The protein produced by the BRCA1 gene. Wikimedia Commons.

It’s rare for a decision involving a genetic predisposition to seem so clearcut — an 87 percent chance of getting breast cancer before you die. Those were the odds Angelina Jolie was given after she was found to have inherited a defective gene called BRCA1. There was also the matter of BRCA-related ovarian cancer, with her lifetime odds put at 50 percent. With no other effective remedies in sight, she decided on a double mastectomy with plans to follow that with an oophorectomy, the removal of her ovaries. For all the talk about sequencing the cancer genome and precisely designed therapies, all that science could offer in the way of prevention was the amputation of healthy body parts.

I was traveling last week when she explained her decision in a widely discussed op-ed piece in the New York Times. I didn’t write much about BRCA in The Cancer Chronicles, so I spent some time this weekend getting a stronger sense of what is known about the disease.

Inherited BRCA defects are very rare, contributing to just a few percent of breast cancer cases, and Jolie’s situation was extreme. The average lifetime risk of women who have inherited the mutation is 65 percent, or about five times the normal odds. It was the actress’s family history that put her at the top end of the scale. A posting on the website of the cancer center where she was treated provided more details. Her mother had both kinds of cancer and died from the ovarian, which had also struck Jolie’s grandmother.

Even with such strong predispositions, cancer is not inevitable. When you dig into the details the ambiguities arise.

BRCA is short for breast cancer. It is a gene, like Rb (for retinoblastoma), perversely named for a condition it is meant to prevent. The healthy genes (there are BRCA1 and BRCA2) produce proteins that help repair the damage to the genome that occurs during normal cellular operations. If a woman inherits certain BRCA mutations, the repair function may be jeopardized. Fortunately people are born with two copies of every gene, one from each parent. It is when the matching gene — the backup — also becomes corrupted that trouble can begin. That might happen because of exposure to a carcinogen, a hormonal imbalance, or a spontaneous mutation — one with no real cause. More damage then accumulates, and the right combination of mutations may turn the cell into a malignant one.

Because of all the complications, the actual risk for an individual with a BRCA1 mutation varies widely around the average. The canonical number — a 65 percent lifetime risk for women — comes from studies of families that carried the mutation and had multiple cases of breast cancer, often occurring at an early age. Because they are closely related, the women may also have shared other inherited mutations — ones whose role science has yet to pinpoint — as well as environmental exposures. They may have eaten the same kinds of food. Any of these factors may have contributed to the cancer.

The result might be that the risk for the BRCA mutation alone has been overstated. BRCA carriers without a family history may face less than a 40 percent chance of getting the disease. Conversely, a University of Toronto study found that women whose families had a propensity for the cancer were four times more likely to get it themselves, even if they did not have BRCA mutations.

Given her own odds and the murky state of the science, Jolie’s decision made sense. BRCA-related breast cancers are often triple-negative, the hardest kind to treat. And for all breast cancers that can’t be stopped from metastasizing, even the most advanced therapies fall far short of a cure. The same is true for ovarian cancer.

There is no way to know if in the next few years less radical alternatives will be found — treatments that arrest the disease rather than merely staving off death a few months longer. Maybe other factors will be identified allowing the risk to be more precisely measured. Someday people may look back on preventive mastectomies as barbaric. But given the glacial pace of progress, Jolie and her doctors had every reason to be pessimistic and to chose the course they did.

Coming Next: Why is there no Gleevec for breast cancer?

Las Conchas Fire, June 26, 2011

Sunday evening I stood on the second-story portal of my house in Santa Fe and looked west toward Los Alamos where smoke billowed like a mushroom cloud from the Las Conchas fire. Hours later in the darkness, the glow of the flames was so bright it looked as though the sun had got stuck on its way below the horizon. I remembered the Cerro Grande fire, 11 years ago, and something I wrote for the Week in Review of the New York Times: Chaos Theory; Harness Fire? Mother Nature Begs to Differ. Reading it again after all these years, I see that my theme was the illusion of control.

Las Conchas, where the fire is said to have begun — the specifics have been maddeningly imprecise — is near the trailhead for the East Fork of the Jemez River, a cool, shady meadowland where two friends and I had gone hiking just the week before. We had planned to hike that day to Nambe Lake in the Sangre de Cristo mountains on the opposite side of Santa Fe. But the forest there had just been closed because another fire, called the Pacheco because it was mistakenly reported to have begun in Pacheco Canyon, was burning out of control. I can see its plume from the east side of my house. I feel surrounded.

Late in the afternoon the smoke from both fires filters the light and gives everything an eerie orange cast. Doomsday, it seems, would look like this. I try not to imagine what is happening now to so many of my favorite places: The high meadows of Rancho Viejo where the Rio Capulin flows on its way to meet the Nambe. The Upper Crossing of Frijoles Canyon, one of the only places in New Mexico where I’ve seen fireflies at night. All of that appears to be burning and there is nothing I, or really anyone, can do about it.

