dropping live worms into alcohol; this penetrated the worm slowly, so that embryos continued to develop for a while inside the dead body of the parent. This chance finding was so exciting that publication of Van Beneden’s paper (230 pages) on the first part of the process was delayed for him to tack on a 125-page addendum.

  The threadworm has only four chromosomes, which made their manoeuvres easy to follow. Towards the end of the formation of both sperm and eggs, something remarkable happened – a ‘reduction’ cell division which shared the four chromosomes equally between the two daughter cells, so that each sperm or egg contained just two. During fertilisation, the opposite process occurred. The nuclei of the sperm and egg both melted away to reveal two chromosomes each, which then glided together to give the new cell its full complement of four.†

  Even clearer observations and a revolutionary insight came from the American prairies and an insect that, had it been able to fly, could have passed for a biblical locust. The plains lubber (Brachystola magna) is a 5-centimetre brute of a grasshopper and another gift from nature, because ‘magna’ also describes the sperm cells in its testes. As Walter Sutton, a twenty-year-old farm boy turned zoologist, put it, ‘The gentleman’s cells are about the biggest that have been discovered.’ Sutton collected the grasshoppers while driving a corn-harvester in Kansas during the summer of 1899. At the time, he was working on his Master’s thesis at the University of Kansas, on sperm formation in Brachystola. He continued his research at Columbia University, New York, intending to do a PhD, but for ‘reasons not entirely certain, possibly financial’, the PhD never happened. Sutton defected to medicine and enjoyed a successful career as a surgeon.

  Charles Sutton’s parting shot to the world of science was a pair of papers which brought together two previously disparate strands of research. His papers are paragons of lucidity and economy; in thirty-five pages, he pushed the boundaries of understanding further than Van Beneden had done in 350. Brachystola has eleven pairs of matching chromosomes and an accessory sex-determining chromosome. Each of these is so distinctive that Sutton could track the movements of individual chromosomes in minute detail – which he recorded in his papers with camera lucida drawings of the microscope images. He showed that each chromosome keeps its identity throughout the life-cycle and when it is passed from one generation to the next. Because of this remarkable constancy, he suggested that the chromosomes carry the ‘units of inheritance’. Crucially, he proved that one chromosome in each pair was paternal in origin and the other maternal, and that the members of each pair separated during the formation of sperm or eggs and went singly into each germ cell.

  The echoes of Mendel’s Studies of Plant Hybridisation inspired Sutton’s farewell statement in which ‘at last, cytology and genetics were brought together into intimate relation’: ‘I may finally call attention to the probability that the association of paternal and maternal chromosomes in pairs and their subsequent separation during the reducing division . . . may constitute a physical basis of the Mendelian law of heredity.’

  The ‘Sutton chromosome theory of inheritance’ soon became ‘Sutton-Boveri’ when the findings were confirmed by Theodor Boveri, the highly respected Professor of Zoology at Würzburg – who was perfectly content to play second fiddle to the medical student who had beaten him to it.

  Once again, timing was everything. Sutton’s first paper was published in 1902. Without the recent rediscovery of Mendel’s work, he would never have made the connection that ushered in a whole new era in genetics.

  Back from the dead

  By the start of the new century, the prism through which Mendel’s work was viewed had tilted a few degrees in his favour. This was just enough for the three ‘Mendel rediscoverers’ – Carl Correns, Hugo de Vries and Erich von Tschermak – to be taken seriously.

  Correns had conducted ‘many years of extensive experiments’ on maize hybrids at Tübingen University. He had come across Studies of Plant Hybridisation and mentioned it briefly in a paper published in 1899, but did not follow up Mendel’s work until something shocking dropped out of the blue in March 1900. This was a reprint of a paper recently published by Hugo de Vries, the eminent Professor of Botany in Amsterdam. Correns was outraged to find that de Vries had replicated Mendel’s findings – and even used the terms ‘dominant’ and
‘recessive’ – but made no reference to Mendel at all. He lashed out with an exposé which the leading German botanical journal printed the following month. In it, Correns explained that he initially thought he had discovered something new, ‘but Abbot Gregor Mendel had obtained the same results and given exactly the same explanation, as far as that was possible in 1866’. To emphasise that Mendel got there first, and to snuff out de Vries’s claim to fame, Correns entitled his paper ‘G. Mendel’s Law on the behaviour of progeny of varietal hybrids’. He also fired a poisoned arrow straight at de Vries, pointing out the ‘strange coincidence’ that de Vries used the exact words – ‘dominant’ and ‘recessive’ – which Mendel had coined.

