Pennywise and pound-foolish: misidentified cells and competitive pressures in scientific knowledge-building.

The overarching project of science is building reliable knowledge about the world, but the way this knowledge-building happens in our world is in the context of competition. For example, scientists compete with each other to be the first to make a new discovery, and they compete with each other for finite pools of grant money with which to conduct more research and make further discoveries.

I’ve heard the competitive pressures on scientists described as a useful way to motivate scientists to be clever and efficient (and not to knock off early lest some more dedicated lab get to your discovery first). But there are situations where it’s less obvious that fierce competition for scarce resources leads to choices that really align with the goal of building reliable knowledge about the world.

This week, on NPR’s Morning Edition, Richard Harris reported a pair of stories on how researchers who work with cells in culture grapple with the problem of their intended cell line being contaminated and overtaken by a different cell line. Harris tells us:

One of the worst cases involves a breast cancer cell line called MDA-435 (or MDA-MB-435). After the cell line was identified in 1976, breast cancer scientists eagerly adopted it.

When injected in animals, the cells spread the way breast cancer metastasizes in women, “and that’s not a very common feature of most breast cancer cell lines,” says Stephen Ethier, a cancer geneticist at the Medical University of South Carolina. “So as a result of that, people began asking for those cells, and so there are many laboratories all over the world, who have published hundreds of papers using the MDA-435 cell line as a model for breast cancer metastasis.”

In fact, scientists published more than a thousand papers with this cell line over the years. About 15 years ago, scientists using newly developed DNA tests took a close look at these cells. And they were shocked to discover that they weren’t from a breast cancer cell at all. The breast cancer cell line had been crowded out by skin cancer cells.

“We now know with certainty that the MDA-435 cell line is identical to a melanoma cell line,” Ethier says.

And it turns out that contamination traces back for decades. Several scientists published papers about this to alert the field, “but nevertheless, there are people out there who haven’t gotten the memo, apparently,” he says.

Decades worth of work and more than a thousand published research papers were supposed to add up to a lot of knowledge about a particular kind of breast cancer cell, except it wasn’t knowledge about breast cancer cells at all because the cells in the cell line had been misidentified. Probably scientists know something from that work, but it isn’t the knowledge they thought they had before the contamination was detected.

On the basis of the discovery that this much knowledge-building had been compromised by being based on misidentified cells, you might imagine researchers would prioritize precise identification of the cells they use. But, as Harris found, this obvious bit of quality control meets resistance. For one thing, researchers seem unwilling to pay the extra financial costs it would take:

This may all come down to money. Scientists can avoid most of these problems by purchasing cells from a company that routinely tests them. But most scientists would rather walk down the hall and borrow cells from another lab.

“Academics share their cell lines like candy because they don’t want to go back and spend another $300,” said Richard Neve from Genentech. “It is economics. And they don’t want to spend another $100 to [verify] that’s still the same cell line.”

Note here that scientists could still economize by sharing cell lines with their colleagues instead of purchasing them but paying for the tests to nail down the identity of the shared cells. However, many do not.

(Consider, though, how awkward it might be to test cells you’ve gotten from a colleague only to discover that they are not the kind of cells your colleague thought they were. How do you break the news to your colleague that their work — including published papers in scientific journals — is likely to be mistaken and misleading? How likely would this make other colleagues to share their cell lines with you, knowing that you might bring them similarly bad news as a result of their generosity?)

Journals like Nature have tried to encourage scientists to test their cell lines by adding it to an authors’ checklist for researchers submitting papers. Most authors do not check the box indicating they have tested their cells.

One result here is that the knowledge that comes from these studies and gets reported in scientific journals may not be as solid as it seems:

When scientists at [Genentech] find an intriguing result from an academic lab, the first thing they do is try to replicate the result.

Neve said often they can’t, and misidentified cells are a common reason.

