by Simon Mawer
Von Niessl nods and writes. Frau Rotwang smiles happily. The lecture is under way, one of the most momentous scientific events of the nineteenth or indeed any century.
And what did he talk of?
He talked of numbers and ratios, of chance and probability, of characters—Merkmale—and segregation. He showed that for a given inherited character—“let us consider, for example, the characters of tall and dwarf in these plants”—each offspring receives two constant characters, the dominating one A from the tall parent and the recessive one a from the dwarf parent. If each parent is a hybrid Aa, then each is capable of contributing either A or a to its offspring. When these factors come together in the offspring, “it is entirely a matter of chance which of the two kinds of pollen combines with each single germinal cell. However, according to the laws of probability, in an average of many cases it will always happen that every pollen from A and a will unite equally often with every germinal cell for A and a. If you will bear with me”—smiling around the audience—“I can best show this with a diagram.”
There is a disturbance while the lamp is lit and the gaslights turned down in the room. People mutter in the shadows. A diagram appears suddenly on the linen sheet, vast, blurred, and upside-down. Muttered apologies come from the figure at the magic lantern while things are put to rights, while the slide is inverted and brought into sharp focus. For the first time the arcane laws of genetics are presented to the world. Mendel’s own diminutive figure is silhouetted against the picture as though dwarfed by his discovery. “In fertilization, you may see that one of the two pollen cells A will meet with a germinal cell A, the other with a germinal cell a; and equally, one pollen cell a will become associated with a germinal cell A, the other with a.
“The result of fertilization can be visualized by writing the designations for associated germinal and pollen cells in the form of fractions, pollen cells above the line, germinal cells below. In this case one obtains—slide, please—”
There are mutterings in the darkness. Do they signify discontent? He casts sharp shadows across the wall and into the future, this small stout friar with the obtuse manner and the abstruse jokes. This is a moment like few others in the history of science and his audience is laboring along in his wake.
“What I show here represents the average course of self-fertilization of hybrids when two differing characters are associated in them. In individual flowers and individual plants, however, the ratio in which the members of the series are formed may be subject to not-insignificant variations. Next slide, please. Here you may see the series for hybrids in which two kinds of differing characters are associated. In fertilization every pollen cell unites, on average, equally often with each form of germinal cell; thus each of the four pollen cells AB unites once with each of the germinal forms AB, Ab, aB, ab:”
Can you wonder that a great silence fell in the room, the silence of incomprehension, of indifference, of boredom? Can you wonder that the applause at the end was thin and the congratulations lukewarm? There were polite questions and a little discussion. But as the members of the Brünn Society for Natural Science dispersed into the cold night, there was a vague sense of embarrassment, a feeling that they had been called out in the cold evening on a fool’s errand. They had come to see about plants and hybrids; they had got mathematics.
“But this is not even hybridization,” someone was heard to remark, a man who had read Darwin and considered himself as well up in the understanding of such things as anyone in the society. “Hybridization is the crossing of separate species. This is nothing more than crossing different varieties.” He pronounced the word varieties with contempt, as though he had said gypsy or Jew. “What is the point of worrying about whether you have green or yellow seeds? What matters is whether species themselves are mutable or whether they are distinct …”
“And what does mathematics have to do with biology?” complained another. “In the whole of Gärtner’s work, or Darwin’s work, come to that, there isn’t a single mathematical formula …”
Wise nods, stern agreement. Not anger, but disappointment and frustration, coupled with a sense of resentment at a wasted evening.
“It was fascinating, Gregor,” Frau Rotwang assured Mendel. She was waiting in the entrance hall as the audience left. She used his Christian name alone. She was solicitous and concerned.
“Do you think they saw it all?” He polished his spectacles and then carefully fitted them on his face. “Do you think it was too much for them?”
“It was fine.” She laid a consoling hand on his arm. She hadn’t understood a word.
And what have I achieved with my dwarfs? I can hear you asking the question. Never mind the personal crises. What has Doctor Benedict Lambert of the Royal Institute for Genetics, remote ancestor of this Gregor Mendel, what has he discovered?
The audience waits, shuffling papers, coughing and muttering. Those noises, minimal enough, fade away into an expectant hush as the side door opens and Benedict Lambert steps onto the stage. All eyes watch the diminutive figure as he lays out his papers and his overhead projector transparencies. He glances up at the tiers of expectant faces almost in surprise, almost as though he had come in here for some other purpose and had not expected this crowd.
“Good morning,” he says conversationally. Then he slips his watch from his wrist and lays it carefully on the lecture bench (a complete affectation this: there are wall clocks sited conspicuously around the theater) before looking back at the audience. The director is there, of course, seated front center: James Histone, CBE (when, oh when, will it be Sir James?). Like a portrayal of the Almighty in a medieval fresco he is surrounded by an aureole of lesser beings—the project directors, the postdocs, the graduate students, and finally, mere peasants on the outer edges, the undergraduates. And somehow Miss Jean Piercey is there, over on the left-hand side, five rows back. Her phenotype has changed. She looks different; but her mere appearance still brings a jolt to Benedict Lambert’s equanimity. She smiles.
