Embryonic stem cell pioneer chose to publish, not patent

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The San Diego Union-Tribune

Ariff Bongso has spent years studying days-old human embryos created through test-tube fertilization.

In the early 1990s, Bongso, a National University of Singapore scientist, figured out how to help these embryos grow for days outside the womb. That discovery almost doubled the success rate of the procedure.

Ariff Bongso became the first scientist to derive human stem cells from an embryo, but he never patented his work. “The climate in Asia at that time was publish, not patent,” he said.

Then one day, as he inspected some embryos — which look like globes of gel with an outer cluster of 100 to 200 stem cells and a dark, inner mass of about 40 to 50 cells — an idea came to him “like a flash.”

If all 210 cell types of the human body come from that inner cell mass, could he extract those cells and grow them in a petri dish? Could he control how they grew and evolved, and direct them to become a specific cell type? Similar work had been done on mice; why not humans?

That inspiration in 1994 led Bongso, now 60, to become the first scientist to derive human stem cells from an embryo. In the process, he laid the foundation for a field that many people hope will lead to new therapies for diseases such as diabetes, Parkinson’s and cancer — and that others oppose because it destroys embryos.

“Bongso made the connection between his area of expertise, human embryology, and stem cells, and just went for it,” said Jeanne Loring, a stem cell researcher at the Burnham Institute for Medical Research in La Jolla. “That’s how great scientific discoveries are made, for the sake of curiosity.”

But Bongso never patented his work.

For almost a decade, the fame and financial benefit of being the first to derive human embryonic stem cells has been heaped upon James Thomson and the University of Wisconsin.

In 1998, the university received its first U.S. patents for Thomson’s work growing monkey and human embryonic stem cells. The university’s three patents give it control of all human embryonic stem cells used in the United States. Anyone in the nation who wants to conduct research using the cells must receive a license from the university, which is reported to charge as much as $250,000.

On April 2, the U.S. Patent and Trademark Office issued a ruling that may invalidate the Wisconsin patents. Bongso’s work was identified as proof that what Thomson did was not new and unique.

Loring and two nonprofit groups, the Foundation for Taxpayer and Consumer Rights in Santa Monica and the New York-based Public Patent Foundation, had filed a challenge of the Thomson patent in July.

The university, which can appeal the ruling at the patent office and also could take its appeal to federal court, has said it is confident the patents will be upheld and that the challenge is fueled by scientists who want to use groundbreaking science without paying a fee.

Bongso had not been following the debate very closely. During a rare interview in his office in Singapore last year, Bongso said he did not want to get involved.

“All I would hope for is that someone find a beneficial use for these mysterious cells in the form of a treatment for some of the incurable diseases that plague mankind,” he said.

Recently, he seemed pleased to hear of the patent office decision.

“My group and I feel elated that our work has been recognized because we were toiling in obscurity in a tiny lab in Singapore for many years, trying to make a difference to mankind,” Bongso said.

Stem cell research is a hot topic right now. But in the early 1990s, the hot field was in vitro, or test-tube, fertilization. Bongso was in the thick of it.

When Bongso figured out how to pull stem cells out of donated human embryos, he thought it was “hot stuff.”

He wrote a scientific paper describing his methods and results. Then he sent the article to the journal Human Reproduction.

“It is the journal in the IVF world, and I thought only people in IVF would be interested in my discovery,” Bongso said.

He never considered broader-circulation scientific publications such as Nature or Science.

He also never considered patenting his discovery.

“The climate in Asia at that time was publish, not patent,” Bongso said. “Publish for scientific glory.”

In October 1994, his article was published — but it failed to generate much interest.

Bongso forged ahead, concentrating on growing the stem cells on fallopian tube cells, which had proved to be the trick with embryos. His method never allowed the stem cells to grow past two generations.

“Through 1995, 1996 and 1997, no one seemed interested in my work,” Bongso said. “A scientist gauges his work based on the interest that other scientists show in carrying forward his work. When there was no interest, I lost interest. I moved on.”

He redirected his focus to human fertilization.

The lack of interest in human embryonic stem cells was a result of several things, primarily the fact that scientists were immersed in mouse embryonic stem cells, said Loring, from the Burnham Institute.

“There were so many things you could do with mouse stem cells at the time; no one was really thinking about humans,” she said. “And there was also an issue of access to human embryos.”

Long before Bongso made his stem cell discovery, Thomson visited his department at the National University of Singapore to see what Bongso’s team was doing in in vitro fertilization.

Both scientists had a background in veterinary science.

Thomson worked with primates. Bongso had done notable work at the behest of the United Nations, figuring out what was causing infertility among water buffalo, a crucial work animal in South Asia.

As a result, Bongso said he considers Thomson a friend.

In the late 1990s, Thomson began applying for a U.S. patent on his technique for deriving stem cells from a primate (monkey) embryo. After several initial denials and revisions, Thomson received his first patent in 1998. In that patent, he said that a few months after pulling stem cells out of a nonhuman primate embryo, he did it with a human embryo.

Thomson’s work went further. He figured out how to grow several generations of stem cells, creating stem cell lines.

“The steps he used are mine,” Bongso said.

“But there was no patent on the process, and the culture of science in the U.S. is patent or perish: Create wealth from your research. Only recently has the life science drive in Singapore changed our culture.”

Thomson declined to be interviewed for this story.

Bongso was quick to credit Thomson for growing several generations of stem cell colonies in 1998. And he reflected on what his lab did wrong.

“We were (separating) our embryonic stem cells into single cells (in separate dishes) for further propagation not realizing that these cells had the unique behavior of being ‘social,’ ” Bongso said. “This means they preferred neighboring cells of their same type in close contact with them for further successful propagation.”

In retrospect, Bongso had the crucial material — embryos — but did not have the technique that Thomson mastered working with primates and stem cells, Loring said.

“But Thomson’s work was an advance, not an invention,” said Loring, summing up the core argument of the patent challenge.

“Thomson made a very important contribution to science,” said John Simpson of the Foundation for Taxpayer and Consumer Rights. “It just wasn’t something that was patentable.”

Thomson grew his embryonic stem cells on feeder cells that included mouse cells. The exposure to animal cells has meant the stem cells could never be used in therapies to treat humans.

When Bongso returned to stem cell research, he started trying to develop a method of growing embryonic stem cells on all-human feeder cells, which would erase the contamination concern.

In 2002, Bongso discovered a way to grow stem cells on human feeders. This time, he patented his discovery.

He also wanted to make stem cell lines, or families of stem cells.

Thomson was concurrently doing the same work, said Martin Pera, who runs the stem cell program at University of Southern California.

“Ariff is a delightful person, very pleasant and open, good to work with,” Pera said. “The fact that he published his initial attempts is important. He didn’t establish permanent cell lines, but he was a real pioneer in the field.”

Whether that makes Thomson’s work an invention rather than an advance is a question better posed to intellectual property experts, Pera said.

Bongso doesn’t begrudge Thomson his acclaim.

“My objective is not commercialization,” he said. “I very sincerely hope that some day this science will lead to treatments for diabetes or heart disease. That would be my greatest joy.”

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