profile

The New Yorker has a fascinating article about Irene Pepperberg and the way people are grieving over her deceased parrot, Alex:

In Wheaton, she quietly worked the crowd into a pleasurable state of shared outrage. At one point, she said that colleagues had admonished her, "Birds can't do what you say he can do. They just don't have the brainpower." Linnea Faris, a woman from Michigan who was wearing a "Remember Alex" T-shirt, shook her head in disbelief. Faris told me, "My husband doesn't really understand it. I can't fully explain it myself. But I've spent hours crying over that damn bird." She went on, "People used to think birds weren't intelligent. Well, they used to think women weren't intelligent, either. They talked about the smaller circumference of our skulls as though it made us inferior to men! You know what? They were wrong on both counts."

The article gives a bit of historical background to studies of intelligence in animals, from Descartes and Darwin through C. Lloyd Morgan and B. F. Skinner. Oh, and the obligatory "Clever Hans" story.

Also, a lot of more current research on animal intelligence, including crows. I liked this part about a smart crow named Betty, which seems to solve problems that other crows have trouble with:

Though some crows, like Betty, cracked the challenge quickly, others took many tries; still others never mastered it. Watching videos of Betty on Kacelnik's Web site, I noticed that she seemed to have a particularly focussed and alert way about her. Even Kacelnik, who is loath to anthropomorphize, confessed to me, "An element of our finding that still puzzles me is that while Betty was not chosen or treated in any special way, she was different. She showed a readiness to coöperate and solve problems that none of the other animals in our study have replicated. We have no idea why."

And to my mind, the saddest statement in the whole article, which echoes a conversation I was having yesterday:

"Irene's work could not really have been planned ahead, as nobody knew what was possible. . . . Alex's development as a unique animal accompanied Irene's as a unique scientist. Hers is not a career trajectory one would advise to young scientists--it's too risky."

It shouldn't have been viewed as risky at all! The worst that could happen is a confirmation of the previous biases against significant learning capacity. But there was nothing in theory that didn't permit what turned out to be the case, and plenty of anecdotal evidence in support. When Darwin cited correspondences with animal breeders in support of the idea of heritable variation, that's good science, reaching out to the edges of what people knew about heredity. Pepperberg began to reach out to the edges of what people know about animal learning.

Frankly, I admire her (and her assistants) the most for their ability to run through the incredible degree of repetition necessary to test these kinds of learning with the parrots. One passage in the article notes that Pepperberg collaborated with an autism researcher on the effects of similar teaching methods (with some success). It's a good comparison in terms of the required patience, also. I think that few researchers are really cut out for the kind of work that Pepperberg does, and that may contribute to some lack of understanding of the results and their limits.

This is a great profile of Alan Mann, on the occasion of the new human evolution exhibit at the University of Pennsylvania Museum of Archaeology and Anthropology:

Describing himself as an evolutionary biologist and a physical anthropologist, Mann remembers that when he began teaching at Penn in 1969, he thought "human evolution was one of the most im portant subjects going." But his students didn't always share his enthusiasm. "So I began thinking about how to make this information not only interesting but also personally important, so they could learn something about themselves that would be useful."

Calling on what he knew about how teeth have changed over time, he asked his students about their own experiences with wisdom teeth and crowded teeth. "Our ancestors had much bigger faces and jaws, with plenty of room for third molars," he says. "But as our faces have evolved, they've become much smaller. They've literally moved under our braincases and the dental arch has shortened. There's no longer room for the third molars" a situation Mann describes as a consequence, or "scar" of evolution.

The article goes though a number of other examples, all fitting the theme of the exhibit. But I especially liked this passage about creationism and evolution:

"Look," he says. "I have been studying human evolution for 40 years. I have traveled around the world. I have handled just about every human fossil, every relic of our evolution. I know them to be genuine. I know that they represent the development of our own kind from creatures who had many resemblances to apes but were not apes, and over time, I see a system of change that can be marked in the record of geology and in dating processes that show that over time, our kind evolved into who we are.

"When I say this to a creationist who has never handled a fossil, who doesn't really have my experience, and they suggest that this is wrong, that I don't know what I'm talking about, I am distressed. It's not to me a proper way of debate."

I pulled the quote for the headline of the post, because it has such a resonance for those of us who study the human fossil record.

It seems to be biomedical profile week in the NY Times, so in addition to the profile of Francisco Ayala, Claudia Dreifus presents a profile of Arno Motulsky. Known for his early work on enzyme interactions, he is now credited for essential ideas leading to pharmacogenomics.

Q. YOUR OBSERVATION IN 1957 ABOUT THE INTERACTIONS BETWEEN THE ENZYMES PRODUCED BY GENES AND SOME DRUGS -- DOES IT PLEASE YOU TO SEE HOW IMPORTANT IT HAS BECOME?

A. Yes, because at first the idea was not well accepted. I remember going to an important pharmaceutical executive and I said, "I found a new way to find out about drug reactions." And he kissed me off: "Drug reactions?"

Things also moved slowly for a long time because it was hard to test for this. But now, with the new DNA testing, you can do many things faster and better. And with the modern computerized genomics, you can even test for reactions to many different enzymes, all at the same time.

On the other hand, I think the promise of pharmacogenetics is sometimes overhyped. There are people who think we'll be able to solve almost everything with an individualized prescription. We need more research, which will be expensive.

It's a short interview, but includes some interesting biographical details.

Cornelia Dean writes a long profile of Francisco Ayala in today's Science Times. The occasion is the publication of his new book, Darwin's Gift to Science and Religion.