He takes a deep, calming breath, and begins:
“The most common form of dwarfism in humans is achondroplasia. This condition, characterized by disproportionate short stature, proximal shortening of the extremities, macrocephaly, midface hypoplasia, bowing of the lower limbs, and exaggerated lumbar lordosis, is inherited as an autosomal dominant character with 100-percent penetrance. Therefore there are no carriers of the condition. To possess one such gene is to own the deformity.”
There is a great silence.
“To possess two ACH genes, one inherited from each dwarf parent, to be homozygous for the condition, is to die in infancy. As a consequence of this, more than 90 percent of cases are sporadic—that is, they are the result of chance mutation. Increased paternal age at the time of conception appears to be a significant factor, suggesting that mutations of paternal origin are involved. Furthermore, with an incidence of approximately one per fifteen thousand live births it is one of the more common de novo Mendelian disorders, which in itself provides sufficient reason for attempting to identify its cause.”
A pause; an ironical smile; just a touch of bitterness: “The more astute among you may be able to work out another motive.”
The director laughs. Thus sanctioned from the center, amusement spreads toward the periphery of the theater like ripples in a pond from a thrown stone. The celebrated Benedict Lambert has done it again: he has laughed to scorn the very gene that has wreaked havoc with his own body. Captain Ahab, perhaps? We have both been mutilated, certainly. But Ahab pursued a vast beast, a phenotypic complex of muscle and bone and blubber and nerve, while I pursue a mere molecule, a fragment of a molecule, a sequence of chemical bases that the human eye will never see. Yet both of us pursue our obsessions with a measure of hatred and a measure of love. Even Jean smiles, although her smile has more than a touch of irony to it.
“Over the last few years I and my team.”—a nod here in the right direction—“have collected a number of pedigrees
associated with this condition, and we believe that we have finally localized and identified the gene.”
A rush of excitement throughout the theater, although they knew it already. That, after all, is why they are here. All this has something of the drama of a well-known play: you know the plot well enough, but at the climactic moment, there is still the thrill of catharsis. Lady Macbeth still terrifies; Uncle Vanya still evokes empathy; the Master Builder still climbs his tower to frighten the watchers below. I point to a chromosome map, striped like a barber’s pole, flung up onto the screen behind me: “Multipoint linkage analysis gives us a location for the achondroplasia gene in the short arm of chromosome 4, distal to the gene for Huntington’s disease. The ACH location is close to the locus of the IDUA gene, and indeed initially IDUA was considered a candidate gene for the condition. However, IUDA mutations are known already to cause a number of symptoms that do not resemble ACH in any way …”
There is silence, anticipation. The surface of the ocean stirs and heaves. Will the great white whale emerge and be revealed in all its power?
“… and at least four other genes in the same area presented themselves as alternatives. One of these was the gene for fibroblast-growth-factor receptor 3. The fact that this gene is expressed in cartilage-forming cells in the mouse made it seem likely to be the one we sought. Subsequent sequencing of this gene has confirmed this suspicion …”
We have read the texts. Like latter-day Bible scholars, like exegetes, we have read the words of the scroll of life. I give you a message from this enigmatic, molecular world:
5′ … GGC ATC CTC AGC TAC GGG GTG GGC TTC TTC CTG … 3′
and this, the cry of the beast:
5′ … GGC ATC CTC AGC TAC AGG GTG GGC TTC TTC CTG … 3′
That is it.1 Can you spot the difference? In all the thousands of letters that make up the message, just one change spells disaster. G to A, a simple transition at nucleotide 1138 of the FGFR3 gene. Guanine becomes adenine. It is a trivial thing in the infinite and infinitesimal machinations of the human genome. It is an error in a single base pair, an error in the transcription of a single letter. There are 3.3 × 109 base pairs in the human genome. So, one mistake in thirty-three billion letters and we (B. Lambert et al.) have focused in on that single letter error. It seems like textual analysis gone mad. But you may rest assured that there is nothing trivial about this error, this one-in-thirty-three-billion chance (how Great-great-great-uncle Gregor would have loved that!). No, this footling mistake means that during the synthesis of a particular protein an amino acid called arginine is slipped into one position that ought to be occupied by a different amino acid called glycine. To be precise, this occurs in the transmembrane domain of the protein, the part of the molecule that fits through the cell membrane. The protein is fibroblast-growth-factor receptor 3.
The result is me.
I would like to make a comment on that word domain, in the manner of a Bible scholar offering a gloss. Domain is, of course, cognate with demesne, the land immediately adjacent to a manor house and retained by the owner for his or her own use. It is also a district, a region; the territory or sphere of. A further glance through the New SOED (1993 edition) gives other, specialist uses: a physics one (in ferromagnetic material, a region in which all the atoms or ions are orientated in the same direction), two mathematical ones (a set with two binary operations defined by postulates stronger than those for a ring but weaker than those for a field and the set of values that the independent variable of a function can take), and a logical one (the class of all terms bearing a given relation to a given term); nowhere does it give this particular biochemical one. I almost wrote a definition myself and posted it off to the editor-in-chief at the Clarendon Press—a more or less functionally distinct region within the tertiary structure of a protein—and then I thought better of it. I will stick with the felicitous nature of the original definition in the OED: “… a heritable property, LME.”
