Search

STEM CELLSBONN-- Germany's main research funding agency issued new guidelines last week paving the way for researchers to import human embryonic stem cells from other countries. The Deutsche Forschungsgemeinschaft also recommended that Parliament pass a law, if needed, that would allow German researchers to derive their own stem cell lines from surplus embryos from in vitro fertilization clinics.

The article presents questions and answers related to embryonic stem cell lines including where the embryos used for stem cell lines come from, the number of stem cell lines that exist, and why the amount that exist is not enough.

any scientists and patient advocates cheered earlier this summer when the National Institutes of Health (NIH) released new guidelines for human embryonic stem cell (hESC) research. The guidelines came after President Obama’s March 2009 executive order lifting the restrictions on federal support for research using embryonic stem cells. Obama’s directive revoked the Bush administration’s restrictions and funding ban on hESC research, which had limited scientists to using only 21 approved cell lines out of about 700 in existence. The directive also ordered the NIH to issue new guidelines for hESC research, which were released in July 2009. These new guidelines specify that NIH funding can be provided for research on hESCs derived from human embryos “that were created using in vitro fertilization for reproductive purposes [but] were no longer needed for this purpose,” and were donated by individuals who were fully informed about embryo treatment and gave their voluntary, written consent to use the embryos for research. The guidelines also stipulate that there can be no financial inducements for embryo donations, and that NIH-funded research must remain separate from privately funded research. Additionally, the NIH will establish a working group of scientists and ethicists to review existing cell lines, determine their eligibility for federal funding, and post those hESCs eligible for federal funds in an online registry. The presidential directive greatly expands the research potential in this field, but Obama noted in his remarks about the order that the “full promise of stem cell research remains unknown, and it should not be overstated.” Many advocates of stem cell research agree: Much more stem cell research will take place, yet much more policy work still awaits action. The spotlight is currently on the NIH working group. This is because until the NIH determines which cell lines are eligible for federal funding, hESC research remains on hold and, as of early September 2009, the NIH registry was still empty. Alan Smith, senior research scientist at Stemina Biomarker Discovery (a metabolomics company in Madison, Wisconsin), says that this void in the registry is a major concern for industry because it is slowing efforts to build new collaborations with other companies that are using yet-to-beapproved cell lines and to spur innovations in stem cell research. It is unclear when new stem cell lines will be entered into the registry—no timeline has been announced—but some researchers are concerned that the addition of the new lines may take years. Other pressing policy issues remain. Some analysts have suggested that the government focus on developing a coalition among all the entities that work on stem cells, perhaps by supporting the formation of geographic innovation hubs. Such a large-scale collaboration between universities and industries could be transformative for the field of regenerative medicine. Other experts, such as Jonathan Moreno, a senior fellow at the Center for American Progress, believe that the next grand policy challenge will be to develop guidelines for

THE NATIONAL INSTITUTES of Health has released its final guidelines for work on human embryonic stem cells (hESCs), opening the door for more stem cell lines to be eligible for federally funded research. The guidelines, which went into effect on July 7, address concerns about preexisting cell lines and establish a registry that will list all approved hESCs. According to the new guidelines, hESCs that were eligible for federally funded research under the George W. Bush Administration's policy will not automatically be eligible now. Instead, researchers must submit documents to NIH showing that the cells were derived responsibly. A special working group will determine whether the principles of informed consent—by embryo donors—outlined in the guidelines were sufficiently met. Cell lines derived on or after July 7, however, will have to follow specific requirements regarding informed consent by embryo donors. All hESCs that are approved will be posted on a new NIH registry. ...

Stem cells derived from human fetal tissue are to be injected into the brains of patients who have had a stroke in a trial to begin in Glasgow later this year. The eventual aim is to determine if neural stem cells can repair tissue damaged by stroke. ReNeuron, the UK based company that has developed the stem cell line, has turned to Britain to carry out the research after failing to get approval in the United States. The UK Medicines and Healthcare Products Regulatory Agency has given the go-ahead for the trial; …

Lack of funding has prevented progress in UK stem cell research that is based on creating human-animal hybrid clones, despite legislation that allows the technique being passed a year ago, researchers warned this week. Two of the three UK researchers who were granted licences last year to conduct research with human-animal hybrid stem cells, Stephen Minger at King’s College, London, and Lyle Armstrong at Newcastle University’s centre for life, said that they had been unable to initiate or continue with early studies because research councils had turned down grant applications. Dr Minger, senior lecturer in stem cell biology at King’s College, London, said that the Medical Research Council had turned down an application by his department for about £1m (€1.1m; $1.5m) to cover a three year project. The aim was to develop stem cell lines from people with genetic forms …