This is a problem that is not just of concern to scientists. The rest of us depend on scientists to build reliable knowledge about the world in part because it might matter for what kinds of treatments are developed for diseases that affect us. Moreover, much of this research is paid for with public money — which means the public has an interest in whether the funding is doing what it is supposed to be doing.

However, Harris notes that funding agencies seem unwilling to act decisively to address the issue of research based on misidentified cell lines:

“We are fully convinced that this is a significant enough problem that we have to take steps to address it,” Jon Lorsch, director of the NIH’s National Institute of General Medical Sciences, said during the panel discussion.

One obvious step would be to require scientists who get federal funding to test their cells. Howard Soule, chief science officer at the Prostate Cancer Foundation, said that’s what his charity requires of the scientists it funds.

There’s a commercial lab that will run this test for about $140, so “this is not going to break the bank,” Soule said.

But Lorsch at the NIH argued that it’s not so simple on the scale at which his institute hands out funding. “We really can’t go and police 10,000 grants,” Lorsch said.

“Sure you can,” Soule shot back. “How can you not?”

Lorsch said if they do police this issue, “there are dozens and dozens of other issues” that the NIH should logically police as well. “It becomes a Hydra,” Lorsch said. “You know, you chop off one head and others grow.”

Biomedical research gets more expensive all the time, and the NIH is reluctant to pile on a whole bunch of new rules. It’s a balancing act.

“If we become too draconian we’re going to end up squashing creativity and slowing down research, which is not good for the taxpayers because they aren’t going to get as much for their money,” Lorsch said.

To my eye, Lorsch’s argument against requiring researchers to test their cells focuses on the competitive aspect of scientific research to the exclusion of the knowledge-building aspect.

What does it matter if the taxpayers get more research generated and published if a significant amount of that research output is irreproducible because of misidentified cells? In the absence of tests to properly identify the cells being used, there’s no clear way to tell just by looking at the journal articles which ones are reliable and which ones are not. Post-publication quality control requires researchers to repeat experiments and compare their results to those published, something that will cost significantly more than if the initial researchers tested their cells in the first place.

However, research funding is generally awarded to build new knowledge, not to test existing knowledge claims. Scientists get credit for making new discoveries, not for determining that other scientists’ discoveries can be reproduced.

NIH could make it a condition of funding that researchers working with cell lines get those cell lines tested, and arguably this would be the most cost-efficient way to ensure results that are reliable rather than based on misidentification. I find Lorsch’s claim that there are dozens of other kinds of quality control of this sort NIH could demand, so they cannot demand this, unpersuasive. Even if there are many things to fix, it doesn’t mean you must fix them all at once. Incremental improvements in quality control are surely better than none at all.

His further suggestion that engaging in NIH-mandated quality control will quash scientific creativity strikes me as silly. Scientists are at their most creative when they are working within constraints to solve problems. Indeed, were NIH to require that researchers test their cells, there is no reason to think this additional constraint could not be easily incorporated into researchers’ current competition for NIH funding.

The big question, really, is whether NIH is prioritizing funding a higher volume of research, or higher quality research. Presumably, the public is better served by a smaller number of published studies that make reliable claims about the actual cells researchers are working with than by a large number of published studies making hard-to-verify claims about misidentified cells.

If scientific competition is inescapable, at least let’s make sure that the incentives encourage the careful steps required to build reliable knowledge. If those careful steps are widely seen as an impediment in succeeding in the competition, we derail the goal that the competitive pressures were supposed to enhance.

A Hallowe’en science book recommendation for kids.

Sure, younger kids may think the real point of Hallowe’en in the candy or the costumes. But they’re likely to notice some of the scarier motifs that pop up in the decorations, and this presents as unexpected opportunity for some learning.

A Drop of Blood by Paul Showers, illustrated by Edward Miller.

The text of this book is straight-ahead science for the grade school set, explaining the key components of blood (red blood cells, white blood cells, platelets) and what they do. There are nice diagrams of how the circulatory system gets involved in transporting nutrients as well as oxygen, pictures of a white blood cell eating a germ, and a step-by-step explanation of how a scab forms.

