This Week in PNAS

By sequencing and comparing tumor and matched normal genome sequences from two sets of identical twins with acute lymphoblastic leukemia, a team from the UK, Italy, and the US was able to identify tumor-associated somatic mutations and track the timing with which they developed. As they reported in the early, online edition of the Proceedings of the National Academy of Sciences, the researchers found that the identical twins tended to share prenatal alterations that seem to spur ALL development. But in each twin pairs, the majority of suspicious mutations differed from one twin to the next, consistent with the notion that most of the genetic changes in tumors were secondary (or in some cases, passenger) mutations acquired in each individual after birth.

Wild gorillas and chimpanzees carrying parasites related to the malaria-causing pest Plasmodium falciparum do not seem to be an ongoing source of human infections, according to another PNAS study. An international team led by investigators at the University of Pennsylvania did targeted mitochondrial gene sequencing on blood samples from hundreds of malaria-infected individuals in Cameroon, looking for genetic signs of Plasmodium species or parasites from a P. falciparum-related Laverania sub-species that's known to be found in apes. The ape-associated Laverania species were not detected in human infections, researchers explain, and their phylogenetic analysis of P. falciparum parasites was consistent with a single historical transmission of this species from gorillas into humans.

Finally, Yale School of Meidicine's Daniel DiMaio and colleagues describe the genome-wide, small interfering RNA strategy they used to find factors in human cells that participate in human papillomavirus infection. Using a library of more than 18,000 siRNAs, the researchers screened for factors altering HPV pseudovirion entry into HeLa cells. The search unearthed several proteins, including so-called retromer sub-units — proteins participating in retrograde transport in the cell.

"These results provide important insights into HPV entry, identify numerous potential antiviral targets, and suggest that the role of the retromer in infection by other viruses should be assessed," DiMaio and co-authors note.

Genealogy, Astrology, Whatever…

Two scientists took to the pages of The Guardian yesterday to contend that their area of expertise, which has been called interpretative phyleogeography is not "genetic astrology," in response to another recent column which said that it may be.

According to Martin Richards, a professor of archaeogenetics at the University of Huddersfield, and Vincent Macaulay, a reader in statistics at the University of Glasgow, they engage in interpretative phyleogeography when they look to mitochondrial DNA and the Y chromosome to study the dispersal of humans.

They were responding to criticisms leveled by Mark Thomas, a professor of evolutionary genetics at University College London, in the same paper two months ago, in which he suggested that the genetic ancestry testing industry, and the media which has been enabling them, are mostly offering a load of hooey.

Thomas had taken the UK media to task for television shows like "Meet the Izzards," in which the ancestral genetics of comedian Eddie Izzard shows him to have a Viking descendant on his mum's side and an Anglo-Saxon on his fathers. Another example, he said, was the recent article in the Daily Telegraph which said that as many as 1 million British men may be directly descended from the Roman legions.

He also said that the results from the genetic ancestry testing products that some of these media reports are based on are convoluted by the complexity of the science.

"The truth is that there is usually little scientific substance to most of them and they are better thought of as genetic astrology," Thomas writes.

Thomas says that if anyone looks very far back in time they will find that they have more ancestors than they have sections of DNA, and that humans move around a lot, making predictions about lineages a difficult business.

If you go back around 5,000 years, he adds, you get to a point where either nearly everybody alive then was a common ancestor of nearly everyone alive today, or they were a common ancestor to no one alive today.

"Nobody is pure this, or pure that, and a substantial proportion of human ancestry is common to all of us. Ancestry is complicated and very messy," Thomas writes.

Richards and Macaulay agree that Thomas "may have a point in his critique of his genetic testing companies," but also say that there are real merits to linking genetics and geography to study ancestry.

Phylogeographers, they write, rely on "the principle that every mutation in the DNA arises at a specific point in space and time, and that a plot pinpointing these locations is effectively an outline of the movement of people across the landscape and around the world."

They also note that "the mitochondrial picture almost exactly matches the archaeological evidence for the colonization of the Remote Pacific, about 3,000 years ago," and that the same is true from the Bantu expansion in Africa.

"Hopefully, the point is made. There are enough archaeologically well-known cases of colonization to show that phylogeographic interpretations can work in principle," they write.

Taxpayer Campaign Bucks for Autism

US House of Representatives Eric Cantor (R – Va.) unveiled on World Autism Day a novel plan to cut federal public funding for presidential campaigns and conventions and to use that money to fuel autism research efforts.

