Northampton, Massachusetts, 1970. Like most of the rambling houses Smith College rented to its faculty, 35 West Street had at some time been partitioned in two. Dorothy Wrinch lived in the smaller apartment, the one on the second floor. Her front room was crowded with bookshelves, a piano, and an old sofa with lace doilies. A narrow hall led to a bedroom and an eat-in kitchen in the back. She was 76, old enough to be my grandmother, and like my grandmother she lived alone. But my grandmother played cards and baked cookies. I can't imagine Dorothy doing that or crocheting doilies either.
"That nature keeps some of her secrets longer than others," wrote her friend D'Arcy Thompson, "that she tells the secret of the rainbow and hides that of the northern lights, is a lesson I learned as a boy." Banished to the outskirts of the scientific community, Dorothy wrestled the secret of secrets, the secret of life: the inner logic of protein molecules. Now, near the end of her own long life, she sought the answer in the shapes of their crystals. She needed an assistant; I wanted to understand crystal geometry. For the past two years I'd worked with her, unofficially and unpaid, in my scarce spare time, making models and drawing illustrations for the book she was writing. We met several afternoons a week in her office in the science center. Her life was her work, her work her life.
But one beautiful fall morning I drove to her apartment instead. Dorothy was waiting with a bag of sandwiches and hardboiled eggs. She had suggested this outing a few weeks before, in the middle of a rare reminiscence. How she'd loved long rambles with friends through the verdant English countryside and picnics on the shores of placid lakes! "Let's go to Lake Norwich on Mountain Day," she'd said. Lake Norwich? I'd never heard of it. Nor did I want to go anywhere on Mountain Day. The annual college holiday celebrating the glorious New England autumn was, for me, a day off to play with my small daughters and grade the math homework piled on my desk. But I agreed to a picnic at the lake because she seemed so eager. And because somehow I didn't feel free to say no.
Dorothy was uncharacteristically silent as I drove along the winding country roads that led to the Berkshire mountains. Maybe the splendid scenery left her speechless, or perhaps she was lost in memories. I found the lake: a Mountain Day postcard, red and gold foothills doubled in the mirror of still blue water. Perfectly still, and perfectly quiet: no rowers, no swimmers, no picnickers. Then we saw the sign: No Trespassing. We drove back and ate the eggs and sandwiches on a desolate stretch of road not far from Smith. Dorothy never mentioned lakes or picnics again.
Recently, I came across an autobiography, long out of print, called The Tamarisk Tree.
"During the summer of 1916 Dot Wrinch rang me at Sutton to ask me to go for a weekend walking tour with her, Bertrand Russell and Jean Nicod, one of his best pupils," the author, then Dora Black, recalled inaccurately (the year in fact was 1917). The girls, both exuberant, irreverent, redheads, had finished their studies at Girton College, Cambridge. Now Dot was studying with Russell in London. His pacifist activism had cost him his Cambridge lectureship.
"Russell, as I later learned, took great pleasure in long walks," Dora continued. "The idea was to walk over the downs near Guildford, spend the night at Shere and go back by train to London on Sunday evening. Dot joined the three of us in the train at Surbiton, carrying a large basket of very fine strawberries from her garden. Russell took charge of our route, indicating short cuts to Shere, while Dot kept whispering to me that she was quite certain 'our dear Bert' was entirely wrong and we were in fact heading for Gomshall."
Rabbits bounced among the wildflowers in the North Downs meadows. At 45, Russell looked rather like the Mad Hatter, Dora noted as the quartet rambled along unmarked paths. Her three companions were mathematicians and philosophers; they talked a lot of shop. Nicod "had a type of whimsical humour that delighted me," Russell would write in his own autobiography. "Once I was saying to him that people who learned philosophy should be trying to understand the world, and not only, as in universities, the systems of previous philosophers. 'Yes,' he replied, 'but the systems are so much more interesting than the world.'"
After dinner they chatted in the candlelit parlor. Dora says the inn was in Gomshall; Russell says Shere. But neither forgot what was said. Russell asked his friends, all half his age, what they most desired in life. In Dora's words: "Nicod, who felt himself plagued by a very sceptical disposition, said he thought that he would like to be really absorbed and caught up in some great belief or cause; Dot, I think, also hoped that she would find something entirely absorbing to which to devote her energies. Conscious that my choice was a bit banal, but speaking with sincerity, I said that I supposed I really wanted to marry and have children."
