Scientists had long assumed that any genetic mutation that does not alter a protein sequence should have no impact on human health. But recent research has shown that such synonymous DNA changes can trigger disease in a number of ways. Alla Katsnelson talks to scientists and biotech companies who are speaking up about ‘silent’ mutations.

It all started with an expression problem. Michael Gottesman and his lab members at the US National Cancer Institute in Bethesda, Maryland were studying a membrane protein involved in drug metabolism called P-glycoprotein to understand why some people develop resistance to chemotherapy during cancer treatment. But when the scientists tried to express large quantities of the protein in bacterial cells, they hit a wall.

“It was a real mess,” Gottesman recalls. “We couldn’t do it.”

The genetic code is read in triplets called codons, 64 of them representing just 20 amino acids. That means there is more than one codon for each amino acid, and different organisms preferentially use certain codons to make translation faster. One standard trick for boosting the expression of human genes in other organisms is to swap around nucleotides to get the DNA triplets most often used by the host’s cellular machinery. But a colleague of Gottesman’s suggested a different tack: as proteins elongate, the translation process needs to slow down and speed up to achieve proper folding, and perhaps the distribution of frequent and rare codons might control that rhythm.

The idea got Gottesman thinking about a niggling problem. The gene that encodes P-glycoprotein, called multidrug resistance 1 (MDR1), has about 50 single nucleotide polymorphisms, a handful of which are located in the coding region but at a position where they don’t affect the protein’s amino acid sequence. One, for example, in exon 26 of this 209-kilobase-long gene switches an ATC codon to ATT, both of which encode the amino acid isoleucine. Scientists routinely assume that such ‘silent’ or ‘synonymous’ mutations don’t affect the protein’s function, but clinical data clearly showed that people carrying these mutations metabolize drugs differently. “We were trying to think of how it could be that these synonymous mutations caused these changes,” Gottesman says. Maybe, he thought, they were meddling with the rhythm, thereby changing the protein produced.

The researchers then expressed the ATT codon along with two other naturally occurring polymorphisms and saw that the expression levels of messenger RNA (mRNA) and protein remained the same, but the protein’s activity was altered. Just as Gottesman had hypothesized, the evidence pointed to a shape shift in the resultant P-glycoprotein, caused by altered timing of translation.

The findings, published online in Science in late 2006, weren’t the only report of this type of mutation at work. A paper published at the same time in the same journal reported that synonymous polymorphisms in a gene encoding a protein called catechol-O-methyltransferase, which modulates responsiveness to pain, affected the loops and turns that make up the structure of the gene’s corresponding mRNA, and, with it, the level of protein expression. The two studies were the first published examples of human genes in which naturally occurring mutations produced proteins with an unchanged amino acid sequence but clearly different functional effects on disease. And, in the five years since, the idea that such mutations can have dramatic and far-reaching effects is beginning to take off.

(Click here to continue reading.)

Since its launch in 2001, the Center for Global Development (CGD) has been instrumental in convening working groups and issuing reports that shape the agenda for a range of topics that affect global poverty and people of the developing world. At the helm of its global health effort is Amanda Glassman. As the daughter of US Foreign Service diplomats, Glassman was exposed to disparities in public health in developing countries from a very young age. So it was a no-brainer for Glassman that she would devote her career to tackling those inequalities. She has spent the last two decades at places like the US Agency for International Development, the Inter-American Development Bank and the Brookings Institution. Last year, she joined CGD as the director of its global health policy division.

One idea that the $10-million-a-year, Washington, DC–based think tank has championed with some success is what’s known as an advance market commitment (AMC), a financial instrument that incentivizes vaccine development for diseases primarily affecting low-income countries. It’s for this influence that the center, which is mainly funded by governments and philanthropic entities, was ranked the fifteenth most important US think tank by Foreign Policy magazine in 2008. In recognition of CGD’s ten-year anniversary last month, Elie Dolgin spoke to Glassman about how the think tank turns its words into actions.

(Click here to continue reading.)

By Sarah C P Williams

The approval this year of the first direct-acting antiviral drugs for the hepatitis C virus has ushered in a new era of treatment. Since the mid-May launch of Incivek (telaprevir) and Victrelis (boceprevir) — both of which disrupt viral replication by inhibiting HCV’s protease protein — physicians have rapidly been prescribing the pills to many of the estimated 180 million people worldwide who are infected with HCV. This is reflected in October earnings reports showing that sales of Incivek reached nearly $420 million in the third quarter of this year alone, which puts it on pace to become the fastest blockbuster in the history of the pharmaceutical industry.

But Incivek, from Vertex Pharmaceuticals of Cambridge, Massachusetts, and Victrelis, from Merck of Whitehouse Station, New Jersey, currently have a catch. Each medicine must be taken with a broad-acting antiviral pill called ribavirin as well as with regular injections of pegylated interferon. Historically, viral clearance occurs in around half of all people who take interferon together with ribavirin, but another 20% can be cured of their HCV when doctors throw one of the new polymerase inhibitors into the mix. Interferon stimulates the immune system but comes with side effects ranging from flu-like fatigue to severe depression to cardiac arrhythmias. Up to a third of people on the protein ultimately stop the therapy early because of adverse reactions.

Against this backdrop, there was much fanfare over the 1 November announcement by the Princeton, New Jersey–based company Pharmasset that it would initiate the world’s first phase 3 clinical study involving an all-oral, interferon-free protocol before the end of the year. The 500-person trial will compare a three-month regimen of the company’s experimental polymerase inhibitor, PSI-7977, together with ribavirin against a six-month course of interferon plus ribavirin. PSI-7977 works by becoming incorporated into RNA chains being made by HCV, stopping the virus from replicating.

“There’s been real concern that we might never be able to get away from interferon entirely, but now we’re starting to get an inkling that that might not be the case,” says Gary Davis, director of the general and transplant hepatology unit at the Baylor University Medical Center in Dallas.

(Click here to continue reading.)

John Darsee was a young clinical investigator with a long list of publications in top-tier journals and a promising career ahead of him in cardiology research. Described by a former supervisor as “one of the most remarkable young men in American medicine,” Darsee was offered a faculty position at the Harvard Medical School in Boston at the age of 33. But then his career quickly started to unravel. One day, colleagues caught Darsee fraudulently labeling data for a study into heart attacks; further investigations revealed scientific misconduct on a massive scale, and, eventually, Darsee was fired and barred from receiving federal grant money for ten years. More than 80 of his papers were withdrawn from the literature. He ultimately apologized for publishing “inaccuracies and falsehoods.”

That was twenty years ago. But the problem of retractions has not gone away — in fact, it may be getting worse, with the number of such notices on the rise. And whereas the Darsee case took more than decade to come to light (and only then because of an accidental discovery), these days image detection software and the vigilance of media outlets such as Retraction Watch (see ‘The Yearbook’) can catch irregularities — be they due to innocent error or misconduct — much sooner. The ability to track these changes provides benefits to biomedicine, as experiments in the scientific literature lay the foundation for future experiments. Here we look back at instances from the past year where multiple papers from certain investigators came under scrutiny.

(Click here to continue reading.)

Retracting a paper is perhaps the most unpleasant task a journal has to face, particularly if the retraction involves scientific misconduct. With the number of retractions on the rise, an improved mechanism to deal with misconduct is necessary.

Click here to read the editorial from the December 2011 issue of Nature Medicine.