A neighbor, fearing fallout from the fire near Los Alamos, is flying with her child to Denver and what she feels instintively is safer ground. The odds of a radioactive release appear to be vanishingly small. It is probably more likely, God forbid, that her plane would crash. As with Cerro Grande the great threat is not from a nuclear reaction but a chemical one: oxidation. It starts as an innocent spark. Fueled by the trees we love and the air we breath it consumes mountainsides and memories.

Pacheco Fire, June 25, 2011

George Johnson
The Santa Fe Review

Note: This week, while I am occupied with the Santa Fe Science Writing Workshop, I will be republishing posts about the extreme whether of 2011. Next to come: The aftermath.

In March Tom Yulsman published this stunning satellite photo in a post on ImaGeo titled Land of Enchantment, Drought and Fire.

The fires of 2011. Landsat photo from USGS.

The 10,000-acre fire scar to the northeast is the Pacheco Canyon Fire (misnamed — it actually ignited two canyons northward). It was a shock, but a sadly familiar one, seeing the smoke plume from my windows. That weekend some friends and I had planned a hike right near that spot, to Nambe Lake in the Pecos Wilderness. So instead we drove to the other side of the river, the Rio Grande, and hiked up the Las Conchas Trail in the Jemez Mountains, along a beautiful stream winding through meadows. A few days later that area caught fire — and with the unseasonable winds it rapidly exploded to cover 150,000 acres, sending plumes down the canyons to the foot of the mountain, incinerating everything in sight.

This was also the year of gargantuan fires in Arizona, which began right around now, in May. The Santa Fe Science Writing Workshop was under way, and near the end of the week we had carpooled to Bandelier National Monument for our traditional hike along the cliff dwellings. The sky was weirdly overcast all day, and the reason didn’t strike me until that evening when I left a restaurant and smelled smoke. At first I thought it was someone’s fireplace — the evening was a little cool. I soon realized it was smoke coming from more than 100 miles away.

This week the workshop is in session again. I won’t have time to think about much of anything else, but I would like to republish, in my next two posts,  some observations about 2011 from my old blog The Santa Fe Review.

Last Sunday, a couple of friends and I drove up Hyde Park Road and, just before the Aspen Vista lookout, turned onto Forest Road 102. We were headed for Aspen Ranch, the trailhead for what I remembered as one of the most beautiful hikes in the Santa Fe mountains. The 13-mile loop leads to La Junta, “the junction,” a mountain meadow where the Rio Nambe and the Rio Capulin meet. Judging from the maps of the Pacheco Fire, the meadow is now toast, but I hoped to get close enough to see what had been spared by the flames.

Long ago Aspen Ranch was the site of a boys school. In his book, An Anthropology of Everyday Life, the late Ned Hall (better known to the world as Edward T. Hall) described a year he spent there. The land is now owned by Tesuque Pueblo, and when I used to go there, maybe a decade ago, there was a sign informing hikers of a $10 parking fee. Since there was never anyone monitoring the trailhead and no visible means of making payment, I would leave a check made out to the pueblo on my windshield. It was always there when I returned, so I would keep it in the glove compartment for a future visit.

This time it was not an issue. The entire ranch was cordoned off with barbed wire and locked gates marked with “No Trespassing” signs. During my long absence, the Forest Service had built a new trailhead on the public side of the gate and cut a detour around Tesuque’s land.

In Rio en Medio Canyon. Photo by Kerry Sherck

The trail is called the Borrego because sheepherders once used it to herd their flocks from Chimayo to Santa Fe for market. We followed it a short distance and then turned onto another trail that descends along the Rio en Medio all the way down the mountain. Most people know this trail from the bottom end — where it starts outside the village of Rio en Medio and climbs past several waterfalls. The canyon looked as lush and shady as ever — green meadows filled with wildflowers and an astonishing number of butterflies flocking to feed on the nectar of Black Eyed Susans. It was hard to believe that just over the ridge so much devastation lay.

I returned to the same area yesterday, staying this time on the Borrego Trail. More idyllic meadows, talls stands of pine and aspen — and suddenly the smell of 10,000 acres of burnt forest. There is a short stretch where the trail follows a power line service road and, at the top of a hill, peels off and heads down to the Rio Nambe. Standing there, I looked down on a hillside of badly burnt trees. Not far in the distance whole landscapes were reduced to gray moonscapes — the way so much of the Jemez looks now. A helicopter, hovering overhead, was dropping loads of straw on denuded mountainsides. The restoration effort was already under way.

A sign that had been posted at the edge of the burn area didn’t say, in so many words, that entry was prohibited. But it gave enough good reasons to stay out — falling limbs and trees, flash floods of ash and mud, burnt-out stump holes, fire maddened nests of hornets — that I almost turned back. Most of the destruction was below the trail (it had acted as a partial fire break) so I followed it a little farther. When I reached a spot where the trail had washed out, I decided to call it a day.

It was a relief to drive home through old familiar aspen groves. I told myself that this beauty now exists because fires, long ago, had cleared the pines, opening new niches in the ecosystem — that someday, decades from now, the ashen lands of the Pacheco Fire would be as beautiful. It was too much of a stretch for my imagination. All I could honestly feel was a terrible sense of loss.

George Johnson
The Santa Fe Review

Note: The last of three posts about the drought of 2011.

