The Cancer Chronicles

Recently in the New York Times, Carl Zimmer wrote about a new study concluding that misconduct is the primary reason for the growing number of retractions in scientific journals. That included plagiarism and other bad behavior, but fraud was suspected about 43 percent of the time.

This is hardly ever like fraud in the financial world. An exception might occur when the experiment involves, for example, a potentially lucrative cancer drug. In a piece today for Reuters, Sharon Begley describes how the results of a clinical trial may have been manipulated so that a treatment for prostate cancer sounded better than it really was.  At best Provenge adds only a few months to life, but even that might have been an illusion. The placebo may have hastened the deaths of people in the control group — the ones not getting the drug.

More often, as Maggie Koerth-Baker points 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 didn’t quite cooperate.

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. That is more important than it might sound. 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.

drawing by Alison Kent from The Ten Most Beautiful Experiments

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.

In chapter 9 of The Cancer Chronicles (or whatever it is called when it appears next spring), I write about how very complex cell biology has become since the revelations of Watson and Crick. I first touched on this (and how it affects our understanding of cancer) in a long piece last year for the Times, which was tied to the annual meeting of the American Association for Cancer Research. “Most DNA,” I wrote, “was long considered junk — a netherworld of detritus that had no important role in cancer or anything else. . . . These days ‘junk’ DNA is referred to more respectfully as ‘noncoding’ DNA, and researchers are finding clues that ‘pseudogenes’ lurking within this dark region may play a role in cancer.” Over the years, while I was attending to other things, Francis Crick’s “standard dogma” (DNA –> RNA –> protein) was becoming laden with complications. Now there were not just messenger RNAs and transfer RNAs — the stuff we learned about in basic biology — but also micro RNAs. And that was just the beginning:

Fueled by the free espresso offered by pharmaceutical companies hawking their wares, scientists at the Orlando meeting moved from session to session and browsed corridors of posters, looking for what might have recently been discovered about other exotic players: lincRNA (for large intervening noncoding), siRNA (small interfering), snoRNA (small nucleolar) and piRNA (Piwi-interacting (short for “P-element induced wimpy testis” (a peculiar term that threatens to pull this sentence into a regress of nested parenthetical explanations))).

The instructions for producing these newly recognized agents are coded in what was once regarded as junk DNA. Some of them appear to be important cogs in the cellular machinery, others may just be flotsam and jetsam — molecular noise.

Long before these discoveries it was recognized that other regions of DNA that don’t directly code for proteins serve important functions — switching genes on and off, providing the layers of complexity through which the genetic program gives rise to life. The importance of these molecular switches began to emerge in the early 1960s with the celebrated work of Monod and Jacob on the lac operon. But for all of that, most of the genome is still considered to be a molecular appendix — damaged genes that no longer serve a purpose or snippets of code smuggled in by retroviruses. Most of the junk really is junk. If every bit of an organisms’s DNA served an important use then why would the genome of an onion be five times bigger than that of a person?

I was taken aback last week when the big news broke about the ENCODE project (“Encyclopedia of DNA Elements”). At least 80 percent of the genome, it was reported, was performing an important function — and the figure might soon approach 100 percent. Junk DNA was a myth. Here is a typical passage from a mainstream news report (there are dozens to choose from):

What has been called junk DNA is actually teeming with an intricate web of molecular switches that play crucial roles in regulating genes. . . . These switches rev genes up. Calm them down. They orchestrate how the whole complex system works. Scientists have already started to figure out which switches control which genes. And that’s uncovered even more surprises. Genes can get instructions from up to dozens of switches. And some of the switches are nowhere near the genes they control.

But none of that was new. What was I missing? As I prepared to embark on serious revisions to my manuscript, I began searching the web, quickly encountering the backlash from scientists who considered the claims to be hype. It wasn’t so much the journalists who were to blame (though they should have been more skeptical) but the ENCODE scientists. John Horgan and I discussed this a few days ago on Science Saturday. But the best explanation of the controversy comes from Jon Timmer, the science editor at arstechnica. In presenting what was otherwise some very impressive research, the scientists chose to loosen the definition of “functional” almost to the point of being meaningless.

