My previous post discussing, among other things, the uncertain impact of mutations in BRAF on melanoma, was written in ignorance of two new and quite relevant papers. One, by Solit et al., and published online in Nature, discusses BRAF in the context of one of its downstream effectors, MEK. The authors show that BRAF mutation is associated with “enhanced and selective sensitivity to MEK inhibition”. Targeting MEK with a specific inhibitor called PD0325901 (Pfizer) completely blocks the growth of xenograft tumors in mice driven by the common V600E mutation in BRAF. They conclude:

Thus far, the use of BRAF inhibitors in clinical trials has met with mixed results. On the other hand, the favourable therapeutic index and selectivity of MEK inhibitors may provide an appealing therapeutic strategy for BRAF mutant cancers. We therefore propose clinical trials of MEK inhibitors in which patients are stratified based on BRAF mutational status.

The second paper, by Curtin et al., and published in The New England Journal of Medicine, describes an array CGH-based assessment of copy number alterations in melanoma. The results show that while BRAF or N-RAS are mutated in more then 80% of melanomas without chronic sun-induced damage, the majority of melanomas in other categories did not have such mutations, but were often associated with amplifications of the genes encoding CDK4 and cyclin D1, both of which are downstream effectors of the RAS-BRAF pathway.

The lesson here is not a new one. As was the case with chemotherapeutic agents like Herceptin for breast cancer and Iressa for lung cancer, the first drug for melanoma will almost certainly not be effective in all cases, but will have to be targeted to those individuals bearing certain mutations. BRAF still points the way.

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Lovers of science-in-culture subject matter may have been following the launch of the magazine Seed, which, if memory serves, first appeared in 2004. Its editorial stance was that ‘science is culture,’ i.e. that science is not an activity somehow separate from mainstream culture but should be covered by journalists the way any other area of modern life might be covered. At times, it may have looked and sounded like a scientific version of George, which covered politics as entertainment, and in the process sometimes forgot that while politics can be entertainment, it’s not just entertainment. These concerns aside, Seed has now been relaunched as part of the Seed Media Group, along with an excellent blog called Sciencegate. Both the redesign and the lively mixture of articles, photographs and reviews look quite promising so far. All of this is prelude to my pointing toward a short piece on the recent paper by Martin Lercher and colleagues that was published in NG on the evolution of metabolic networks in bacteria. The piece, by Maggie Wittlin, is on Seed's website, and Lercher provides some helpful commentary therein.

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Nowack et al.
A positive signal from the fertilization of the egg cell sets off endosperm proliferation in angiosperm embryogenesis

Rosenbauer et al.
Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1

Ferrante et al.
Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification

Lerner-Ellis et al.
Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type

Comments welcome.

Posted by Alan Packer at 10:07 AM | Permalink | Comments (0) | TrackBacks (0)

Nybakken et al.
A genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signaling pathway

Zenker et al.
Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome)

Pál et al.
Adaptive evolution of bacterial metabolic networks by horizontal gene transfer

Comments welcome.

Posted by Alan Packer at 09:36 AM | Permalink | Comments (0) | TrackBacks (0)

I’d like to thank Paul (PZ) Myers for giving Free Association a plug. For those of you who may not be regular readers of science blogs, PZ’s Pharyngula is one of the most frequently read blogs in the life sciences. When he’s not battling creationists and generally defending the values of the Enlightenment on his blog, he’s an associate professor in the Department of Biology at the University of Minnesota Morris. His research interests are in the developmental biology of zebrafish and, for my money, he writes some of the best explanations of the evo-devo literature to be found anywhere on the web. As an example, there’s his summary of a recent paper by Albertson et al. published in PNAS, entitled “Integration and evolution of the cichlid mandible: The molecular basis of alternate feeding strategies”. What makes the paper so appealing is its integration of genetics (QTL mapping), biomechanics, developmental biology, gene expression, and morphometry—all in the service of new insights into the evolution of the opening and closing mechanisms of the cichlid jaw, which relate to different modes of feeding. PZ’s tour through the paper is well worth reading.

As for his plug of Free Association, he titles his post “But don’t they have anything better to do with their time?”

The answer, of course, is yes. But if a full-time, no doubt overcommitted academic can start a blog, why can’t we?

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Steve Warren’s tenure as editor of The American Journal of Human Genetics is at an end, and he’s penned an interesting ‘letter from the editor’ in the December issue of the journal. Here’s an excerpt:

Being editor has developed into a very enjoyable activity. It is a singular opportunity to learn in depth all the diverse scientific disciplines that actually compose what we refer to as “human genetics.” I came to enjoy not only population genetics, particularly those studies linking molecular data with historical accounts of population movement and/or dynamics, but also, surprisingly to me, the intricacies of statistical genetics.

