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In cancer science, many "discoveries" don't hold up

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By Sharon BegleyPosted 2012/03/28 at 1:05 pm EDT

NEW YORK, Mar. 28, 2012 (Reuters) — A former researcher at Amgen Inc has found that many basic studies on cancer -- a high proportion of them from university labs -- are unreliable, with grim consequences for producing new medicines in the future.

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During a decade as head of global cancer research at Amgen, C. Glenn Begley identified 53 "landmark" publications -- papers in top journals, from reputable labs -- for his team to reproduce. Begley sought to double-check the findings before trying to build on them for drug development.
Result: 47 of the 53 could not be replicated. He described his findings in a commentary piece published on Wednesday in the journal Nature.
"It was shocking," said Begley, now senior vice president of privately held biotechnology company TetraLogic, which develops cancer drugs. "These are the studies the pharmaceutical industry relies on to identify new targets for drug development. But if you're going to place a $1 million or $2 million or $5 million bet on an observation, you need to be sure it's true. As we tried to reproduce these papers we became convinced you can't take anything at face value."
The failure to win "the war on cancer" has been blamed on many factors, from the use of mouse models that are irrelevant to human cancers to risk-averse funding agencies. But recently a new culprit has emerged: too many basic scientific discoveries, done in animals or cells growing in lab dishes and meant to show the way to a new drug, are wrong.
Begley's experience echoes a report from scientists at Bayer AG last year. Neither group of researchers alleges fraud, nor would they identify the research they had tried to replicate.
But they and others fear the phenomenon is the product of a skewed system of incentives that has academics cutting corners to further their careers.
George Robertson of Dalhousie University in Nova Scotia previously worked at Merck on neurodegenerative diseases such as Parkinson's. While at Merck, he also found many academic studies that did not hold up.
"It drives people in industry crazy. Why are we seeing a collapse of the pharma and biotech industries? One possibility is that academia is not providing accurate findings," he said.
BELIEVE IT OR NOT
Over the last two decades, the most promising route to new cancer drugs has been one pioneered by the discoverers of Gleevec, the Novartis drug that targets a form of leukemia, and Herceptin, Genentech's breast-cancer drug. In each case, scientists discovered a genetic change that turned a normal cell into a malignant one. Those findings allowed them to develop a molecule that blocks the cancer-producing process.
This approach led to an explosion of claims of other potential "druggable" targets. Amgen tried to replicate the new papers before launching its own drug-discovery projects.
Scientists at Bayer did not have much more success. In a 2011 paper titled, "Believe it or not," they analyzed in-house projects that built on "exciting published data" from basic science studies. "Often, key data could not be reproduced," wrote Khusru Asadullah, vice president and head of target discovery at Bayer HealthCare in Berlin, and colleagues.
Of 47 cancer projects at Bayer during 2011, less than one-quarter could reproduce previously reported findings, despite the efforts of three or four scientists working full time for up to a year. Bayer dropped the projects.
Bayer and Amgen found that the prestige of a journal was no guarantee a paper would be solid. "The scientific community assumes that the claims in a preclinical study can be taken at face value," Begley and Lee Ellis of MD Anderson Cancer Center wrote in Nature. It assumes, too, that "the main message of the paper can be relied on ... Unfortunately, this is not always the case."
When the Amgen replication team of about 100 scientists could not confirm reported results, they contacted the authors. Those who cooperated discussed what might account for the inability of Amgen to confirm the results. Some let Amgen borrow antibodies and other materials used in the original study or even repeat experiments under the original authors' direction.
Some authors required the Amgen scientists sign a confidentiality agreement barring them from disclosing data at odds with the original findings. "The world will never know" which 47 studies -- many of them highly cited -- are apparently wrong, Begley said.
The most common response by the challenged scientists was: "you didn't do it right." Indeed, cancer biology is fiendishly complex, noted Phil Sharp, a cancer biologist and Nobel laureate at the Massachusetts Institute of Technology.
Even in the most rigorous studies, the results might be reproducible only in very specific conditions, Sharp explained: "A cancer cell might respond one way in one set of conditions and another way in different conditions. I think a lot of the variability can come from that."
THE BEST STORY
Other scientists worry that something less innocuous explains the lack of reproducibility.
Part way through his project to reproduce promising studies, Begley met for breakfast at a cancer conference with the lead scientist of one of the problematic studies.
"We went through the paper line by line, figure by figure," said Begley. "I explained that we re-did their experiment 50 times and never got their result. He said they'd done it six times and got this result once, but put it in the paper because it made the best story. It's very disillusioning."
Such selective publication is just one reason the scientific literature is peppered with incorrect results.
For one thing, basic science studies are rarely "blinded" the way clinical trials are. That is, researchers know which cell line or mouse got a treatment or had cancer. That can be a problem when data are subject to interpretation, as a researcher who is intellectually invested in a theory is more likely to interpret ambiguous evidence in its favor.
The problem goes beyond cancer.
On Tuesday, a committee of the National Academy of Sciences heard testimony that the number of scientific papers that had to be retracted increased more than tenfold over the last decade; the number of journal articles published rose only 44 percent.
Ferric Fang of the University of Washington, speaking to the panel, said he blamed a hypercompetitive academic environment that fosters poor science and even fraud, as too many researchers compete for diminishing funding.
"The surest ticket to getting a grant or job is getting published in a high-profile journal," said Fang. "This is an unhealthy belief that can lead a scientist to engage in sensationalism and sometimes even dishonest behavior."
The academic reward system discourages efforts to ensure a finding was not a fluke. Nor is there an incentive to verify someone else's discovery. As recently as the late 1990s, most potential cancer-drug targets were backed by 100 to 200 publications. Now each may have fewer than half a dozen.
"If you can write it up and get it published you're not even thinking of reproducibility," said Ken Kaitin, director of the Tufts Center for the Study of Drug Development. "You make an observation and move on. There is no incentive to find out it was wrong."
(Note: Amgen researcher C. Glenn Begley is not related to the author of this story, Sharon Begley)
(Reporting By Sharon Begley; Editing by Michele Gershberg and Maureen Bavdek)

