8/3/2019 Science-2011-Vogel-441-2

http://slidepdf.com/reader/full/science-2011-vogel-441-2 1/2

NEWS & ANALYSIS

www.sciencemag.org SCIENCE VOL 334 28 OCTOBER 2011

NEWS & ANALYSIS

C R E D I T S ( T O P T O

B O T T O M ) : F A B R I Z I O

B E N S C H / R E U T E R S / L A N D O V ; H

E R M A N N J . K N I P P E R T Z / A P P H O T O

Has the environmental group Greenpeacedealt a major blow to the medical use of human embryonic stem (hES) cells inEurope? That’s what biologists, patent spe-cialists, and lawyers are furiously debatingafter the European Union’s Court of Justice

ruled last week that processes and productsthat involve such cells are not patentable. Pat-ents 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 thatGreenpeace had initiated.

Not surprisingly, Greenpeace welcomed the decision. “The court has clearly strength-ened protection of human life over economicinterests,” says its patent adviser, ChristophThen. However, others found the ruling and itslikely impact far from clear. Some patent ana-lysts speculated that the decision might havethe counterintuitive effect of stimulating hEScell research, while many stem cell scientistsexpressed fear it would discourage clinicaldevelopment of hES cells or their products.

“It’s a disaster,” says Oliver Brüstle, theneuroscientist 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 theworld. It’s a very discouraging message for young researchers.” A few European inves-tigators even wondered if the decision could

end up threatening funding for basic researchwith hES cells.

The European ruling involved a challengefrom Greenpeace to a German patent granted to Brüstle in 1999 on methods for turningmammalian ES cells into neural precursor

cells. In 2006, the German Federal PatentCourt invalidated the patent for applicationsusing hES cells. Brüstle, who works at theUniversity of Bonn, appealed the decision tothe German Federal Court of Justice, whichreferred the case to the E.U.’sCourt of Justice. That court wasasked to decide several questions,including what the E.U. law means

by “human embryos” and whether the ban also covers patents thatdon’t involve embryos directly

but where the use of embryos “isa necessary precondition.”

The 13-judge panel ruled on18 October that the term “humanembryo” in the European Direc-tive covers “any human ovumafter fertilization” as well as the

product of a nuclear transfer experiment or a parthenote: an unfertilized egg that is prompted to start dividing. Thecourt also ruled that an invention is not patent-able if “the subject matter of the patent appli-cation requires the prior destruction of humanembryos or their use as base material.”

Several factors, however, may blunt thedecision’s impact on potential productsinvolving hES cells. European companiesand researchers can still le for patents in theUnited States and other countries that allowsuch protection. Indeed, Brüstle’s patent has

been granted in the United States, Australia,Japan, and Israel.

Independent of any patent protection, ther-apies using hES cells will have to surmountsignicant regulatory hurdles before they areapproved for use in Europe. That complexand expensive process will make it difcultfor a company to bring a copycat therapy tomarket. “Under the current regulatory frame-work, it will be virtually impossible to con-

vince a regulator to approve a generic” hEScell therapy, says Alexander Denoon of theLondon law rm Lawford Davies Denoon,which specializes in biotechnology patents.“I don’t see any company wanting to makemoney with a cell therapeutic that is goingto ignore the European market,” concludesGregory Graff, an economist at ColoradoState University, Fort Collins, who studiesintellectual property and biotechnology.

Companies likely will protect themselves by keeping more trade secrets, predicts RobinLovell-Badge, a stem cell researcher at the

MRC National Institute for Medical Researchin London, who helped coordinate the Hinx-ton Group’s recent analysis of patents in thestem cell eld. “If you create a situation whereyou don’t have patents anymore, then things

go secret,” Brüstle says.The ruling will jeopar-

dize dozens of patents involv-ing hES cells that various E.U.member countries have alreadygranted. “Those patents are

practically invalid,” says ClaraSattler de Sousa e Brito, one of Brüstle’s lawyers.

That change may help somestem cell researchers. TheUnited Kingdom has granted roughly 100 patents involvinghES cells, including one thatgrants Geron, a California bio-

tech company, rights over cell populations inwhich at least 5% of the cells express certainheart cell markers or have “spontaneous peri-odic contractile activity”—and treatmentsderived from them. Those are much broader claims than the U.S. Patent and Trademark

Dismay, Confusion GreetHuman Stem Cell Patent Ban

E U R O P E

Long-running feud. At the German Reichstag2004, Greenpeace activists demonstrate againpatents involving embryos.

Disappointed. Neuro-scientist Oliver Brüstle callsthe ruling “a disaster.”

Published by AAAS

8/3/2019 Science-2011-Vogel-441-2

http://slidepdf.com/reader/full/science-2011-vogel-441-2 2/228 OCTOBER 2011 VOL 334 SCIENCE www.sciencemag.org442

NEWS& ANALYSIS

Ofce allowed, and if such claims can’t beenforced, 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 frus-trates many stem cell scientists because of the

broad way it denes embryos. It even leavesopen the question of whether hES cells areembryos. The ruling refers that question back to the German court, saying it should “ascer-tain, in the light of scientic developmentswhether [hES cells] are capable of commenc-ing the process of development of a human

being and, therefore are included within theconcept of ‘human embryo.’ ” For stem cellscientists, that question has been settled for years: ES cells alone cannot form a viableembryo. “On scientific grounds, we find itslightly bizarre,” Lovell-Badge says. That partof the ruling is troubling, Sattler de Sousa e

Brito says, because it could lead to a patch-work of interpretations in different member countries, going against the court’s mandateto unify European law.