Dr. Ayala gives about 50 talks a year, he said in a recent interview in New York, a day after he delivered the inaugural Louis Levine-Gabriella de Beer lecture in genetics at City College. (He had spoken the day before, at North Carolina State University, on the evolution of morality, and spoke two days later at McGill University in Toronto, where his subject was Darwinism and religion.)

Because of his eminence -- he is a member of the National Academy of Sciences, a former president of the American Association for the Advancement of Science and a winner of the National Medal of Science -- Dr. Ayala "has a bully pulpit," said Eugenie Scott, who heads the National Center for Science Education, a group that advocates for the teaching of evolution and against creationism in public schools. "When Francisco speaks, people listen."

Ayala is a fascinating person to talk to, and his vines make some of the best wine I've ever had. The article is a nice portrait of his current work.

The sad part of this story is that nobody cares about the identity of the other guy:

The mystery surrounding the skulls began in 1826, 21 years after [Friedrich] Schiller died in Weimar, when the local mayor had 23 skulls retrieved from a mass grave in which the poet was buried. Many eminent people at that time were buried in mass graves.

The mayor identified the largest skull as Schiller's and it was brought to the home of his contemporary Goethe, who wrote a poem about it, according to German scholar Albrecht Schoene.

In 1911, another skull was disinterred from the mass grave which researchers claimed was the real one. A long debate amongst academics, historians, medics and anthropologists about the identity of the skulls ensued.

So, naturally, they're digging up his relatives and plan to sample their DNA for a match.

I suppose it's a real advance when we go beyond testing live people who are purporting to be long-dead celebrities, against the live relatives, and move on to testing dead skeletons that people purport to be celebrities against dead relatives. How long can it be before we establish a catalog of dead celebrities' DNA profiles?

Yves Coppens and colleagues have found a frontal bone, and a bit more, in Mongolia. They do not report a date for the specimen beyond Late Pleistocene; it comes from a pit dug for gold mining. The site is north of Zhoukoudian and other northern Chinese sites by several hundred kilometers, and is approximately the same latitude (though further east) as Okladnikov Cave (discussed in my interview with Mica Glantz). The place is called Salkhit.

They describe the anatomy of the specimen: it has a complete supraorbital torus, thicker in the superciliary area than laterally; a slight frontal keel, and an overall sloping profile. In other words, it looks to be generally archaic in morphology. Their metrical comparisons put it generally with Middle Pleistocene crania like Zhoukoudian, Steinheim, and Petralona.

(via Paleoanthro)

References:

Coppens Y, Tseveendorj D, Demeter F, Turbat T, Giscard P-H. 2008. Discovery of an archaic Homo sapiens skullcap in Northeast Mongolia. Compte Rendus Palévol (in press) doi:10.1016/j.crpv.2007.12.004

Amy Harmon profiles Dan Stoicescu, a Swiss-living millionaire who has become the first paying customer of the genome-sequencing company, Knome.

Mr. Stoicescu said he worried about being seen as self-indulgent (though he donates much more each year to philanthropic causes), egotistical (for obvious reasons) or stupid (the cost of the technology, he knows, is dropping so fast that he would have certainly paid much less by waiting a few months).

But he agreed to be identified to help persuade others to participate. With only four complete human genome sequences announced by scientists around the world -- along with the Human Genome Project, which finished assembling a genome drawn from several individuals at a cost of about $300 million in 2003 -- each new one stands to add considerably to the collective knowledge.

"I view it as a kind of sponsorship," he said. "In a way you can also be part of this adventure, which I believe is going to change a lot of things."

"Sponsorship" seems like a good way to look at it, as long as they don't start including companies' names in the sequence, like "Pepsi" on a high school scoreboard!

Amy Harmon brings several patients' stories to this article, "Fear of insurance trouble leads many to shun or hide DNA tests."

In some cases, doctors say, patients who could make more informed health care decisions if they learned whether they had inherited an elevated risk of diseases like breast and colon cancer refuse to do so because of the potentially dire economic consequences.

Others enter a kind of genetic underground, spending hundreds or thousands of dollars of their own money for DNA tests that an insurer would otherwise cover, so as to avoid scrutiny. Those who do find out they are likely or certain to develop a particular genetic condition often beg doctors not to mention it in their records.

Some, like Ms. Grove, try to manage their own care without confiding in medical professionals. And even doctors who recommend DNA testing to their patients warn them that they could face genetic discrimination from employers or insurers.

According to the article, many people are choosing to pay out of pocket for genetic tests to avoid insurance or medical involvement. If this precedent becomes more common -- people paying for single-disorder tests -- then companies that offer genome-wide SNP typing may have an easy time growing their market.

This one I hadn't heard about:

When the Equal Employment Opportunities Commission sued the Burlington Northern Santa Fe Railway for secretly testing the blood of employees who had filed compensation claims for carpal-tunnel syndrome in an effort to discover a genetic cause for the symptoms, the case was settled out of court in 2002.

That is creepy.

It seems likely that the insurance risk fear will be addressed soon by legislation:

The Genetic Information Nondiscrimination Act, which passed the House of Representatives by a wide margin last year, would prohibit insurers from using genetic information to deny benefits or raise premiums for both group and individual policies. (It is already illegal to exclude individuals from a group plan because of their genetic profile.) The bill would also bar employers from collecting genetic information or using it to make decisions about hiring, firing or compensation. But it has yet to reach the Senate floor.

The article deals with both kinds of fears -- the fear of insurance consequences, and the fear of testing itself. It ends with a woman who feared being tested for the BRCA1 mutation so much that she chose surgery to remove her ovaries. Before a double mastectomy, she had the testing anyway -- and learned that she did not carry the risk allele after all.