More reason to shudder:

Declaring War on Newborns

The disgrace of medical ethics.

Weekly Standard Mar 19, 2012, Vol. 17, No. 26 • By ANDREW FERGUSON

On the list of the world’s most unnecessary occupations—aromatherapist, golf pro, journalism professor, vice president of the United States​—​that of medical ethicist ranks very high. They are happily employed by pharmaceutical companies, hospitals, and other outposts of the vast medical-industrial combine, where their job is to advise the boss to go ahead and do what he was going to do anyway (“Put it on the market!” “Pull the plug on the geezer!”). They also attend conferences where they take turns sitting on panels talking with one another and then sitting in the audience watching panels of other medical ethicists talking with one another. Their professional specialty is the “thought experiment,” which is the best kind of experiment because you don’t have to buy test tubes or leave the office. And sometimes they get jobs at universities, teaching other people to become ethicists. It is a cozy, happy world they live in. 

But it was painfully roiled last month, when a pair of medical ethicists took to their profession’s bible, the Journal of Medical Ethics, and published an essay with a misleadingly inconclusive title: “After-birth Abortion: Why should the baby live?” It was a misleading title because the authors believe the answer to the question is: “Beats me.” 

Right at the top, the ethicists summarized the point of their article. “What we call ‘after-birth abortion’ (killing a newborn) should be permissible in all the cases where abortion is, including cases where the newborn is not disabled.”  The argument made by the authors​—​Alberto Giubilini and Francesca Minerva, both of them affliliated with prestigious universities in Australia and ethicists of pristine reputation​—​runs as follows. Let’s suppose a woman gets pregnant. She decides to go ahead and have the baby on the assumption that her personal circumstances, and her views on such things as baby-raising, will remain the same through the day she gives birth and beyond.