Cantor said last week that he and other colleagues in the House plan in the coming weeks to introduce the Kids First Research Act, which will eliminate the public funding for Republican Party and Democratic Party presidential conventions and campaigns, and instead will "use these funds to expand pediatric research at the National Institutes of Health through the NIH Common Fund…."

Cantor notes that a recent report stated that one out of 50 school-aged children are affected by autism spectrum disorder.

"And that’s why I can think of no better use for the millions of taxpayer dollars currently spent on presidential campaigns and political party conventions than funding the medical research that holds the key to improving the quality of life for so many Americans," he said.

The Hill reports on the plan, and points out that "the $200 million Cantor's proposal would restore is about 8 percent of the $1.6 billion cut from the NIH under sequestration.

Strategy, What Strategy?

There are two general ways to go about managing a lab, says Vicki Doronina at Bitesize Bio. One she calls the seagull strategy while the other she dubs the commons strategy.

Seagulls, she writes, may live all together, but they don't hunt for food together. Rather, they scavenge food from each other. In the lab, such a management strategy leads to each person being self-reliant. Though, Doronina notes, it can lead to inefficient use of resources.

"Applying the seagull strategy (SGS) to the lab, each person develops their own SGS so that, at least in theory, everyone's work speed depends on their individual organization skills," she writes, adding that this approach also leads to "an environment where everybody spends time making the same reagents."

At the other end of the spectrum, then is the commons strategy in which such reagents and other stocks are communal property. However, Doronina points out that it is subject to the tragedy of the commons in which people use but do not contribute to the communal property. "However, this can be prevented by establishing a rota and applying peer pressure on colleagues who don't pull their weight," she adds.

She also notes that if researchers find themselves in a "seagull" lab, but want a "commons" one, they can always make a stock solution and encourage others to use it.

Shaking Signs for Science

In Washington, DC, yesterday thousands of protestors from the biomedical and patient activists communities drew attention to the stagnation of funding for biomedical research and the negative impact of the sequester, and urged that money that has been lost over the last decade be restored to the National Institutes of Health.

"Funding medical research is a no-brainer when it comes to our national interests," said Rep. Chris Van Hollen, (D - Md.) according to an article posted in USA Today. "Let's make sure we have more progress, more hope and more lives."

The event's organizers said they are seeking at least $32 billion for NIH in next year's budget, which would be an increase of around $1.3 billion over this year's funding. They also said that the automatic sequestration cuts have whacked the NIH budget down from the initial $31 billion to around $29 billion, according to the USA Today item.

The Hill also covered the rally, and aims its focus on the statements of Van Hollen and Rep. Rosa DeLauro (D - Conn.).

"We need to make it clear to my colleagues exactly what these cuts mean for the health of America's families," DeLauro said in her statements to the crowd, The Hill reports. "When they see a grassroots movement rising up, from doctors, from scientists, from advocates and patients, you are impossible to ignore … You need to overwhelm the institution with your voices."

Science's Jocelyn Kaiser notes that NIH Director Francis Collins had been billed to speak at the event but was a no-show. She pointed out that while "federal employees cannot participate in lobbying activities, Collins was initially going to speak as a private citizen, according to sources, but ultimately cancelled."

She also cites American Association for Cancer Research CEO Margaret Foti as saying that for a while during the event tweets with the hash tag #RallyMedRes were rated second only to tweets about former UK Prime Minister Margaret Thatcher's death.

The Dark Side of Open-Access Journals

A growing number of open-access journals of questionable reputation are offering to publish "seemingly anything" for a fee and are preying on researchers to lend them credibility, The New York Times reports today.

One doctor who submitted two articles to The Journal of Clinical Case Reports was billed $2,900 for their publication, a fee he had not been told about. When he tried to withdraw the papers, they were published anyway, and his fee was waived after a year of back-and-forth.

A plant pathologist at Rutgers University agreed to join the editorial board of another journal, Plant Pathology & Microbiology, only to find himself listed by the publisher as an organizer and speaker for a conference called Entomology-2013."I am not even an entomologist," he told the Times. The conference is trying to mimic a well-known meeting called Entomology 2013.

Up to 4,000 such "predatory journals" exist today – at least a quarter of all open-access journals – according to Jeffrey Beall, a research librarian at the University of Colorado, who keeps a blacklist of them called "Beall's list."