In the aftermath of the Jonah Lehrer scandal, there have been calls for science stories to be vetted in advance by scientists. The revelations about ENCODE suggest that this would make as much sense as having politicians review political coverage before publication.

Before a full year has passed, I am finally filing a progress report. I have completed the manuscript for The Cancer Chronicles. At this point I am revising and refining — sending the manuscript to friends, colleagues, and scientists. I’ve described this before as feeling like there are two readers perched on my shoulders — the layman who, like me, longs for clarity and simplification, who is moved by the right metaphor — and the scientist, who is pushing and pushing for more precision. Steering a course between these ideals is the hardest part of this kind of writing.

I had intended to post here more frequently while working on the book. But I never resolved the dilemma of how much to reveal of the surprising things I have been learning about cancer and how much to save for the book. What makes sense to me now is to hold off on writing much about the content until publication date approaches next spring or summer.

Meanwhile I’ll post more often about the process of writing the book — some of the problems I’m struggling with in this final stage. How much, for example, should I include about the so-called cancer stem cell hypothesis? As cancer cells evolve and compete inside a tumor, any one of them is capable of acquiring the characteristics — what Hanahan and Weinberg called “the hallmarks” — of cancer: the ability to break through an intricate web of checks and balances and grow indefinitely. That is the dominant view. Cancer stem cell theory holds, to the contrary, that only a few of the tumor cells — the cancer stem cells — have this proliferative power. That they are the ones that should be aimed at with chemo.

A prominent scientist who recently read a chapter where I mention cancer stem cells cautions that I should not give the idea too much prominence — that it is rapidly losing ground. Others however continue to support the theory.

As I ponder this (and do more research), I’ll mention one of my other projects. A story — three years in the making! — on the science of lightning appears in this month’s National Geographic Magazine: http://ngm.nationalgeographic.com/2012/08/chasing-lightning/johnson-text.

Readers of my other online endeavor, The Santa Fe Review, know that one of my frequent interests has been a psychiatric condition in which otherwise intelligent people become fixated on the idea that cell phones cause brain tumors. I also wrote about the phenomenon last year for Slate (please see On Top of Microwave Mountain) and described my experiments with a microwave meter to John Horgan on Bloggingheads.tv.

A disproportionate number of electro worriers seem to live in Santa Fe where they write letters to the editor of the New Mexican speaking with mock authority of hundreds — even thousands — of studies supposedly linking cell phones with cancer and other neurological disorders. A couple of them proudly point to their credentials as holistic medical practitioners, which gives them no more expertise on the subject than on Egyptian archaeology or the effect of gamma rays on Man in the Moon marigolds. In the Electromania Archives you can find pointers to a large body of genuine, peer-reviewed research, concurring that it is extremely unlikely that the feeble emissions from cellphones are carcinogenic. These are dismissed by the true believers as part of a secret coverup.

Measuring microwaves on Sandia Crest in New Mexico

In last Sunday’s New York Times Magazine, Siddhartha Mukherjee, an oncologist and author of an excellent new book about cancer, The Emperor of All Maladies, has written the best overview I have read on the issue. Or rather nonissue. Among thousands of presentations at the international cancer research meeting I described in my previous post, there was precisely one that touched on the subject, a poster entitled Low-dose radiation exposure and the risk of developing acoustic neuroma. For cell phones it was zero.

As someone who considers cell phones a social abomination (private, nonlocal conversations should take place inside booths) and whose annual cell phone bill is way less than $100, I perversely wish that the devices would be found dangereous. For that to happen new laws of physics would have to be discovered or a new understanding of the fundamentals of cancer. Either way it would be a scientific breakthrough of the first magnitude and something fascinating to write about. Cold fusion seemed like that for awhile.