Then she gives birth. Perhaps the baby is disabled or suffers a disease. Perhaps her boyfriend or (if she’s old-fashioned) her husband abandons her, leaving her in financial peril. Or perhaps she’s decided that she’s just not the mothering kind, for, as the authors write, “having a child can itself be an unbearable burden for the psychological health of the woman or for her already existing children, regardless of the condition of the fetus.”

The authors point out that each of these conditions​—​the baby is sick or suffering, the baby will be a financial hardship, the baby will be personally troublesome​​—​​is now “largely accepted” as a good reason for a mother to abort her baby before he’s born. So why not after?

“When circumstances occur after birth such that they would have justified abortion, what we call after-birth abortionshould be permissible.” (Their italics.) Western societies approve abortion because they have reached a consensus that a fetus is not a person; they should acknowledge that by the same definition a newborn isn’t a person either. Neither fetus nor baby has developed a sufficient sense of his own life to know what it would be like to be deprived of it. The kid will never know the difference, in other words. A newborn baby is just a fetus who’s hung around a bit too long. 

As the authors acknowledge, this makes an “after-birth abortion” a tricky business. You have to get to the infant before he develops “those properties that justify the attribution of a right to life to an individual.” It’s a race against time.

The article doesn’t go on for more than 1,500 words, but for non-ethicists it has a high surprise-per-word ratio. The information that newborn babies aren’t people is just the beginning. A reader learns that “many non-human animals … are persons” and therefore enjoy a “right to life.” (Such ruminative ruminants, unlike babies, are self-aware enough to know that getting killed will entail a “loss of value.”) The authors don’t tell us which species these “non-human persons” belong to, but it’s safe to say that you don’t want to take a medical ethicist to dinner at Outback.

But what about adoption, you ask. The authors ask that question too, noting that some people​—​you and me, for example​—​might think that adoption could buy enough time for the unwanted newborn to technically become a person and “possibly increase the happiness of the people involved.” But this is not a viable option, if you’ll forgive the expression. A mother who kills her newborn baby, the authors report, is forced to “accept the irreversibility of the loss.” By contrast, a mother who gives her baby up for adoption “might suffer psychological distress.” And for a very simple reason: These mothers “often dream that their child will return to them. This makes it difficult to accept the reality of the loss because they can never be quite sure whether or not it is irreversible.” It’s simpler for all concerned just to make sure the loss can’t be reversed. It’ll spare Mom a lot of heartbreak.

Now, it’s at this point in the Journal of Medical Ethics that many readers will begin to suspect, as I did, that their legs are being not very subtly pulled. The inversion that the argument entails is Swiftian​—​a twenty-first-century Modest Proposal without the cannibalism (for now). Jonathan Swift’s original Modest Proposal called for killing Irish children to prevent them “from being a burden to their parents.” It was death by compassion, the killing of innocents based on a surfeit of fellow-feeling. The authors agree that compassion itself demands the death of newborns. Unlike Swift, though, they aren’t kidding.

They get you coming and going, these guys. They assume​—​and they won’t get much argument from their peers in the profession​—​that “mentally impaired” infants are eligible for elimination because they will never develop the properties necessary to be fully human. Then they discuss Treacher-Collins syndrome, which causes facial deformities and respiratory ailments but no mental impairment. Kids with TCS are “fully aware of their condition, of being different from other people and of all the problems their pathology entails,” and are therefore, to spare them a life of such unpleasant awareness, eligible for elimination too​—​because they are not mentally impaired. The threshold to this “right to life” just gets higher and higher, the more you think about it. 