But this unassuming text is illustrated in classic horror movie style.

All the “people” in the drawings are either vampires or … uh, whatever those greenish hunchbacked creatures who become henchmen are. And this illustration choice is brilliant! Kids who might be squicked out by blood in real life cannot resist the scary/funny/cool cartoonish vamps accompanying the text in this book. The drawing of the Count offering Igor a Band-aid for his boo-boo is heart-warming. So is the multigenerational picture that accompanies this text:

Little people do not need much blood. Cathy is one year old. She weighs twenty-four pounds. She has about one and a half pints of blood in her body. That is less than one quart.

Big people need more blood. Russell is eleven years old. He weighs eighty-eight pounds. He has about five and a half pints of blood in his body. That is a little less than three quarts.

Russell is a young vampire, while Cathy is a cute green toddler with purple circles under her eyes.

This is a really engaging book. And, the science looks pretty good.

CD review: Baba Brinkman, “The Rap Guide to Evolution: Revised”

Baba Brinkman, "The Rap Guide to Evolution: Revised"

Baba Brinkman
“The Rap Guide to Evolution: Revised”
Lit Fuse Records, 2011

This is an album that is, in its way, one long argument (in 14 tracks) that the theory of evolution is a useful lens through which to make sense of our world and our lives. In making this argument, Brinkman also plays with standard conventions within the rap genre, pointing to predecessors and influences (not only rappers but also the original Chuck D), calling out enemies, bragging about his rapping prowess, and centering himself as an illustrative example of the processes he’s describing. There is also a healthy dose of swearing (as befits the genre). The ordering of the tracks is clearly thematic, with a substantial stretch near the middle of the album focused on sexual selection. Most of the tracks hold up well enough that you could listen to the album on shuffle, but I recommend listening to the whole thing in order first to get the fullest impact.

The first track, “Natural Selection 2.0,” opens by taking aim at people who can’t or won’t wrap their heads around the explanatory power of Darwin’s theory of evolution. Brinkman specifically targets creationists and other “Darwin-haters” for scorn, but his focus is less on their bad arguments than on their resistance to evolutionary biology’s good ones.

Track 2, “Black-eyed Peas,” borrows a strategy from Origin of Species and connects natural selection with the principles of domestication. Here, Brinkman includes not just cattle and peaches and black-eyed peas, but also artists struggling for survival within the music industry (including Black-Eyed Peas), and the chorus features a Fugees sample that rewards listeners of a certain age for surviving as long as they have.

Track 3, the catchy as Hell “I’m A African 2.0,” flips an Afrocentric anthem into a celebration of the common origins of all humanity. The verses also gesture towards ways that archaeologists, anthropologists, and geneticists are scientists taking different angles, and producing different evidence, on the same natural processes.

In track 4, “Creationist Cousins 2.0,” Brinkman offers a description of dinner-table debates about evolutionary theory that is really a song about the strategy of engagement (with hypotheses, empirical data, and objections) central to scientific knowledge-building. It’s also a song that reflects Brinkman’s faith that rational argumentation from evidence we can agree upon should ultimately lead us to shared conclusions. The reality of dialogic exchanges (and of scientific knowledge-building) is more complicated, but it’s hard to fully do justice to any real practice you’re trying to describe in a four minute song.

Track 5, “Survival of the Fittest 2.0,” starts with a shout-out to a bunch of evolutionary psychologists and then takes up the question of how to understand violent behavior and what might be construed as “poor life choices” in the environment of American inner cities. Brinkman pushes the gangsta rap genre’s description of harsh living conditions further by examining whether thug life might embody rational reproductive and survival strategies, all the while pointing us toward the possibility of addressing the economic and social inequalities in the environment that make these behaviors adaptive.

Track 6, “Group Selection 2.0,” simultaneously calls out Social Darwinism as unscientific (“Just because something exists in a state of nature/Doesn’t give it a moral basis, that’s a false correlation”) and explores the value of altruistic behavior. Here, Brinkman explicitly voices openness to group selection as a real evolutionary mechanism (“Some people say group selectionism is false/But I say let the evidence call it”).