Pfizer is launching Pfizer Regenerative Medicine, a unit that will combine its current work in stem cell research into a single organization based jointly in Cambridge, England, and Cambridge, Mass. It will be headed by Pfizer Chief Scientific Officer Ruth McKernan. Expected to employ 70 researchers, the group will straddle Pfizer’s new Biotherapeutics & Bioinnovation Center and Pfizer Global Research & Development. McKernan will report to both Corey Goodman, head of BBC, and Rod MacKenzie, head of worldwide research. The regenerative medicine unit is intended to coordinate and expand stem cell research, including small-molecule screens of stem cell lines, according to Goodman. Last year, he says, the company broadened its research policy to include embryonic stem cell lines that qualified for federal funding. It’s a coincidence that the launch comes within weeks of the election of Barack H. Obama as the next president, Goodman says. When Obama takes office, he is expected to ...

Despite the restrictions and controversy confronting stem cell research, labs around the world continue to derive new human embryonic stem cell lines and make them available to the global research community. The EU-funded Human Embryonic Stem Cell Registry (hESCreg) seeks to bring order to the growing number of available stem cell lines and the flood of related data, beginning with the cell lines created in European labs. The web-based registry, launched in January 2008 and accessible at http://www.hescreg.eu, aims to serve as a one-stop source of information about the origins and traits of these cell lines. Anna Veiga, the hESCreg scientific coordinator and director of the stem cell bank at the Centre of Regenerative Medicine in Barcelona, talks with Doug Sipp about how the project was conceived and where it might lead.

Restrictions on United States federal funding have thrust state governments into a leadership role in funding and establishing standards for human embryonic stem cell (hESC) research. In 2004, California voters approved $3 billion over 10 years for public funding of stem cell research through the California Institute for Regenerative Medicine (CIRM), making CIRM one of the world's largest supporters of this pioneering new field. CIRM recently adopted strong, comprehensive, and legally binding regulations for the human stem cell (hSC) research that it funds. Box 1 describes the historical background of CIRM regulations. Because other states and jurisdictions may also be developing standards for hESC research, consideration of the principles that guided the CIRM efforts and the innovative measures that it enacted may be useful to others.

Last week, a European team reported creating a line of human embryonic stem cells that did not involve the destruction of human embryos, cultivating a line of stem cells from an "arrested" or nonviable embryo. (Read more.)

PRESIDENT GEORGE W. BUSH issued the first veto of his presidency to strike down a bill that would have expanded current federal policy on embryonic stem cell research. The veto came less than 24 hours after the Senate passed the House-approved Stem Cell Research Enhancement Act(H.R.810). The bill, which passed the House last May, would have removed some federal restrictions and allowed federally funded research to include stem cell lines created ethically from excess in vitro fertilization embryos scheduled to be discarded as medical waste. Researchers have advocated such an expansion of federally approved research because the 21 cell lines currently approved for study have become contaminated by mouse feeder cells and cannot be used in humans. Bush reiterated his belief that the current policy, which he set in August 2001, is sufficient to allow research to move forward with only the cell lines derived before the policy was in place. ...

lines is important but it might not have relevance,” he said. “Finding changes in genes that are known to have phenotypes really tells us that we should look into this more deeply.” The identification of such genetic alterations in the federally approved lines, along with the recent discovery that the lines are contaminated by proteins from the mouse feeder cells they have been grown on, are the latest in a string of findings suggesting that the federally approved lines may have limited therapeutic potential. Chakravarti said it will be necessary to examine some or all of the existing stem cell lines to determine whether these changes are a characteristic of all stem cells, a function of the age of the cell lines, or related to how they were derived and cultivated. Although he does not believe these findings detract from the enormous potential of stem cells, Chakravarti said they demonstrate the need to carefully monitor stem cell lines, particularly those that might be used therapeutically. Such monitoring may “show that some stem cell lines are much more useful than others for therapeutic purposes,” he said. Daley agreed, explaining that scientists developing stem cell–based therapies will want to use the most genetically normal cell lines available.

