Stem cell plaintiff’s institute takes sides against him in court battle

Adult stem cell researcher James Sherley is suing the federal government to prevent the funding of embryonic stem cell research. Is Sherley a radical pro-life advocate? No, but he thinks that the funding of embryonic stem cell research great detracts from funding of adult stem cell projects.

Sherley’s home institute, the Boston Biomedical Research Institute (BBRI), last week asked the US Court of Appeals for the District of Columbia Circuit if it could join as a signatory to a friend-of-the-court brief filed in October by the state of Wisconsin, the Coalition for the Advancement of Medical Research and The Genetics Policy Institute.

The BBRI, in requesting the permission, argued that patients would experience a “severe adverse impact” if government funding for the research was halted.  This is a remarkable assertion given that embryonic stem cell research has yet to treat a single human patient. It also said that its 25 principal investigators and other scientific staff would be hobbled by the institute’s inability to draw National Institutes of Health funding for its program in regenerative biology. Already, it said, it has been obliged to reject offers from a university and a foundation of human embryonic stem cells with mutations conferring muscular dystrophy, a disease in which the institute specializes.

Those groups argued that U.S. District Court judge Royce Lamberth was wrong on several legal points when he issued a preliminary injunction halting US-funded human embryonic stem cell research in August (the injunction has been temporarily stayed while the case is heard on its merits). Today, the Appeals Court allowed the BBRI to that argument.

The Watertown, Massachusetts-institute’s request to join the amicus brief came late in the process; one week from today, a three-judge panel of the Court of Appeals will hear oral arguments from lawyers representing Sherley and his co-plaintiff, Theresa Deisher, urging it to uphold the preliminary injunction on the grounds that US funding contravenes existing law (which forbids support for research in which embryos are destroyed).  Embryonic stem research does exactly that – destroys embryos.  Since the Dickey-Wicker amendment forbids such research, it seems to be a no brainer, but such is American politics.  Government lawyers will argue that upholding the injunction would cripple stem cell research and misinterpret that law, called the Dickey-Wicker amendment upholding the injunction would cripple stem cell research and misinterpret that law, called the Dickey-Wicker amendment.

The BBRI was at pains to highlight its request to join the case one week ago. The institute posted on its website both the text of its request to the appeals court and a letter to its executive director from the president of its board of trustees, noting that the board had unanimously decided to seek leave to join the case as a friend-of-the-court.

The California Stem Cell Boondoggle

Silicon Valley millionaire Bob Klein launched a ballot drive to create a $3-billion state fund for stem-cell research in 2004. The 65-year old entrepreneur was inspired to find money for stem cell research after his son was diagnosed with juvenile diabetes. He originally pitched the campaign as a way to take politics out of science and focus on finding cures for diseases. His drive pulled out all the emotional stops as they even showed former big screen actor Christopher Reeve paralyzed in a wheelchair, struggling for breath and imploring California voters to “stand up for those who can’t.”

Unfortunately California’s stem cell initiative is nothing more than a boondoggle that has cost the tax payers of California enormous sums of money. Now Klein wants to ask the voters for another $3 billion in a bond measure on the 2014 ballot to keep the program going.

Next month, Klein’s six-year term as chairman of the California Institute for Regenerative Medicine expires. The institute has funded research that has published a large quantity of scientific papers but no marketable therapies. In fact most stem cell scientists say that such therapies for maladies such as cancer, Alzheimer’s and spinal cord damage promised during the campaign remain years, if not decades, away.

California voters supposedly approved the agency as a rebuke to President George W. Bush’s ban on federal funding for research that did not use approved embryonic stem cell lines. Bush made it clear that he imposed the ban because the process of obtaining the stem cells involves the destruction of human embryos. Supporters of the research accused the Bush administration of allowing politics to trump science. However, morality is not politics, and this accusation has always rung quite hollow.

