One Japan Stem Cell Institute Soars, One Struggles

As Nobel Prize-winning scientist Shinya Yamanaka regaled a New York crowd with advances that may send his Japanese institute to the top of the global stem cell field, investigators in Tokyo said the stem cell division at his sister institute is so wracked with problems it should dismantle—or dramatically revamp.

The above advances were made largely by Yamanaka’s Center for iPS Cell Research and Application (CiRA). CiRA plans many clinical trials of induced pluripotent stem cells (IPSCs).

The above problems involve the Riken Institute’s famous “acid bath” stem cells, which recent evidence suggests may never have existed, pioneering cloner Teru Wakayama told Bioscience Technology by email this Wednesday.

All told, “hyper” best describes Japan stem cell research right now, former Riken CDB Deputy Director Shinishi Nishikawa saidvia email this week.

“Those hyper-reacting have included the media, politicians, bureaucrats, and a considerable number of scientists,” he said.

Nobel-Prize Winner Collects Another Prize

At Rockefeller University last Wednesday, Yamanaka was his usual engaging self, throwing credit to his students for his Nobel-Prize winning 2007 coup of turning ordinary cells into potent stem cells by tweaking four genes (the iPSC approach). But unlike many past speeches, Yamanaka mentioned four-plus planned iPSC clinical trials at CiRA (which he heads). All would be world-firsts.

Masayo Takahashi, a Riken MD/PhD, is enrolling patients in a Riken/CiRA clinical study of iPSCs for macular degeneration. The first patient gets iPSCs this summer. Her brain surgeon husband Jun Takahashi of CiRA plans to give dopaminergic neurons from iPSCs to Parkinson’s patients in two to three years.

Showing a video of what he called a “smiling” mouse healed of spinal cord injury, Yamanaka said his group plans, with Keio University’s Hideyuki Okano, to give neurons from iPSCs to spinal cord patients in three years. And CiRA’s Koji Eto is making commercial numbers of blood cells, using iPSCs, for clinic use in three or four years, Yamanaka said.

Yamanaka’s CiRA is also helping build a national iPSC bank from 140 people who are immunological matches for 90 percent of the nation. This, too, is a world-first.

Showing a film of iPSC-generated heart cells beating in a dish, he noted iPSCs make cardiac drug-screening easy. “My own heart contracted when I saw these cells,” Yamanaka said, his voice hushed with a characteristic mix of humor and awe. His talk drew thunderous applause from the scientific crowd before he was given an honorary Rockefeller degree.

Meanwhile, Back in Japan

Meanwhile, researchers at Riken CDB, Japan’s top developmental biology institute, were getting a public drubbing by outside investigators at a Tokyo presser the same day. Another report had surfaced regarding Riken’s “acid bath” stem cells—suggesting they were simply cultured embryonic stem (ES) cells.

In January, Riken’s Haruko Obokata had published two widely-read Nature papers claiming she could turn ordinary cells into stem cells faster and easier than Yamanaka’s iPSC method—using coffee-mild acid. (Obokata was lead author.) But in ensuing months, other researchers and Riken investigators found the papers to be tainted by falsification and fabrication acts committed by Obokata.

More recently, the outside investigators said Thursday, senior Riken researcher Takaho Endo found Obokata’s own “acid bath” stem cell genomic analyses showed her cells possess a trisomy associated with cultured ES cells, not STAP cells. For STAP cells were supposedly made from newborn mice. That trisomy kills off mice in the fetal stage.

Wakayama Finds More Discrepancies

Prominent co-author Wakayama added to the chorus by telling a press conference this Monday genetic analyses he ordered of “acid bath” (aka STAP) cells showed none came from mice Obokata said they did. “There is no proof of the existence of STAP cells,” he said, confirming this with Bioscience Technology on Wednesday.

He says his current university (Yamanashi, to which he moved from Riken in March 2013, when the “acid bath” papers were submitted to Nature), will not punish him for failing to catch problems earlier. But he says he bears some responsibility as a senior staffer. “The presentation I made to many reporters was extremely hard for me. While the president of my university is understanding, and will give me no penalty, I bear responsibility and must give penalty to myself.”

On June 16, the CDB apparently backed up his findings, noting its genetic analysis of cells marked “ES cells” in Obokata’s lab showed they were “compatible with” discrepancies Wakayama detailed, says the Asahi Shimbun.

Turbulence Beyond the “Acid Bath”

Still others believe more is at play. In 2012, a report—issued by a Riken global advisory committee headed by Cambridge University’s Austin Smith—had advised that Riken CDB’s top brass step down, to invigorate the center. It was never done. The outside investigators’ recent “fairly severe” comments (as Riken representatives characterized them to Bioscience Technology) may be partly due to that failure, too, other sources say.

With regard to the “acid bath” situation, the outside investigators’ report claimed too many shortcuts were taken by Riken management—especially by CDB deputy director Yoshiki Sasai—in his/their eagerness to keep the work secret and safeguard the Big Money the cells might generate. The report said Obokata was promoted fast, and allowed to skip English interview and recommendation-letter requirements. Fierce competition with Yamanaka was also cited. (Riken representatives said, in an email to Bioscience Technology, the above “motivations” were “speculation.” Riken also said the investigators used the Japanese word for “dismantling” the CDB in the report, but used the gentler word “revamping” at Thursday’s presser.)

But Big Money was spent on—if not generated by—the cells. A Japanese newspaper says the budget of Obokata and Sasai was some $7.4 million.

Nishikawa Speaks Out

Nishikawa stepped down as deputy director of Riken CDB in late 2012, just after the papers were taken on by Riken. Riken finessed them, and resubmitted them to Nature in the spring of 2013. (Prior to all that, the work took the form of one paper helmed by Harvard University’s Charles Vacanti and Obokata—then in Vacanti’s lab. That paper was rejected by Science and Nature, among others.) Nishikawa served as a CDB advisor until this week, when he resigned to speak more freely, he said.

He had introduced Obokata to Riken, via Wakayama, who worked with her on other Vacanti projects. Obokata, Nishikawa told Bioscience Technology, impressed him at first. “About Obokata’s recruitment, I was also involved in the selection meeting. Her presentation was very impressive and I found her a good addition to fill the reprogramming area of CDB which Wakayama was about to leave.”

Her elevation was “not unusual,” he said. The CDB had appointed two other young people to her level: at 27 and 30 (her age.) “Her case was not extraordinary.”

But, Nishikawa said: “I have to confess we never imagined she had committed so many fabrications. I believe the major cause of this affair lies” with Sasai’s press release decisions. In one January release—later taken down, but found here—Sasai called the work a “Copernican revolution.”

“Unfortunately, Yoshiki and other Group Directors never imagined that she fabricated. Whether STAP is reproducible is now being re-tested by (Riken leader) Shinichi Aizawa with help of Obokata herself. He will reach a conclusion soon. “

What led to all the hype? “According to what I have analyzed so far, the situation was much more complex than you may imagine,” Nishikawa said. “One factor is the inherent problem of the Japanese funding system. The second is the problem that the Japanese media does not check and evaluate original papers by themselves. The third is scientists who abuse the media” due to “competition.”

All the co-authors agree to retract the Nature papers.