A work by Israeli artist David Gerstein. Wikimedia Commons.

Shortly after my post earlier this spring about the dubious idea of π day, I started reading David Foster Wallace’s Everything and More: A Compact History of Infinity. It was the last book he published before his suicide. He called it a booklet. It was part of a series of what were intended as short accounts of Great Discoveries, but it was 319 pages long. That is short for Wallace, I guess. His novel Infinite Jest was more than 1,100 pages. And who knows how long A Pale King might have been had he lived to complete it? It was published unfinished after his death.

It’s fair to say that Everything and More was not very well received, with some particularly nasty comments from mathematician/writers like Rudy Rucker (his review was titled “Infinite Confusion”). Another critic, in Notices of the American Mathematical Society, complained that the book was “laced through and through with blunders of every magnitude.”  Others admired the book but with great reservations: ‘Not just a bit difficult,” a reviewer wrote, “but frequently, intensely, skull-clutchingly difficult.”

I think it was wonderful. There were parts I only sort of understood, and I’ve been bogged down for awhile on page 186. But more than anything I can remember, Everything and More captured the shivering feeling — wonder, exhilaration, horror — that can come from contemplating the infinitely large and the infinitely small. It is astonishing how vast a picture of this territory Wallace held in his head and how he was able to at least convey the contours of his obsession.

“The dreads and dangers of abstract thinking are a big reason why we now all like to stay so busy and bombarded with stimuli all the time,” Wallace wrote. “Abstract thinking tends most often to strike during those moments of quiet repose. As in for example the early morning, especially if you wake up slightly before your alarm goes off. . . .”

It is a reliable way to “drive yourself crazy in bed in the morning” and without anyone there to help.

In those yellow-grey hours, one of the things Wallace would think about was numbers. Natural numbers, real numbers, irrational numbers, imaginary numbers, transcendental numbers. It had been a long time since I had thought of these names. The last three sounded particularly tantalizing.

The real numbers are those that can be plotted on an infinitely long and infinitely dense number line — quite an abstraction in itself. They include the natural numbers (“counting numbers” like 1, 2, 3 . . .), the integers (the counting numbers and their negatives), and the rational numbers — those that can be expressed as a ratio of two integers. Anything expressed as a ratio can be written as a decimal that is either finite in size (1/4 = .25) or in structure, repeating indefinitely with the same pattern (2/3 = .6666 . . . or, more interesting, 1/7 = .142857 142857 142857 . . . and 11/13 is 0.846153 846153 . . .)

Irrational numbers, as I wrote in the earlier post about π day, are irrational only in that they cannot be expressed as ratios. Their decimal expansions extend infinitely and never repeat.

Pi is not just irrational. It is also transcendental, meaning that it is “not a root of a non-zero polynomial equation with rational coefficients.” What I think that means is that these numbers transcend description by a simple algebraic formula. (Someone please correct me if that is too loose. I am already in over my head.)

Though irrational and transcendental, pi can be computed to any degree of precision. You just have to devote the time and the will, knowing that you will never really be done.

As exotic as they sound, all of these numbers can be thought of as infinitely small points on the endlessly inward and endlessly outward number line. The next step in weirdness leads to the imaginary numbers like i, which is the symbol for the square root of -1.  These are off the real number line, plotted instead on a perpendicular axis. Combine an imaginary and a real and you get a complex number, occupying a point on “the complex plane” — the great space hovering between the arms of the orthogonal boundaries. Multiplying by i is the equivalent of a rotation — a handy tool but what is i really? Do we invent this stuff or does it exist in a separate realm?

Far more recalcitrant than all of these are the noncomputable numbers. These cannot be calculated by any conceivable computer. Worse still, there are infinitely more noncomputable numbers than computable ones. The proof can be traced to the 19th-century mathematician Georg Cantor — the “diagonal argument” might ring a bell or the idea of countable versus uncountable infinities.

The way I try to think about this is that for any computable number there is an algorithm — a computer program — that can churn it out in a finite amount of time. This program, like all programs, would consist of a string of 1s and 0s — the binary rendition of a number that can be represented as a point on the real number line. There is an infinity of these bit strings. But if you plotted every one, there would still be huge gaps in between — the numbers that no algorithm can produce. Noncomputable. And if you can’t compute them, in what sense do they exist?

Cantor is the consuming passion of Wallace’s book. The mathematician suffered from severe depression and was in and out of asylums, dying in 1918 in a sanatorium. Wallace rejects the romantists’ notion that Cantor was driven mad by infinity, that he was a modern-day Prometheus, “the one who goes to forbidden places and returns with gifts we all can use but only he pays for.” Cantor’s fire was his understanding of infinity. But that, Wallace writes, is not what killed him.

Cantor’s work and its context are so totally interesting and beautiful that there’s no need for breathless Prometheusizing of the poor guy’s life. The real irony is that the view of ∞ as some forbidden zone or road to insanity . . . is precisely what Cantor’s work overturned.

He made infinity less scary, manageable by our little minds.

“Saying that ∞ drove Cantor mad is sort of like mourning St. George’s loss to the dragon: it’s not only wrong but insulting.”