FOR THE FIRST TIME, REsearchers have been able to reprogram adult somatic cells to behave like human embryonic stem cells (ESCs) by simply fusing the somatic cells with ESCs from existing stem cell lines ( Science 2005 , 309 , 1369). ESCs are of interest because of their potential to form replacement cells and organs for disease treatment. Until now, published methods to derive ESCs all have involved direct destruction of an embryo. This new process will help scientists understand details about how adult cells can be transformed back to ESCs?information that could provide less ethically charged alternatives to somatic cell nuclear transfer (or therapeutic cloning) for deriving stem cell lines. Word of this new process comes as Congress debates the need to expand the federal ESC research policy which allows federally funded research on a limited number of stem cell lines. The House has already passed legislation to allow federal funds to be used to study additional ESC ...

Scientists in the United States, supported by private funds, are circumventing the so called “presidential” stem lines approved by President Bush in August 2001 for publicly funded research and are managing to conduct further stem cell research. Currently, federal funding for stem cell research in the US is possible only on the 22 lines in existence before 9 August 2001. The US House of Representatives recently passed a bill to increase government funding for research on human embryos, and a Gallup poll in early May showed that 60% of Americans said medical research involving stem cells was morally acceptable. However, President Bush has said he would veto the bill ( BMJ 2005;330:1285), because of his Christian belief that embryos were “emerging human life.” The 22 stem cell lines are all thought to be unsuitable for human treatment, because they were grown on mouse …

New treatments based on stem cell technology moved nearer to becoming a realistic possibility, with a UK research group reporting last week that it had successfully cloned a human blastocyst and South Korean researchers reporting that they had created stem cells to match individuals for the first time. Researchers from the University of Newcastle upon Tyne's Centre for Life reported that they had removed the nuclei from oocytes obtained from 11 women and replaced them with DNA from embryonic stem cells. Three of the resulting clones lived and grew in the laboratory for three days, and one survived for five days. The blastocyst had identical DNA to the stem cell line, proving that it had resulted from cloning. The study was published on 19 May in Reproductive and BioMedicine Online (http://www.rbmonline.com/, search for article number 1872). The critical factor for successful cloning seemed to …

The British research team that created Dolly the sheep has been granted a licence to clone human embryos to study motor neurone disease. The licence will allow researchers at the Roslin Institute in Edinburgh and King's College in London to generate stem cell lines from embryos created using DNA from patients with motor neurone disease. They will focus on uncovering the cause of the motor neurone disease in patients whose condition cannot be linked to the genes already identified as causing the disease. It is only the second time that the United …

The few stem cell lines approved in the United States are probably contaminated with a non-human molecule, says a study published online ahead of print publication in Nature Medicine (www.nature.com/nm/). The researchers recommend starting afresh with human embryonic stem cells that have never been exposed to animal products. The authors, researchers at the University of California at San Diego and the Salk Institute in La Jolla, California, report that the human embryonic stem cells they studied are contaminated with non-human sialic acid that could cause rejection if the stem cells were transplanted into humans. “In …

The first stem cell bank in the world opened last week in the United Kingdom, with the aim of providing an international resource for storing, characterising, and supplying ethically approved, quality controlled, stem cell lines for research and, ultimately, for treatment. The bank is being run by the National Institute for Biological Standards and Control—a government funded organisation involved in quality assurance of research related to biological medicines. Its key aims are to improve access to high …

A LETTER TO CONGRESS FROM NIH Director Elias A. Zerhouni defends the Bush Administration's policy on human embryonic stem cell research while suggesting that more stem cell lines might increase the pace of research. The letter is a response to one from Congress that called for the White House to expand current policy (C&EN, May 3, page 22). Zerhouni, who wrote the letter on behalf of President George W. Bush, outlined NIH's commitment to funding stem cell research that uses the approved 78 cell lines—19 of which are currently usable. He addressed representatives' concerns over the impact of limited federal funding in terms of attracting new scientists and in possibly pushing stem cell research overseas. He also noted that the usable cell lines are sufficient to support basic research. However, he added, it is not clear just what can be accomplished with those cell lines. "And although it is also fair to say ...