  In fact, de Vries had acknowledged Mendel, in a paper already submitted and published some weeks later, but his tribute was grudging. ‘A certain Mendel’ had formulated ‘the essential parts of the principles’ that de Vries had discovered, but in ‘a special case’ (peas) and ‘a long time ago’ – and anyway Mendel’s findings had long since disappeared ‘into oblivion’.

  The third ‘rediscoverer’ was Erich von Tschermak, a twenty-six-year-old graduate student working on plant hybridisation at the Vienna Agricultural Institute. Alerted by the row brewing between de Vries and Correns, Tschermak declared himself amazed to find that Mendel’s findings matched his own results. He immediately wrote a paper to claim his share of the ‘honour’, noting that ‘the simultaneous discovery of Mendel by Correns, by de Vries and myself appears to me especially gratifying’.

  Observers with suspicious minds might have noted some remarkable coincidences. Correns had studied with Carl von Nägeli, Mendel’s long-term correspondent and confidant. Tschermak was the grandson of one of Mendel’s classmates in Vienna, who later became an honorary member of the Brünn Natural History Society. De Vries later confessed that he had come across Mendel’s paper, but only ‘after finishing most of [my] experiments’; later still, it was revealed that he had been given a reprint much earlier.

  Only Correns had done original research without knowing about Mendel, and only he emerged from the mess smelling of anything close to roses. Casting himself as Mendel’s ambassador, Correns went on to invent the grandiose title ‘Mendel’s Laws’, then published the letters between Mendel and Nägeli, and began raising money for a memorial to Mendel in Brünn.

  Tschermak was branded an opportunist and a ‘non-discoverer of Mendelism’, but he still went on to have a long and successful research career. There was also little impact on de Vries. He refused Correns’s invitation to contribute to the Mendel Memorial fund and later wrote to a friend: ‘Honouring Mendel is just a fashion which appeals to everyone, including those without much understanding.’ He added sagely, ‘It is a fashion which is bound to disappear.’

  Paradoxically, it was de Vries who ensured that the ‘fashion’ of Mendel is still remembered today. Without him, Studies of Plant Hybridisation could easily have disappeared for ever in the burgeoning literature about plant breeding. But the high-visibility squabbling which followed de Vries’s plundering of Mendel’s findings caught the eye of an Englishman who made it his mission to get the abbot the recognition he deserved.

  William Bateson FRS, Fellow of St John’s College in Cambridge, was a man of great influence in botany and evolutionary zoology (and an eccentric who always wore a fez to play croquet). According to his wife Beatrice, Bateson was smitten by Studies of Plant Hybridisation on 8 May 1900, while on the train to address the Royal Horticultural Society in London. Whether or not that it is true, Bateson’s conversion was dramatic; he published a translation of Mendel’s paper and began broadcasting its novelty and importance in lectures and commentaries. And in 1902, Bateson took Mendelism into the animal kingdom when he identified various characteristics in poultry that were passed on as Mendelian dominant or recessive traits.

  In the same year, Archibald Garrod at St Bartholomew’s Hospital in London went further by showing that a human disease was also inherited according to Mendelian rules. This was alkaptonuria, extremely rare but instantly spotted in babies because their urine stained diapers black. Garrod worked out that a metabolic ‘freak’ blocked the formation of a vital amino acid, tyrosine. In a brilliant piece of deduction, he suggested that this ‘inborn error of metabolism’ was due to an inherited lack of the enzyme that normally converts a precursor to tyrosine,‡ and that the defective form of the enzyme behaved like a Mendelian recessive. A double dose of the recessive therefore wiped out the enzyme completely and caused the disease – just as a double dose of the recessive ‘short’ in peas produced a dwarf plant. Mendelian inheritance had moved from the abbey garden to Homo sapiens.

  Bateson’s Mendel awareness campaign culminated in his presidential address to the Third Conference on Hybridisation and Plant Breeding, held in London in 1904. He compared the process of scientific discovery to that of prospecting for gold. Before Mendel, researchers had chanced upon ‘the occasional nugget’, but the abbot had located the mother lode. In the same address, Bateson laid down another important milestone by suggesting ‘the term Genetics’, to embrace the study of ‘the phenomena of heredity and variation’. The congress approved, and when the proceedings were published (with an adulatory preface about Mendel, together with his portrait), the Third Congress on Hybridisation and Plant Breeding had mutated into the first-ever Third Conference on Genetics and Allied Sciences.