After I put down Everything and More, I picked up the biography of Wallace by D.T. Max. You don’t get the impression that it was infinity that drove Wallace to suicide.

It may have had more to do with MAO inhibitors, the primitive but apparently effective antidepressant he had taken for years, and his decision, supported by doctors, to give them up because of their side effects. Nothing he went on to try worked better, even electroconvulsive shock, and when he came back to the old drug it didn’t help him anymore.

“Everything had been tried, and he just couldn’t stand it anymore,” his father said. (This is all from his obituary in the New York Times.

Still, you have to wonder what was going through Wallace’s mind when he walked inside his garage while his wife was away and hung himself.

The epigraph in Everything and More is a streak of Greek letters, liked a squished mathematical formula. Wallace  said that it was meant as a joke. Translated, it means, “It is not what’s inside your head, it’s what your head’s inside.” In the end it was a noose.

He wrote this, about suicide, years earlier in Infinite Jest:

The so-called ‘psychotically depressed’ person who tries to kill herself doesn’t do so out of quote ‘hopelessness’ or any abstract conviction that life’s assets and debits do not square. And surely not because death seems suddenly appealing. The person in whom Its invisible agony reaches a certain unendurable level will kill herself the same way a trapped person will eventually jump from the window of a burning high-rise. Make no mistake about people who leap from burning windows. Their terror of falling from a great height is still just as great as it would be for you or me standing speculatively at the same window just checking out the view; i.e. the fear of falling remains a constant. The variable here is the other terror, the fire’s flames: when the flames get close enough, falling to death becomes the slightly less terrible of two terrors. It’s not desiring the fall; it’s terror of the flame yet nobody down on the sidewalk, looking up and yelling ‘Don‘t!’ and ‘Hang on!’, can understand the jump. Not really. You’d have to have personally been trapped and felt flames to really understand a terror way beyond falling.

But what was it that was on fire?

Obituary for the helix. Wellcome Library.

Led astray by her own evidence, she had missed, just barely, making the greatest discovery in the history of biology: the coiled, interlaced structure that explained with such clarity the working of the gene. “The secret of life,” Crick called it.

Gosling, the other signatory, was Franklin’s assistant at King’s College in London, and Wilkins was her boss and bête noire. “Besselised” refers to Bessel functions, a mathematical tool used to analyze the photographic images she so expertly produced of DNA. But the most significant word in her mocking postcard was the one in parentheses: crystalline.

Several months earlier, having mastered better than anyone a technique called x-ray crystallography, she had taken the clearest pictures yet of the molecule. It came in two forms, depending on whether it was crystallized (shape A) or dissolved in water (shape B). It was the longer, stretched-out wet form, her Photo 51, that went on to become legendary. Horace Freeland Judson describes it in The Eighth Day of Creation:

The overall pattern was a huge blurry diamond. The top and bottom points of the diamond were capped by heavily exposed, dark arcs. From the bull’s-eye, a striking arrangement of short, horizontal smears stepped out along the diagonals in the shape of an X or a maltese cross. The pattern shouted helix.

The question that has dogged historians ever since is why Franklin didn’t shout out the same. Instead she put image B aside, concentrating instead on the far less certain pattern in image A. No matter how hard she looked, she couldn’t see a helix there.

Franklin’s Photo 51. Wellcome Library.

She bristled when Crick, working with Watson at the Cavendish Laboratory in Cambridge, told her she was allowing herself to be misled by ambiguous markings and that both forms must be helical. But she couldn’t be persuaded. Cautious by nature, she believed in holding back on interpretation and grand theories until all the data were gathered and understood, the seeming contradictions resolved. Her style was to work from the bottom up, meticulously trying to piece together the big picture.

She thought it was rash and premature that Crick and Watson, with their top-down approach, were enthusiastically building models — castles in the air — before they had laid the foundation. As they put together their sheet-metal and wire sculpture, the details, they believed, could be filled in along the way.

By now Crick was already puzzling over what he saw as the next key issue: How are the nucleotide bases (what we now think of as the DNA letters) zipped together in pairs? He assumed it would be a matter of like with like — that adenine would stick to adenine, thymine to thymine, cytosine to cytosine, guanine to guanine. Then a mathematician told him that his calculations showed the pairing was complementary: A-T, C-G. Crick also finally saw the significance of Chargaff ratios. In his analysis of nucleic acid, Erwin Chargaff at Columbia had shown that A and T and C and G exist in roughly the same proportions. Suddenly it all made sense: two interlocking helical templates forming a molecule that could carry information, and that could replicate.

Over a span of about 40 pages, Judson explains the reasoning with a satisfying verve and turns the realizations and false leads into an absorbing drama. At first Watson had the helix inside out. Then he tried to cram together, like mismatched puzzle pieces, the wrong forms for the bases. In the final weeks before the discovery, another contender, Linus Pauling in Pasadena, had convinced himself that DNA was a triple helix. (Watson and Crick had been up that cul-de-sac before.) Meanwhile Franklin had become intent on proving that DNA — the crystal, at least (it’s not entirely clear what she was thinking) — was shaped like a figure 8. All the while her image B remained on a shelf, in a filing cabinet — wherever it was kept — ignored month after month until Wilkins showed it to Watson, resulting in his famous epiphany. A few weeks later he and Crick had the structure.

