Cell boom: Shown here is a colony of embryonic stem cells.
Credit: NIH

Scientists get ready for the end of federal restrictions on embryonic-stem-cell research

MIT Technology Review, February 10, 2009, by Emily Singer — Three years ago, when Rene Rejo Pera was setting up a new lab at the University of California, San Francisco (UCSF), she had to make sure she had two of everything: one microscope for her federally funded lab, for example, and one for a privately funded replica next door. Because of funding restrictions on stem-cell research ordered by President George W. Bush in 2001, this was a redundant scenario played out in labs across the country. The edict specifically limited federal funding for embryonic stem-cell research to a small number of cell lines already in existence, leaving scientists who wanted to conduct cutting-edge research in this area scrambling for private money.

Scientists are now looking forward to an end of that edict. President Barack Obama promised during his campaign to overturn the order, and most expect the action to happen soon. “The imminent change in policy will quite literally allow us to take down these walls and integrate the laboratories in a way that will make the work move much more efficiently,” says Arnold Kriegstein, director of the Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

The new policy is expected to mean that scientists will have unfettered access to newer, better embryonic stem cells, which will speed the pace of research. Even without funding restrictions, however, scientists receiving government grants could not use that money to generate new lines, which requires the destruction of an embryo. Kriegstein and others hope that the change will bring a new sense of legitimacy to an often embattled field, as well as return a leadership role to the National Institutes of Health (NIH), the nation’s premier biomedical funding agency, in one of the most promising areas of biomedical research. Much of the research has shifted to institutes funded by state initiatives, such as the California Institute for Regenerative Medicine, or by private donors. In addition to limiting funding, “the other reality of [the Bush] policy is all the negative publicity it has created,” says Tim Kamp, codirector of the Stem Cell and Regenerative Medicine Center at the University of Wisconsin. “Frankly, I think it did greater damage than funding restrictions, [in] that it scared many researchers away.”

Despite the restrictions, U.S. scientists have employed embryonic stem cells for a broad range of research. Because the cells can develop into any tissue type, scientists are coming up with ways to prod them to differentiate into brain cells, heart cells, and other cell types, both to better understand the diseases that strike these tissues and to potentially create replacement tissue for therapies. But much of the most promising research has moved overseas.

Once the restriction is lifted, labs funded by federal dollars will be allowed to use most of the estimated 600 stem-cell lines that have been created around the globe. Researchers broadly agree that the newer lines, which were derived using more refined methods, are superior to the older ones. Using only the old lines is like “being required to use Microsoft Word 1998,” says Jeanne Loring, director of the Center for Regenerative Medicine at the Scripps Research Institute, in La Jolla, CA.

In addition, the earlier lines were derived using animal products, making them largely unfit for therapeutic use. “There are hundreds of embryonic stem-cell lines out there that have been made under the best conditions, and some of them are patient ready,” says John Gearhart, director of the Institute for Regenerative Medicine at the University of Pennsylvania, in Philadelphia. “They have greater utility, performance, and safety than [the Bush-approved] lines.”

Scientists will also be able to study cell lines that are genetically encoded for specific diseases–perhaps one of the most promising near-term uses of embryonic stem cells. (None of the Bush-approved lines have these qualities.) “One of the clear opportunities that has not been available are lines generated from embryos that carry mutations for Huntington’s disease, amyotrophic lateral sclerosis (ALS), and cystic fibrosis,” says Story Landis, director of the National Institute for Neurological Disorders and Stroke, in Bethesda, MD, and chair of the NIH’s Stem Cell Task Force. These cells provide unprecedented access to the molecular processes underlying disease; they can be prodded to develop into the cell type affected in a specific disease, such as motor neurons in ALS, so that scientists can watch the disease unfold at a cellular level. These cells can also be used to screen new drugs.

Scientists and policy makers are still guessing as to when and how President Obama will reverse the restrictions–whether he will issue an executive order, or let Congress decide the matter. But according to White House press reports last week, the president promised the former. Prior to Obama’s presidency, Congress twice passed a bill reversing the restrictions, the Stem Cell Research Enhancement Act, which Bush twice vetoed.

It’s not yet clear how quickly the field will rebound from the funding limits. Many scientists were discouraged from studying embryonic stem cells during the past eight years because they couldn’t secure private funds, or because they or their universities did not want to deal with the extensive accounting required. “The effect of the restrictions was to create a few centers going forward, like mine and like Harvard, Stanford, and UCSF, which had access to private and state money,” says Loring. “Now there will be more room for people to get involved, but they’ll be eight years behind.”

The field has changed dramatically since President Bush’s edict, especially in the past two years, which may make new funding freedom less significant. A newly developed technique to create stem cells–called induced pluripotent stem (iPS) cell reprogramming–does not require the destruction of human embryos, and scientists hesitant to take on embryonic stem cells have been flocking to the new approach in droves.