Nevertheless, California’s stem cell agency quickly found itself mired in another form of politics: legislators and government watchdogs criticized the program for paying its president more than twice the governor’s salary. It also distributed nearly $1 billion to universities with representatives on its board of directors and greatly oversold the promise of stem cell cures.

John Simpson of the Santa Monica based Consumer Watchdog said, “Unfortunately, the campaign fell into sound bites and most people voted for it with the expectation that there were going to be stem cell cures in a year, that Superman would walk again. Also, since the Obama administration has restored federal support for embryo-destructive stem cell research, a separate state program is simply necessary, and will probably attract little voter support.

Klein shrugs off the criticism and political doubts, and is supremely confident that there will be “plenty of evidence” to present to voters by the time they are asked to approve more money. “I passionately believe there will be some remarkable new therapies that will save lives and mitigate suffering substantially,” Klein said during an interview in the gleaming new stem cell research building at his alma mater, Stanford University. Stanford was new stem cell center was partially funded by a $43-million grant from the state stem cell program.

Of the roughly $1.1 billion committed from the agency’s budget so far, Stanford has received more than any other institution (~ $176 million). UCLA is second with $135 million, and UC San Francisco is third with $111 million. All three schools have direct representation on the agency’s board; the deans of their medical schools are voting members. All in all, $930 million has gone to institutions with faculty or administrators on the board.

Another big chunk of the money, roughly $270 million, went to the construction of new labs — built without federal funds so research can’t be cut off if a new administration in Washington once again turns off federal support for work using stem cells. “These buildings represent academic and nonprofit safe harbors where that research can be protected and proceed despite radical changes in Washington,” Klein said.

Last year, the Little Hoover Commission, a state panel devoted to accountability and transparency, suggested reducing the number of seats on the 29-member board, in part, so the tremendous amount of money going to board members’ institutions wouldn’t look so awkward. “Criticism that CIRM’s governing board remains an insider’s club undermines the legitimacy of the agency,” the commission’s June 2009 report stated. However, other critics have gone further. “When you’re talking about spending $1.1 billion dollars, there’s absolutely no excuse for people making the decision to give themselves the money,” said Robert Fellmeth, executive director of the Center for Public Interest Law at the University of San Diego. While board members recuse themselves from voting on grants where they have a direct conflict, the mere presence of so many conflicted members is a concern, Fellmeth said. “There is a quid pro quo atmosphere that develops, because you defer to each other.”

Another sore point has been the high salaries paid to top administrators, who handle a staff of about 50. In 2009, President Alan Trounson, a renowned stem cell scientist from Australia, was paid $490,000, the second highest salary in state government outside the university system, records show. This is more than twice the salary of the governor of California and the director of the NIH. California taxpayers are paying for high executive salaries and special favors to their already cash-bloated schools. They need to rise up and say no the use of their hard-earned tax dollars to murder unborn children who are too young and small to fight back.