After negotiations between both labs, papers by Wilkins and by Franklin and Gosling appeared in the same issue of Nature along with the one by Watson and Crick. (They can all be found on a website at Nature, and an annotated version of the Watson-Crick paper is at the Exploratorium’s site.) Toward the end of their paper, they flatly state that “We were not aware of the details of the results presented [by the King's scientists] when we devised our structure, which rests mainly though not entirely on published experimental data and stereochemical arguments.” Yet they go on to write in an acknowledgment, three paragraphs later: “We have also been stimulated by a knowledge of the general nature of the unpublished experimental results and ideas of Dr. M. H. F. Wilkins, Dr. R. E. Franklin and their co-workers at King’s College, London.”

The sentences seem to contradict each other, and in any case Watson made a point, in his book The Double Helix, to describe the pivotal moment when he saw Photo 51.

So the controversy continues. Was it ethical for Wilkins to show Watson his colleague’s work without asking her first? Should she have been invited to be a coauthor on the historic paper? Watson hardly helped his case with his belittling comments about Franklin in The Double Helix.

In Brenda Maddox’s biography, Rosalind Franklin: The Dark Lady of DNA (it was Wilkins who called her that) she makes a strong argument that her subject knew all along that the B form of DNA was helical. But she didn’t advertise the fact or begin to see the significance until shortly before Watson and Crick made their breakthrough. With a little more time she might have gotten the structure first. Or maybe Wilkins would have done so if Franklin hadn’t left him with the impression that a helical structure had been ruled out. After the discovery was made, she figured out how the crystalline A form was just a foreshortened version of the B. Like so many things it was clear in retrospect.

During the last week or so I’ve reread Judson’s account of that year before the discovery and then the relevant pages in Maddox’s biography and Robert Olby’s detailed history, The Path to the Double Helix. There are many other wrinkles to the story — the “gentlemen’s agreement” by the Cavendish not to tread on King’s turf, the role of Max Perutz as another conduit between the two laboratories. All of this was hashed out during the 50th anniversary in 2003 and it will be rehashed again for the 70th. That is how fascinating a story it is, revealing how human curiosity vies with human competitiveness in the unfolding of great science.

Related posts: My Letter from Francis Crick

The Best Science Book Ever Written

Francis Crick’s drawing of the double helix, from his letter to his son. Christie’s.

Earlier this year, the 23-karat gold medal awarded to Francis Crick was auctioned off for £1.3 million, or more than $2 million. When I heard the news, I thought it seemed a little tacky. Then I went on to read that Crick’s family will donate 20 percent of the money to the establishment of the Francis Crick Institute in London. That took out some of the sting.

Not long afterward another bit of Crick memorabilia went on the auction block at Christie’s: a letter, dated March 19, 1953 from Crick to his 12-year-old son, Michael, who was away at boarding school. It went for £3.45 million or about $5.3 million. Half will go to the Salk Institute in La Jolla, where Crick worked for many years.

It is easy to see why the letter was worth so much more than the piece of gold. In just a few hundred words, Crick provides as crisp a description of DNA as you will every see, complete with his hand-drawn sketch of the double helix and other rough diagrams. It was a discovery clear enough for a 12-year-old to understand, and one that completely transformed the life sciences.

I have my own letter from Crick, long buried in a file drawer in my office, though I doubt it would fetch much on the market. In the year 2000 after my biography of Murray Gell-Mann was published, I heard from a reader in Pasadena. He knew Crick, and he was urging me to write his biography. He offered to ease the way by approaching the great man himself. I wasn’t certain that I was ready to take on another huge project but I followed up with a letter, sounding Crick out about the idea.

I was spared the postcard Crick was famous for using to fend off any and all requests. Here is a copy from the Francis Crick Archive at the Wellcome Library:

But I did receive a short reply:

And so I did. Nine years later Robert Olby, a historian of science, published Francis Crick: Hunter of Life’s Secrets.

Brenda Maddox is now doing Watson’s life story. She is also the author of Rosalind Franklin: The Dark Lady of DNA, which probably did more than anything to bring recognition to Franklin — both for the important role her x-ray crystallographic work played in the discovery of the double helix and for the condescending way she was treated by Watson and other colleagues. Many people were surprised last month when, in a short essay on DNA’s 60th anniversary, she ended like this:

Watson has been much criticized for his portrayal of the “terrible Rosie” in The Double Helix but, as Franklin’s biographer, my answer to critics is that if it weren’t for Watson, no one would have heard of Rosalind Franklin. . . .

I guess it is natural for a biographer’s allegiances to shift with a change of subjects. We won’t really know until her book is published.

Meanwhile I was reminded of a remarkable section in Judson’s The Eighth Day of Creation where he recreates, through Franklin’s journal and other sources, what she knew and when she knew it, every step along the way. He writes of her “grievous slowness of intuitive response,” of her working “head down and doggedly, ingeniously struggling in the wrong direction.” “It is easy to feel great sympathy with Franklin,” he concludes. “The fact remains that she never made the inductive leap.”

