Chimeric mice are one of the most important tools in biological research. By studying composite animals with tissues from distinct genetic lineages, scientists have gained important insights into the molecular mechanisms of disease. This powerful biomedical research tool has largely been restricted to rodents and farm animals that are distantly related from humans, and, thus, might not best approximate human disease. Now, however, rhesus monkeys have joined the chimera club—an advance that researchers hope will help bridge the gap between mice and humans.

“It is not enough to jump from mouse right to human in transplanting tissues,” says Shoukhrat Mitalipov, a developmental biologist at the Oregon National Primate Research Center in Beaverton who led the study. “We need primate models to know if tissues are truly functional.”

In their study, Mitalipov and his colleagues plucked cells from early-stage monkey embryos containing only four cells each. They then mixed the cells together into aggregates containing cells from between three and six different embryos. After growing the cells up to the blastocyst stage, they implanted 14 of the cell clusters into five females. The scientists terminated three of the pregnancies for genetic analysis, but the other two monkeys gave birth to healthy baby boys: a pair of twins named Roku and Hex (pictured here), and a singleton name Chimero. These monkeys were indeed chimeric—with some cells originating from female embryos, too—as the researchers detected multiple genotypes in the animals’ blood cells. The findings were published today in Cell.

This method stands is in stark contrast to that typically used to create chimeric rodents. In mice and rats, scientists usually inject cultured embryonic stem cells into developing embryos from another animal strain. Although Mitalipov has cloned monkey embryos in the past, and even derived embryonic stem cells, his attempts to create chimeric monkey fetuses using cultured embryonic stem cells failed repeatedly because the stem cells didn’t incorporate properly into the host embryo.

Rhesus monkeys are currently used for a host of different biomedical applications, including studies of HIV and influenza viruses. For such studies, especially those on drug therapies, which often now go directly from mouse to human testing, the addition of a chimeric monkey model will be a crucial bridge for vetting the potential translation of findings to humans.

Image courtesy of Oregon Health & Science University

Cross-posted from the Nature News Blog

An American university scientist was arrested on 27 December, accused of supplying stem cells for use in unapproved therapies.

The US Department of Justice says Vincent Dammai, a researcher at the Medical University of South Carolina (MUSC) in Charleston, supplied the stem cells without the approval of his university or of the US Food and Drug Administration. Two other men, Francisco Morales of Brownsville, Texas, and Alberto Ramon, of Del Rio, Texas, were also arrested this week as part of the case. A fourth man, Lawrence Stowe of Dallas, Texas, has been charged and a warrant is out for his arrest, according to an FBI press release.

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Crossposted from Nature’s news blog

A company that pioneered embryonic stem cell research is walking out on the field it helped to create. Geron, based in Menlo Park, California, announced yesterday that it would kill off its stem cell program — and its landmark clinical trial of a treatment for spinal cord injuries — so that it can focus on cancer therapies.

For supporters of the technology, Geron’s exit is a blow. “This is very unfortunate for the field,” says Robert Lanza, chief scientific officer of Advanced Cell Technology, the only other embryonic stem cell company with regulatory approval to conduct clinical trials in the United States. “It is a big deal. It certainly puts a lot of pressure on us to deliver now.”

Geron was the first company to gain approval from US regulators to conduct a clinical trial using human embryonic stem cells. The company has treated four patients with spinal cord injuries since it launched the trial in 2010, and has reported that the treatments appear to be safe though they have not yielded any improvement in spinal cord function. The trial was only designed to test safety, however, and Geron has made it clear from the start that the company did not expect the treatment regimen — including the number of cells injected — to be sufficient to relieve paralysis in the ten patients it ultimately aimed to treat in its first trial.

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Yesterday, Mississippi voters headed to the polls to weigh in on a highly controversial ballot initiative that would give embryos in that state ‘personhood’ status, and wreak havoc on reproductive therapy and research in the process. Despite the fact that the constitutional amendment, known as Initiative 26, was supported by Republican and Democrat candidates for Mississippi Governor as well as the state’s Attorney General Jim Hood, it ultimately failed as 58% of the voters rejected it.