UPDATE (2008-02-24): Hsien-Hsien Lei picks up the story also, and adds a perspective from Britain:

Two years ago, Cancerbackup found in a survey of regional genetics centers that waiting time for appointments to receive a BRCA genetic test can be as long as nine months with a further wait of 1 to 2 years for results. In some ways, this could be construed as discrimination in that other forms of testing are probably taken more seriously and performed more speedily.

She also provides a raft of links to other blogs that have posted on the Harmon story.

Identical twins may be genetically different due to somatic variations, and a new study by Bruder and colleagues finds that large deletions contribute to some of that difference:

The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant or discordant phenotype by using two platforms for genome-wide CNV analyses and showed that CNVs exist within pairs in both groups. These findings have an impact on our views of genotypic and phenotypic diversity in monozygotic twins and suggest that CNV analysis in phenotypically discordant monozygotic twins may provide a powerful tool for identifying disease-predisposition loci. Our results also imply that caution should be exercised when interpreting disease causality of de novo CNVs found in patients based on analysis of a single tissue in routine disease-related DNA diagnostics (Bruder et al. 2008:1).

If this is a large source of phenotypic discordance between twins -- that is, one twin gets a disease and the other doesn't because of a non-shared somatic CNV -- then our estimates of the heritability of phenotypes based on MZ-DZ twin comparisons will all be too low. This research group is involved in finding genetic risk factors for Parkinson's disease, and they think somatic SNVs are a promising avenue to explain phenotypic discordance where one twin has Parkinson's and the other does not.

But their study cannot say (because of a lack of power) that phenotypically discordant MZ twins have CNVs that explain the discordance. It's possible that most of the CNVs they observe have no phenotypic effect.

MZ twins represent an excellent focus for such studies [of somatic CNVs] because any genotypic difference between twins derived from the same zygote highlights an irrefutable case of somatic variation. It is likely that the confirmed CNVs shown here represent only the "tip of an iceberg" of all CNVs that are actually present in the studied twins. The notion of somatic variation being more far more common than previously assumed agrees well with our other, recent results showing CNVs between normal, fully-differentiated tissues within an individual human subject (Bruder et al. 2008:4).

This does raise an important question. CNVs are a newly-understood component of human genetic variation, for example in the current paper by Jakobsson and colleagues (2008). But if people often exhibit CNV mosaicism, then some of the rare variants in global samples may be somatic mutations that do not occur in the gene pool of their respective populations. And if there are "hotspots" of CNV mutations, then multiple people might show somatic mutations for the same
variant. It's probably a rare event, but given how little we know about the evolution of CNVs, it might be nice to know how rare.

References:

Bruder CEG and 21 others. 2008. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Hum Genet 82:1-9. doi:10.1016/j.ajhg.2007.12.011

Jakobsson M and 23 others. 2008. Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451:998-1003. doi:10.1038/nature06742

Another thing I didn't expect to see today: DeCode Genetics went looking through James Watson's genome sequence for evidence he is secretly black:

A new analysis of Dr. Watson's genome shows that he has 16 times the number of genes considered to be of African origin than the average white European does -- about the same amount of African DNA that would show up if one great-grandparent were African, said Kari Stefansson, the chief executive of deCODE Genetics of Iceland, which did the analysis.

...

Dr. Stefansson's company is one of several marketing genome scans that promise to reveal anyone's genetic propensities for disease, origins and more, for a price. Dr. Watson had already placed his own genome information online, as has another genetics pioneer, J. Craig Venter. Dr. Stefansson said he simply ran the data through his company's analytical system.

Dr. Stefansson said that because his company had not produced the original data, "I am reluctant, personally, to make much of the analysis." He added, however, that "on my face, it would elicit smiles."

I find this incredibly strange. Not that Watson may have a mixed ancestry -- ultimately, everyone's ancestry is mixed.

No, I find it strange that the leader of one of the major genetics firms in the world is cheerily showing one of the worst possible abuses of personal genomics, in the most high-profile way possible! I find it just flabbergasting.

Sure, you can argue that Watson deserves the abuse he's gotten, and that his genetic ancestry is legitimately related to the story about his race comments. I don't agree, but there's a sense to which all this couldn't happen to a better person.

But the entire reason why many people think public genomics is a bad idea revolves around privacy and informed consent. People want to believe that their genes won't be used against them -- that information about risk alleles won't be used to deny employment or insurance, for example. Information about one's ancestry clearly falls in that category: most people want to keep such information private.

Informed consent is a problem in public genomics because your genes are not only yours -- they are also the genes of your parents, children, and other relatives. When you make your gene sequence public, you are taking with it information about your kin, who may not want such information out there. At present, they have no way of stopping you -- they have to live with your decisions. Which has created ticklish situations: a number of anonymous sperm donors have been tracked down by their children, using the donors' relatives' DNA sequences available from genealogy testing services.

If you want to advance the field, then you want to find ways to build confidence that genomic data won't lead to these "gotcha" moments.

I mean, what is the purpose really of spreading a news story that Watson may be 1/16 African, without adding the context of how common this degree of genetic mixture has been in American history in particular, and between populations generally? Why would a geneticist working with humans not realize the ethical problem? It has exactly the same salacious quality as a story about a political candidate's ancestry -- remember the story about former senator George Allen's Jewish mother? I can't believe that a credible researcher would want to bring this to genomics.

Maybe this is a play to discredit public genomics and advance the idea of some kind of data security system. From Stefansson's quotes, it seems possible he is trying to make his company look good and other ideas, like George Church's sequencing project, look bad.

But somehow I doubt it was that closely thought out. Probably their zeal to "get" Watson carried them away, to the detriment of the field.