I went back and reread those passages a couple of nights ago and then got a copy of Maddox’s book from the local library. I’m still trying to reconcile the two accounts and will write more about that in my next installment.

Postscript: After my last post, The Best Science Book Ever Written, I received a nice email from Terrence Monmaney, the executive editor of Smithsonian magazine, pointing me to his beautiful remembrance of Judson, who was his teacher. It was posted at The Last Word On Nothing, an excellent forum by science writers created by Ann Finkbeiner, another Judson protégé.

The Eighth Day of Creation, Cold Spring Harbor Press edition

The New Yorker recently started a blog about science and technology called Elements. I wish it had confined itself more tightly to science. There is too much about social networking — Facebook, in particular — and the Internet. But there are also plenty of posts — articles really — by some very good science writers: Gareth Cook, Michelle Nijhuis, and David Dobbs. (All three have been instructors at the Santa Fe Science Writing Workshop, which my former New York Times colleague, Sandra Blakeslee, and I organize every year. Before that Michelle was a student there.) Virginia Hughes, another talent, has a post in Elements today.

The blog has also included dispatches from some of the magazine’s excellent staff writers like Michael Specter and Elizabeth Kolbert. Good science writing is a New Yorker tradition, and Joshua Rothman, on a different part of the website, recently noted some of the great examples that have appeared over nearly a century in the printed edition — works by Freeman Dyson, John McPhee, Oliver Sacks, and other luminaries.

I know he couldn’t mention everyone, but for me two omissions particularly stood out: Jeremy Bernstein and Horace Freeland Judson. Beginning in the early 1960s Bernstein, a physicist who knew and worked with some of the biggest names in his science — Hans Bethe, I. I. Rabi, Robert Oppenheimer, Murray Gell-Mann, Frank Yang, and T.D. Lee — wrote about them and others in fullscale profiles or in shorter “Talk of the Town” pieces. He also ventured beyond physics, writing profiles of Arthur C. Clarke, Marvin Minsky, Lewis Thomas, and Joshua Lederberg. Along with the science were reports from “our far-flung correspondent” as Bernstein climbed the Alps and trekked in the Himalayas, often conversing with colleagues about particle physics — a modern day version of Bohr and Heisenberg rambling across the Danish countryside arguing about quantum theory.

Judson, when he appeared in the magazine, sprawling across three separate issues, was the European cultural correspondent for Time. The subject of his New Yorker articles, however, was molecular biology and the chain of insights and experiments that led from the early inkling that nucleic acids were the carriers of genetic information to the triumphant discovery of James Watson and Francis Crick: that deoxyribonucleic acid was shaped in just such a way that suggested its function as a self-replicating molecule capable of conveying the instructions for making proteins. With Judson’s superb journalism and narrative sense, you can almost feel what it was like in the early days when it wasn’t even clear what information was in a biological sense or how it could be coded within the arrangement of the atoms that bind to form molecules. The series about DNA became the first part of an even longer book, The Eighth Day of Creation: Makers of the Revolution in Biology.

It begins like this:

We were crossing London in one of those commodious taxicabs, Max Perutz and I, on a sun-washed Wednesday afternoon late in May 1968, heading for Liverpool Street Station and the train to Cambridge, when Perutz, reflecting on the ways men do science, paid James Watson the most exact yet generous compliment I have ever heard from one scientist to another.

The sentence, leaving us in suspense, may seem long compared with what people are used to reading now, and some will object to Judson’s using (in the style of the time) “men” as the collective noun for people. But more than once that first sentence has pulled me right into the story.

As the paragraph continues Crick makes his first appearance, and there is a mention of the scandal created by The Double Helix, Watson’s tell-all account of the DNA story. We learn that Perutz is a molecular biologist, “a frail-seeming man . . . of gentle courtesy, shy brown eyes, vast information,” that he is “precise, worrying, abstracted,” but “with the wiry will to climb for sport the Alps of his native Austria, and to spend forty years working at the cliff face of a problem — the three-dimensional, atomic structure of the hemoglobin molecule, all ten thousand atoms of it — that was so nearly impregnable it took him fifteen years just to discover how to do it. . . .”

What immediately propels the story forward is the contrast between the careful, methodical way that Perutz unravelled hemoglobin — this lump of a molecule — and the flashes of intuition that ultimately lead Watson and Crick to the vastly simpler and lither structure of DNA.

At the end of this first paragraph — about 1,000 words, the size of a long blog post — we finally learn what Perutz’s compliment was:

People sneer at Jim’s book, because they say that all he did in Cambridge was play tennis and chase girls. But there was a serious point to that. I sometimes envied Jim. My own problem took thousands of hours of hard work, measurements, calculations. I often thought that there must be some way to cut through it — that there must be, if only I could see it, an elegant solution. There wasn’t any. For Jim’s there was an elegant solution, which is what I admired. He found it partly because he never made the mistake of confusing hard work with hard thinking. . . . Of course he had time for tennis and girls.