Researchers have been able to do many of the same experiments with these iPS cells as they have with embryonic stem cells. However, they caution that these cells have not been shown to carry all the power of embryonic cells–for example, they cannot differentiate into as many cell types. “It’s very important that labs be able to do experiments with both kinds of cells side by side,” says Kriegstein. “Relaxing presidential policies will make this much easier to accomplish.”

One area of research that won’t change with removal of the restrictions is therapeutic cloning. In therapeutic cloning (also called somatic cell nuclear transfer), scientists transplant DNA from an adult skin cell into an egg that has had its DNA removed. Unknown factors in the egg reprogram the adult DNA to resemble embryonic DNA, and, in theory, the cell begins to develop like a normal embryo. Scientists would like to create stem cells from cloned human embryos, both for research and potentially for therapy: the cells would be genetically matched to their human donors and thus could be transplanted without fear of rejection. But no one has yet accomplished this with human cells and eggs. Research that involves destruction of human embryos, which includes both cloning and derivation of new stem-cell lines, is prohibited from federal funding under the Dickey Amendment, a rider to the appropriations bills that have been passed in

U.S. Department of Health and Human Services
National Cancer Institute (NCI)

For Release: Monday, February 9, 2009

Researchers have generated altered immune cells that are able to shrink, and in some cases eradicate, large tumors in mice. The immune cells target mesothelin, a protein that is highly expressed, or translated in large amounts from the mesothelin gene, on the surface of several types of cancer cells. The approach, developed by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and at the University of Pennsylvania School of Medicine, shows promise in the development of immunotherapies for certain tumors. The study appeared online the week of Feb. 9, 2009, in the Proceedings of the National Academy of Sciences.

Expression of mesothelin is normally limited to the cells that make up the protective lining (mesothelium) of the body’s cavities and internal organs. However, the protein is abundantly expressed by nearly all pancreatic cancers and mesotheliomas and by many ovarian and non-small-cell lung cancers. Although the biological function of mesothelin is not known for certain, it is thought to play a role in the growth and metastatic spread of the cancers that express it.

“Since tumor cells are derived from the body’s normal cells, the immune system often does not recognize tumor molecules as dangerous or foreign and does not mount a strong attack against them,” said Ira Pastan, M.D., chief of the Laboratory of Molecular Biology in NCI’s Center for Cancer Research, a study collaborator. Moreover, even though it is possible to genetically engineer immune system cells to recognize molecules on tumor cells, most of the molecules found on tumor cells are also found on normal cells. But, Pastan notes, “Mesothelin is a promising candidate for generating tumor-targeting T cells, given its limited expression in normal tissues and high expression in several cancers.”

Previous laboratory research has shown that certain immune system cells, called T cells, can kill tumor cells that express mesothelin. In addition, studies in both animals and humans have shown that antibodies directed against mesothelin protein can shrink tumors.

In the new study, the research team genetically engineered human T cells to target human mesothelin. To produce them, a modified virus was used as a delivery vehicle, or vector, to transfer synthetic genes to T cells. These genes directed the production of hybrid, or chimeric, proteins that can recognize and bind to mesothelin and consequently stimulate the proliferation and cell-killing activity of the T cells. In laboratory studies, the team found that the engineered T cells proliferated and secreted multiple cytokines when exposed to mesothelin. Cytokines are proteins that help control immune functions. The cells also expressed proteins that made them resistant to the toxic effects of tumors and their surrounding tissues.

To study the effects of the engineered T cells on tumor tissue, the researchers implanted human mesothelioma cells underneath the skin of mice. About six weeks later, when tumors had formed and progressed to an advanced stage, the engineered T cells were administered to the mice. Direct injection of the T cells into tumors or into veins of the mice resulted in disappearance or shrinkage of the tumor.

“Based on the size of the tumors and the number of cells administered, we estimate that one mesothelin-targeted T cell was able to kill about 40 tumor cells,” said study leader Carl H. June, M.D., professor of Pathology and Laboratory Medicine at the University of Pennsylvania School of Medicine and director of Translational Research at Penn’s Abramson Cancer Center. “This finding indicates that small doses of these cells may have potential in treating patients with large tumors. Clinical trials are being developed to investigate this approach in patients with mesothelioma and ovarian cancer.”

PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System.

Penn’s School of Medicine is currently ranked #4 in the nation in U.S.News & World Report’s survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s top ten “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation’s first hospital; and Penn Presbyterian Medical Center. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit .


REFERENCE: Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, Varela-Rohena A , Haines KM, Heitjan DF, Albelda SM, Carroll RG, Riley JL, Pastan I, and June CH. Control of large established tumor xenografts with genetically re-targeted human T cells containing CD28 and CD137 domains. PNAS. Online the week of February 9, 2009.