It is also unclear whether the ruling cov-ers hES cells derived from single embryoniccells, called blastomeres. The technique“does not require the destruction of a humanembryo at any point,” says Robert Lanza,chief scientific officer of Advanced CellTechnology (ACT) in Marlborough, Mas-sachusetts. ACT, which developed the tech-nique, has clearance in the United Kingdom

to test blastomere-derived cells on an incur-able eye disease. It will be the rst Europeanclinical trial involving hES-derived cells.“The ruling doesn’t appear to affect us,”Lanza says.

Others aren’t so sure. The court’s pro-hibition of patents that require “use [of human embryos] as base material, what-ever the stage that takes place,” could cover

blastomere-derived lines as well, Sattler deSousa e Brito says.

The court’s decision does not directly affectthe legality of research with hES cells. Butsome observers worry that it may affect fund-ing for such work. Under a hard-won compro-mise reached in 2006, current E.U. funding

programs support several projects that usesuch cells. But Aurora Plomer, a lawyer and

bioethicist at the University of Shefeld inthe United Kingdom who studies stem cell

patents, says opponents of hES cell researchmay 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.”

–GRETCHEN VOGEL

A key, decade-old finding by a prominentJapanese cancer researcher based at the

National University of Singapore (NUS) isunder re from a group in Israel that calls it“irreproducible.” If the challenge overturnsthe original work, which identified a genecalled Runx3 as a tumor suppressor, hun-dreds of scientic papers might be affected.The dispute began with a scientic disagree-ment almost a decade ago and escalated sharply after the group in Israel led a formalcomplaint earlier this fall with NUS, whichrecently launched an investigation.

The challenge comes from a group led by Yoram Groner of the Weizmann Insti-tute of Science in Rehovot, Israel. In 2001,Groner’s group published a paper in Mech-anisms of Development cataloging, amongother things, the tissues in which Runx3 is expressed; they did not nd it in gastro-intestinal tract epithelium. Little was thenknown about Runx3 ’s function. A year later,a team of researchers at institutes in Japanand South Korea led by Yoshiaki Ito, then atKyoto University, published a paper in Cell claiming that Runx3 is expressed in gastro-intestinal tract epithelium and that it func-tions as a tumor suppressor, concluding that“a lack of Runx3 function is causally related to the genesis and progression of human gas-tric cancer.” The two groups have defended their clashing results ever since.

Groner and his colleagues launched their recent salvo in a paper rst published onlineon 8 August by EMBO Molecular Medi-cine . In it, they claim that “using seven dif-

ferent stringent measures, we herein providecompelling evidences that not only directly,definitely and unequivocally rule out the

possibility that Runx3 is expressed in [wildtype gastrointestinal tract epithelium], butalso challenge the notion that Runx3 func-tions in this tissue as a TSG [tumor suppres-sor gene].” The team reported that it tried butfailed to replicate the results of the originalCell paper using the same line of knockoutmice Ito’s team used.

In supplemental material publishedwith the EMBO Molecular Medicine papGroner’s team lists 286 papers that the teamsays are based at least partly on the 2002 C

paper by Ito’s 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 thetissue in which it was reported to be expressed,”the team writes. Groner’s group claims that145 of those papers rely on an analysis of thestatus of Runx3 DNA methylation that “doenot and cannot represent a proof or even acredible indication/suggestion that the meth-ylated gene is a TSG.” Other papers, accord-ing to the challengers, got unreliable results,and some failed to nd Runx3 expressionthe gastrointestinal tract epithelium.

At the request of an official at NUSGroner says, he led a formal complaint withthe university. The Ito group’s results “areirreproducible, and because of the natureof the irreproducibility, and [because] theycannot be reproduced in the original micethat they are supposed to be reproduced in,the only conclusion [is that the experimentalresults] could not possibly be reached in therst place,” Groner says.

The university conrmed in a statementthat Groner “has contacted us and an inquiryis in process according to the university’sresearch integrity code” but declined further comment. The inquiry came to light whenSingapore’s Straits Times newspaper reportit on 19 October.

In response, Ito says, “I strongly believethat scientic disagreements can be solvedonly in the scientic arena.” Shortly after pub-lishing the Cell paper in 2002, Ito and severamembers of his team moved to the Instituteof Molecular and Cell Biology, part of Sin-gapore’s Agency for Science, Technology and Research, and later to the Cancer ScienceInstitute of Singapore at NUS.

Condent.Yoshiaki Ito says his designation of

Runx3

as a tumor suppressor will stand up to scrutiny.

Dispute Over Tumor SuppressorGene Runx3 Boils Over

C A N C E R R E S E A R C H

Published by AAAS