NIH is the government agency that funds biomedical research, including stem cell research.

This includes embryos created by in vitro fertilization (IVF), a treatment for infertility whereby a woman’s eggs are fertilized in a Petri dish. The fertilized egg is then implanted in the woman’s uterus where pregnancy can continue as usual.

If multiple eggs are fertilized, people can choose to have embryos frozen for later use. Frozen IVF embryos are often no longer needed for fertility treatments, and many people choose to donate their embryos for scientific research. Scientists and stem cell advocates have argued that it is ethical to derive stem cells from discarded IVF embryos. The new guidelines require that people who agree to donate IVF embryos do so voluntarily, with full knowledge of the ramifications and without compensation.

The new guidelines state “NIH funding for research using human embryonic stem cells derived from other sources, including somatic cell nuclear transfer, parthenogenesis, and/or IVF embryos created for research purposes, is not allowed.” In plain English, the U.S. government will not fund any work that generates human, fertilized eggs in order to harvest embryonic stem cells. Research aimed at cloning humans will not be funded, but the NIH will continue to fund research on stem cells derived from adults.

Other research ineligible for NIH funding:

• Adding any type of human stem cell to non-human primate embryos. The generation of human animal hybrids, a la British writer H.G. Wells’s The Island of Dr. Moreau, will not be funded.

• Breeding any animal that was created using any type of human stem cell.

Here in the United States, the new guidelines are not much of a surprise. How do you think these will influence stem cell research in other countries, if at all?

The scientific community is buzzing now that President Obama has lifted the ban on federal funding for human embryonic stem cell research. In his announcement, the president was careful not to overstate the therapeutic promise of stem cells, but other sources, including some news outlets, have been less cautious. I’m going to follow up on that point by discussing a recent study published in PLoS Medicine that shows just how little we know about using human embryonic stem cells to treat disease.

Ataxia telangiectasia is a devastating and rare genetic disease with no cure, marked by difficulty walking and controlling one’s limbs, impaired eye movements, slurred speech and immune deficiencies. Patients usually die by their early twenties. Many symptoms are due to cells dying in the cerebellum, the part of the brain that coordinates movement. One idea is that stem cells from the brains of human embryos could replace the dying cells in the cerebellum of patients with ataxia telangiectasia.

In May 2001, a 9-year-old boy with ataxia telangiectasia was taken to Russia for the first of three injections of stem cells from fetal brain cells. In February 2005, the boy, suffering from recurring headaches, was examined by neurologists at Sheba Medical Center in Israel. MRI scans showed lesions at the base of the brain (near the cerebellum) and in the spinal cord. The latter tumor was surgically removed. Analysis of the DNA from tumor cells and the patient’s blood cells indicated that the tumor cells did not originate in the patient. The tumor cells must have grown from the transplanted stem cells. (Many tumor cells possessed two X chromosomes, indicating that they are female, but the patient is male.)

This study might teach us something about brain tumors. One theory is that stem cells acquire mutations that lead to unchecked growth; this small population of cells multiplies and forms a tumor. The results of this study suggest it is possible that brain tumors could come from stem cells. Of course, these were stem cells from fetuses implanted into a diseased brain – treating the fetal stem cells with growth hormones before injection could have triggered them to form tumors. Another possibility is that stem cells from fetal brains are more predisposed to unrestricted growth than other types of stem cells, or that the brain of a 9-year-old with ataxia telangiectasia is an environment more conducive to tumor growth than a normal juvenile or adult brain.

Clearly more research is needed to understand how stem cells grow.

Injecting this boy with stem cells does not appear to have been conducted as part of a clinical trial with multiple participants and rigorous follow up. Detailed methods describing how the fetal cells were grown and analyzed in dishes before injection were not published. From the methods that were provided to the Israeli researchers who analyzed the tumor, “cells of various size and form” were used, suggesting that many different types of fetal brain cells were injected into the boy.