U.S. Department of Health and Human Services
National Institute of Dental and Craniofacial Research (NIDCR)

For Release: Monday, February 9, 2009

Darwin had his finches, Morgan had his fruit flies, and scientists today have cichlid fishes to trace the biological origins of jaws and teeth. In this week’s issue of the journal PLoS Biology, researchers supported by the National Institute of Dental and Craniofacial Research, part of the National Institutes of Health, report they have deduced a network of dental genes in cichlids that likely was present to build the first tooth some half a billion years ago.

The researchers say their finding lays out a core evolutionary list of molecules needed to make a tooth. These original dental genes, like a four-cylinder Model T engine to the marvels of modern automotive engineering, were then gradually replaced, rewired, or left in place to produce the various shapes and sizes of teeth now found in nature, from shark to mouse to monkey to human.

Todd Streelman, Ph.D., a scientist at Georgia Institute of Technology in Atlanta and senior author on the study, said the discovery should provide useful information for researchers attempting to coax diseased teeth back to health with biology rather than the traditional hand-held drill. “To truly understand any part of the body, you must know how it was originally designed,” said Streelman. “This is especially important when it comes to teeth. The teeth of fishes not only develop distinct sizes and shapes, they are also repaired, shed, and replaced throughout life.”

“But these characteristics, once intertwined, have been decoupled through the ages in higher organisms, and the ability to repair and regrow teeth has been largely lost,” he added. “If we could learn to selectively restore these traits in the dentist’s office, it would mark a major step forward in helping people protect and repair their teeth. I think this gene network provides a nice evolutionary clue on how best to proceed.”

Teeth are extremely ancient structures that arose in early vertebrates — animals with a backbone — but interestingly predate jaws. The fossil record indicates the first patterned set of teeth, or dentition, arose in the back of the pharynx of jawless fish. The pharynx is a tube-like part of the throat that functioned in early fish as a rudimentary jaw in which pharyngeal teeth filtered and processed food.

Over the millennia, as vertebrates developed more powerful opposing jaws for feeding in water and on land, most species adapted their dentitions there. Today, scientists can offer a real-life glimpse of this developmental bifurcation by pointing to vertebrates, such as zebrafish, that retain pharyngeal teeth only; others, such as mouse and human, that have oral teeth only; and a subset, including cichlids, that thrives with both.

That’s where the cichlids enter the research picture. In Lake Malawi, one of East Africa’s Great Lakes, scientists can find a great diversity of dentitions among more than 1,000 cichlid species. Most species are endemic to East Africa and closely related, but they have evolved into a rainbow of colors, shapes, and sizes over the last one to two million years to enable them to inhabit the lake’s diverse terrain.

“They really are quite unique,” said Gareth Fraser, a postdoctoral fellow in the Streelman laboratory and lead author on the paper. “Some cichlids have in total more than 3,000 teeth lining their pharynx and mouth. Each tooth gets replaced every 50 to 100 days with each tooth position maintaining its own stem cell niche, or environment, that initiates development of the next generation of teeth.”

Last year, Fraser and colleagues described a gene network that seemed to control the patterning of tooth size, number, and spacing in Lake Malawi cichlids. Interestingly, the genes began this patterning very early in embryonic development. This indicated to the scientists that teeth are patterned similarly to other ectodermally-derived organs, such as feathers and hairs. The ectoderm is one of three germ layers, or groups of cells, that form the external covering of a developing embryo.

They then asked a follow-up question: Is tooth number controlled similarly in the pharyngeal and oral jaw? As straightforward as the question seemed, it made no obvious biological sense. The two jaws are developmentally decoupled, as separate and distinct spatially in the embryo as Africa and North America. What’s more, the oral jaw is a relative evolutionary newcomer that is thought to have originated from the loss of a particular set of genes during the transition from jawless to jawed vertebrates.

As described in their current PLoS Biology paper, co-author Darrin Hulsey, Ph.D., now at the University of Tennessee, found tooth number was indeed correlated in the two jaws. This surprising finding then raised the all-important question of how this was developmentally possible.

The scientists hypothesized that their previously described gene network might hold the key. The term “network” is used here to connote multiple genes that broadly synchronize their expression during a phase of development, not in the systems biology sense of nodes of direct temporal interaction.

Their hunch turned out to be correct. “We found that even though these two jaws are evolutionarily and developmentally distinct, they share a network of genes that pattern and limit tooth number,” said Fraser. “What’s really interesting is this network includes genes that are known to be involved in the patterning of hairs, feathers, and other ectodermally-derived tissues. This tells us that the network is quite ancient and fundamentally important to creating a dentition; otherwise, it would have been lost in time between the evolution of the two jaws.”