I know what he means. Being an editor is like getting another graduate degree, without the experiments, but with several exams every day. And the joys of statistical genetics are indeed underappreciated. He goes on, commenting on the problem of receiving more good papers than the journal can publish:

Being unable to publish all these papers, then, requires decisions resting upon the editor’s perception of widespread interest, utility to the field, and general impact. This is a problem, since any practicing scientist has inherent biases, likes, and dislikes. If someone stays in the position too long, the journal begins to take on these personal attributes and morphs into the editor’s weekly reader…

That’s another good point, which also suggests a need for editors to solicit advice from a broad range of people in the community, rather than just a select few. At NG, we have five manuscript editors, which helps to prevent one person’s view of the field from taking hold, and we do try to bring new referees into the fold all the time. At the AJHG, Cynthia Morton will be the new editor. Dr. Morton is a distinguished cytogeneticist whose interests range from uterine fibroids to hereditary deafness to chromosomal rearrangements that cause disease.

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Here’s my favorite recent headline, topping an October 18 piece in Slate by Arthur Allen:

The Disappointment Gene: Why genetics is so far a boondoggle.

Huh? Just to be sure that I wasn’t misinterpreting, I consulted a dictionary, which defines the word ‘boondoggle’ as “unnecessary, wasteful, and often counterproductive work”. Well, that sounds pretty bad. What are we to make of it? To begin with, I suppose we have to assume that the headline-writer is referring specifically to twenty-first century genetics, rather than to a big-spending classical geneticist like, say, T.H. Morgan (how many drugs did he develop?) No, it must be the age of genomics that is a major disappointment. And if that’s the case, then surely it’s worth reminding everyone that the ink on the HapMap publication is barely dry, and that there are several human chromosomes whose finished sequence has not yet been published. But after reading Allen’s full piece, I realized that the headline, which bears little relation to what comes after, is meant to convey much more than the author intends. For the article is a good one. It takes aim at some of the ‘nutrigenetics’ companies that aim to turn a profit by peddling the most obvious advice imaginable. It reminds readers of the complex relationship between genotype and phenotype, made even more complex by recent discoveries of non-coding transcripts and regulatory RNAs. It explains to readers how the usefulness of the HapMap depends to a great extent on the assumption that there are common variants underlying common disease. In other words, science as we know and love it. All good stuff. So why the sense of doom?

Perhaps part of an answer can be found in a somewhat similar piece by Sharon Begley in the Wall Street Journal (freely available here in the Pittsburgh Post-Gazette). Begley’s piece, entitled “Nature’s quirks limit DNA-based drug possibilities” describes recent findings where gene-based drug discovery has come up short. The first is the disappointing lack of efficacy of an inhibitor of B-Raf in treating melanoma. She follows with other examples of gene-based interventions that turn out to much less precise (and effective) than one would have hoped. Vipin Garg, CEO of Tranzyme Pharma, is quoted as saying “The gap between understanding the genetics of a disease and drug development is actually growing”.

But surely that gap has always been the same; it’s an appreciation of the scope of our own ignorance that’s been growing. That’s a good thing, which genetics has been partly responsible for. By all means, let’s expose the hype. But at the same time, let’s acknowledge that the only way to conquer all of this complexity is to understand it. And if B-Raf is not the Achilles’ heel of melanoma, then it seems likely that it will be among the best available entry points into finding out what is.

In any case, if you were wondering how soon it will be before there’s a backlash if Big Pharma’s pipeline doesn’t fill up with genomically inspired drugs, the answer may be: sooner than you think.

Posted by Alan Packer at 04:00 PM | Permalink | Comments (1) | TrackBacks (1)

Anttonen et al.
The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone

Senderek et al.
Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy

Monsuur et al.
Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect

Choi et al.
Robust signals of coevolution of interacting residues in mammalian proteomes identified by phylogeny-aided structural analysis

Comments welcome.

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The launch of Free Association coincides with another new beginning for the Nature Genetics editorial team - the relocation of one of our team members (Kyle Vogan) to Nature Publishing Group's Boston office.

The move is something of a homecoming for me: before making the leap into the world of editing, I was a postdoc in Cliff Tabin's lab in the Department of Genetics at Harvard Medical School. It's good to be back among familiar sights and faces, and I look forward to reconnecting with the Boston research community through lab visits and local meetings. Invitations welcome!

My initial impression is that the city hasn't changed much in the two years that I've been away: the fall colors are beautiful, the Big Dig is still the Big Dig, and the Patriots and Red Sox continue to dominate local headlines. But behind the familiar backdrop, I expect I'll discover dynamic changes to the local research community as I venture out and explore my new surroundings. I look forward to taking it all in.

