In the fall of 2003, researchers at Advanced Cell Technology in Worcester, MA, thought they were on the verge of a breakthrough. They had generated cloned human embryos and were coaxing those embryos to live long enough to harvest their stem cells – the crucial, final step in generating stem cells that are perfectly matched to an individual. But in February 2004, the researchers’ hopes were dashed. South Korean stem cell scientist Woo Suk Hwang and colleagues announced in the journal Science that they had achieved this feat. ACT rapidly lost its funding and supply of eggs because investors and donors assumed this important stem cell objective had already been achieved.

Now two years – and a scientific scandal – later, ACT scientists are devastated all over again. In December 2005, investigations revealed that Hwang faked his human cloning research. “The Koreans were so far ahead of us, we were perceived as a failure, when in fact we were the furthest ahead,” says Robert Lanza, vice president of medical and scientific development at ACT. “The Korean episode is a blow for stem cell research and for the patients who may die in the future because this research has been held up,” he says. ACT plans to start the program up again, as soon as it can find a new supply of eggs.

Therapeutic cloning, also called somatic cell nuclear transfer, involves inserting the nucleus of a differentiated cell, such as a skin or nerve cell, into an unfertilized egg whose nucleus has been removed. The cell then develops into an early embryo, from which stem cells can be extracted. Stem cell lines currently used in research were derived from naturally fertilized human embryos.

Therapeutic cloning has the potential to create patient-specific stem cells because scientists can generate embryos using differentiated cells from an individual, such as a skin cell. Because the cells are genetically matched to a patient, they could one day be used in transplant therapies for diseases such as Parkinson’s and diabetes without the risk of immune rejection. Patient-derived stem cells could also be used to create disease-specific cell lines, which scientists can use as a human model to study disease.

While scientists have been able to generate stem cells from cloned embryos in mice, replicating that feat in humans has been a daunting task. The scientific community thought that hurdle had been overcome when Hwang first published his Science paper in 2004. Hwang elaborated on that technique in another paper in Science in June 2005, claiming to have generated 11 patient-specific stem cell lines using very few eggs. Because human eggs are difficult to obtain in great supply, an efficient cloning technology is crucial for the clinical success of stem cell therapy.

However, scientists now know that Hwang had faked almost all of his human cloning research. “It’s a setback from where we thought we were,” says Rudolf Jaenisch, a stem cell expert at the MIT-affiliated Whitehead Institute for Biomedical Research in Cambridge, MA. “We thought [human cloning] was efficient, now we don’t know.”

Meanwhile, the few U.S. institutions that plan to pursue therapeutic cloning in the near future are in limbo. Douglas A. Melton and Kevin Eggan, both at Harvard University, announced plans to try to derive stem cells from clones over a year ago. However, their proposals are still under review by various institutional review boards. B.D. Colen, a spokesman for Harvard, says a final decision is likely within three months.

The state of California, which in 2004 seemed to be a hotbed of stem cell research, is suffering its own setbacks. The $3 billion in state funds approved for stem cell research by Proposition 71 in 2004 has been held up in legal disputes. In the interim, the California Institute of Regenerative Medicine, the state agency that will oversee grants funded by the proposition, is raising money from bonds to try to support stem cell programs. Despite the hold-up, scientists are still optimistic. “Here in California, things are little different,” says Arnold Kriegstein, director of the Institute for Stem Cell and Tissue Biology at the University of California, San Francisco (UCSF). “Even though we don’t yet have funding from Prop 71, just the potential has galvanized universities and companies to respond to funds.”

UCSF is likely to be a frontrunner in therapeutic cloning. It was the first U.S. institution to attempt therapeutic cloning, albeit unsuccessfully. “Now we hope to start again where those studies left off,” says Kriegstein.

The university is using private funding to build research labs for scientists studying human embryonic stem cells and stocking those labs with equipment bought with nongovernment dollars. They expect the facilities to be finished in 10 to 11 months and have created an ethical review board to review cloning proposals. Susan Fisher and Renee A. Reijo Pera, codirectors of UCSF’s human stem cell biology program, will lead the research.

Stanford University’s newly formed stem cell institute also plans to make therapeutic cloning a major focus. However, those plans are still in the development phase.

ACT’s Lanza also plans to restart his therapeutic cloning program, as soon as he can find a new source of eggs. He says he expects rapid progress, generating cloned embryos within a week or two. “After that, we are in unknown territory. However, there’s no biological reason we shouldn’t be able to generate stem cells,” he says.

Lanza adds that he was particularly dismayed when he heard reports of the actual number of eggs Hwang used in his cloning attempts: more than 1,000 as opposed to 180 eggs reported in the paper. “Just think what we could have done with that number of eggs.”

While generating patient-matched stem cells is a major area of stem cell research, with the potential for broad therapeutic and scientific benefits, it’s not the only goal. Scientists are also trying to understand the basic biology of stem cells, to shed light on both normal development and disease. Ultimately, scientists hope to understand stem cells well enough to take an adult cell in a test tube and revert it back into its stem cell state.

Photo on home page courtesy of Robert Lanza, Advanced Cell Technology.

(A story appearing on Wednesday, January 18, will explore how scientists are learning to control stem cells.)