A candlelit evening 95 years ago now. The young people's wishes would be granted — but, like characters in the short story "The Monkey's Paw," with consequences they could not have foreseen and would not have wished. In 1921, Dora Black would become the second Mrs. Russell and, in short order, the mother of four children, but the marriage ended bitterly 12 years later. Jean Nicod "managed to maintain his pacifist objection and survived the war, but only at the great cost of making himself ill and unfit, since in France there was no provision for conscientious objection." He died of tuberculosis at the age of 31.
As for Dot Wrinch, this book is her story.
CULTURE CLASH AT COLD SPRING HARBOR
A few years after our aborted picnic, Dorothy left Northampton to live year-round in her summer home in Woods Hole. I visited her from time to time to talk about the book, but she gradually lost interest in it, and anyway, my viewpoint was diverging from hers. In 1974, she suffered a stroke. In December 1975, her only child, Pamela, died in a fire. Dorothy never spoke again. She died in February. Snow crystals muffled the clergyman's graveside eulogy. She would have liked that.
Dorothy left her papers — her notebooks, correspondence of 40 years, reprints, and models — to Smith College. Pamela's husband asked me to organize them for the archivist. And so I slipped into the maelstrom of her life and career, about which she'd told me very little, and into the controversy that still lingers three decades after her death.
I stir the pieces of her story around and around in the dense soup of ambient issues, coaxing them to crystallize, to arrange themselves in a shape I recognize and understand.
The arrangement of atoms in a crystal is the mark of its species. Stack carbon atoms one way, and you get graphite, the soft "lead" in pencils; stack the same atoms another way, and you get diamond, tops on the hardness scale. Table salt is a three-dimensional checkerboard of sodium and chlorine. Silicon and oxygen link in helices to make quartz.
A crystal's outer shape — its faceted geometric form — refracts the nature/nurture conundrum. As the crystal grows, atom joining atom in its characteristic pattern, the "mother liquor" (as chemists call it) nudges the crystal toward the shape that we see. Her action is subtle: trace ingredients in the liquid or its rate of cooling can make some facets grow larger and others disappear. Left to its own devices, a salt crystal becomes a cube; in 2005 the United States government granted patent #20050136131 for a method of growing salt in a shape less likely to clog up the shakers. Quartz grows in prisms, long ones, pointed at one end. But in Herkimer County, New York, the prisms are short and both ends are pointed. Der Diamant, a 1911, still-definitive, two-volume treatise on diamonds, has over 200 drawings of uncut diamond crystals with subtly and not-so-subtly different shapes.
Dorothy Wrinch's story crystallizes slowly and its form is unstable. It varies with the teller's temperature and trace elements in the teller's eye. I'm looking for patterns and facets. Where should I begin? "Science too," George Eliot reminds us in Daniel Deronda, "reckons backwards as well as forwards, divides his unit into billions, and with his clock-finger at Nought really sets off in medias res."
In medias res, then. In the middle of things. In the eye of the storm.
July 1938, Cold Spring Harbor, Long Island. The Biological Laboratory in this pleasant village is already renowned in scientific circles, though Barbara McClintock hasn't planted corn here yet, and James Watson is only 10 years old. It's playing midwife to a scientific revolution—a revolution as momentous as the Copernican and Darwinian. Inspired by the "molecular vision of life," the Rockefeller Foundation and the lab are jump-starting a new biology, crosscutting and interdisciplinary. Warren Weaver, the Foundation's visionary director for Natural Sciences, has just come up with a name for it: molecular biology. 1 Scientists jump and crosscut for invitations to Cold Spring Harbor conferences. To arrive here is to have arrived.
Once you've arrived, you can relax a little. Dress is casual, sport is sporting. The tennis court is down the road. The redhead slamming balls across the net is Dorothy Wrinch. She plays athletically and energetically — the same way, friends note, that she plays the piano.
Dorothy is 44, but she looks younger. She signs her letters like this: [symbol: a Greek letter delta, enclosed in a hexagon] and her friends call her Delta.
What is she doing here, in Cold Spring Harbor? Place the emphasis wherever you wish: what is she doing here? what is she doing here? what is she doing here? Someone is asking it that way.