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Most of our readers will know that all Nature Genetics research papers are published online on Sundays, in advance of print publication. Starting next Monday, and on every Monday, Free Association will feature links to the abstracts of that week’s papers, as a way of inviting discussion (see “The Sunday Papers” heading).

On rare occasions we will publish a paper online mid-week, if it is particularly timely for an upcoming conference at which the data in such a paper are sure to attract attention. This afternoon we have posted a paper by Anna Helgadottir et al., entitled “A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction”. This papers reports an association study for a common, complex disease, and shows the same haplotype conferring differential risk on two populations. It’s a top-flight conversation piece.

Posted by Alan Packer at 02:50 PM | Permalink | Comments (2) | TrackBacks (1)

In the October issue of the journal we published an editorial on the possibility of a medical sequencing program at the NHGRI that would be aimed at speeding the identification of genes underlying mendelian forms of disease in humans. Recently, the NHGRI issued a press release announcing the approval of such a program by the National Advisory Council for Human Genome Research. At first glance, the plans seem even more ambitious than was initially suggested.

As expected, part of the program will be an effort to sequence large intervals that harbor mutations underlying rare, autosomal mendelian disorders. A pilot project is to begin next year, and will target familial forms of atrial fibrillation, aortic aneurysms, and other heart disorders, as well as four other rare disorders, including Joubert syndrome. This last disease, which affects the brain and overall physical development, has been the subject of one recent paper in the journal, by Christopher Walsh and colleagues. They identified mutations in AHI1 as one cause of Joubert syndrome, which is of particular interest given the authors’ evolutionary speculation that it may be involved in some aspects of “the distinctive motor programs that characterize humans”. The identification of additional Joubert genes may shed light on this hypothesis.

But the press release also announces a program to identify the mutated genes underlying every X-linked disorder:

While researchers have identified the genes responsible for a number of X-linked disorders, the precise genetic basis for approximately 130 of these disorders remains to be determined. The study would entail completely sequencing all genes on the X chromosomes of individuals affected with the disorders, and looking for variations that consistently correlate with each disorder.

In other words, if the project is successful, we will have for the first time a complete list of genes on an entire human chromosome that when mutated cause known mendelian forms of disease. A landmark in human genetics in the offing.

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Yesterday I outlined the kinds of posts that you would see on a regular basis at Free Association. The list is by no means exhaustive. A word here about posts that you won't see. While we are looking forward to using this space to clarify editorial policies in general terms, the specifics of the peer review process obviously remain confidential. In a way, a blog run by editors at a peer-reviewed journal is a bit of an outlier, in that stream of consciousness posts describing "what I did today" have to omit much of what we spend our time doing, which is overseeing a confidential peer review process (by analogy, there aren't too many clerks for Supreme Court justices who have blogs, to my knowledge). That said, we're confident that there will be than enough for us to discuss to make this site a lively and worthwhile read. Your contributions will no doubt ensure this. And if anyone wants to weigh in on whether the peer review process should continue to be confidential, I'm sure you'll get a good argument on either side.

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Welcome to Free Association, the new blog from the editors of Nature Genetics.

If it sometimes seems to you as if everyone with an internet connection has his or her own blog, rest assured we’ve noticed that as well. Given that, how can we justify claiming a space on the bandwagon?

Well, it turns out that the bandwagon in science blogging has lots of room. As noted by Richard Gallagher in this editorial in The Scientist, the life sciences in particular have been late to embrace blogging as a way to spark interesting conversation, promote more of a sense of community among scientists, and, possibly, to increase awareness of the process and substance of science among non-scientists.

So, with a great deal of excitement, we are launching Free Association, accompanied by our colleagues at Nature Neuroscience, who are launching their own blog called Action Potential . What might you find here? Here’s some of what we have in mind:

· Commentary on papers published in Nature Genetics or in other journals. We’re particularly interested in inviting authors to follow up on points in their work that may not have found space in the formal manuscript.

· Links to and commentary on genetics (and geneticists) in the news.

· Updates on books and websites of interest to the community.

· Notes on editorial policies that may not have made it into one of journal’s printed editorials.

· Announcements of editors’ attendance at meetings, which may also generate posts to the blog.

· Round-ups of genetics coverage in the popular press and in the blogosphere (for better or worse).

And…no doubt some things we haven’t yet thought of. Perhaps the most important component of Free Association will be reader comment, which is strongly encouraged

Science is hard work. But if you need a break from the bench, or a break from the heavy lifting of the peer-reviewed literature, just run that gel a bit more slowly and check in with our own ongoing experiment.

Posted by Alan Packer at 09:51 AM | Permalink | Comments (6) | TrackBacks (2)