Michael Balter wrote a nice "Scientist at Work" profile of paleoneurologist Ralph Holloway.

Ralph is one of my real idols in the field, so it's a pleasure to read this. Of course it begins with the hobbit, but Balter devotes much of the piece to explaining the lunate sulcus controversy of the 1980's and 1990's.

I think that Balter really captures the most important aspect of Holloway's scientific work with this:

Most notably, during his 43 years at Columbia, Dr. Holloway has argued that hominid brains began to evolve important anatomical alterations several million years ago, when they were ape-size and had yet to undergo the striking expansion often seen as humanity's hallmark.

We humans are rightly proud of our big brains. But most anthropologists now agree with Dr. Holloway that increases in size alone cannot explain advanced human cognition. There have also been structural changes that distinguish the brain of Homo sapiens from those of our hominid ancestors, as well as those of close cousins like the chimpanzee.

The lunate sulcus story illustrates this point quite well, but far more important (and less controversial) has been Holloway's identification of an enlarged Broca's area in the KNM-ER 1470 endocast. Only recently has imaging analysis been able to flesh out some of the internal ways that brain reorganization has characterized primate and human evolution. But the external manifestations on endocasts were a leading indicator -- and remain the only direct source of evidence about brain function from fossils.

There's much more to say than this, but start with the profile!

New York Times reporter Cornelia Dean writes about a unique retraction by 84-year-old chemist Homer Jacobson:

Nobody paid much attention to the paper at the time, he said in a telephone interview from his home in Tarrytown, N.Y. But today it is winning Dr. Jacobson acclaim that he does not want - from creationists who cite it as proof that life could not have emerged on earth without divine intervention.

So after 52 years, he has retracted it.

Wow, can you imagine how much time it would save us if people would retract old papers more often? I mean, there are a lot of scientists who are open and honest when new results overturn their old papers, and that is always refreshing. But even then, it can be hard to figure out which earlier results were shown to be definitely wrong, and which were just forgotten. A good retraction, linked to the original, would make everything much clearer.

Still, most papers don't deserve retracting. Most papers are full of good, logical ideas, even if some of the empirical results were later shown to be wrong.

Tracing the history of these old ideas is a very fruitful source of new ideas. I was telling a student just today that reading the literature supporting old, discredited ideas is much more intellectually demanding than reading about the new, trendy ideas, and often leads to more new thoughts.

I'm not sure that's universally true, but it certainly seems to be the case in paleoanthropology. The modern human origins problem emerged, more or less in its current form, more than 60 years ago. Old papers in this area sometimes seem quaint, and of course we have many more empirical points now in support of various arguments, but the basic themes have hardly changed.

These themes were established 20 years before any substantial molecular information about human evolution, purely on the basis of skeletal comparisons. Better, if you strip away much of the recent empirical evidence, the basic claims are often clearer and more succinct in old publications.

So, I think retractions should be limited to cases where genuine errors were made -- the point and power of a retraction is to prevent a real mistake from propagating itself. A retraction may help stop some high-profile misinterpretations, but it is almost never worth it.

In Jacobson's case, he identified what he considers to be genuine errors in the paper; errors that tend to support the misinterpretations he now rues. So, I suppose a retraction is appropriate. But it will hardly stop misinterpretation.

In paleoanthropology, misinterpretation usually rules the day!

Nicholas Wade profiles the work of Dorothy Cheney and Robert Seyfarth in this article, "How Baboons Think (Yes, Think)."

Dr. Cheney and Dr. Seyfarth have summed up their new cycle of research in a book titled, after Darwin's comment, "Baboon Metaphysics." Their conclusion, based on many painstaking experiments, is that baboons' minds are specialized for social interaction, for understanding the structure of their complex society and for navigating their way within it.

The shaper of a baboon's mind is natural selection. Those with the best social skills leave the most offspring.

"Monkey society is governed by the same two general rules that governed the behavior of women in so many 19th-century novels," Dr. Cheney and Dr. Seyfarth write. "Stay loyal to your relatives (though perhaps at a distance, if they are an impediment), but also try to ingratiate yourself with the members of high-ranking families."

In other words, Jane Austen would be right at home. I suppose they could have chosen baboons for a "reality" series instead of meerkats, if baboons didn't live so long. It seems like the meerkat deaths generate much of the drama.

The article describes their recent work, playing back sounds at controlled intervals to try to establish when baboons are using social cognition of various flavors.

In some of their playback experiments, Dr. Cheney and Dr. Seyfarth have tested baboons' knowledge of where everyone stands in the hierarchy. In a typical interaction, a dominant baboon gives a threat grunt, and its inferior screams. From their library of recorded baboon sounds, the researchers can fabricate a sequence in which an inferior baboon's threat grunt is followed by a superior's scream.

Baboons pay little attention when a normal interaction is played to them but show surprise when they hear the fabricated sequence implying their social world has been turned upside down.

If they were computers, this would be known as "spoofing." I suppose if they strung together all their wild vocalizations at once, it would be like a Denial of Service attack. Anyway, I think the computer network analogy is helpful -- Cheney and Seyfarth attempt to discover the workings of each node by watching its reactions to various inputs.

The difficulty of field research continues to be the researchers' inability to set up replicated trials of a given sequence of events, and for this reason field primatology has been primarily descriptive. Cheney and Seyfarth mess around with their animals more than most field researchers are willing to do; that provides the opportunity to test certain kinds of hypotheses, but alters the animals' behavior in the process -- precisely why many researchers hesitate to conduct similar playback experiments.

But unlike many other primates, these baboons are not threatened, and their population is healthy. So spoof 'em.