I might have entitled my story The Lost Domain. It has the same sense of remoteness, of abstracted innocence, as Alain-Fournier’s strange masterpiece. But now the domain that was lost is found. Ahab has spotted the whale. Now what?
The audience stirs with admiration, and with the thrill of malice, of—Uncle Gregor would have known the word—Schadenfreude. Each and every member thinks: There, but for the grace of God, go I.
I look up at the hanging gardens of academics and aspiring academics, and each looks back at me: close on a thousand eyes. “Of course, treatment of this condition is out of the question.” I change the transparency on the overhead projector and the message is writ large across the screen of the lecture theater. “But there is this:”
5′ … GGC ATC CTC AGC TAC A*GG GTG GGC TTC TTC CTG … 3′
“This is the mutant section of the gene. I have marked the mutated base with an asterisk. The double underline indicates a restriction site for the endonuclease enzyme SfcI. This restriction site is not present in the unmutated sequence. This leads us to a very simple method for identifying the mutation.”
I pause while they argue it through in their minds, the ones who are in the trade getting there and whispering to their neighbors to show they have worked it out; the others, those who are just here for the sensation, the bizarre theater, waiting patiently for me to produce the solution like a conjurer returning the torn five-pound note whole and undamaged after showing it to everyone in shreds.
“We have designed PCR primers that will amplify this section. The section includes the entire transmembrane domain and includes the mutation site. It is one hundred sixty-four base pairs long. As I said, in the normal form it does not present a restriction site for SfcI. The mutant form, because of the restriction site created by the transition2 from G to A, will be digested by SfcI into two fragments, respectively fifty-five and one hundred nine base pairs long. Such fragments may easily be resolved by electrophoresis in polyacrimide gels, and may be readily distinguished from the full hundred-and-sixty-four base section. We have shown that all three segments are present in heterozygotes, only the full-length one is present in unaffected controls, and in the three homozygous patients tested so far, only the two fragments are present. Thus we have a straightforward prenatal test.”
The applause rings around the theater. The act is over. Ahab has harpooned the whale.
Or merely spotted it?
Ah, there’s the rub. We’ve found the mistake, we’ve identified the error, but how does that become me? How does the single spelling mistake end up as a total distortion of the whole meaning of the book? Developmental genetics is, in some way, a question of pattern-making. It is also a matter of complexity and of sensitivity to initial conditions, the sure signature of that modish department of mathematics, chaos theory. For, after all, the most noticeable aspect of genetics to the man or woman in the street is not what proteins you can or cannot make, nor even whether you have dark or light skin, or brown or fair hair—the most noticeable aspect of genetics is family resemblance. “Doesn’t he look like his mother?” they say. “Hasn’t she got her father’s nose?” “Isn’t he the spitting image of his grandfather?” You hear it up and down the High Street. They lean over the prams and they wiggle their fingers around and they make their little genetic judgments. Mother used to assure everyone with an air of desperation that I possessed Great-uncle Harry’s BIG TOE.
All this is fine, but unfortunately there is no gene for the shape of your nose, or the cast of your brow or the shape of your toe. Genes only work through proteins. It is one gene: one protein; not one gene: one big toe, or one gene: one Grandfather Reginald’s face. Each gene carries the message for a particular sequence of amino acids, which in turn makes a protein, and a particular protein may do a number of things, but one thing it does not do, ever, is make a particular shape. Proteins are enzymes (can you metabolize galactose? can you make the pigment melanin?) or they are signalers (grow faster, become a woman, become a man, become a homicidal maniac) or they are workers
(contractors, transporters). They are not Father’s nose or Mother’s chin; or Great-uncle Harry’s big toe.
Yet in some sense father’s nose exists; and mother’s chin; and, possibly, Uncle Harry’s big toe. In some way the proteins do conspire together to make patterns, and the patterns are the things that you recognize, and if you change some of the crucial proteins (but not others) the pattern changes. I’ve said it before, haven’t I?—I don’t resemble my mother or my father or my sister. I had that sense of dispossession from the very start. With the dubious exception of my big toe (pace, dear Mother), I don’t look like anyone from my family: but I do look like every other achondroplastic in the world. All because of a single-letter spelling mistake in thirty-three billion.
If you want a real research project, if your ambition is to pick up a Nobel Prize or two, if you want to become Lord Histone, O.M., C.H. (forget the bloody knighthood), if you want to be remembered by posterity as Uncle Gregor Mendel is remembered, then
FIND OUT HOW.
After the lecture I received the plaudits. A whole congeries of the interested and the fascinated gathered round, almost suffocating me in their enthusiasm to touch. And on the edge, Miss Jean Piercey. I finally encountered her in the corridor outside.
“Hello, Benedict.” She was too shy to bend and plant a kiss on my cheek, but bold enough at least to stay and talk, to make a suggestion, to issue an invitation to lunch. I detached myself from the grasp of others and we went off together, not to the usual pub but to a wine bar somewhere in the King’s Road, all wooden wine racks and chalked notices announcing the latest bargains; somewhere with no associations.