She's here because Eric Ponder, director of the Biological Laboratory, has invited her to lecture in a month-long conference, the Sixth Symposium on Quantitative Biology. Quantitative: the very name suggests a break with biology's descriptive, compartmentalized past. Each year's symposium treats a cutting-edge topic. In 1938, proteins are as hot as July. Proteins are a topic whose time has come. It's now an established fact: proteins are molecules. Dorothy Wrinch is an international superstar of modern protein science. Her model for the molecular architecture of proteins is catalyzing research on both sides of the Atlantic.
Dorothy Wrinch is one of 72 promising, mostly young, scientists who have traveled here by boat, car, and train from England, France, and many states. She's the only mathematician among these chemists, botanists, bacteriologists, physiologists, zoologists, physicists, physicians, and x-ray crystallographers. Fourteen of them work in the Biological Laboratory or in the Rockefeller Institutes for Medical Research in New York or Princeton (and several have in the past); the research of others, including Dorothy's, is supported by Rockefeller Foundation grants.
The conference is informal: just one lecture a day, leaving hours unstructured for casual discussion and sporadic debate. In the lecture hall, at the breakfast table, lunch table, dinner table, swimming in the Harbor, sailing on the Sound, lolling on the lawn, strolling through the woods, even on the tennis court, the scientists talk about proteins. Most of them stay the whole month.
Whatever you think of Dorothy Wrinch — opinions differ — you have to grant she's prodigious. She holds a D.Sc. in mathematics from Oxford — the first Doctor of Science degree Oxford University ever gave to a woman. She also holds master's degrees from Cambridge University and the University of London, and a D.Sc. from the latter. Dorothy has been teaching mathematics at Oxford for 14 years. She lists 50 papers in mathematics, philosophy, and scientific method on her resume, all published in sterling journals. She doesn't list her book The Retreat from Parenthood; she wrote it under a pseudonym.
But Dorothy is no grind. She loves company; she's vivacious. Her wit is mordant. She has something to say on almost every subject: Shakespeare, Don Quixote, the Kama Sutra, Schoenberg's twelve tones, Roger Fry's Omega Workshop, Russell's philosophy, quantum mechanics and aerodynamics, the continuum hypothesis, the need for national child-rearing services, and the looming war. She can say it in Oxford English, Parisian French, Viennese German.
Dorothy doesn't talk about her husband John, his madness and institutionalization, their recent divorce. She doesn't talk about her struggle to support their daughter, now 11 years old. She keeps her loneliness to herself. She shows no one the anguished jottings, the painfully honest lists of pros and cons she makes for every big decision.
Sixty years later, in Stockholm for the Nobel ceremony honoring his discoveries (they led to Viagra), Robert Furchgott, the youngest participant in the Cold Spring Harbor gathering of 1938, would remember that summer as his metamorphosis from student to professional. His professor, an expert on the protein egg albumen, had brought him along; in exchange for room and board he tended the lantern slide projector in the lecture hall. The symposium, packed with famous scientists, was a heady experience for a 22-year-old aspiring chemist.
Irving Langmuir was the most famous chemist at the gathering, maybe the most famous physical chemist in the world. He'd already invented the gas-filled incandescent lamp and discovered atomic hydrogen. He'd won the Nichols Medal (twice), the Hughes Medal, the Rumford Medal, the Cannizzaro Prize, the Perkin Medal, the School of Mines Medal, the Chandler Medal, the Willard Gibbs Medal, the Popular Science Monthly Award, the Franklin Medal, the Holly Medal, and the John Scott Award. And of course, the Nobel. No one else there had won a Nobel yet.
Tall, loquacious, larger than life, Langmuir climbed mountains and flew his own plane. And when a trembling neophyte dared to challenge his remarks in the lecture hall, in front of everyone, the great man replied thoughtfully, as he would to a colleague. Bob Furchgott, the neophyte, never forgot that.
Langmuir was Wrinch's staunchest supporter. They'd written several papers together and would write several more. The next year, he nominated her for a Nobel Prize.
He tended the lantern slide projector ... how quaint, how ancient, that sounds, in our digital era, our world of streaming video and jpegs, YouTube and PowerPoint.