  Bateson was seduced by the neatness of Mendel’s results and the brilliance of his mathematics. However, others came to bury Mendel, not to praise him. The sceptics included Karl Pearson, a heavyweight statistician whose suspicions were aroused by the uncannily close match (99.993 per cent) of Mendel’s results to the theoretical ideal. Pearson was supported by Thomas Hunt Morgan, Professor of Experimental Biology at Columbia University in New York, who mocked the ‘superior jugglery’ of the ‘Mendelian ritual’ (and therefore was described by Bateson as ‘a thickhead’). The anti-Mendel offensive was rounded off by Sir Ronald Fisher FRS, who bluntly accused the abbot of fraud: ‘The paper is only intelligible if the experiments reported in it were fictitious . . . The data of most, if not all of the experiments have been falsified so as to agree closely with Mendel’s expectations.’

  The unholy war over Mendel grumbled on for years and left ominous question marks hanging over his science and his reputation. In 2001, over a century after the row broke out, an independent scientific tribunal re-examined all that they could of the evidence and concluded that Mendel was ‘not guilty of fraud’. St Augustine, who declared that ‘God is Truth’, would have approved. And of course, Mendel got it right.

  Thanks to Bateson and his fellow crusaders, the scientific community eventually caught up with Mendel. In 1909, the Danish botanist Wilhelm Johannsen took his cue from Bateson’s word ‘genetics’ (from the Greek meaning ‘born of’) and proposed the word ‘gene’ to describe a package of inherited information. He also coined two new terms to highlight the crucial difference between the outward appearance of an organism (the ‘phenotype’) and its genetic makeup (‘genotype’). The distinction was implicit in Mendel’s results. For example, there were two phenotypes for the height of pea plants – tall and short – but these did not necessarily reflect their genotype. Short plants could only have a double dose of the recessive ‘short’ variant (tt), but tall plants could be either hybrids (Tt) or pure dominant (TT). The new vocabulary continued to expand. The variants of a trait (e.g. short or tall) were named ‘alleles’. The genotype was described as ‘homozygous’ if both alleles were the same (e.g. TT or tt), or ‘heterozygous’ if these were different (e.g. the hybrid Tt).

  All this left unanswered the big question of what the enigmatic ‘gene’ might actually be. During the 1890s – even before the name was invented – the air had been thick with hypothetical hereditary particles, all desperately seeking credibility. Darwin believed that ‘gemmules’ broke out of dividing cells into the bloodstream and entered the sperm or eggs to carry traits to the next gene
ration (his cousin, Francis Galton, demolished the theory by showing that transfusing blood from a grey male rabbit into a white female did not create grey baby rabbits). Carl von Nägeli proposed ‘micellae’, tiny subunits of a hypothetical ‘idioplasm’ which was smeared throughout the cell, while Ernst Haeckel dreamed up molecules with a memory (‘plastidules’) which came together to mould the offspring.

  In short, confusion had reigned, and it still did during the early 1900s. But thanks to a pest that would have irritated Gregor Mendel, clarity was about to emerge.

  A room with no view

  Picture the scene: a sombre, silent corridor high above the brightness and bustle of Manhattan. The corridor is lined with display cabinets full of glass jars – like an old-fashioned pharmacy, but these jars contain biological specimens in formalin. As you approach a dark wooden door, you realise that you are passing a line of pickled human fetuses, neatly ranked by size to show the stages of intrauterine development.

  The smell has seeped into the corridor but has not prepared you for the powerful stench of rotting fruit that hits you on opening the door. Your next impressions are of darkness and clutter. Sheets of tissue paper have been glued over the windows to kill the sunshine; on a long workbench, light pours from a lamp on to the stage of a bulky binocular microscope, down which a man is peering, intent on something invisible. Crammed around the workbench are several desks, occupied by men deep in concentration. One wall is mostly hidden behind a pinned-up array of large filing cards, each covered in writing and drawings. And quarter-pint milk-bottles are everywhere: regiments of them lined up on shelves and benches, overflowing on to desks, trolleys and the floor. Each bottle has a wad of cotton wool stuffed in its neck. By the window stands another peculiar thing, a wooden pillar like a massive square-section fencepost, which is taller than the man stooping beside it to inspect one of its sides.