A new strategy for spinal cord injury

Researchers at Ohio State University are trying to determine how to improve healing after spinal cord injuries by simultaneously stop damage and promote neuron growth with a single, targeted signal. After the initial insult to the spinal cord, further damage is continued by cells called macrophages, a type of white blood cell found in injured tissue. After spinal cord injury, macrophages travel to the injury site from at least three known locations in the body as part of an intense inflammatory response, and after several days, these cells promote inflammation and toxicity, which exacerbates effects of the original injury. But these same cells might also offer hope for restoration of function in people with injured spinal cords.
In previous research, scientists determined that macrophages receive signals at the site of a spinal cord injury that cause them to both promote the growth of axons (those extensions that allow for communication among nerve cells), and cause tissue damage. This new study suggests that there could be a way to manipulate these signals to silence the damaging effects while enhancing the repair function. John Gensel, a postdoctoral researcher at Ohio State University and lead author of the study, said, “We know a single population of macrophages has both capabilities, but we’ve also found that there are some specific receptors we can target that reduce the pathological potential of macrophages while retaining their regenerative characteristics.”
The goal of this research was to manipulate the immune response after spinal cord injury. An estimated 1.3 million people in the United States are living with a spinal cord injury, and they experience paralysis and complications that include bladder, bowel and sexual dysfunction and chronic pain. By using synthetic molecules to stimulate macrophages, the researchers previously showed that multiple receptors on these cells were involved in their activation, and that these receptors dictate how the macrophages behave. If more than one receptor is stimulated, the macrophage has the potential to either kill a nerve cell, stimulate it to grow, or both.
Director of Ohio State’s Center for Brain and Spinal Cord Repair, Phillip Popovich, who was also a coauthor of this study,  noted:  “What we’re trying to do is split the activation switch, so there could be two switches and you can keep one off and turn the other one on. We think we have learned how to do that, at least with regard to one signaling pathway.” There are actually thousands of potential activators present in these complex injuries, and by exploring signals that control the cells’ behavior at a specific time point in the injury, Gensel and his colleagues are getting closer to zeroing in on which receptor on the cell surface to target to promote repair.
Two receptors, known as TLR-2 and dectin-1, are present on the surfaces of macrophages and when both receptors are activated, the macrophages simultaneously perform damaging and reparative functions in the spinal cord. But when only the TLR-2 receptor was stimulated, the cells retained their regenerative effect without creating a toxic environment. In contrast, when only dectin-1 was stimulated, the macrophages killed the nerve cells. An experimental compound used in the study was able to activate the TLR-2 receptor alone in cell cultures, which enhanced the growth of axons without causing cell death. When introduced to the spinal cords of rats, the compound caused inflammation, but little tissue damage.
“Now we have to go into the cell to figure out what part of that signaling process we can manipulate and if that manipulation can stop the toxicity,” Gensel said. Ultimately, the scientists hope to identify a precise target for drug therapy that could alter the immune response after the devastating effects of the injury and tip the balance of macrophage activity toward nerve cell repair.

Stem Cell Patch May Result In Improved Function Following Heart Attack

Researchers at the University of Cincinnati have discovered that applying a stem cell-infused patch in combination with the overexpression of a specific cell instruction molecule promoted the migration of cells to damaged heart tissue after a heart attack, which resulted in improved heart function in animal models.  They also found that heart function improved more so than when stem cells were directly injected in heart tissue—a therapy that is being studied elsewhere.

Yi-Gang Wang and his research group in the department of pathology and laboratory medicine found that when a tri-cell patch, made up of heart muscle cells (cardiomyocytes, which can restore heart contractility), blood vessel cells (endothelial cells which build new blood vessels) and embryonic fibroblasts (to provide support to the cell structure), was applied to the surface of the damaged area of the heart, better outcomes in overall heart function resulted.

Following heart attacks, the heart tissue becomes damaged and scarred.,  Heart muscle cells die and the pumping function of the heart is reduced.  While therapies exist, other researchers are examining stem cells injections directly into damaged heart muscle to see if contractile function can be restored.

This stem cell-based study differed other studies in that Wang’s s group wanted to determine if overexpression of a small RNA called miR-29 could enhance the effectiveness of an implanted cell patch.  The strategy behind overproducing this gene was to reduce barriers between cells in the infarcted area.  miR-29 is a small RNA molecule that is made in increased quantities once the heart undergoes a heart attack, and it seems to be involved in the scarring reaction that occurs after a heart attack.  Overexpression of miR-29 should lead to enhanced regeneration of heart tissues and restoration of heart function after a heart attack.

Researchers first generated cardiac progenitor cells—cells that can become various cardiac tissue cell types—from induced pluripotent stem cells (iPSCs).  These stem cells can differentiate into any type of cell in the body and are artificially derived from common body cells and are induced from a forced expression of several desired genes.