In Erika Check's Nature article on celebrity genomes, she includes a passage in which Francis Collins points out a problem with public access to private genomes:

But it's not clear that all of the genome pioneers are acting altruistically. Watson said at the Cold Spring Harbor meeting on 10 May that he has not asked either of his grown sons for permission to publish his genome sequence, which 454 has said will be publicly posted in some form. That has raised questions about the responsibility of sequenced individuals to family members who share their DNA.

"This will be a challenging question, because if you're planning to put this information in a truly open database, there are issues of risk not just to you, but to your relatives," Collins says. "Jim clearly felt those risks were not such as to cause him to take action on them."

Putting your genome information online is not only about you: it includes half the genome of each of your children, half the genome of your parents, a fourth that of your grandchildren, nieces, and nephews, and so on.

I wrote about this problem two years ago, linking to a New Scientist article that described how a young man had tracked down his biological father -- using DNA samples put online by the man's relatives.

The boy paid FamilyTreeDNA.com $289 for the service. His genetic father had never supplied his DNA to the site, but all that was needed was for someone in the same paternal line to be on file. After nine months of waiting and having agreed to have his contact details available to other clients, the boy was contacted by two men with Y chromosomes closely matching his own. The two did not know each other, but the similarity between their Y chromosomes suggested there was a 50 per cent chance that all three had the same father, grandfather or great-grandfather.

OK, so this particular situation must be pretty rare. But it is a good example of a case where a parent and child may have divergent interests with respect to genetic information. On the obvious level, the son wants to discover his father's identity while the father may want to conceal it. On the not-so-obvious level, a grandfather may want to find children that his son may have fathered, irrespective of the father's wishes. The father in question might even be dead, might have specified in his will his wishes for all sperm donations to remain private, but a grandfather can easily circumvent those wishes through the simple expedient of publicizing his DNA profile.

Families with inherited genetic conditions are already dealing with these privacy issues, such as mothers who don't want a Huntington's test and daughters who get it anyway, revealing the mother's status (my post earlier this year, referring to Amy Harmon's NY Times article). Whole-genome scans for most people will not reveal the same, tragic, level of risk, but will generate hundreds of smaller questions -- like a load of tiny skeletons-in-the-closet.

This week in Science, Collins and coauthor William Lowrance expand on the problem. Their "Policy Forum" article notes existing U.S. federal law and regulations concerning personal data and the problems that genomic information is likely to generate in the current legal context.

Until recently, most genomic research used data and biospecimens obtained fairly directly, from the data subjects themselves or clinical repositories or specialized research collections. This will continue, as it has many advantages. But now, in efforts to increase the range and quantity of data, large-scale research platforms are being built that assemble, organize, and store data, and sometimes biospecimens, and then distribute these to researchers (see figure). The advantages of such platforms, in addition to scale, are that they can be a robust staging-point for screening data quality, fostering uniformity of data format, and facilitating analysis. Some platforms accumulate data directly (as the Framingham Heart Study does); others assemble them from a variety of sources (as The Cancer Genome Atlas, the Genetic Association Information Network, and the Wellcome Trust Case Control Consortium do and U.K. Biobank will) (7). Among the design and governance issues are whether and how to de-identify the data and at what stages to conduct scientific and ethics review.

These new data flows, genomewide analyses, and novel arrangements such as the Informed Cohort scheme recently proposed by Kohane et al. (8) are relatively uncharted territory with respect to human subjects and privacy considerations. Precedent doesn't provide sufficient guidance. For example, the Human Genome and HapMap Projects have geno-typed DNA from only a few hundred carefully selected people who prospectively consented to the analysis and to open publication after thorough explanation, discussion, and community consultation. The projects have been scrutinized closely all along. But when the data relate to more people (by orders of magnitude) or to retrospective analysis of biospecimens, then for pragmatic reasons such painstaking selection, consent negotiation, and scrutiny can't generally be achieved (Lowrance and Collins 2007:600).

The article does not really arrive at any conclusions about what should be done -- Lowrance and Collins limit themselves to a fairly dry listing of potential problems and conditions leading to them. Throughout, they emphasize the reliance of the current regulations on "de-identification" -- that is, the removal of most identifying information from sequences or samples. Under today's U.S. guidelines, data that have had identifying information removed may be used quite broadly without further consideration of human subjects protections:

Construal of genomic "human subject." If data have been de-identified but include large amounts of genetic information, are the individuals still considered "human subjects"? The answer has important implications for consent, ethics review, and safeguards. McGuire and Gibbs have urged that "genomic sequencing studies should be recognized as human-subjects research and brought unambiguously under the protection of existing federal legislation" (22), but this could be unnecessarily extreme. In the United States, the Office of Human Research Protections considers that data or biospecimens collected for one purpose but then key-coded and used secondarily for research are not "individually identifiable," and therefore the research is not human-subjects research (7). This is a strong incentive to support de-identification and to de-identify data (Lowrance and Collins 2007:602).

Lowrance and Collins mention that "de-identification" is by no means as simple as applied to substantial parts of genomes, particularly when accompanied by phenotypic data such as redacted medical histories. Routine data-mining techniques would be sufficient to identify individuals within medical research studies; matching individual genome profiles to a name may be accomplished without need to match data to a "key" if the information is unique enough.

I favor the protection of individual privacy over greater research access to research data, particularly since DNA sampling and data retention by governmental agencies has become increasingly routine. In a post directly before her Personal Genome Project Q&A, Hsien-Hsien Lei wrote "Police want to collect abandoned DNA from everyone," noting that UK police will soon have authority to collect DNA with the same legal standing as trash -- if you throw it away, it's not private. We have to assume that governments will keep multiple databases of DNA barcodes for people, that these will include other personal information, and that they will be insecure. One may argue that most of the privacy threat actually comes from these other databases, and that personal genome information adds relatively little. Nevertheless, it would be better to add nothing at all, or to generate new models accentuating security.