The Long-Read Game

Long-reads sequencing is once again at the forefront, writes Michael Eisenstein at Nature Biotechnology. A few years ago, Pacific Biosciences made a splash at the 2010 Advances in Genome Biology and Technology meeting with its RS machine, which it said at the time could produce sequences as long as 20,000 bases. However, as Eisenstein notes, the approach was limited by a low throughput and high error rate.

The company, though, has improved its machine, and other companies are hot in pursuit. Talks at AGBT this year, Eisenstein says, showed that a PacBio approach could be applied to de novo sequence assembly of repetitive genomes as well as to elucidate structural variations. "In the past year, the read lengths have improved by a factor of four," Michael Schatz from Cold Spring Harbor Laboratory tells Nature Biotechnology. "If this were Apple, they would have branded it as a new model — it really feels like a new instrument."

At the same time, Illumina and Nabsys are developing long-read sequencing capabilities. Illumina acquired Moleculo earlier this year, and that technology is slated to launch this summer. It, too, has been used to sequence a de novo, repetitive plant genome, Eisenstein notes. While it has its drawbacks in dealing with GC regions, CSHL's Schatz notes that there is time for improvement before its launch. And Nabsys says that its semiconductor-based system will allow for fast and precise sequencing.

DNA as Search and Seizure

The US Supreme Court recently heard arguments in Maryland v. King concerning whether obtaining DNA samples from people as they are arrested violates Fourth Amendment protections against unreasonable searches and seizures. In The Nation, Jason Silverstein writes that a factor beyond privacy comes into play with the collection of DNA samples upon a person's arrest. "Because people of color are disproportionately stopped, searched and arrested, they will disproportionately bear the burden of this genetic dragnet," he writes. "And because DNA samples can be used to establish family relationships, it has the potential to widen the surveillance to entire communities."

Indeed, the Los Angeles Police Department has said that it was able to make an arrest in the 'Grim Sleeper' serial killer case because of a familial search. Christopher Franklin was arrested in conjunction with a weapons charge and his DNA test showed a similarity to samples from the serial killer case; his father Lonnie Franklin, Jr., was subsequently arrested and charged in the Grim Sleeper case.

However, Silverstein notes that such police DNA databases likely contain a significant portion of samples from people who were never convicted or sometimes even charged with a crime. The American Civil Liberties Union estimates that about 19 percent of people arrested in California for a felony were never charged with a crime, Silverstein writes. Getting removed from the database is also difficult, with the procedures differing from state to state.

The Court is expected to rule on the case this summer. How the Court votes, Silverstein says, may be unusual. "When Maryland's chief deputy attorney general, Katherine Winfree, recited the number of convictions won through DNA matches, Justice Antonin Scalia fired back, 'If you conducted a lot of unreasonable searches and seizures, you'd get more convictions, too. That proves absolutely nothing.'" On the other hand, Justice Stephen Breyer pushed back against King's attorney, saying DNA tests are "no more intrusive" than fingerprints but "much more accurate."

This Week in PLOS

A PLOS One study by Swiss researchers suggests individuals may have distinct and distinguishable metabolite profiles in their breath. The research team used real-time mass spectrometry to assess exhaled compounds in breath samples from six men and five women. Analyses of the samples — taken at multiple times per day for each individual over nine days — revealed consistent core metabolite "breathprints" that were specific to each individual and remained stable over time. "Consistent with previous metabolomic studies based on urine," authors of the study explain, "we conclude that individual signatures of breath composition exist."

Members of the Gentrepreneur Consortium brought together genotyping and employment data for more than 50,000 European individuals as part of a meta-analysis looking for genetic contributors to entrepreneurial personality traits. As they report in PLOS One, the researchers did not find individual SNPs of significant effect, though their findings hint that common genetic variants spread across many genes may explain a considerable proportion of self-employment heritability (as estimated using twin data). "Although self-employment is a multi-faceted, heavily environmentally influenced, and biologically distal trait," study authors note, "our results are similar to those for other genetically complex and biologically more proximate outcomes, such as height, intelligence, personality, and several diseases."

A PLOS Genetics study by the Uppsala University's Siv Andersson and colleagues from Sweden, Greece, and Austria outlines a multiple displacement amplification-based scheme for sequencing the genomes of bacterial endosymbionts that can't be cultured in the lab. The group sequenced representatives from two strains of Wolbachia (an intracellular symbiont) that seem to co-infect the Drosophila simulans fly. Comparative genomic analyses of these so-called wHa and wNo strains revealed that the strains are not only genetically distinct Wolbachia clades, but also that they can co-exist in the same host without mixing.