The ballot initiative came out of an ongoing nation-wide campaign launched by Personhood USA, a Colorado-based Christian non-profit.

Many doctors in Mississippi are letting out a collective sigh of relief. Had this initiative passed, every fertilized human egg would have become a ‘person’ protected under US law. This would have subsequently made abortion illegal and restricted use of birth control pills and fertility treatments such as in vitro fertilization, in which embryos are sometimes destroyed.

Initiative 26 could have also affected the state’s embryonic stem cell research. “Any stem cell research that leads to destruction of the pre-embryonic person would have been problematic,” says Jonathan Will, director of the Bioethics and Health Law Center at Mississippi College in the state capital, Jackson.

Even though the initiative failed, some still worry that it might have a snowball impact in areas of the country with more high-profile stem cell research communities. “I don’t know that there’s a huge amount of stem cell research going on in Mississippi,” says bioethicist Ron Green of Dartmouth College, in Hanover, New Hampshire. But if this legislation were to encourage other, larger states to go down the same road, “the implications are going to be somewhat chilling,” Green says.

This possibility is not far from the truth—activists are working to get personhood initiatives on the ballots of seven states in the 2012 election, including Oregon, Florida, Ohio, Nebraska, Montana, Alabama and Kansas. “If you extend this to states like Oregon and Florida, it would put a halt to the development of new stem cell lines by any of the standard methods which are now permissible under the Obama Administration’s policies,” Green says.

According to Will, the debate has been raging for years and Personhood USA who is “very vocal” will continue to lobby for its cause. “This issue is not going away,” Will says.

Image by Shawn Rossi via Flickr Creative Commons

Researchers in New York have succeeded where the disgraced South Korean Hwang Woo-suk failed. They have successfully derived the world’s first stem cells from a cloned human embryo. But, notably, the new stem cells are not suitable for therapeutic use because they contain three sets of chromosomes, instead of the regular two.

In work published today in Nature, a team led by Dieter Egli at the New York Stem Cell Foundation took skin cells from healthy and diabetic volunteers and inserted the cells’ nuclei into unfertilized human eggs. Within a few days cloned embryos developed allowing researchers to pluck out and propagate stem cells. These cells displayed all the hallmarks of embryonic stem (ES) cells, including characteristic gene activity and the ability to differentiate into all three germ layers in the teratoma test — the gold standard of pluripotency.

“It is the first demonstration that human oocytes have the ability to reprogram a specialized adult cell to the state of a pluripotent stem cell,” Egli told Nature Medicine.

However, the cells are not your typical ES cells: in addition to the two sets of chromosomes derived from the skin cells, the stem cells contained a full set from the egg as well, making them triploid. These new cells have been dubbed “somatic cell genome, oocyte genome pluripotent stem cells”, or soPS (rhymes with ‘hops’) cells for short. As triploid cells, they are not true donor-matched, patient-specific cells, and have a higher chance of immune system rejection when transplanted. This is likely to prove a sticking point, according to Robert Lanza, chief scientific officer of Advanced Cell Technology, a Santa Monica, California-based stem cell biotechnology company, who points out that personalized cell-therapy “is the whole purpose of this technology.”

Method makeover

This failure to create ES cells with only the donor cell’s genome was not for lack of trying. In early experiments, Egli’s team attempted to create normal cloned embryos through a process known as ‘somatic cell nuclear transfer’ (SCNT), which involves removing the egg’s haploid nucleus before inserting the adult diploid nucleus. This technique has worked in many mammalian species, ranging from mice to nonhuman primates, and, indeed, it’s the method that scientists used to create Dolly the sheep. But when Egli’s group swapped the egg and skin cell nuclei in their unfertilized eggs, they found that all the resulting embryos stopped dividing after just 6 to 10 cells. Some research groups have used SCNT to create later-stage human embryos with better success. Yet, barring Hwang’s fraudulent claims in 2004, none have reported any success at creating stem cell lines from these clones.