Track 7, “Worst Comes to Worst 2.0,” continues the exploration of how much environment matters to what kinds of traits or behaviors are adaptive or maladaptive. Brinkman notes that Homo sapiens are apex predators who have a choice about whether to maintain environments in which violence against other humans works as an adaptive strategy. Since violence isn’t something to which our genes condemn us, he holds open the possibility that we could remake our environment to favor human behavior as “peaceful as Galapagos finches”.

Track 8, “Dr. Tatiana,” is an ode to the multifarious ways in which members of the animal kingdom knock boots (and a shout-out to the author noted for documenting them), as well as the track on the album least likely to be approved as a prom theme (although the decorating committee could have a lot of fun with it). It makes a compelling musical environment for examining the environments and intraspecies competitions in which particular intriguing mating practices might make sense.

Track 9, “Sexual Selection 2.0,” considers the hypothesis that complex language in general, and Baba Brinkman’s aptitude for rhyming in particular, is something that might have evolved to help win the competition for mates. Brinkman’s hip hop flow is enticing, but in this song it exposes his adaptationist assumption that all the traits that have persisted in our population got there because they were selected for to help us evade predators, combat parasites, or get laid. What would Stephen Jay Gould say?

Track 10, “Hypnotize 2.0,” continues in the theme of sexual selection, exploring secondary sexual characteristics (including, perhaps, mad rhyming skills) as adaptive traits:

So now this whole rap thing seems awfully strange

Talkin’ ‘bout, “He got game, and he’s not real

And he’s got chains” but wait, that’s a peacock’s tail!

‘Cause you never hear them say they got it cheap on sale

Which means that bling is meant to represent

How much they really spent, and at the end of the day
That’s the definition of a “fitness display”

Like a bowerbird’s nest, which takes hours of work

And makes the females catch a powerful urge

Just like a style of verse or an amazing flow

But it takes dedication and it takes a toll

‘Cause the best displays are unfakeable

The lyrics here make the suggestion, not explored in depth, that mimetic posers in the population may complicate the matter of mate selection.

Track 11, “Used To Be The Man,” fits nicely in the neighborhood of hip hop songs expressing young men’s anxiety and nostalgia for a world where they feel more at home. The lyrics note that we may be dragging around traits (like impressive upper body strength) that are no longer so adaptive, especially in rapidly changing social environments. Here, Brinkman gives eloquent voice to pain without committing a fallacious appeal to nature.

Track 12, “Don’t Sleep With Mean People,” is an up-tempo exhortation to take positive action to improve the gene pool. Here, you might worry that Brinkman hasn’t first established meanness as a heritable trait. However, doubters that being a jerk has a genetic basis (of which I am one) may be persuaded by the infectious chorus that a social penalty for being a jerk could improve behavior, if not the human genome.

Track 13, “Performance, Feedback, Revision 2.0,” suggests the ubiquity and usefulness of processes similar to natural selection in other parts of our lives. The album version (2.0) differs from the original (which you can find here) in instrumentation, precise lyrics, and and overall feel. Noticing this, a dozen tracks in to the album, made this listener consider whether the song functions like a genotype, with the particular performance of the song as the phenotypic expression in a particular environment.

In the last track of the album, “Darwin’s Acid 2.0,” Brinkman explores what the world of nature and of human experience looks like if you embrace the theory of evolution. The vision he weaves is of a world that is not grim or nihilistic, but intelligible and hopeful, where it is our responsibility to make good.