I’ll leave the authors with the final word:

“Conventional therapies such as chemotherapy, radiotherapy, and bone marrow transplantation used to treat life threatening diseases are associated with morbidity and mortality. Our findings therefore do not imply that the research in stem cell therapeutics should be abandoned. They do, however, suggest that extensive research into the biology of stem cells and in-depth preclinical studies, especially of safety, should be pursued in order to maximize the potential benefits of regenerative medicine while minimizing the risks.”

Is the promise of stem cell therapy exaggerated? How much preclinical study is required before a therapy should be tested in humans?

Source: “Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient” by Ninette Amariglio, Abraham Hirshberg, Bernd W. Scheithauer, Yoram Cohen, Ron Loewenthal, Luba Trakhtenbrot, Nurit Paz, Maya Koren-Michowitz, Dalia Waldman, Leonor Leider-Trejo, Amos Toren, Shlomi Constantini, Gideon Rechavi, published in the February 2009 issue of PLoS Medicine (doi:10.1371/journal.pmed.1000029)

The U.S. government will now be able to fund research that involves human embryonic stem cell lines derived since August 9, 2001.

President Bush had prohibited the National Institutes of Health (NIH) from funding research on cell lines created after that date, but today President Obama signed an executive order that lifts this restriction.

You can read all about the details in a separate article, but I want to highlight the accuracy of Obama’s remarks.

“Ultimately, I cannot guarantee that we will find the treatments and cures we seek. No President can promise that. But I can promise that we will seek them – actively, responsibly, and with the urgency required to make up for lost ground. Not just by opening up this new frontier of research today, but by supporting promising research of all kinds, including groundbreaking work to convert ordinary human cells into ones that resemble embryonic stem cells.”

This statement is great because it doesn’t exaggerate the promise of human embryonic stem cell research. But, even more important, Obama nails the description of induced pluripotent stem cells: “groundbreaking work to convert ordinary human cells into ones that resemble embryonic stem cells.”

That one word, ‘resemble,’ is crucial. For all of the excitement surrounding induced pluripotent stem cells, and the fact that they avoid the ethical problems posed by working with human embryos, they are not the same as embryonic stem cells. Scientists are working hard to understand the differences, but achieving that understanding will require more research on human embryonic stem cells.

Science Planet has had a lot to say about stem cells lately, including a post last week on possible ethical problems with induced pluripotent stem cells.

Today’s post deals with patents. In November 2008 , the European Patent Office (EPO) declined the Wisconsin Alumni Research Foundation’s (WARF) and James Thomson’s patent application for a method to derive embryonic stem cell cultures from primates and humans.

The Enlarged Board of Appeal of the EPO ruled that under European patent law “it is not possible to grant a patent for an invention which necessarily involves the use and destruction of human embryos.” The board did not concern itself with the general question of human stem cell patentability.

Europe does not allow patenting inventions whose use would be “contrary to public order or morality.”

As for the European patent, it’s not clear whether this morality clause applies to just the derivation process or also to cells derived from human embryonic stem cells. Geron is testing a treatment whereby oligodendrocyte cells are injected into the injured spinal cord of patients. These cells were derived from human embryonic stem cells, but are not themselves stem cells. If the treatment is effective and ultimately approved for use in the United States, how will the EPO’s ruling affect the introduction of Geron’s therapy into Europe?

The use of human embryonic stem cells for research and therapeutic purposes sparked an ethical debate, but discussion has largely ignored the use of stem cells that are not derived from embryos.

Induced pluripotent stem cells (iPS) are mature cells taken from adults, such as skin cells, and transformed in the laboratory into pluripotent cells that can mature into a variety of different cell types. Researchers have generated more than 10 disease-specific iPS cell lines derived from patients with a variety of genetic diseases, such as diabetes and Parkinson’s disease.

Because iPS cells are derived from adult tissue, they seemingly sidestep the ethical issues of working with human embryos. A 2005 report by the President’s Council on Bioethics called iPS cells “ethically unproblematic and acceptable for use in humans.”

A recent paper argues that the potential uses of iPS cells might pose ethical issues to the donors.

iPS cells could be used to identify and test new therapeutics and might also themselves be used as part of cell replacement therapy. Because the technology is so new, there are many unknown applications – which is fine, because it looks like iPS cells can be grown in the laboratory indefinitely. Hence the ethical issue: People who donate their cells for iPS research might not have intended that their cells be used in a particular application.