In a clever workaround, Egli and his colleagues left the egg’s nucleus in place, and fused it with the nucleus taken from the skin cell. Around 20% of the triploid eggs developed to the blastocyst stage (a mass of 70–100 cells), demonstrating the viability of the manipulated embryos. From the 13 blastocysts the researchers created, they obtained two stem cell lines — one containing the DNA of a man with type 1 diabetes and another from a healthy adult male donor.

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An embryonic field seems to be developing rapidly. Just two months after Advanced Cell Technology (ACT) launched the second and third trials involving human embryonic stem cell (ESC) derived products in an operating room at the University of California–Los Angeles, the Santa Monica-based biotech announced today that it had gained approval from the UK Medicines and Healthcare products Regulatory Agency to conduct the first ESC cell trial outside the US.

“This is extremely significant,” Robert Lanza, ACT’s chief scientific officer, told Nature Medicine. “This is the first time there’s been an embryonic stem cell therapy trial anywhere else in the world.”

The trial will essentially be a repeat performance of one of ACT’s ongoing trials in the US, but this time conducted at the Moorfields Eye Hospital in London. Led by Moorfields ophthalmologist James Bainbridge, the trial, which is scheduled to begin before the end of the year, will use retinal cells derived from ESCs to treat 12 people suffering from Stargardt’s macular dystrophy, a progressive juvenile vision loss disorder that affects about one in every 10,000 children.

According to Lanza, in the near future ACT also expects to gain UK approval to use the same cell therapy to treat people with age-related macular degeneration, a common cause of blindness in the elderly and the other disease currently under investigation by the company in US trials. Meanwhile, ACT is also in late-stage talks with regulators and clinicians in France, China and elsewhere to launch further global trials.

“We have things ready to move forward in other parts of the world,” says Lanza. “But we don’t want to put the cart before the horse. We want to see how the patients do first. Between the US and UK studies, we should have enough data before we storm ahead.”

In other clinical stem cell news, Geron Corp., the Silicon Valley biotech behind the world’s first ES cell trial, announced this week that it had treated a fourth patient with its experimental therapy involving ESC-derived neural precursor cells. The unidentified study subject, who recently suffered a serious spinal cord injury and is now paralyzed from the waist down, was treated over the weekend at Santa Clara Valley Medical Center near San Jose, California, the San Francisco Chronicle reported yesterday. Geron plans to treat at least ten people in its phase 1 safety study.

More than a decade after Japanese scientists implanted the first bioengineered blood vessel into a child with a congenital heart defect, the experimental treatment has finally made its way into clinical testing in the US. Elie Dolgin asks what took so long and what lessons have been learned along the way.

Click the image above for a PDF of the full story from the September 2011 issue of Nature Medicine.

Last week, a team of around a dozen doctors and nurses in Connecticut performed a 12-hour operation to insert a cigar-shaped plastic tube, seeded with bone marrow cells, around the heart of a toddler born with only a single functioning ventricle. The delicate surgery, performed at the Yale-New Haven Hospital, represents the first time that surgeons have implanted a tissue-engineered blood vessel into someone on US soil. It could radically alter the future treatment of this type of congenital heart defect — which affects around 3,000 babies born each year in the US — and could have implications for more common heart procedures down the road.

For the trial investigators, the surgery has been more than a decade in the making. “See the black binders,” says Christopher Breuer, gesturing to a bookshelf in his small, sunlit office. Breuer, a pediatric surgeon at the Yale University School of Medicine who has spearheaded the experimental surgery, stands up and pulls out one of more than a dozen thick binders lining the wall. “All but three of these constitute a single copy of the first application” to the US Food and Drug Administration (FDA) to approve the clinical protocol, submitted in August 2009. “Things moved along very slowly,” he admits. That’s especially true when you consider that the same surgery had already been performed on 25 people, starting ten years earlier, by Toshiharu Shinoka and his colleagues at the Tokyo Women’s Medical University Hospital in Japan.

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