NEWS & ANALYSIS

NEWS & ANALYSIS

Long-running feud. At the German Reichstag in 2004, Greenpeace activists demonstrate against patents involving embryos.

EUROPE

Dismay, Confusion Greet Human Stem Cell Patent Ban

Has the environmental group Greenpeace dealt a major blow to the medical use of human embryonic stem (hES) cells in Europe? Thats what biologists, patent specialists, and lawyers are furiously debating after the European Unions Court of Justice ruled last week that processes and products that involve such cells are not patentable. Patents on hES cells are forbidden by a 1998 E.U. Directive on biopatents that bans the use of human embryos for industrial or commercial purposes, the court concluded in a case that Greenpeace had initiated. Not surprisingly, Greenpeace welcomed the decision. The court has clearly strengthened protection of human life over economic interests, says its patent adviser, Christoph Then. However, others found the ruling and its likely impact far from clear. Some patent analysts speculated that the decision might have the counterintuitive effect of stimulating hES cell research, while many stem cell scientists expressed fear it would discourage clinical development of hES cells or their products. Its a disaster, says Oliver Brstle, the neuroscientist whose patent was the subject of the case. It leaves European scientists with just basic research. They have to watch as their research gets made into treatments around the world. Its a very discouraging message for young researchers. A few European investigators even wondered if the decision could

Several factors, however, may blunt the decisions impact on potential products involving hES cells. European companies and researchers can still le for patents in the United States and other countries that allow such protection. Indeed, Brstles patent has been granted in the United States, Australia, Japan, and Israel. Independent of any patent protection, therapies using hES cells will have to surmount signicant regulatory hurdles before they are approved for use in Europe. That complex and expensive process will make it difcult for a company to bring a copycat therapy to market. Under the current regulatory framework, it will be virtually impossible to convince a regulator to approve a generic hES cell therapy, says Alexander Denoon of the London law rm Lawford Davies Denoon, which specializes in biotechnology patents. I dont see any company wanting to make money with a cell therapeutic that is going to ignore the European market, concludes end up threatening funding for basic research Gregory Graff, an economist at Colorado with hES cells. State University, Fort Collins, who studies The European ruling involved a challenge intellectual property and biotechnology. from Greenpeace to a German patent granted Companies likely will protect themselves to Brstle in 1999 on methods for turning by keeping more trade secrets, predicts Robin mammalian ES cells into neural precursor Lovell-Badge, a stem cell researcher at the cells. In 2006, the German Federal Patent MRC National Institute for Medical Research Court invalidated the patent for applications in London, who helped coordinate the Hinxusing hES cells. Brstle, who works at the ton Groups recent analysis of patents in the University of Bonn, appealed the decision to stem cell eld. If you create a situation where the German Federal Court of Justice, which you dont have patents anymore, then things referred the case to the E.U.s go secret, Brstle says. Court of Justice. That court was The ruling will jeoparasked to decide several questions, dize dozens of patents involvincluding what the E.U. law means ing hES cells that various E.U. by human embryos and whether member countries have already the ban also covers patents that granted. Those patents are dont involve embryos directly practically invalid, says Clara but where the use of embryos is Sattler de Sousa e Brito, one of a necessary precondition. Brstles lawyers. The 13-judge panel ruled on That change may help some 18 October that the term human stem cell researchers. The embryo in the European Direc- Disappointed. Neuro- United Kingdom has granted tive covers any human ovum scientist Oliver Brstle calls roughly 100 patents involving after fertilization as well as the the ruling a disaster. hES cells, including one that product of a nuclear transfer grants Geron, a California bioexperiment or a parthenote: an unfertilized tech company, rights over cell populations in egg that is prompted to start dividing. The which at least 5% of the cells express certain court also ruled that an invention is not patent- heart cell markers or have spontaneous periable if the subject matter of the patent appli- odic contractile activityand treatments cation requires the prior destruction of human derived from them. Those are much broader embryos or their use as base material. claims than the U.S. Patent and Trademark
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NEWS&ANALYSIS
Ofce allowed, and if such claims cant be enforced, researchers and companies could have an easier time pursuing some lines of research. A lot of us are really intrigued. This is going to be a natural experiment, Graff says. Its practical impact aside, the ruling frustrates many stem cell scientists because of the broad way it denes embryos. It even leaves open the question of whether hES cells are embryos. The ruling refers that question back to the German court, saying it should ascertain, in the light of scientic developments whether [hES cells] are capable of commencing the process of development of a human being and, therefore are included within the concept of human embryo. For stem cell scientists, that question has been settled for years: ES cells alone cannot form a viable embryo. On scientific grounds, we find it slightly bizarre, Lovell-Badge says. That part of the ruling is troubling, Sattler de Sousa e Brito says, because it could lead to a patchwork of interpretations in different member countries, going against the courts mandate to unify European law. It is also unclear whether the ruling covers hES cells derived from single embryonic cells, called blastomeres. The technique does not require the destruction of a human embryo at any point, says Robert Lanza, chief scientific officer of Advanced Cell Technology (ACT) in Marlborough, Massachusetts. ACT, which developed the technique, has clearance in the United Kingdom to test blastomere-derived cells on an incurable eye disease. It will be the rst European clinical trial involving hES-derived cells. The ruling doesnt appear to affect us, Lanza says. Others arent so sure. The courts prohibition of patents that require use [of human embryos] as base material, whatever the stage that takes place, could cover blastomere-derived lines as well, Sattler de Sousa e Brito says. The courts decision does not directly affect the legality of research with hES cells. But some observers worry that it may affect funding for such work. Under a hard-won compromise reached in 2006, current E.U. funding programs support several projects that use such cells. But Aurora Plomer, a lawyer and bioethicist at the University of Shefeld in the United Kingdom who studies stem cell patents, says opponents of hES cell research may again try to block funding for the work under the next large-scale research funding program, Horizon 2020. The ruling, she says, will now very much strengthen their case.
CANCER RESEARCH