Lantern slides — glass slides, 3.5 x 4 inches, with photographic images transferred to them by any of several methods — were patented in 1850. The invention brought the inventors, William and Frederick Langenheim of Philadelphia, a medal at the first of the great world fairs, the Great Exhibition at the Crystal Palace in London in 1851. The brothers meant to entertain, nothing more. But the impact of these replicable, portable slides was far greater: the lantern slide brought the world to the lecture hall. In its century-long heyday, from the invention of photography to the Second World War, the "magic lantern" transformed the transmission of art and science.
The old boxy lantern slide projectors are museum pieces now, and lantern slides are collectors' items. My Google search for "lantern slides" turned up 18,200 images in .18 seconds: grape harvesters in Germany, circa 1900; villagers in India; a tiger in a London zoo; white-hatted archaeologists digging in a desert; and faded images of the great pyramids. No mathematics, chemistry, botany, bacteriology, physiology, zoology, physics, x-ray crystallography. Not the stuff of lectures on proteins.
Some years ago, the director of the Smith College Science Center implored us, the faculty, to clear out our sub-basement storage cages. I poked around the ill-lit jumble for an hour or so, retrieving a few long-forgotten models, tossing old notes in the trash. I found lantern slides in a green metal cabinet; they weren't mine to throw away. I gathered up my models and relocked the cage.
Now, Cold Spring Harbor on my mind, I remember that green metal cabinet. Is it still there? Are the slides still inside? Might some of them be Dorothy's?
The storage cage is still stuffed with boxes, broken furniture, unrecognizable pieces of forgotten instruments. I push my way around chairs with missing legs, decrepit desks, outmoded balance scales, dials pointing to nowhere, abandoned machine parts. The green metal cabinet still rests against the wall. And yes, it still holds the slides in its top two drawers—1374 glass slides, each in a yellowing envelope, each carefully numbered by hand. A mosquito, a grasshopper, a corn earworm, trees, vegetation, landscapes. The ice sheet over North America, a map of the location of dinosaur remains. Workers transplanting trees, an onion field, a sisal hemp plantation in Uganda, portraits of Swammerdam and Darwin and other bearded venerables, and gastric pouches patented December 29, 1896. No crystals, no molecules. These are the staples of Smith science courses long ago, the biology the scientists at Cold Spring Harbor learned in school.
As I grope my way back through the cluttered cage, I spot a cardboard box on a high shelf of metal staging. It's very heavy; I can scarcely lift it down. It's filled with lantern slides. These slides have no numbers, and most have no envelope. I browse through them: models, crystals, diffraction patterns. The images are elegant, concise, precise. My heart skips a beat; then tears blur my eyes: these are Dorothy's slides. She must have stashed them here when the science center opened, to great fanfare, in 1965. Her new office was small and by then lantern slides were history, supplanted by new technology: Kodak carousels, overhead projectors. She would never use her lantern slides again.
The oldest slides in the box are hand-made: disintegrating negatives clamped between glass plates, bound with red or black tape. I hold one up to the light. The glass is cracked, the aged tape disintegrating.
Dorothy's protein model. Simple, beautiful, elegant. The geometrical objet d'art that catalyzed research on both sides of the Atlantic.
Today all freshmen in Bio 101 know that a protein is "analogous to a string of Christmas tree lights, with the wire corresponding to the repetitive (polymer) main chain, and the sequence of colors of the lights to the individuality of the sequence of (amino acid) side chains,"2 just as DNA is a double helix, and genomes Я us.
The case is long since closed. "Proteins are now so well understood and so much a part of our knowledge that it is almost impossible to put ourselves in the position of the participants in the 1938 Symposium," says the Cold Spring Harbor website.
Almost impossible to put ourselves in the position ... but let's try. In 1938, the case is open. We are aware of the chain hypothesis, of course, but there are other, maybe better hypotheses, like Dorothy's. Experiment will decide
Dorothy Wrinch's cracked lantern slide showing her protein model. The model was constructed and photographed in Niels Bohr's laboratory in Copenhagen; the lantern slide was made for Irving Langmuir, 1940.
the matter someday, but so far it has had little to say. Meanwhile, we debate the merits and demerits of competing suggestions.