The iPSCs were then labeled with green fluorescent protein (GFP) and firefly luciferase (a glowing laboratory reagent) to help trace cell migration and proliferation into the animal’s system.

Researchers injected either the virus-mediated miR29b or a control material into the heart of the animal model and then experimentally induced a heart attack.  Wang said, “These models allowed us to determine the possible benefits of miR29b and outcomes observed in two different control groups.”

Three days following the heart attack, researchers placed a cell patch on the damaged region and measured the expression of cardiac-related genes, collagen levels in the damaged tissue and scar formation-related signaling pathways.  Collagen is the main component in scars and heart muscle scars that fill in heart tissue after heart attacks are no different.

One month after the cell patch implantation, echocardiograms were performed to evaluate heart function.  Cells mobilized into the infarcted region of the heart.  Analysis of these hearts by imaging determined the number of GFP-containing cells and the number of cells expressing firefly luciferase.  The researchers found the number of GFP cells, bio-luminescence signals and heart function as a whole significantly increased in animals with cells that overexpressed miR-29b and were treated with the tri-cell patch.

According to Wang:  “These findings show that an overexpression [sic] of miR-29 results in heart tissue changes that favor enhanced mobilization of desired cell types into infarct regions after heart attack, leading to improved heart function.  Hopefully, one day such treatments will restore cardiac function in patients who have experienced a heart attack, leading to a longer and better quality of life.”

Patients with rheumatoid arthritis constantly suffer with joint pain, inflammation, and join destruction.  Rheumatoid arthritis is normally treated with anti-inflammatory drugs, many of which have profound side effects, or injected monoclonal antibodies that are unbelievably expensive and also have bad side effects.

Now stem cell treatments might give rheumatoid arthritis patients new hope.  Mesenchymal stem cells from umbilical cord blood can suppress inflammation and attenuate collagen-induced arthritis in animals.

Professor Zhan-guo Li and a team from Peking University People’s Hospital, China used mesenchymal stem cells (MSCs) to treat arthritis in an animal model of rheumatic arthritis.  Little is known about umbilical cord MSCs, and there has been no previous report about their use in the treatment of RA.  Nevertheless, MSCs can exert profoundly suppress the immune response.  and this encourages their use in the treatment of autoimmune diseases, such as RA.  At present, the most common source of MSCs has been bone marrow.  However, aspirating bone marrow is an invasive procedure and the number and the differentiation potential of bone marrow MSCs decrease with age. In contrast, the collection of umbilical cord MSCs does not require any invasive procedure.

The researchers took immune cells from rheumatoid arthritis patients and showed that the umbilical MSCs could suppress the cells’ proliferation, invasive behavior and inflammatory responses in culture.  Systemic infusion of the umbilical MSCs into mice was shown to significantly reduce the severity of collagen-induced arthritis.

Professor Li said, “RA imparts a massive burden on health services worldwide and none of the currently used agents reaches long term drug-free remission. Therefore, a new and more effective therapy for RA will be very welcome.”

The article is “Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis,” by Yanying Liu, et al., Arthritis Research & Therapy (in press).

A better way to grow embryonic stem cells

Culturing embryonic stem cells can be a genuine pain.  These finicky, constantly-shifting cells require quite a bit of care and growing them can be more art than exact science.

However, a team of researchers at the University of Wisconsin-Madison has reported the development of a fully defined culture system that could provide much more uniform results and for those cells that might be used for therapy, they could provide a safer product.

The research team, UW-Madison professor of chemistry Laura Kiessling, unveiled an inexpensive system that takes much of the guess work out of culturing the embryonic stem cells.

“It’s a technology that anyone can use,” says Kiessling. “It’s very simple.”

Presently, human embryonic stem cells are cultured for research purposes, mostly. Culture systems have improved over time, but cell scientists still use plastic surfaces covered with mouse cells or mouse proteins to grow batches of human embryonic stem cells. Both embryonic or induced stem cells are grown with these cell culture conditions. These culture conditions, however, increases the chances of contamination of the cells by animal pathogens such as viruses, a serious concern for cells that might be used in therapy.