“Our work also shows the power of evolutionary models like cichlids in biomedical research,” added Streelman. “You don’t need to artificially turn genes on or off under controlled laboratory conditions to see what might happen. The cichlids are nature’s own experiment, and they open up exciting biological opportunities that you just can’t glean as possibilities from traditional model organisms.”

The National Institute of Dental and Craniofacial Research (NIDCR) is the Nation’s leading funder of research on oral, dental, and craniofacial health.

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit .

U.S. Department of Health and Human Services
National Institute of Arthritis and Musculoskeletal and Skin Diseases

For Immediate Release: Tuesday, February 10, 2009

For the first time, scientists can see an elusive protein that forms part of the shell of a retrovirus — a finding that may help in the development of therapies to disrupt the functioning of retroviruses, which include the HIV/AIDS virus. The study, led by scientists at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health, appears in the current issue of the journal “Nature.”

The target of the research was a retrovirus capsid pentamer protein — a protein composed of five subunits that forms part of the capsid, the shell containing the nuclear material of a retrovirus. To date, scientists have only been able to visualize capsid hexamer proteins, which are composed of six subunits. Since structure often impacts function on the molecular scale, these findings may further our understanding of capsid assembly in retroviral replication and may lead to interventions to disrupt it.

The NIAMS scientists, led by Alasdair Steven, Ph.D., a senior investigator in the Laboratory of Skin Biology of the NIAMS ‘ Intramural Research Program, and in collaboration with scientists from The Pennsylvania State University College of Medicine in Hershey, studied a retrovirus called Rous sarcoma virus (RSV), a cancer-causing virus found in chickens. However, since many retroviruses have similar proteins in the capsid, the scientists’ work has implications for many retroviruses, including other cancer-causing viruses and human immunodeficiency virus (HIV).

Retroviruses vary in the shape and size of their capsids. HIV has a capsid in the shape of an ice cream cone. RSV’s capsid has an icosahedron shape, with 20 sides and 12 points. Despite the fact that scientists have only been able to visualize hexamer proteins in two-dimensional sheets or tubes, they knew mathematically that pentamers had to exist in order to create the various capsid shapes seen in retroviruses.

The scientists used a technique called cryo-electron microscopic analysis of in vitro-assembled capsids from RSV to visualize the capsid proteins in three dimensions. In short, they froze the capsid proteins, made a cast of their shapes, and then used electron microscopy to simulate a three-dimensional model of the shapes. They discovered the subunits that make up the hexamer and pentamer proteins are practically identical in shape and chemical make-up, and are also practically identical to the subunits found in HIV capsid proteins. The scientists investigated further to see how these subunits interacted to create such diverse capsid protein shapes and sizes.

The answer had to do with tops and bottoms. Each protein subunit is like a balled-up string with two ends. The top end is called the N-terminal domain (NTD) and the bottom end is called the C-terminal domain (CTD). Each subunit is connected to its neighboring two subunits through the connection of the ends of the strings. This provides for three types of binding: top to top (NTD-NTD), top to bottom (NTD-CTD), and bottom to bottom (CTD-CTD). These different interactions determine the shapes and sizes of the various capsid proteins. And, it is the combination of these capsid proteins that determines the shapes and sizes of the capsids themselves.

These findings contribute to our understanding of the structure, function, and creation of retroviral capsids. Currently, research is investigating the potential to disrupt capsid assembly during viral replication. Discoveries in this area could lead to treatments to prevent or halt the progression of a retroviral infection.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, a part of the Department of Health and Human Services’ National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at .

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit .


Reference: Giovanni C, Purdy JG, Cheng N, Craven RC, Steven AC. “Visualization of a missing link in retrovirus capsid assembly. “Nature,” Vol 457, 5 February 2009. DOI:10.1038/nature07724.

February 10, 2009 — NYC Mayor Michael R. Bloomberg addressed the industry’s most influential executives at the Eleventh Annual BIO CEO & Investor Conference held yesterday in midtown Manhattan’s prestigious Waldorf Astoria. Mayor Bloomberg spoke to the importance of commercial bioscience in NYC’s diversification strategy and discussed current efforts to create two new research parks to accommodate the 20 companies that spin-off annually from NYC’s 9 academic medical institutions.

BIO CEO is the largest independent investor conference for the life sciences industry focused on publicly-traded biotechnology companies. The Conference was expected to attract over 2,000 senior biotechnology executives.

With $1.3B in NIH funding, the largest concentration of academic medical institutions, over 120 bioscience companies, the creation of two new research parks – the East River Science Park and BioBAT – and the #1 metro area in bioscience employment, NYC is where life science entrepreneurs are going for opportunities.

For more information about the NYC Bioscience Initiative, please contact Lenzie Harcum or visit www.nycbiotech.com.