A valid hypothesis must fit the facts. One fact is: proteins have specific jobs to do. Take insulin, for example (it's the example everyone takes). Insulin has given diabetics all over the world a new lease on life. "Who could have imagined that an assortment of amino acids put together in a certain combination could exert such a profound physiological effect?" muses Vincent du Vigneaud. He heads Cornell University's biochemistry department; the Nobel Prize in Chemistry will come his way in 1955.
A "certain combination" — du Vigneaud knows that's the nub of it. Whatever structure you propose for the insulin molecule must be able to account for that profound physiological effect. If you say insulin is a chain, a string of 10,000 Christmas tree lights, then tell us precisely how it works. Meanwhile, we will keep an open mind. Maybe insulin isn't a chain at all.
Experiment has settled the case of fibrous proteins like silk, wool, linen, mammalian hair, hoof, feather, and horn. Fibrous proteins are solid state; they're built of submicroscopic crystallites. Crystallites diffract x-rays. Bill Astbury's diffraction photographs show that these proteins are chainlike. No one disputes that.
But insulin isn't a fibrous protein, it's "globular." In its "native" or active state, its overall shape is more or less round. Hemoglobin, the albumins, pepsin, gamma globulin, and other proteins critical for life are globular too. Their structure is the prize. Are globular proteins chains wound up like golf balls? Or is their architecture something else entirely? That's the big question here at Cold Spring Harbor.
X-ray diffraction hasn't helped, so far. Globular proteins can be crystallized, but that takes care and skill and luck — it's something of an art form. And these crystals are delicate, their diffraction patterns bewildering, in 1938.
If x-rays don't reveal the molecular architecture of globular proteins, cooking might. Anyone who's fried an egg or beaten an egg white knows that egg albumen's native state is transformed by heating or beating. The protein unfolds and flattens out. The unfolded — "denatured — state can be studied by chemical techniques. Maybe the protein's native state can be inferred from its denatured remains.
Bill Astbury, the British physicist who x-rayed the fibrous proteins, thinks all proteins are one big happy family. Denatured globular proteins look fiberlike to me, he says.
Alfred Mirsky, a protein chemist at the Rockefeller Institute in New York, disagrees. "To regard fibre formation as the criterion of denaturation and to 'reserve' the term 'denaturation' for the fibrous state is apt to be misleading."
Others doubt there is such a thing as the denatured state.
"It is to be expected that a denatured protein is in general not a definite substance but is rather a mixture of many," says Irving Langmuir.
Henry Bull from Northwestern, Bob Furchgott's professor, agrees. "The term denaturation has no meaning except in connection with operations which one performs."
Dorothy Wrinch's model accounts for different denatured states. "The fact that surface pattern can fragment into line patterns implies that line polypeptides, as well as pieces of fabric, can result from the process of denaturation," she says.
What is she doing here?
"Sir," said Samuel Johnson 200 years before, "a woman's preaching is like a dog's walking on his hinder legs. It is not done well; but you are surprised to find it done at all." Dorothy is not the only woman at Cold Spring Harbor. The symposium group photograph shows smiling wives in summery dresses and children large and small. (Eleven-year-old Pamela Wrinch is not among them; she's home in England with her "godless godmother," Margery Fry.) But only five of the 72 invited scientists are female, and of these only two, Dorothy and Eloise Jameson, a chemist from Stanford University, will give lectures. Just two women speakers, but it is 1938. You are surprised to find any at all.
Dorothy does it very well. She's a pro. She sizes up her audience, pitches her talk to just the right level. She doesn't read a written text; scientists rarely do. But Dorothy doesn't just not read: she shows. She shows elegant models and exquisitely drawn pictures. Their beauty speaks for her, or rather with her, for her words are eloquent too.
Dorothy dazzles everyone, or almost everyone — the men at her lecture, their wives in the dining room — with her scintillating conversation. But a little bit of Dorothy Wrinch can go a long way. She can get on your nerves. "A queer fish," Warren Weaver of the Rockefeller Foundation records in his diary, "with a kaleidoscopic pattern of ideas, ever shifting and somewhat dizzying."3 Max Bergmann and Carl Niemann, two chemists here, can't abide her. The feeling is mutual.
But most of those who ask what she's doing here have stayed away. Linus Pauling stayed in California. John Desmond Bernal and Dorothy Crowfoot Hodgkin stayed in England. In 1938, we have no e-mail and the snail is slow. The phone down the hall is a party line. We can't dial long distance directly, we have to call the operator, and we do that only in emergencies. It's not exactly calm here in the eye of the storm, but it could be — and will be — worse.