Since I've been thinking about information theory a lot lately, I can't help but think that some kind of cryptographic solution should be applied -- so that nobody can read a person's sequence data without her private key. A person might choose to opt-in to research studies or other projects that require genotyping data, but still the sequence would be secured by encryption.

The objection to such an approach is that large-scale, long-term studies of health attributes require samples of many thousands -- even tens or hundreds of thousands of people. Today, these datasets are routinely deindividualized and dispersed around the world to researchers involved with many different projects. There is little chance of centralized control over this information after it is dispersed -- and Lowrance and Collins describe the potential problems with changing the system. With so many participants, the genotype data are a tempting target for black-hats. Any very large-scale study, in which hundreds of researchers have access to deindividualized data, there are many chances for unscrupulous researchers to steal information or put it in situations where theft by outsiders may occur.

But practices can be implemented to reduce the risk of data loss or theft. For one thing, the main reason why those studies need so many participants is because they are waiting for people to have rare adverse health events, and don't want to wait so long for results. So they really only need to know genotype data for the small group of people who have these conditions. If decryption is restricted to such small groups of study participants, the risk of unauthorized data access would be greatly reduced.

No system is perfectly safe, but in this case the agglomeration of data from thousands or millions of individuals in single databases leads to risks that scale nonlinearly with database size. So reducing the size of data chunks available to any one person may be a significant protective step.

References:

Lowrance WW, Collins FS. 2007. Identifiability in genomic research. Science 317:600-602.doi:10.1126/science.1147699

Check E. 2007. Celebrity genomes alarm researchers. Nature 447:358-359. doi:10.1038/447358a

Back in May, Nature ran an article (non-free) titled, "Celebrity genomes alarm researchers," by Erika Check. The article's premise:

Genome researchers are questioning the plans of some of their number to stage high-profile releases of their very own genome sequences.

The article lumped together at least four distinct sequencing efforts, including Venter's sequencing of his own genome, 454 Life Sciences sequencing of James Watson's genome, the "privately funded" Personal Genome Project, and the Archon Genomics X Prize. The first two are already complete; the others are still ongoing, and details about progress have been relatively quiet.

The "freakshow" aspect of Check's Nature article was supplied by the Archon X Prize. This $10 million award is only a proof-of-technology test: sequence 100 genomes in 10 days, for less than $10,000 per genome, and you win the prize. But that's really too dry to make headlines -- nothing so interesting as the spaceflights that won the Ansari X Prize, so they've instituted a super bonus round:

The prizewinner can claim a $1-million bonus by sequencing a list of 100 individuals, including people nominated by disease advocacy groups, and celebrities such as television journalist Larry King, cosmologist Stephen Hawking, Google co-founder Larry Page, Microsoft co-founder Paul Allen and former junk-bond trader Michael Milken.

Will the winning group go for the bonus? Who knows? If their technology hits the $10,000-per-genome price point, the $1 million bonus just pays for the 100 bonus genomes. So it's not exactly a bonus. Still, a company that saw the headlines 454 got for delivering Watson's DNA on DVD will probably salivate at the chance to do the same for Stephen Hawking.

Michael Milken, not so much.

But it's all quite obvious that when complete genome sequencing is first made available, rich people will be among the first to have them. And since many rich people are also famous, we'll be hearing about the rich and famous. But we won't be hearing about them too soon, because it will be a while before the technology gets to the X Prize level.

Which leaves us with the more interesting project in the short term -- the Personal Genome Project (PGP). This has its detractors also, because of the decision to sample well-known geneticists as volunteers, instead of anonymous donors or, well, non-geneticists.

Check's article lumped this criticism together with the celebrity angle in her article -- one of the reasons I didn't link it at the time. For instance, the article included a quote from Michael Ashburner that clearly applies to the X Prize:

"I'd hate the availability of single-genome sequencing to be based purely on money and fame," says Michael Ashburner, a geneticist at the University of Cambridge, UK. "Just doing famous or very rich people is bloody tacky, actually."

While a quote from Francis Collins appears directed toward the PGP:

"If all the sequences obtained over the next year or two are done on scientists with strong financial positions, that will send a message quite contrary to what the genome project aimed to achieve," says Francis Collins, head of the US National Human Genome Research Institute (NHGRI) in Bethesda, Maryland.

That's confusing. There seems to be a general feeling that it's unseemly not to sample ordinary people, since the hope is that everyone will benefit from genomics; but disdain toward celebrity sequencing only applies to a small part of the overall situation.

Plus, Collins is concerned with a policy question himself, since the NHGRI is going to sample its own set of 100 people:

The NHGRI is now planning to sequence about 100 individual genomes at its three publicly funded sequencing centres over the next couple of years. Collins says the institute will ask for scientific advice on who should be sequenced first. One question is what pool of sequenced individuals will yield the most useful information.

So that means at least two directly competing whole-genome sequencing projects going on right now, with a large prize waiting for the first private company that can lay a claim on it by sequencing DNA fast enough and cheaply enough.

The volunteers

So, why did I choose to write about this now? This week, the Personal Genome Project announced its first 10 sequencing volunteers. Nine of them are listed along with their bios on Blaine Bettinger's Genetic Genealogist blog. One volunteer did not choose to be listed publicly.

These are not celebrities. It is probable that if you're not a geneticist, you haven't heard of any of them. On the other hand, they are all accomplished people with substantial resumes -- some academic, many in business.