George Johnson
talaya.net

I had the good feeling this week of getting over a hump: I have four chapters solidly drafted and the beginning of a fifth. That’s approaching about 20,000 words, perhaps a quarter of a book. Before I surrender the manuscript I will have gone through each of those chapters maybe a hundred more times, tweaking sentences, double and triple-checking facts, tearing apart paragraphs and pages that suddenly don’t seem so solid after all.  A chapter that has gotten too big might split mitotically into two chapters, which each in itself will start to grow. In a kind of violation of the arrow of time, seeds will be planted retrospectively in early chapters — foreshadowing ideas already written into later parts of the book. Sometimes I think of them as chords partially plucked, later to be resolved. A little grandiose maybe for what is at best prestidigitation.

I tried to describe the process in the prologue to an earlier book, in which I decided to let some of the seams show:

Like any kind of writing, science writing involves spinning an illusion. All the hard intellectual work — digging through the piles of papers and reference books, reading the same paragraph a dozen times before firing off yet another emailed plea for clarification — all this takes place behind a curtain, carefully hidden from view. What ultimately emerges, Oz-like, is a narrator who speaks with the resounding, omniscient voice of authority, a being seemingly born with encyclopedic knowledge instantly retrieved and dispensed. And that, of course, is a fiction. A friend who was reading one of my books once asked, “Do you actually know all those things you put in there, or do you have to look them up?” She was relieved to hear that what seemed a smooth flow of erudition was haltingly cobbled together after multiple trips to the library.  “But isn’t that cheating?” she said. I think she was kidding, but sometimes I feel that way. I leaf through the index of a book I’ve written and marvel, “What in the world did I have to say about Plotinus or Aristotle?”

This time I have tried not to cheat. In the pages that follow, the surface has been left somewhat translucent offering dim glimpses of the man behind the curtain fumbling at the controls — straining to grasp an idea with an imprecise metaphor, only to discard it for another with a tighter fit, closing in on an airy notion from several directions, triangulating on approximate truth.

I’ve also tried to resist the temptation to say too much. Fascinating as they are, many of the more tangential details will remain wrapped inside their boxes. We are operating here on a need to know basis. (Those who want to look deeper can refer to my annotations at the end of the book, called “The Fine Print,” a section that can also be taken as a gloss on the nature and limitations of science writing.)

More than ever, I want the reader to feel that we are both on the same side — outsiders seeking a foothold on the slippery granite face of a new idea.

My guiding light has been a statement by the writer Alan Lightman about what makes a good essay. I think it applies as well to a good nonfiction book:

“For me, the ideal essay is not an assignment, to be dispatched efficiently and intelligently, but an exploration, a questioning, an introspection. I want to see a piece of the essayist. I want to see a mind at work, imagining, spinning, struggling to understand.”

— A Shortcut Through Time

Here is the whole prologue: Inside the Black Box.

George Johnson
talaya.net

You see this figure a lot when you start reading about cancer: About 78% of all malignant disease is diagnosed in people 55 years or older. (American Cancer Society. Cancer Facts & Figures 2010) For that reason alone one would expect to find fewer cases in earlier centuries, a point I made in my recent Times story. By examining skeletons from the days of the Neanderthals through the year zero (when B.C. became A.D.) anthropologists have calculated that the mean lifespan was 30 years with a maximum of about 45. I read that in an interesting new book, How It Ends: From You to the Universe by Chris Impey, a professor of astronomy at the University of Arizona. (The book is not only about human longevity but also the longevity of the universe, a dizzying sweep across subjects. So far I’m up to page 50.)

Life Expectancy at Birth, 1900 to 2050. Department of Commerce, Bureau of the Census.

The same low life expectancy continued through the Renaissance, Dr. Impe writes, except for royalty who could expect to live until 50. (Reading that brought to mind the autopsy of the mummy of Ferrante I of Aragon, the 15th century King of Naples, who died at 63 apparently from metastatic colon cancer.) It has been only in the last two centuries that lifespan has been increasing. By 1900 the rest of us (at least in the developed world) had caught up with Renaissance kings and queens: Children born in 1900 could expect to die at 50. For those born in 2000 life expectancy is 80.