The authors write: “First, if the perception that iPS research poses no ethical concerns is not corrected, there could be a backlash against iPS cells later. Second, the virtual genetic identity between iPS cells and donor cells raises particular concerns regarding respect for donors.”

U.S. regulations allow scientists to use biological materials for research without donor consent if the material is de-identified from the donor, which many of the pioneering iPS studies did. However, genome sequencing could allow donor’s cells to be re-identified. Moreover, donors might support use of their cells in research, but not in sensitive areas such as reproduction biology or transplantation.

The authors propose voluntary ethical guidelines, which include directing researchers to obtain additional permission from donors to use their iPS cells for potentially sensitive studies in reproduction biology or transplantation, and having researchers recontact donors to discuss future studies.

Source: “Obtaining Consent for Future Research with Induced Pluripotent Cells: Opportunities and Challenges” by Katriina Aalto-Setälä, Bruce R. Conklin and Bernard Lo, published in PLoS Biology on February 24, 2009.

The biotech company Geron received approval from the U.S. Food and Drug Administration (FDA) to test a treatment for spinal cord injury using cells derived from human embryonic stem cells. This is the world’s first clinical trial using a treatment based on human embryonic stem cells, and will likely begin this summer at “up to seven U.S. medical centers,” according to the company’s Web site. Their locations have not been disclosed.

The Phase I clinical trial will measure the safety, not the efficacy of the treatment (that comes during later trials, assuming the treatment is shown to be safe). Less than a dozen patients will receive the experimental treatment.

Geron’s drug, GRNOPC1, is a collection of oligodendrocyte precursor cells (OPC) that will be injected into the spinal cord of patients with spinal cord injury. Scientists hope that the injected OPCs will mature into oligodendrocytes and form myelin, the fatty sheath that surrounds neurons much like the insulation surrounding electrical wires.

In severe spinal cord injury, some individual neurons (bundles of neurons form nerves) might be severed, others will be intact but the surrounding myelin might be damaged. GRNOPC1 won’t repair or replace severed neurons – it will only replace myelin. Much like a wire with damaged insulation can short circuit, myelin damage impairs nerve function, and, if not repaired, can cause permanent nerve damage. Of course, if the wire is irreparably damaged, replacing the insulation won’t help.

To make GRNOPC1, scientists took a line of human embryonic stem cells and grew them in conditions such that they matured into oligodendrocyte precursor cells. Hans S. Keirstead and colleagues at the University of California in Irvine published a proof-of-concept experiment in rodents in 2005.

It is not clear to what extent the OPCs grown from stem cells in a dish mimic the OPCs found in the brain and spinal cord. How well the injected cells remyelinate neurons is also not clear. According to neuroscientist Ben Barres, it is difficult to distinguish the original myelin from the new myelin formed by the injected OPCs. In 2005, Brian Cummings and colleagues injected human neural stem cells into the spinal cord of injured mice. Motor function improved. Researchers then selectively killed the human cells in the mice (by treating with diphtheria toxin—human cells are 100,000 times more sensitive to the toxin than mouse cells) and the motor recovery was abolished. This might suggest that remyelination helps spinal cord injury, except Cummings injected neural stem cells, not OPCs, some of which became neurons. Geron may have performed but not published extensive follow-up studies clarifying these questions—only the scientists at the FDA who reviewed the 22,000+ page new drug application know for sure.

Growing up in Suwon, South Korea, In-Hyun Park’s interest in biology was sparked by a middle-school teacher. Two decades later Park made a discovery hailed as the scientific breakthrough of 2008 by Science magazine. (See “Scientists Generate Stem Cells from Adult Tissue.”)

Park came to the United States in 2000 to earn a doctoral degree in cell and structural biology from the University of Illinois in Urbana-Champaign. “I wanted to develop my potential as a scientist,” Park told me, adding he felt he would progress better in the United States, where schools focus more on creative thinking than on memorization.