Esther Dyson went public with an op-ed before this week's announcement, listing her reasons for volunteering:

But what about the people who are less fortunate than me? I want to push questions about those less lucky to the fore -- and get us all to think about them. It's not just who gets health care and how it gets paid for, or whether employers can discriminate against people with certain conditions or just a greater-than-average propensity for them. What of someone who has a particular susceptibility to, say, alcohol? Does he pay an extra tax on booze? Or does he get a tax credit for behaving well, while a less susceptible person is denied the opportunity to benefit by behaving "properly"? (Subsidies and penalties cut both ways.) Should people have the right to refuse subsidized medical care and live as they wish? These questions may sound far-fetched, but they won't be once society knows enough information to start asking them.

From her description, it appears that the volunteers are not only donors but also stakeholders in the project -- in terms of directing its handling of results and protocols. Project leader George Church did an interview last year with MIT Technology Review that discusses his ideas at the beginning of the project:

TR: Are you recruiting participants for the pilot project? Who will be the pioneers?

GC: It took a year for us to get permission for the project from our institutional review board. The recruiting process will go in stages. The board asked that I start with myself because I am well-informed and could stop the project if I saw a problem. We will expand to two more people in March; and once we've worked out a mechanism to show that the benefits outweigh risks for the first three people, we can recruit more people. We have 140 people who would like to participate. The total number of participants [at this phase] will be limited by funds and by the review board's assessment of how it went. We are trying to get funds for a large number of people.

The initial participants will probably be tenured human geneticists, because they know the risks and other issues. Eventually, we want a broad, diverse set of people from different social and economic groups, and both healthy and unhealthy people. But they will need to be specifically up to speed on how genetics works. This could be something very big once people tune into it. Not many know people know about it so far.

Hsien-Hsien Lei has been following this story, and she has given some reasons why geneticists may be the best subjects for the initial project:

I don’t look upon the PGP-10 as people of privilege who got access to something that everyone wants but few people get like iPhones. They are actually guinea pigs doing something that few of us dare! Those commenting on the PGP-10’s money and fame come off green with jealousy. In their world, whole genome sequencing might be something of great value, but a general population survey will surely find more fear than desire.

It is clear from Church's description that there is really no alternative to people with substantial genetics training as volunteers, because informed consent on a project of this scale is extravagantly difficult to demonstrate. It is essential to the project that the subjects be public, because otherwise they cannot truly assess the risks of public genome information.

But the skeptic in me has to point out that not only are these volunteers trained in genetics, almost all of them are poised to profit if personal genomics takes off. Many are investors or founders of companies in the new field. Those who aren't are in a position to be at any time they choose. And some of them occupy academic positions with substantial power to influence potential critics. So collectively, they have a level of safety that other people typically lack, as well as a strong pecuniary interest in the project's success.

Kind of like that dude from Blade Runner with the Coke-bottle glasses. Which is not the best image for your friendly personal genome project....

I don't think it matters a bit if the first public genomes are all famous people. I mean, we've been looking at Venter's sequence for quite a while now. Heck, if we could get the genomes of all the Hollywood tabloid starlets, we could probably do some good by identifying genes that make them have unusual affinities for teeny-weeny dogs.

But if Paris Hilton and Ivanka Trump went to Las Vegas to help Steve Wynn with a secret project involving hotel design, we would probably figure their interests were not purely altruistic.

So, I actually think it will be a little comforting to see them churning out real celebrity genomes, because it will mean that the project is already successful. I assume that Oprah will be out there first -- I mean, not only was she early on the whole-body scan bandwagon, but she has already had her DNA taken for ancestry testing.

Hey, she can afford it now...maybe it's already on her fall TV schedule!

That would make the whole thing a write-off.

Carl Zimmer's profile of mathematical biologist Martin Nowak is well worth reading. Zimmer does a good job of describing the relevance of Nowak's modeling work, centered on the Prisoner's Dilemma:

Dr. Nowak and his colleagues found that when they put players into a network, the Prisoner's Dilemma played out differently. Tight clusters of cooperators emerge, and defectors elsewhere in the network are not able to undermine their altruism. "Even if outside our network there are cheaters, we still help each other a lot," Dr. Nowak said. That is not to say that cooperation always emerges. Dr. Nowak identified the conditions when it can arise with a simple equation: B/C>K. That is, cooperation will emerge if the benefit-to-cost (B/C) ratio of cooperation is greater than the average number of neighbors (K).

"It's the simplest possible thing you could have expected, and it's completely amazing," he said.

This work branches out into cancer etiology and social dynamics, among other things. My students will be reminded that I think the Prisoner's Dilemma is overrated -- but that's a topic for another day...

(not via Gene Expression, although Razib got there first!)

David Biello writes a nice profile of demographic researcher Virpi Lummaa:

The 33-year-old Finnish biologist, aided by genealogists, has pored through centuries-old tomes (and microfiche) for birth, marriage and death records, which ended up providing glimpses of evolution at work in humanity's recent ancestors. Among them: that male twins disrupt the mating potential of their female siblings by prenatally rendering them more masculine; mothers of sons die sooner than those of daughters, because rearing the former takes a greater toll; and grandmothers are important to the survival of grandchildren. "I'm trying to understand human reproductive behavior from an evolutionary perspective," Lummaa says.

I wrote about Lummaa's most recent work, on twin fertility, last month (It's the second post here, because for whatever reason, the permalink isn't working right.). That's the post that includes the long update about freemartins -- a twinning effect associated with sterility in cattle and sheep.

Anyway, this is a really good profile of a young scientist -- maybe someday I'll do something interesting enough to merit the same!