Researchers in the United States have derived and identified 17 new stem cell lines from human embryos, in addition to the 15 that are currently known to be available for publicly funded research in the United States. The research, released on the internet this week by the New England Journal of Medicine (www.nejm.com), is bound to stir up controversy in a country where stem cell research is a highly contentious issue. The new stem cell lines were derived from human …

APROPOSED SET OF STANdards for evaluating human embryonic stem (hES) cells has been put forth by a group of molecular biologists { Science , 300 , 913, (2003)}. It remains to be seen how their proposal will be received by the wider scientific community and the public. The authors of the proposal explain that their goal "was to initiate a scientific discussion that may help to establish standards for evaluating hES cells, in particular, to enable the comparison and classification of existing and future cell lines." Lead coauthor Ali H. Brivanlou, a professor of molecular embryology at Rockefeller University, observes that the number of stem cell lines said to be available to U.S.-funded researchers is anumber that has fluctuated. "A lack of standards is the problem with stem cell research today," he explains. "We don't know how to appreciate or define stem cells, to assess their qualities. What is a stem cell?" As it happened, even before the group could put ...

BETHESDA, MD—A year and a half after President Bush announced his decision topermit federal fundingforsomehuman embryonic stem cell research, the National Institutes of Health (NIH) has disbursed$25million touniversities and launchedanon-campuseffort todescribe and standardize various cell lineages. An NIH stem cell registry now lists nine lines of “distribution quality” cells available to researchers: five from ES Cell International, Brisbane, Australia; two from WiCell Research Institute, Madison, Wis; one from BresaGen Inc, Atlanta, Ga; and one from the University of California, San Francisco. Such cell lines have been tested for specific markers and shown to grow into somatic cells in vitro.

The world9s first embryonic stem cell bank should be up and running within a year. The U.K. Medical Research Council announced on 9 September that it has awarded a contract to establish the new bank, which will collect and distribute stem cell lines derived from human embryos and fetal and adult tissue.

The UK Human Fertilisation and Embryo Authority has granted the first licences for research teams to proceed with programmes designed to develop human embryonic stem cell lines. The authority, the regulatory body that oversees human fertilisation and related research in the United Kingdom, last week approved applications from two research groups to develop stem cell lines from human embryos. Previously, researchers have only been licensed to study embryos up to 14 days old with a view to improving infertility treatment. They were not allowed to produce human embryonic stem cell lines that were maintained long term. A group at Edinburgh University has been licensed to develop embryonic stem cell lines to be used in studies designed to develop new therapeutic approaches to Parkinson's disease, and a team at King's College, London has been approved to use stem cells to investigate neural disorders, infertility, and miscarriage. The …

The Michael J. Fox Foundation for Parkinson's Research has pledged US$2.2 million to fund efforts aimed at establishing a publicly available line of dopamine-producing neurons from stem cells. This and similar initiatives from other private sources will fill gaps in research support that have been created by the US government's recent refusal to fund projects creating new stem cell lines. LO

The US National Institutes of Health is preparing to award the first federally funded grants for research into human embryonic stem cells following President George W. Bush's limited approval for projects using existing stem cell lines. The NIH expects the first grants from a US$ 100m budget to be awarded early next year, but several uncertainties still surround Bush's decision. Some researchers have questioned the quality and quantity of the ∼60 cell lines that are currently available, and are wary of any patent or licensing restrictions commercial suppliers might place on their use. These and wider issues are discussed in The Scientist (3 September). MJD

AS THIS ISSUE OF C&EN GOES TO PRESS, the Bush Administration is agonizing over a decision that could affect the future of medical research: whether to use federal funding to carry out research on stem cells obtained from human embryos. Here is the background on this important controversy: On Aug. 25, 2000, the Clinton Administration lifted the moratorium put in place in January 1999 on federal funding to conduct research on stem cells from human embryos. (However, a ban on using federal funding to create human embryos "for research purposes" or for research that destroys an embryo remains in place. Thus, federal funding cannot be used to create stem cell lines, only to investigate their utility.) An enormous amount of effort and discussion went into the Clinton decision on stem cells. The National Institutes of Health received more than 50,000 comments from members of Congress, patient advocacy groups, scientific societies, religious organizations, and private citizens. ...

The prognosis of the glandular neoplasms of the uterine cervix is related to the clinical stage and, to a lesser extent, to the histologic type, growth pattern, and degree of differentiation of the neoplasms. To determine further the prognostic significance of the stem cell ploidy levels as determined by nuclear DNA quantitation, the authors separated the tumors into low ploidy (less than 3N) and high ploidy (greater than 3N) groups. Of the clinical Stage I and II neoplasms, low ploidy tumors had a better prognosis than high ploidy tumors of comparable stage. Low ploidy tumors had a better prognosis than high ploidy tumors irrespective of the degree of differentiation. Mixed carcinomas had a poorer prognosis than pure adenocarcinomas of comparable clinical stage. This might be explained by the greater proportion of high ploidy stem cells in mixed carcinomas than in pure adenocarcinomas. Although advanced clinical Stage III and IV neoplasms had a poor outlook regardless of the DNA ploidy level, there was a proportional increase of high ploidy tumors with increasing clinical stage. These findings suggest that cervical granular neoplasms having high ploidy stem cell lines are biologically more aggressive than those with low ploidy stem cell lines.

