Harsh Reaction to Chemistry Claims Cast Doubt on Reactome Paper

A newly developed research tool called a reactome array, which has attracted widespread interest from biologists, has come under intense fire from scientists who say the description of the device in the 9 October issue of Science includes “impossible” chemical reactions and makes little sense. The publication drew immediate attention because the array promises to establish the functions of a myriad of enzymes and probe the metabolisms of bacteria and other kinds of cells.

Last week, Science acknowledged the furor, publishing online an “Editorial Expression of Concern” in which the journal’s editor-in-chief, Bruce Alberts, notes that “serious questions have been raised about the methods and data presented.” “It was just so obvious the chemistry was flawed,” says biochemist Laura Kiessling of the University of Wisconsin, Madison, editor-in-chief of ACS Chemical Biology.

While admitting to serious errors in describing the methods used to create the reactome array--which required the synthesis of thousands of compounds representing cellular metabolites and other enzyme substrates, linking them to a fluorescent dye, and fixing them on a glass slide--the study’s corresponding authors stand behind the device. “We’re confident in the results and technology. Many researchers have used the array without problems,” says Manuel Ferrer of the Spanish National Research Council’s (CSIC's) Institute of Catalysis in Madrid.

According to Ferrer, at the request of Science, CSIC will conduct an investigation of his lab, and related inquiries will be held at collaborators’ labs in Germany and the United Kingdom. He says that Nobel laureate Richard Roberts of New England Biolabs and other researchers have also agreed to conduct blinded tests to verify that the reactome array works. Roberts confirmed that fact, noting that he recently visited the Madrid lab and came away “impressed” after initially thinking the reactome array “was too good to be true.”

In private chats and online postings, chemists began expressing skepticism about the reactome array as soon as the article describing it was published, noting several significant errors in the initial figure depicting its creation. Some also questioned how a relatively unknown group could have synthesized so many complex compounds. The dismay grew when supplementary online material providing further information on the synthesized compounds wasn’t available as soon as promised. “We failed to put it in on time. The data is quite voluminous,” says co-corresponding author Peter Golyshin of Bangor University in Wales, a microbiologist whose team provided bacterial samples analyzed by Ferrer’s lab.

Science is also coming under fire. “It was stunning no reviewer caught [the errors],” says Kiessling. Ferrer says the paper’s peer reviewers did not raise major questions about the chemical synthesis methods described; the journal’s executive editor, Monica Bradford, acknowledged that none of the paper’s primary reviewers was a synthetic organic chemist. “We do not have evidence of fraud or fabrication. We do have concerns about the inconsistencies and have asked the authors' institutions to try to sort all of this out by examining the original data and lab notes,” she says.

Ferrer says he takes responsibility for all the mistakes and apologizes: “I understand the disappointment of Science and Science’s readers.” Yet some chemists, including those who have sought clarifications from the authors, remain unconvinced by supplementary data that has since been posted and the explanations offered so far. Many colleagues “think it must be fraud. I’m trying to keep an open mind,” says chemical biologist Ben Davis of the University of Oxford, U.K., who wrote a skeptical review of the reactome array article (registration or subscription required) on the Faculty of 1000 Web site. “But clearly there are a lot of unexplained elements.”