“The Rap Guide to Evolution: Revised” is — to me, anyway — a compelling rap album, with its balanced mix of tracks featuring flashy dextrous delivery, slower jams, and shout-along anthems. It’s worth noting, of course, that while I haven’t yet hit the post-menopausal granny demographic that Brinkman identifies (in “Sexual Selection 2.0”) as central to his existing fan base, my CD shelf is mostly stuck in the 20th Century, with Run DMC, Salt-N-Pepa, Beastie Boys, De La Soul, and Arrested Development — the band, not the show — as my rap touchstones. However, these tracks also find favor with my decidedly 21st Century offspring, whose appreciation of the scientific content and clever wordplay would not have been granted if they didn’t like the music. (Note to Mr. Brinkman: My daughters are now more likely to seek out a Baba Brinkman show than a gangsta rap show, but they will be restricting their efforts in propagating your lyrical dexterity — is that what the kids are calling it nowadays? — to Tumblr and the Twitterverse, at least while they’re living under my roof.)

While some (including The New Yorker) have compared Mr. Brinkman to Eminem in his vocal delivery, to my ear he is warmer and more melodic. As an unapologetic Richard Dawkins fanboy, he sometimes comes across like a hardcore adaptationist (rapping about bodies as mere machines for spreading our genes), but he also takes group selection seriously (as in track 6). Perhaps future work will give rise to a levels-of-selection rap battle between partisans of group selection, individual selection, and gene-level selection.

Baba Brinkman’s professed admiration for the work of evolutionary psychologists doesn’t manifest itself in this album in defenses of results based on blatantly bad methodology (at least as far as I can tell). “Creationist Cousins 2.0” does, however, include a swipe at a “gender feminist sister” — gender feminist being, of course, a label originated by a hater (and haters gonna hate). It’s not clear that any of this warrants an answer song, but if it did, I would be rooting for Kate Clancy, DNLee, and the appropriate counterpart of DJ Spinderella to deliver the response.

What’s notable in “The Rap Guide to Evolution: Revised” besides Baba Brinkman’s lyrical mastery is how exquisitely attentive he is to the importance of environment — not just its variability, but also the extent to which humans may be able to change our social, economic, and political environment to make traits we like bumping up against in the world more adaptive. Given that much visceral resistance to evolutionary theory seems grounded in a worry that it reduces humans to helpless cogs in a mechanism, or robots programmed to do the bidding of their genes, this reminder that environment can be every bit as much a moving part in the system as genes is a good one. The reality that could be that Brinkman offers here is fiercely optimistic:

In each of these cases, our intentional efforts
Can play the part of environmental pressures
I can say: “This is a space where a peaceful existence
Will never be threatened by needless aggression”
I can say: “This is an ecosystem where people listen
Where justice increases over egotism
This is a space where religions achieve co-existence
And racism decreases with each coalition”

As Darwin wrote, and Brinkman agrees, there is a grandeur in this view of life.

Via Twitter, I’ve been reminded to point out that the album is a collaboration between Baba Brinkman and DJ and music producer Mr. Simmonds, “who is as responsible for the sound as [Baba Brinkman is] for the ideas”.

* * * * *
Baba Brinkman’s website

Videos of ancestral versions of the songs, produced with funding from the Wellcome Trust

Movie review: Strange Culture.

The other day I was looking for a movie I could watch with instant streaming that featured Josh Kornbluth* and I came upon Strange Culture. Strange Culture is a documentary about the arrest of artist and SUNY-Buffalo professor of art history Steve Kurtz on charges of bioterrorism, mail fraud, and wire fraud in 2004 after the death of his wife, Hope.

At the time Strange Culture was released in 2007, the legal case against Steve Kurtz (and against University of Pittsburgh professor of genetics Robert Ferrell) was ongoing, so the documentary uses actors to interpret events in the case about which Kurtz could not speak on advice of counsel, as well as the usual news footage and interviews of people in the case who were able to talk freely. It also draws on a vividly illustrated graphic novel about the case (titled “Suspect Culture”) written by Timothy Stock and illustrated by Warren Heise.