Dispute Over Tumor Suppressor Gene Runx3 Boils Over

A key, decade-old finding by a prominent Japanese cancer researcher based at the National University of Singapore (NUS) is under re from a group in Israel that calls it irreproducible. If the challenge overturns the original work, which identified a gene called Runx3 as a tumor suppressor, hundreds of scientic papers might be affected. The dispute began with a scientic disagreement almost a decade ago and escalated sharply after the group in Israel led a formal complaint earlier this fall with NUS, which recently launched an investigation. ferent stringent measures, we herein provide compelling evidences that not only directly, definitely and unequivocally rule out the possibility that Runx3 is expressed in [wild type gastrointestinal tract epithelium], but also challenge the notion that Runx3 functions in this tissue as a TSG [tumor suppressor gene]. The team reported that it tried but failed to replicate the results of the original Cell paper using the same line of knockout mice Itos team used. In supplemental material published with the EMBO Molecular Medicine paper, Groners team lists 286 papers that the team says are based at least partly on the 2002 Cell paper by Itos group. None of the previous reports has gone back and carefully examined, using a variety of highly stringent measures, whether Runx3 is actually expressed in the tissue in which it was reported to be expressed, the team writes. Groners group claims that 145 of those papers rely on an analysis of the status of Runx3 DNA methylation that does not and cannot represent a proof or even a credible indication/suggestion that the methylated gene is a TSG. Other papers, according to the challengers, got unreliable results, and some failed to nd Runx3 expression in the gastrointestinal tract epithelium. At the request of an official at NUS, Groner says, he led a formal complaint with the university. The Ito groups results are irreproducible, and because of the nature of the irreproducibility, and [because] they cannot be reproduced in the original mice that they are supposed to be reproduced in, the only conclusion [is that the experimental results] could not possibly be reached in the rst place, Groner says. The university conrmed in a statement that Groner has contacted us and an inquiry is in process according to the universitys research integrity code but declined further comment. The inquiry came to light when Singapores Straits Times newspaper reported it on 19 October. In response, Ito says, I strongly believe that scientic disagreements can be solved only in the scientic arena. Shortly after publishing the Cell paper in 2002, Ito and several members of his team moved to the Institute of Molecular and Cell Biology, part of Singapores Agency for Science, Technology and Research, and later to the Cancer Science Institute of Singapore at NUS.

Condent. Yoshiaki Ito says his designation of Runx3 as a tumor suppressor will stand up to scrutiny.

GRETCHEN VOGEL

The challenge comes from a group led by Yoram Groner of the Weizmann Institute of Science in Rehovot, Israel. In 2001, Groners group published a paper in Mechanisms of Development cataloging, among other things, the tissues in which Runx3 is expressed; they did not nd it in gastrointestinal tract epithelium. Little was then known about Runx3s function. A year later, a team of researchers at institutes in Japan and South Korea led by Yoshiaki Ito, then at Kyoto University, published a paper in Cell claiming that Runx3 is expressed in gastrointestinal tract epithelium and that it functions as a tumor suppressor, concluding that a lack of Runx3 function is causally related to the genesis and progression of human gastric cancer. The two groups have defended their clashing results ever since. Groner and his colleagues launched their recent salvo in a paper rst published online on 8 August by EMBO Molecular Medicine. In it, they claim that using seven difVOL 334 SCIENCE

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