AACR Throws a Birthday Party for James Watson

The American Association for Cancer Research honored James Watson's 85th birthday at its annual meeting this weekend with a special session that included a round of "Happy Birthday to You" and a birthday cake.

After blowing out his candles, Watson spoke about his recent work investigating the hypothesis that antioxidants play a role in cancer. He published a paper earlier this year in Open Biology outlining his views on the subject, but apparently that journal wasn't his first choice.

He said during his talk on Saturday that he initially submitted the paper – his first since 1972 – to the New England Journal of Medicine, but was rejected because, he said he was told, NEJM "doesn't publish ideas, only facts." Several other journals also turned him down.

This experience, he said, led him to believe that journal publishers see it as their mission to reject papers rather than publish them. "I hate the editors of these journals more than I hate Republicans," he said. "They're anti-science."

He wrapped up by calling for a more concerted research effort into the role that antioxidants play in cancer, noting that the cancer research community can make faster progress if it considers new ideas. "We can do it if we don't spend all our money investigating RAS," he said.

Cost Conscious

With sequestration-driven budget cuts and waning bipartisan support, the environment for medical research funding in the US is looking bleak and could turn bleaker still unless researchers work to turn things around, the University of Pennsylvania's Ezekiel Emanuel writes in a commentary published this week in the Journal of the American Medical Association. (Emanuel is the brother of Rahm Emanuel, the Chicago mayor and former chief of staff for President Barack Obama.)

Emanuel attributes this fall-off in support for medical research to four factors: the increased politicization of science; the current lack of strong Congressional champions for agencies like the National Institutes of Health; the increased scrutiny large NIH budgets have drawn; and, in an irony worthy of Alanis Morissette herself, the role of medical advances have played in increasing healthcare costs.

Of that last factor, Emanuel writes that roughly half the increase in healthcare costs can be attributed to "technology, that is, advances in biomedical science."

"And a main source — if not the main source — of advances in biomedical technology is the NIH," he notes.

So what's a person to do? Go back to bleeding patients with leeches?

Well, no. But, Emanuel says, NIH and the larger medical research community would be well served by focusing more seriously on developing "technologies that are not just 'incredibly exciting' but also cost lowering and value enhancing."

"Focusing research on cost-lowering, quality-improving interventions has not been an NIH priority," he writes. "This change in focus is vital to the future of both the country and the NIH."

Which Is It?

Big science can lead to big reactions, and Greg Miller at Wired has put together a poll comparing reactions to the announcement of the Human Genome project to those in response to the new brain mapping initiative, conveniently called BRAIN.

"Today [the Human Genome Project] is widely viewed as a success, but in the early days it too was controversial," Miller writes. "Just because the critics of the genome project got it wrong doesn’t mean that the critics of the brain project aren't raising good points, but there's a similar ring to many of the arguments for and against the two projects."

For example, respondents to the poll split 48 to 52 that this phrase referred to the brain project or the genome project: "Arguments are made that the ... project will give birth to a new generation of technologies. What good will that do in the absence of individuals trained and capable of applying these technologies?"

For the answer, and more comparisons, take Miller's poll.

LncRNA, the Place to Be

The field of long non-coding RNAs is moving from the fringe into mainstream research, bringing a number of young researchers with it, writes Amy Maxmen at Nature. While there is enthusiasm for the field, she adds, lncRNA studies can still be difficult to tackle. "There are no optimized experimental protocols and few clues to the habits of individual lncRNAs, so experiments often fail," she says. "And when they do work, investigators need to go the extra mile to convince reviewers that their results are real."

"I have had so many conversations where people think I'm just full of crap," Kevin Morris, from the Scripps Research Institute tells Nature. "You need a thick skin to be in this field. You need to do it because you love it."

And researchers who are taking on the problem are in demand, Maxmen says. Case Western Reserve University's Saba Valadkhan "was consumed with curiosity about the possibility that long RNA sequences that do not encode proteins nevertheless have a function — enhancing or suppressing gene expression," and more senior researchers noticed. Valadkhan says that before she even began to look for a job, she was hearing about job openings.

Further, there are funding opportunities for lncRNA studies. Maxmen notes that 28 grant applications for lncRNA studies were approved in 2012, and that more a announcements are specifically targeted at lncRNA studies.