Then what is Dorothy doing here? What makes her a superstar of protein science? Why is her model such a sensation?
Step once more in their sandals. It's miserably hot in the lecture hall, though the whirring electric fans do their best. Forget today's jargon: CT, NMR, MRI, and DNA mean nothing at all in 1938; the word "acronym" won't be coined for another five years. We glimpse no connection between heredity and nucleic acids, though Astbury, whose lecture here will long be quoted, insists they're worth looking at. If there really is such a thing as a gene, and some still doubt it, it's probably protein. Just as the hormone insulin has turned out to be. The tomato bushy stunt virus is pure protein too — Wendell Stanley, who is here, created quite a stir when he proved that last year. His picture was in all the papers; he was compared to Louis Pasteur.
Data pour in from Uppsala, Sweden, where Theodor Svedberg is studying proteins with an ultracentrifuge of his own design. "When a slurry, an emulsion, is put into a rapidly rotating motion, its heavier constituents are thrown outwards in the direction of the periphery of the motion," the Nobel Committee explained on awarding him its prize in 1926. "This happens in the most used of all centrifuges, the milk separator, where the skimmed milk is pressed outwards whilst the lighter fat particles, the cream, accumulate inwards and can therefore be separated." With the help of his ultraprecise ultracentrifuge, Svedberg calculates the molecular weights of the separated material. He's studied a great many proteins by now, but he has not found a great many weights. It seems proteins fall into a small number of weight classes. Why is that?
That's not all. Poring over Svedberg's data, Bergmann and Niemann have found unexpected regularities. Invariably, the estimated number of amino acid residues in every protein is a product of powers of 2 and 3! For example, the number for hemoglobin is 576, and 576 = 26 x 32. The pattern goes deeper. The fraction of each type of amino acid residue in any protein is also a product of 2s and 3s. Why is that?
The answers are elusive, but we're closing in on them. It's 1938, morning in protein science! We don't know that the dawn is false.
In her student days, in Cambridge, Dorothy and her best friend Dora Black cycled to meetings of the Heretics Society. Twenty years later, she's a heretic still.
Globular proteins aren't chains, says Dorothy, they are fabrics. She dubs them "cyclol" fabrics because they're made up of rings. Rings, not chains, of Christmas tree lights. Twinkling hexagons joined together like lace. The fabric folds up into cages like origami. And what folds up, unfolds out. "The disorganization of the compact and orderly structure of the native protein is simply the ripping open and fragmentation of cage structures in general," she says.
Dorothy's cage is symmetrical, nearly Platonic. It explains many facts. It's the first specific model for proteins that anyone, anywhere, has ever devised. I hear the audience gasp.
Is there a protein fabric? That's the title of her lecture, but it's a rhetorical question; Dorothy's sure she's right or at least on the right track. She's quick on her feet, she holds her own in the after-lecture give-and-take of probing comments and questions. She passes her model around the audience; they turn it this way and that. It's a model of her model, actually: a material, elegant, realization of her abstract, elegant idea.
"I am not sure just where the side chains go in your picture," says Lawrence Moyer, a botanist from the University of Minnesota. "Do they point out off the surface of the fabric or do they go into the center?"
"If we take any kind of a fabric structure like the cyclol fabric there should be two kinds of proteins," Dorothy replies. "Those in which the side chains start by emerging from the cage and those which start by penetrating the cage."
"That might explain why the amino groups are not essential for the physiological activity of insulin," says Abraham White, Yale School of Medicine.
Chains, or cages? Fibers, or fragments? We, the assembled scientists, disagree on this and almost everything else. But, happily, we are unanimous on one point: the Bergmann-Niemann formula is of utmost importance. Everyone at Cold Spring Harbor cites it as established fact; everyone is convinced it says something profound about proteins. But what that is, no one knows. No one but Dorothy Wrinch.
"You have various ratios which are multiples of 2 and 3," Conrad Waddington, a geneticist from Edinburgh, says to Niemann. "You do not have ratios of numbers like 5 and 7. Why are some numbers excluded?"
Like Newton, Niemann declines to hypothesize. "I cannot explain it; it is an experimental fact."