The central question of the documentary is how an artist found himself the target of federal charges of bioterrorism. I should mention that I watched Strange Culture not long after I finished reading The Radioactive Boy Scout, which no doubt colored my thinking. If The Radioactive Boy Scout is a story of scientific risks taken too lightly, Strange Culture strikes me as a story of scientific risks blown far out of proportion. At the very least, I think there are questions worth pondering here about why the two cases provoked such wildly different reactions.

In 2004, as part of the Critical Art Ensemble, Steve and Hope Kurtz were working on an art installation for the Massachusetts Museum of Contemporary Art on genetically modified agriculture. The nature of the installation was to demonstrate (and involve museum-goers in) scientific techniques used to isolate genetic information from various food products and to identify genetically modified organisms. The larger aim of the installation was to help the audience better understand the use of biotechnology in agriculture, and to push the audience to think more deeply about the scientific decisions made by agribusiness and how they might impact everyday life.

Regardless of whether one thinks the Critical Art Ensemble was raising legitimate worries about GMOs, or ignoring potential benefits from this use of biotechnology**, there is something about the effort to give members of the public a better understanding of — and even some hands-on engagement with — the scientific techniques that I find deeply appealing. Indeed, Steve and Hope Kurtz were in active collaboration with working biologists so that they could master the scientific techniques in question and use them appropriately in assembling the installation. Their preparations included work they were doing in their home with petri dishes and commercially available incubators using benign bacteria.

However, this was where the problems began for Steve Kurtz. One night in May of 2004, Hope Kurtz died in her sleep of heart failure. Steve Kurtz dialed 911. The Buffalo first responders who responded to the call saw the petri dishes and freaked out and notified the FBI. Suddenly, the Kurtz home was swarming with federal agents looking for evidence of bioterrorist activities and Steve Kurtz was under arrest.

Watching Strange Culture, I found myself grappling with the question of just why the authorities reacted with such alarm to what they found in the Kurtz home. My recollection of the news coverage at the time was that the authorities suspected that whatever was growing in those petri dishes might have killed hope Kurtz, but at this point indications are that her death was due to a congenital heart defect. First responders are supposed to be alert to dangers, but they should also recognize that coincidence in space and time is not the same as causation. Hope Kurtz’s death was less than three years after the September 11th attacks, and the anthrax attacks that came close on their heels, which likely raised anxiety about the destructive potential of biological agents in the hands of someone who knows how to use them. I wonder, though, whether some amount of the reaction was not just post-9/11 hypervigilance but a deeper fear of biological material at the microscopic level. If you can grow it in a petri dish, the reaction seemed to say, it must be some seriously dangerous stuff. (I am grateful that these first responders didn’t stumble upon the forgotten leftovers in the back of my fridge and judge me a bioterrorism suspect, too.)

More baffling than the behavior of the first responders was the behavior of the federal agents who searched the Kurtz home. While they raised the specter that Steve Kurtz was producing biological weapons, they ended up leaving the place in shambles, strewn with bags of purportedly biohazardous material (as well as with the trash generated by the agents over the long course of their investigation). Leaving things in this state would be puzzling if the prime concern of the government was to protect the community from harmful biological materials, suggesting that perhaps the investigative teams was more interested in creating a show of government force.

Strange Culture raises, but does not answer, the question of how the government turned out to be even more alarmed by biotechnology in widespread agricultural use than was an art group aiming to raise concerns about GMOs. It suggests that scientific understanding and accurate risk assessment is a problem not just for the public at large but also for the people entrusted with keeping the public safe. It also suggests that members of the public are not terribly safe if the default response from the government is an overreaction, or a presumption that members of the public have no business getting their hands dirty with science.

It’s worth noting that a 2008 ruling found there was insufficient evidence to support the charges against Steve Kurtz, and that the Department of Justice declined to appeal this ruling. You can read the Critical Art Ensemble Defense Fund press release issued at the conclusion of Steve Kurtz’s legal battle.

*Yes, it’s a very particular kind of thing to want. People are like that sometimes.

**On the question of GMOs, if you haven’t yet read Christie Wilcox’s posts (here, here, and here), you really should.