All that was mostly familiar but Dr. Impey surprised me with this observation: almost all of the gain in lifespan came from a reduction in childhood mortality. “In other words it’s a myth,” he wrote, “that our ancestors endured lives that English philosopher Thomas Hobbes had labeled ‘nasty, brutish, and short.'”

Now I’m not sure what to think. If an abundance of infant deaths, through accident or infanticide, dragged down the average life span, then a significant number of people who survived childbirth might have lived well past 50. If so that would cast some doubt on the assertion that old age is the predominant reason there is more cancer today. What we need to know is the median, not the mean. More things I need to sort out.

I have been grappling all week with the issue of longevity as I try to finish a draft of my third chapter, which concentrates on ancient cancer. Archaeologists of the future exhuming a 21st century graveyard will surely find more cancer than in, say, a medieval crypt. But some scholars like Luigi L. Capasso, an Italian anthropologist, have argued that the discrepancy cannot be explained entirely by our living longer. He points to “the very strange fact that an increase in cancer prevalence has also been noted in countries in which life expectancy was minimal in the past century.” (Capasso, L. L. (2005), Antiquity of Cancer. International Journal of Cancer, 113: 2–13). I just read in the CIA World Fact Book that life expectancy at birth ranges from 38.48 (so precise!) in Angola to 89.78 in Monaco.

But isn’t there an easy rebuttal to Dr. Capasso’s argument? These countries would also be the ones with poorer nutrition, higher rates of chronic infection, and rising tobacco use. More people in the third world, mostly children, die from diarrhea than people die from cancer in the developed world. (That is also from the Impe book.) In poor countries now undergoing rapid development there will be increased urbanization, with more chances of spreading human papilloma virus and hepatitis, which are associated with cervical and liver cancers. If medical care in these countries is improving (from abysmal to mediocre) more cancer might be detected and better records kept. Some of the rise would be an illusion. As the country grows more prosperous people will be slowly adopting the lifestyles of the industrialized world, gaining weight (obesity is strongly linked with cancer incidence) and longer lifespans.

Dr. Capasso’s implication is that there is more cancer today because of industrial carcinogens. So many friends I talk to take that for granted. Until recently I would have too. But the deeper I dig, the less evidence there seems to be. It is all so much more complicated.

George Johnson
talaya.net

Medieval skeleton with cancerous lesions

When I began reading about paleo-oncology last summer, I came across an estimate by the Czech anthropologist Eugen Strouhal of how many cases of suspected cancer had been found in ancient European skeletons: 176. The number, from a paper published in 1996 in the International Journal of Paleopathology, didn’t include Egyptian mummies or cases from other continents. And by the time I was writing the Times story referred to in my previous post, I had found about 20 more recent discoveries. Adding all of these reports together, I felt safe in concluding that about 200 cases of ancient and prehistoric cancer have been found by archaeologists.

That doesn’t sound like a lot, and some scholars like Luigi Capasso, an Italian anthropologist, have argued that cancer was extremely rare before the environmental assaults that came with industrialization. Others, like Dr. Strouhal, have suggested that the few cases researchers have stumbled across might be the tip of an iceberg — that there is a core rate of cancer that has remained fairly steady since prehistoric times.

The issue can quickly become political, and I was looking for some perspective. Of all the people who lived and died in millennia past, how many can paleo-oncologists possibly have examined? I was surprised to learn that by 1 A.D. the cumulative population of the earth was already approaching 47 billion and had nearly doubled by 1750. (The estimate, obviously very rough, is from a study by Carl Haub of the Population Reference Bureau.) So much for the notion that more people are alive today than have ever walked the earth. Not even close.

The next number I needed was one that, as far as I can see, had not been published before: the total number of human skeletons that have been dug up by archaeologists and made available for scientific study. Two experts I asked arrived independently at the same approximation: About 100,000. That would make the sample size only about 1/10,000th of 1 percent. For palaeo-oncologists it is even smaller than that: only a portion of those skeletons has been systematically examined for bone cancer. That is not much to hang an argument on, and I am left in the same quandary. Is cancer a natural (though unwanted) biological phenomenon, or a Frankensteinian creation of modern times?

George Johnson
talaya.net