We immediatley know we are reading a book not just about science but about scientists — people — and how they think. Then we quickly hear just enough about Judson himself before he fades into the background — how as a “journeyman theater critic and book reviewer stationed in London,” who also did some science writing, he interviewed Perutz for a story — and then interviewed others and others, becoming swept up in the “bracing,”  “intellectual daring” of their venture, to explain life molecularly. We know we are in the hands of a smart, literate, curious outsider — someone at about our level — with enviable inside connections and a determination to lead us through the winding path of one of the great discoveries of all time.

I  remember the moment one of my best friends, Richard Freedman, thrust all three issues into my hands. “You have to read this,” he said. I was home from graduate school on a visit to New Mexico with my girlfriend, and I brought the magazines with me when we drove up to my family’s cabin in the Jemez Mountains. Hours after she had gone to bed upstairs, I was sitting by the fire, stoking it with more wood, as I read Judson.

The climax comes with the publication of Watson and Crick’s 1953 paper in Nature — its 60th anniversary is next Thursday. When Judson’s book came out (it was reviewed in the New York Times by Jeremy Bernstein), that entire saga comprised part 1. In the second part, with the structure of DNA nailed down, Crick and other scientists like Jacques Monod and Francois Jacob go on to decipher the genetic code — discovering how triplets of nucleic acids each “stand for” an amino acid, one of  20 building blocks of proteins. Part 3 describes how Perutz finally chipped his way through to reveal every nook and cranny of hemoglobin. Here too, the structure suggested the function, with the molecule imbibing and expelling oxygen atoms almost like a submicroscopic lung.

I never got around to reading every word of parts 2 and 3. I wish they would be published as three free-standing volumes. Or just publish the first one. It alone is the best book about science I have ever read.

To be continued.

The best journals take great care in the laborious process of receiving papers, sending them out for review, and eventually publishing those that make the cut. “And yet mistakes happen,” Marcus and Oransky noted in their introductory post.

Sometimes these slips are merely technical, requiring nothing more than an erratum notice calling attention to a backwards figure or an incorrect address for reprints. Less often but far more important are the times when the blunders require that an entire article be pulled. . . .

Retractions are born of many mothers. Fraud is the most titillating reason, and mercifully the most rare, but when it happens the results can be devastating.

A falsehood that has already been cited by a hundred other researchers and incorporated into their thinking can never be cleanly excised.

One of the most interesting cases Retraction Watch has been following is that of Bharat Aggarwal, a cancer researcher at M.D. Anderson who has been accused of manipulating images in papers about natural substances that can puportedly fight cancer. The story has also been covered by Todd Ackerman in the Houston Post:

The whistle-blowers allege Aggarwal manipulated his images — adding or subtracting features, cropping, stretching, rotating, flipping horizontally or vertically — to leave the impression the same ones represented different experimental conditions.

Ackerman has also been covering the controversies at Anderson over the new president, who I wrote about in my previous dispatch.

Earlier this week a lawyer for Dr. Aggarwal sent a threatening letter to Retraction Watch demanding that the editors retract their posts about his case, and Marcus and Oransky  have reported on that with the same dispassionate objectivity they bring to their other work.

Last fall in the New York Times, Carl Zimmer wrote about a study concluding that the primary reason for a growing number of retractions is not simply error but misconduct, which includes scientific fraud.

Bad as that sounds, this is hardly ever like fraud in the financial world. An exception might occur when an experiment involves, for example, a potentially lucrative medicine. Earlier this year an investigation by the University of Connecticut found that a researcher had faked data from experiments with resveratrol, a substance found in red wine that has been touted as a possible means of extending life. It was reported at the time that he was involved with a company that sold resveratrol supplements.

We don’t yet know where on the spectrum the Aggarwal case will lie. But most often, as science writer Maggie Koerth-Baker has pointed out, the reasons for fudging data are subtle:

It’s about having spent years on a project and really, really, really not wanting to believe that time was wasted. . . . It’s about convincing yourself that you can cheat a little, just this one time, because your particular circumstances are just.

You know in your heart that your hypothesis is right. You rush to stake your claim, even if the data doesn’t quite cooperate.

Drawing by Alison Kent from The Ten Most Beautiful Experiments.

In The Ten Most Beautiful Experiments, I wrote about allegations that Robert Millikan cherry-picked his data when he became the first to measure the charge of the electron. Before Millikan it was unclear whether electricity came in a continuous flow like water or was parceled out in precise units, like pocket change. It is a difficult experiment, and I describe how I tried it at home with an old Millikan apparatus from eBay and a 10,000-volt power supply.

The idea is to use a perfume atomizer to spray a cloud of oil droplets into a gap between two brass plates and then apply a high voltage, manipulating the dial until a droplet is suspended in mid air. Then you let go, timing its fall with a stopwatch. After you have followed a dozen or so, you plug the numbers into some equations and calculate the fundamental unit of charge. It’s scary work and I failed miserably. If science had depended on me, electrons would come in all shapes and sizes. Or there would be no electrons.