In 2005 Park, remaining in the United States because of its abundant resources for scientific research, moved to Boston to do a postdoctoral fellowship in the well-funded laboratory of George Q. Daley. His project was to identify factors that could reprogram male mouse germ cells into pluripotent stem cells.

In August 2006, Shinya Yamanaka’s lab identified four factors that transformed adult mouse fibroblasts into pluripotent stem cells, so Park changed tactics, adapting Yamanaka’s method for use on human cells, reporting his successful results on January 10, 2008, in Nature. Yamanaka and another group led by James Thomson independently published similar results several weeks earlier. (Park characterizes this as “healthy competition.”)

Using his reprogramming techniques, Park generated 10 disease-specific stem cell lines derived from patients with a variety of genetic diseases, such as diabetes and Parkinson’s disease. Published in Cell on September 5, 2008, Park’s work immediately was recognized as a breakthrough. Again Park had competition: Kevin Eggan’s laboratory published similar results the week before, but researchers there generated only one disease-specific cell line.

Park’s wife and young child are in the United States, but his and his wife’s parents and other family members remain in South Korea, a place Park found difficult to leave. In the United States, Park has no extended family to help take care of the baby; without this support, his wife is a stay-at-home mother.

The young scientist “worries a lot” about the isolation from his extended family and doesn’t rule out returning to South Korea in the future, but when is the right time to return? Park will remain in the United States to try and get a job as an assistant professor at a major research university, establish an independent laboratory and study how a handful of factors can reprogram adult cells into stem cells.

He offers this advice to other scientists: “The old phrase, that the U.S. is the land of opportunity? It still applies.”

Do you agree? Share your thoughts with Science Planet.

Source: Disease-Specific Induced Pluripotent Stem Cells, In-Hyun Park, et al., Cell, September 5, 2008.
Reprogramming of human somatic cells to pluripotency with defined factors, In-Hyun Park, et al., Nature, January 10, 2008.

This week’s news concerns a major breakthrough in stem cell technology. In November 2007 Shinya Yamanaka and colleagues at Kyoto University in Japan published a method to transform adult human skin cells into stem cells. Mature cells, such as skin cells, are normally locked into their identities — skin cells don’t transform into brain cells, much like middle-aged scientists don’t have the ability to leave the lab and become professional athletes.

Yamanaka’s breakthrough was the identification of four factors, four genes, that when added to and turned on in mature cells could reprogram them into stem cells. These stem cells could, under the right conditions, develop into heart cells, or brain cells, or a number of other different types of cells. In the jargon of science, such stem cells are called induced pluripotent stem cells: induced because their creation was not spontaneous, pluripotent because they can become any cell type found in an embryo, fetus, or developed organism.

The problem was that Yamanaka used a virus to insert the genes into a mature cell and generate a stem cell. Using a virus to generate stem cells poses tremendous safety concerns for therapeutic applications in humans. The virus inserts itself into the cell’s genome and remains there forever, with the potential to disrupt the way genes normally function.

Now Yamanaka has generated stem cells without using a virus. In an article published on October 9 in Science magazine, his laboratory generated induced pluripotent stem cells from mouse embryonic fibroblasts (cells that make up connective tissue). Instead of using a virus, Yamanaka applied a well-known chemical cocktail to allow the critical genes to slip into the fibroblasts.

Scientists still have work to do. Yamanaka’s nonviral technique is much less efficient at generating stem cells than using a virus. Future studies need to apply this method to cells from adult humans — Yamanaka used cells from a mouse embryo — and confirm that there are no adverse affects. However, this week’s breakthrough brings us one step closer to a nontoxic method for generating human stem cells from adult tissue.

If this technique is perfected, will it eliminate the need to harvest stem cells from embryos? Does this work bring Yamanaka one step closer to winning the Nobel Prize in medicine or physiology?

Source: “Generation of Mouse Induced Pluripotent Stem Cells Without Viral Vectors” by Keisuke Okita, Masato Nakagawa, Hong Hyenjong, Tomoko Ichisaka, and Shinya Yamanaka.