Andrew Curry profiles ancient DNA researcher Eske Willerslev, of the University of Copenhagen. Willerslev is best known for the characterization of chloroplast and mitochondrial DNA from old tundra cores, and this week's paper interpreting local biotic diversity from Greenland ice cores.

Willerslev began to wonder about the ignored ice core bottoms in the building his lab shared with Steffensen's climate research group. "I did the permafrost stuff, and then suddenly it hit me: Silty ice is icy permafrost, right?" Judiciously cutting and melting the core bottoms, Willerslev and his colleagues analyzed the resulting water for signs of DNA. What Willerslev found, and reports on page 111, broke his own record for the oldest DNA ever recovered, and promises to rewrite the history of Greenland's climate. His team identified and dated genetic sequences from coniferous trees, butterflies, beetles, and a variety of other boreal forest plants--traces of ancient forests that Willerslev says covered southern Greenland perhaps as far back as 800,000 years ago.

The paper itself is interesting and brief -- Willerslev and colleagues found DNA from boreal forest tree and insect species at the bottom of a 2-km ice core from south-central Greenland. The trick was dating the thing, and using 4 different methods they conclude the ice is between 500,000 and 1 million years old.

References:

Willerslev E and 29 others. 2007. Ancient Biomolecules from Deep Ice Cores Reveal a Forested Southern Greenland. Science 317:111-114. doi:10.1126/science.1141758

This is from the Nicholas Wade article on James Watson's genome:

Some scientists believe that it will be medically useful to sequence patients' genomes when the cost of sequencing falls to around $10,000 or less. Dr. Egholm said that with improvements already under way, the 454 sequencing machine would soon be able to sequence a human genome for $100,000. The cost of sequencing has been dropping so fast in the hands of groups like 454 Life Sciences and Solexa Inc., a subsidiary of Illumina Inc., that some technologists predict the $10,000 genome will be attained in a few years.

Doesn't $10,000 seem like an interesting price point? I've written a couple of times about the idea of $1000 whole-genome sequencing. Here's what I wrote last year:

My question is, why are they shooting for $1000? It seems to me that if you can go from $2.2 million to $1000, it won't take very much longer to go to $100, or even less. The materials cost and computational resources certainly won't cost that much in volume.

They are framing the cost in terms of the cost of a personal computer, but it wasn't so long ago that the "accepted" cost of a PC was over $3000, and now most buyers spend a lot less than $1000. So that's arbitrary too.

My guess is that the magic $1000 figure that keeps getting quoted is an attempt to prime insurers to expect that billing amount when the process becomes common. The question is not how much you would pay for a genome, but how much an insurance company would pay on your behalf. A lot of diagnostic procedures approach that billing amount, so it is a convenient pricing hook.

If I'm right, then you can place the $1000 genome in the same category as MRI scans and X-rays, neither of which is priced at what it is worth in materials or energy, but in terms of amortization of equipment and expert interpretation.

But $1000 won't be practical for quite a long while. So what are the implications of the $10,000 genome?

Remember that most young people just don't care very much about their genomes. Here's what I found of my students in 2005:

The results: only two would pay more than the price of a CD, around $16.00. Most didn't want the information at all --- they didn't see what possible use it could have for them.

In contrast to my undergraduates, an insurer would probably find a $1000 genome pretty useful, particularly for current customers. That's too expensive for screening potential clients, but well in the price range of procedures that they normally cover.

$10,000, on the other hand, is not in the usual range of diagnostic procedures. We have to think about what would make a genome worth that much more than a typical diagnostic procedure. It seems pretty obvious that you would only pay that much for a procedure if it had the potential of preventing something much more expensive. But for this much money, it can't be a mere long-term potential, it must be an immediate potential.

So we are looking for medical bills far in excess of $10,000 that would be prevented by a genome sequence. Read that carefully: bills that would be prevented, not diseases that could be cured.

It seems like the main application of a $10,000 genome sequence would be to prevent people from having expensive surgeries, particularly transplants.

Suppose you are an insurer that might normally approve a $250,000 transplant surgery, with a 30 percent failure rate. For $10,000, suppose you could gain some better prediction of long-term survival or organ rejection rates. So you implement a required whole-genome screening before approving surgery, and require that the patient's genetic "risk" factors don't exceed some threshold. If you eliminate 10 percent of surgeries, your investment in whole-genome sequencing yields a 250% return -- assuming the cost of care without surgery approximates that after failed surgeries.

Now, I have my doubts about whether this scenario will come to pass. For one thing, SNP screening is going to be a lot cheaper than whole-genome sequencing for a long time, and probably will be just as informative. The benefit of the whole-genome sequence -- that it finds the rare variants that no one else has -- also makes it much less medically useful, since nobody knows what your unique rare variants actually do.

Michael Balter has a nice profile of archaeologist Randall White in the NY Times:

Despite Dr. White's early success, he found it difficult to begin a dig of his own in the Périgord. Dr. White says that the French prehistorian responsible for issuing permits to excavate in the area preferred that he work as part of his team rather than independently.

"I was shut out of working in France the way I wanted to do it," Dr. White said. Rather than agree to work as part of the team, he began to look at collections of artifacts stored in museums in Canada and the United States, where he found thousands of objects from digs by Peyrony and other archaeologists, including artifacts from the Abri Castanet, sometimes stored in terrible conditions.

"I saw Upper Paleolithic engravings with drawers on top of them," Dr. White said, adding that these experiences fueled his early anger about the antiquities trade.

The profile starts with a quick summary of the argument in White's new book, about Otto Hauser and Denis Peyrony's early 20th century excavations. Sounds interesting -- I hope I get a review copy!