This is, to our knowledge, the first report of combined Rh and MNSs antigen alteration in a leukemic patient. Red blood cells of a chronic myelogenous leukemia patient demonstrated mixed field reactions with anti-Rho (D) reagents in August 1980. Earlier tests indicated he was Rho (D) positive in 1967, but Rho (D) and Du negative from 1973 to 1980. Titration studies with anti-hr' (c) and anti-hr" (e) indicated depressed expression, and there was also very weak s expression. One hundred per cent of cells studied from 1967 to 1980 were Philadelphia chromosome (Ph1) positive. No abnormalities in chromosomes associated with the Rh or MNSs blood groups 1 and 4, respectively, were noted. Phenotypes from August 1980 through September 1981 revealed normalization of red blood cell antigen status with an increase of Rho (D) positive cells from 35% to 100%. Chromosomal studies in October, 1980 and June, 1981 revealed Ph1 mosaicism with 25 and 75% Ph1 negative cells, respectively. These findings suggest that normalization of previously altered red blood cell antigen expression may reflect resurgence of normal stem cell lines.

We studied the DNA histograms obtained by flow cytometry from a series of six giant fibroadenomas and ten phyllodes tumors to determine if the analysis of DNA ploidy would help to predict clinical behavior. We were unable to document any relation between ploidy and histologic appearance, recurrence, metastasis, lesion size, or patient age. DNA aneuploid stem cell lines were seen in 75% of histologically benign phyllodes tumors, 50% of histologically malignant phyllodes tumors, and approximately 33% of giant fibroadenomas.

Marrow stem cell lines from old and young donors in parallel experiments were transplanted into genetically anemic W / W v recipients. These recipients were populated and their anemias were cured by stem cell lines from WCB6F 1 or C57BL/6 donors that had been repeatedly transplanted up to five times at annual intervals into successive W / W v recipients. Old marrow cell lines produced erythrocytes normally for as long as 2600 to 3000 days. However, after three to four serial transplantations many stem cell lines failed to cure at least two-thirds of the recipients, and all failed by transplantation six. This decline occurred in a similar pattern whether the original stem line donor was old or young. Two experiments suggested that the decline was caused by the transplantation procedure: (1) chromosomally marked donor cells from old and young donors permanently populated lymph nodes in lethally irradiated recipients after the first transplantation, but under the same conditions cell lines from the same donors transplanted a second time were substantially infiltrated by regenerating recipient cells; (2) the ability to compete with the same chromosomally marked cell line in populating irradiated recipients declined markedly in both old and young marrow stem cell lines that had been previously transplanted.

A human round cell line, KLM-2, is considered to be precursor B-cell by immunologic surface marker analysis and histochemical studies. The effect of 12-O-tetradecanoyl phorbol-13-acetate (TPA) and/or colony- stimulating factor (CSF) on KLM-2 cells was investigated. KLM-2 cells became adherent to the bottom of the flask on day 2 after liquid culture with TPA, and the number of macrophage-like adherent cells (mAC) with pseudopodia showed a TPA dose-dependent increase to the peak level on day 3 or 4. The mAC had a phagocytic activity. The suspending cells were positive for alpha-naphthyl acetate esterase (NAE) up to about 50% in culture with TPA. A TPA concentration of 100 ng/ml was optimal to provide a maximum number of mAC and NAE-positive suspending cells. Particularly, such effects of TPA on KLM-2 cells were markedly accelerated in the presence of CSF. These findings indicate macrophage differentiation of KLM-2 cells in the presence of TPA and CSF. KLM-2 cells may be a bipotential stem cell line differentiating into B-cell and monocyte-macrophage lineages.

The generation of human embryonic stem cell banking networks has ensured that well-characterized and quality controlled stem cell lines are broadly accessible to researchers worldwide. Here, we provide recommendations for engaging these established networks in efforts to build similar resources for the distribution and collection of induced pluripotent stem cells.