These things sound so easy in the physics books. You don’t hear about the brass plates shorting out and sparking because a metal clip slipped into the wrong position. . . . I’d confuse one drop with another or with a floater in my eye. . . . Sometimes a drop would be so heavy that it sank like a stone, or carry so much charge that when I turned on the voltage it rocketed out of sight. I tried and failed too many times before I realized: for me to master so delicate an experiment would be like learning to play the violin or at least make good cabinetry.

Maestro Millikan, I called him.

Here are some observations from his notebooks:

Very low something wrong . . . not sure of distance . . . Possibly a double drop . . . Beauty Publish . . . Good one for very small one . . . Exactly Right . . . Something the matter . . . Will not work out . . . Publish this Beautiful one. . . . Perfect Publish . . . Best one yet. . . .

Years after Millikan’s death, entries like these led to suspicions that he had cooked the books. I found myself siding with his defenders.

This is not an accusation that rings true to someone who has struggled with the oil-drop experiment. Millikan, I suspect, had simply developed a feeling for the mechanism, a sixth sense for when something had gone wrong: a slip of the thumb on the stop watch, a sudden fluctuation in temperature or plate voltage, a dust particle masquerading as an oil drop. He knew when he had a bad run.

More interesting than the unfounded allegations is the question of how you keep from confusing your instincts with your suppositions, unconsciously nudging the apparatus, like a Ouija board, to come up with the hoped-for reply. It’s something every experimenter must struggle with. The most temperamental piece of laboratory equipment will always be the human brain.

The charge, Millikan concluded, was 1.5924 x 10^-19 coulombs. (One coulomb is about what flows each second through a 100-watt bulb.) A century later the accepted value is 1.6022 x 10^-19.

Note: The second part of this post was adapted from one I wrote last year in my blog The Cancer Chronicles.

Ronald A. DePinho. courtesy University of Texas M.D. Anderson Cancer Center

At the annual meeting of the American Association for Cancer Research, which begins tomorrow in Washington D.C., what you notice right away is how every PowerPoint presentation starts with an obligatory conflict-of-interest disclosure slide. Many university researchers, including Nobel prizewinners, consult for pharmaceutical corporations and some even have their own startups. If they can develop a new targeted cancer treatment that staves off death a few months longer, their company might be snapped up by Genentech. The financial stakes are as high as anything happening in Silicon Valley.

At an AACR meeting I sat through a couple of years ago, the disclosure requirement often met with resentment, and in The Cancer Chronicles (which will go to press this summer) I describe how some of the speakers expressed their displeasure. A few proudly declared, to a round of applause, that they had no conflicts. They were scientists not businessmen. Others recited their disclosures so quickly that you could barely catch a word. I was reminded of television car commercials where the announcer, in a chipmunk voice, speeds through the warranty disclaimers.

Some took a loftier approach. In the opening plenary session, a prominent researcher who was then at Dana-Farber simply said that she had lost her slide and then proceeded with a fascinating presentation on sequencing the cancer genome. Her name was Lynda Chin, and I had all but forgotten the incident until a controversy arose last year over an $18 million grant. By this time her husband and business partner, Ronald DePinho, had become president of the M.D. Anderson Cancer Treatment Center, and he had come under suspicion after the speedy approval of the grant to a group led by Dr. Chin. The money was awarded by the Cancer Prevention and Research Institute of Texas, whose chief scientific officer resigned in protest. Since then a number of other prominent scientists have followed him out the door complaining that the integrity of the grant process has been undermined by favoritism, politics, and commercialization. In my previous post, I wrote about an internal survey, leaked to The Cancer Letter, about morale problems at Anderson.

When the issue over the grant first arose, husband and wife defended themselves in an interview with Nature. A day later Dr. DePinho was at the center of another controversy following reports that he had enthusiastically described the couple’s company, Aveo Oncology, on a CNBC stock market show called “Closing Bell with Maria Bartiromo.” When confronted, Dr. DePinho apologized: “I am a public official in a position of trust, and I should never comment on any of my personal holdings or give investment advice . . . It was a mistake for me to do so on the CNBC interview.” Aveo has an impressive board of scientific advisors, which includes some of the field’s most prominent researchers: Lewis Cantley of Beth Israel Deaconess Medical Center, Douglas Hanahan of the University of California San Francisco, Tyler Jacks of the Koch Institute at M.I.T., and Charles Sawyers of the Memorial Sloan Kettering Cancer Center. Dr. Jacks is a former president of AACR and Dr. Sawyers will assume that position at this week’s meeting.

In recent months Aveo’s stock has not done so well. Trading before the CNBC show at about $11 a share, it has dropped since then to $7.25. (It has traded in the past for as high as $20.) According to The Cancer Letter, Dr. DePinho and his family trust hold nearly 600,000 shares, which still comes to more than $4 million.

When my wife (now former wife) was diagnosed years ago with a Stage 4 metastatic cancer, we made the customary pilgrimage to M.D. Anderson. It is an impressive place with some of the best doctors and scientists in the world. Many are tireless in their dedication to seek better treatments. What hadn’t occurred to us, however, was just how much money a few of them stand to make.

(This post was adapted and updated from one I wrote for my old blog, The Cancer Chronicles.)

Related Posts: The Trouble at M.D. Anderson

On Dwarves, James Watson, and the Oddities of Cancer