Dorothy Wrinch does hypothesize and she can explain it. Those 2s and 3s come from the symmetries of the protein fabric: two hexagons share each edge, three share each corner. That's why her exquisite cages come in different sizes, but not just any size. When you work out the details, as she has, you find that C1, the smallest cage, accommodates 72 amino acid residues, C2 can hold 288, C3 has 648, and so on; the general formula is 72 n2. Since 72 itself is a product of twos and threes, 2 3 x 32, the formula 72 n2 will be a power of 2 and 3 when n is 1 or 2 or 3 or 4 or 6 or 8 or 9. That's what the Bergmann-Niemann formula means, says Dorothy. It means that proteins are cages.
"The beauty of mathematics faces you" — I quote the mathematician David Ruelle — "in those moments when the underlying simplicity of a question appears and its meaningless complications can be forgotten. In those moments . . . some of the meaning hidden in the nature of things is finally revealed."
But the mathematician's "meaningless complications" may be the experimentalist's devil in the details.
The molecular vision of life needs time to focus, longer than a get-together, even one lasting a month. The Cold Spring Harbor Symposium is a three-way culture clash.
Ralph Wyckoff, an x-ray crystallographer from the Lederle Laboratories, pleads for cooperation. Macromolecules are "perhaps the last great blind spot in our knowledge of the material composition of our immediate environment," he says. And biologists and chemists view this blind spot through opposite ends of the telescope. "The biologist enters this region from above through the investigation of microorganisms that become progressively smaller. The physical chemist approaches it from below by finding molecules or by producing aggregates of particles that are bigger and bigger."
"To progress in this field," says Wyckoff, "we must learn to effect a compromise between two disciplines which in a real sense are out of touch with one another."
Not two out-of-touch fields, but three. Dorothy Wrinch, the mathematician, approaches this blind spot from outside the telescope, outside the bounds of space-time. Her fabrics and cages come from Plato's world of abstract geometric forms.
Fabrics, or chains: let's decide that principle first, says Dorothy. Whether a particular protein is this fabric or that chain, my fabric or your chain, we can leave for later. The details — how and where the amino acids pack in, what holds them together — will sort themselves out. May I ask for criticism specifically directed toward the idea that the essential entity in proteins is a fabric, leaving to one side the question of the nature this fabric must have if it exists?
No, you may not, they say in effect. But in fact, they don't even hear her.
Three approaches to one blind spot, three long scientific traditions. In the seventeenth century, Robert Hooke in London looked through his 20x microscope and drew what he saw with "a sincere hand and faithful eye." The edge of a razor, tiny crystals, a flea, watered silk, a sliver of linen, a thin slice of cork: his monumental Micrographia was an instant best seller. Jonathan Swift dashed off a witty ditty:
So nat'ralists observe, a flea
Hath smaller fleas that on him prey,
And these have smaller fleas that bite 'em,
And so proceed ad infinitum.
Hooke coined the word "cell" in his description of cork:
I could exceedingly plainly perceive it to be all perforated and porous,
much like a Honey-comb ... these pores, or cells ... were indeed the first
microscopical pores I ever saw, and perhaps, that were ever seen.
Now, in 1938, vastly more powerful microscopes show much the same thing. In Cold Spring Harbor Wanda Farr, a botanist from the Boyce Thompson Institute, sees fabrics everywhere: "In our microscopic study of plant cell membranes we are constantly confronted with their fabric-like appearance ... The fabric-like nature of these first visible aggregations may be significant as an indication of one of nature's observable methods in building up organic structures."
The blind spot looks blank from the telescope's other end. The words "atom" and "molecule," used interchangeably for millennia, acquired their present meanings only in 1871, the year of the Great Chicago Fire. That the atoms composing a molecule are arranged in a specific way was another hard sell. As late as 1874, J. H. van't Hoff (who, in 1901, would be the first Nobel laureate in chemistry) was ridiculed for suggesting that the bonds of the carbon atom point toward the corners of a tetrahedron. The atomic scale was still hazy in 1900: "atom" meant one thing to chemists, another to physicists, and yet another to crystallographers, while others doubted the reality of atoms at all. Einstein's explanation of Brownian motion in 1905 helped end the doubts and confusion. But how nature puts atoms together — "producing aggregates of particles that are bigger and bigger" — remains, in 1938, unimaginable.