And of course it is their business to think about it. It’s what medical ethicists get paid to do: cogitate, cogitate, cogitate. As “After-birth Abortion” spread around the world and gained wide publicity​—​that damned Internet ​—​non-ethicists greeted it with derision or shock or worse. The authors and the editor of the Journal of Medical Ethics were themselves shocked at the response. As their inboxes flooded with hate mail, the authors composed an apology of sorts that non-ethicists will find more revealing even than the original paper.

“We are really sorry that many people, who do not share the background of the intended audience for this article, felt offended, outraged, or even threatened,” they wrote. “The article was supposed to be read by other fellow bioethicists who were already familiar with this topic and our arguments.” It was a thought experiment. After all, among medical ethicists “this debate”​—​about when it’s proper to kill babies​—​“has been going on for 40 years.”

So that’s what they’ve been talking about in all those panel discussions! The authors thought they were merely taking the next step in a train of logic that was set in motion, and has been widely accepted, since their profession was invented in the 1960s. And of course they were. The outrage directed at their article came from laymen​—​people unsophisticated in contemporary ethics. Medical ethicists in general expressed few objections, only a minor annoyance that the authors had let the cat out of the bag. A few days after it was posted the article was removed from the publicly accessible area of the Journal’s website, sending it back to that happy, cozy world.

You’d have to be very, very well trained in ethics to see the authors’ argument as a morally acceptable extension of their premises, but you can’t deny the logic of it. The rest of us will see in the argument an extension of its premises into self-evident absurdity. Pro-lifers should take note. For years, in public argument, pro-choicers have mocked them for not following their belief in a fetus’s humanity to its logical end. Shouldn’t you execute doctors who perform abortions? Why don’t you have funerals for miscarriages? 

As one pro-choice wag, writing about the Republicans’ pro-life platform, put it in the Washington Post a few years ago: “The official position of the Republican Party is that women who have abortions should be executed.”

And now we know the pro-choice position is that children born with a facial deformity should be executed too, as long as you get to them quick enough. Unwittingly the insouciant authors of “After-birth Abortion” have shown where pro-choicers wind up if they follow their belief about fetuses to its logical end. They’ve performed a public service. Could it be that medical ethicists really are more useful than aromatherapists?

Read and shudder:

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• LIFE & CULTURE
• Updated March 12, 2012, 10:16 a.m. ET

What You Lose When You Sign That Donor Card

Giving away your organs sounds noble, but have doctors blurred the line between life and death?

By DICK TERESI

Photo Illustration Joel Holland, Gallery Stock (photo)

Doctors don't have to tell you or your relatives what they will do to your body during an organ harvest operation because you'll be dead, with no legal rights.

The last time I renewed my driver's license, the clerk at the DMV asked if she should check me off as an organ donor. I said no. She looked at me and asked again. I said, "No. Just check the box that says, 'I am a heartless, selfish bastard.'"

Becoming an organ donor seems like a win-win situation. Some 3.3 people on the transplant waiting list will have their lives extended by your gift (3.3 is the average yield of solid organs per donor). You're a hero, and at no real cost, apparently.

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But what are you giving up when you check the donor box on your license? Your organs, of course—but much more. You're also giving up your right to informed consent. Doctors don't have to tell you or your relatives what they will do to your body during an organ harvest operation because you'll be dead, with no legal rights.

The most likely donors are victims of head trauma (from, say, a car or motorcycle accident), spontaneous bleeding in the head, or an aneurysm—patients who can be ruled dead based on brain-death criteria. But brain deaths are estimated to be just around 1% of the total. Everyone else dies from failure of the heart, circulation and breathing, which leads the organs to deteriorate quickly.

The current criteria on brain death were set by a Harvard Medical School committee in 1968, at a time when organ transplantation was making great strides. In 1981, the Uniform Determination of Death Act made brain death a legal form of death in all 50 states.