Dorothy doesn't look through either end of the telescope: she doesn't need it at all. Galileo, whose own telescope opened the grand book of the universe for all to see, taught her to read the book without it. This grand book is written in the language of mathematics, he said. "Its characters are triangles, circles, and other geometric figures, without which we cannot understand a word of it, but only wander aimlessly in a dark labyrinth." Geometry is the language of the universe and everything in it. Including proteins, says Dorothy.
Two decades before C. P. Snow made "the two cultures" a household phrase, he observed the gulf between two scientific cultures, chemistry and physics. Snow knew whereof he wrote: he'd begun his career as a physicist at Cambridge; he knew Bernal and Dorothy and all the rest of their crowd. His 1934 novel, The Search, is a roman á plusiers clefs. Arthur Miles, Snow's stand-in narrator, is an ambitious young physicist who dreams of, and schemes for, a research institute of his own. When an influential physics colleague lectures to the Chemical Society, a "long and petulant discussion" ensues. As the two men leave the meeting, the politically savvy Miles tries to butter him up.
"A queer, fierce, quarrelsome crowd they are," I said. "Why is chemistry the most conservative of sciences?" "Because it's got no mathematical basis," he said promptly ... "You mean," I said, "that there's nothing to test the new ideas by? And the old ones have all the force of tradition behind them."
Cross-disciplinary discussions at Cold Spring Harbor are long and petulant too.
"It seems to me that Wrinch's theories have great interest for us and that it is to be hoped that conclusive evidence may be found," Edwin Cohn, Harvard School of Medicine, remarks politely, "but I do not think that there is any evidence for the spatial arrangement."
"We should stay on experimental ground, and if someone claims that there are other linkages in proteins, he should try to find an experimental way to prove the presence of these linkages," Bergmann says acidly.
"I wished to refer to the much broader issue as to whether or not it is reasonable to postulate that some fabric or other is the essential entity in protein structures," Dorothy insists yet again.
Up and down the hierarchical levels, back and forth between main chain and side chain: the arguments rage for the month.
"There is, it would seem, in the dimensional scale of the world a kind of delicate meeting place between imagination and knowledge, a point arrived at by diminishing large things and enlarging small ones, that is intrinsically artistic," Nabokov will write.
If she's right, Dorothy's elegant protein fabric is that hoped-for meeting ground of imagination and knowledge: lace for the biologists, twinkling lights for the chemists, and Plato gets the cage. Her model accounts for many of the myriad questions that swirl around proteins. It folds and unfolds. It gives meaning to the Bergmann-Niemann formula. It accounts for Svedberg's data on weights. But Dorothy can no more explain why a protein fabric, if there is one, should fold and unfold as she says it must, than her doubters can explain how a chain could do better.
The statistician George Box will later quip, "All models are wrong, but some are useful." But by then the role of models will be better understood. In 1938, the mathematician and the chemists talk past one another. It is not so very long after The Search.
On and on they argue — sometimes head-on. And at the end of the month they all go home, all but young Furchgott, who stays on to work in the lab.
The published volume of symposium lectures and discussions, from which I've drawn most of this account, "provides an illuminating snapshot of the uncertainties and confusion that surrounded the nature of proteins." The false dawn faded to darkness as many of the Roman candles that lit these lively debates fizzled and landed in history's dustbin.
Svedberg was wrong: proteins do not belong to a small number of weight classes.
Stanley was wrong: viruses are not pure proteins.
Bergmann and Niemann were wrong: their formula does not hold for most proteins.
And Dorothy was wrong: globular proteins are not folded fabrics.
Yet – and yet. Theodor Svedberg is still revered for his earlier discoveries. Wendell Stanley won a Nobel Prize in 1946 for his work on the virus. Max Bergmann remained the Rockefeller Institute's protein expert until his death in 1944. Carl Niemann teamed up with Linus Pauling.
Dorothy Wrinch made a difference in half a dozen fields: mathematics, philosophy, seismology, genetics, protein structure, and the theory of x-ray diffraction.
So why was she marginalized? Why is she forgotten?
I stir the pieces of her story around and around, again and again.
From I Died for Beauty: Dorothy Wrinch and the Cultures of Science, by Marjorie Senechal, copyright 2012 by Marjorie Senechal. Excerpted with permission from Oxford University Press.