The exam for brain death is simple. A doctor splashes ice water in your ears (to look for shivering in the eyes), pokes your eyes with a cotton swab and checks for any gag reflex, among other rudimentary tests. It takes less time than a standard eye exam. Finally, in what's called the apnea test, the ventilator is disconnected to see if you can breathe unassisted. If not, you are brain dead. (Some or all of the above tests are repeated hours later for confirmation.)

Here's the weird part. If you fail the apnea test, your respirator is reconnected. You will begin to breathe again, your heart pumping blood, keeping the organs fresh. Doctors like to say that, at this point, the "person" has departed the body. You will now be called a BHC, or beating-heart cadaver.

Still, you will have more in common biologically with a living person than with a person whose heart has stopped. Your vital organs will function, you'll maintain your body temperature, and your wounds will continue to heal. You can still get bedsores, have heart attacks and get fever from infections.

"I like my dead people cold, stiff, gray and not breathing," says Dr. Michael A. DeVita of the University of Pittsburgh Medical Center. "The brain dead are warm, pink and breathing."

You might also be emitting brainwaves. Most people are surprised to learn that many people who are declared brain dead are never actually tested for higher-brain activity. The 1968 Harvard committee recommended that doctors use electroencephalography (EEG) to make sure the patient has flat brain waves. Today's tests concentrate on the stalk-like brain stem, in charge of basics such as breathing, sleeping and waking. The EEG would alert doctors if the cortex, the thinking part of your brain, is still active.

But various researchers decided that this test was unnecessary, so it was eliminated from the mandatory criteria in 1971. They reasoned that, if the brain stem is dead, the higher centers of the brain are also probably dead.

But in at least two studies before the 1981 Uniform Determination of Death Act, some "brain-dead" patients were found to be emitting brain waves. One, from the National Institute of Neurological Disorders and Stroke in the 1970s, found that out of 503 patients who met the usual criteria of brain death, 17 showed activity in an EEG.

Even some of the sharpest critics of the brain-death criteria argue that there is no possibility that donors will be in pain during the harvesting of their organs. One, Robert Truog, professor of medical ethics, anesthesia and pediatrics at Harvard Medical School, compared the topic of pain in an organ donor to an argument over "whether it is OK to kick a rock."

But BHCs—who don't receive anesthetics during an organ harvest operation—react to the scalpel like inadequately anesthetized live patients, exhibiting high blood pressure and sometimes soaring heart rates. Doctors say these are simply reflexes.

What if there is sound evidence that you are alive after being declared brain dead? In a 1999 article in the peer-reviewed journal Anesthesiology, Gail A. Van Norman, a professor of anesthesiology at the University of Washington, reported a case in which a 30-year-old patient with severe head trauma began breathing spontaneously after being declared brain dead. The physicians said that, because there was no chance of recovery, he could still be considered dead. The harvest proceeded over the objections of the anesthesiologist, who saw the donor move, and then react to the scalpel with hypertension.

Organ transplantation—from procurement of organs to transplant to the first year of postoperative care—is a $20 billion per year business. Average recipients are charged $750,000 for a transplant, and at an average 3.3 organs, that is more than $2 million per body. Neither donors nor their families can be paid for organs.

It is possible that not being a donor on your license can give you more bargaining power. If you leave instructions with your next of kin, they can perhaps negotiate a better deal. Instead of just the usual icewater-in-the-ears, why not ask for a blood-flow study to make sure your cortex is truly out of commission?

And how about some anesthetic? Although he doesn't believe the brain dead feel pain, Dr. Truog has used two light anesthetics, high-dose fentanyl and sufentanil, which won't harm organs, to quell high blood pressure or heart rate during harvesting operations. "If it were my family," he said, "I'd request them."

—Mr. Teresi is the author of "The Undead: Organ Harvesting, the Ice-Water Test, Beating-Heart Cadavers—How Medicine Is Blurring the Line Between Life and Death."

A version of this article appeared Mar. 10, 2012, on page C3 in some U.S. editions of The Wall Street Journal, with the headline: What You Lose When You Sign That Donor Card.

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