The new culture system utilizes a synthetic, chemically-made substrate of protein fragments, and peptides that have an affinity for binding stem cells. If used in combination with a defined growth medium, the system devised by the Wisconsin team can culture cells in their undifferentiated states for up to three months and possibly longer. The culture system, according to the new report, also works for induced pluripotent stem cells, those adult cells genetically reprogrammed to behave like embryonic stem cells.

Kiessling noted that embryonic stem cells maintained in this culture system were subsequently tested to see if they could differentiate into desired cell types.  Embryonic stem cells grown in the defined culture medium performed just as well as cells grown in less defined, commercially available cell culture systems.

The first clinical trials involving human embryonic stem cells are underway and that as more tests in human patients are initiated, confidence in the safety of the cells will be central to patients and clinicians.

“The disadvantages of the culture systems commonly used now are that they are undefined – you don’t really know what your cells are in contact with – and there is no uniformity, which means there is batch-to-batch variability,” Kiessling explains. “The system we’ve developed is fully defined and inexpensive.”

Firefly gene reporter allows scientists to track the exact fate of transplanted stem cells

Researchers from the University of Central Florida’s College of Medicine’s Burnett School of Biomedical Sciences (BSBS) and the Gazes Cardiac Research Institute at the Medical University of South Carolina have used firefly luciferase to track, in real-time, the differentiation of transplanted cardiac embryonic stem cells. They expressed the firefly luciferase reporter gene (luc) in a mouse embryonic stem (mES) cell line that constitutively expresses the enhanced yellow fluorescent protein (EYFP). Researchers were able to follow differentiation and proliferation of transplanted cardiac stem cells both in vivo and post-mortem with traditional histological assays. Steven N. Ebert, an associate professor at Burnett School of Biomedical Sciences, said, “Cardiac muscle cells are the holy grail in the cardiac world. We were able to clearly demonstrate that the stem cells were becoming heart muscle cells, and we could see that not only in histological sections, as is traditionally done; the firefly activity let us see them glow in vivo.”
With previous stem cell therapies, researchers could not monitor the activity of transplanted cells once they had been inserted into the subject. However, this dual reporter system allows researchers to observe the functionality of the cells and then even exactly document exactly where the transplanted cells wound up through histological examinations.
Ebert’s team previously attempted to track mES cells by loading the cells with super paramagnetic microparticle beads and using magnetic resonance imaging (MRI). Unfortunately even though this technique was able to determine the location of the cells and provide high-resolution images, but the beads migrated out of the target cells. Additionally, this method did not provide any new insights into the function of the cells. Ebert admitted, “Fundamentally, there’s a lot that we don’t know about how stem cells behave once they’ve been put back into the heart and become stimulated under natural conditions. An impetus behind the firefly strategy was to give us a way to see if the cells were actually becoming heart muscle by observing the functional activity.”
Although the current paper only documents the incorporation and differentiation of basic cardiac embryonic stem cells, Ebert says the reporter system can be adapted for a variety of clinical uses. His lab is testing the mES dual-reporter cell line to different application. The team is also developing new lines for more specialized investigation, such as examining the rehabilitation differences for damaged cardiac cells that produce adrenaline and those that do not.
Ebert concluded, “We’d like to put [the cardiac stem cells] into disease models where there’s actual damage to the heart and see if they can regenerate some of the cardiac muscle that has been lost. There’s a lot of potential in the field and a lot we don’t know yet, so there’s a lot more investigation to keep us busy for a while.”

Scientists convert skin cells into mature blood cells

Canadian researchers have succeeded in transforming human skin cells into different types of blood cells. McMaster University scientists have achieved a feat that might one day help patients who need blood transfusions for surgery, potentially treat deadly blood disorders, or to offset the destructive side-effects of chemotherapy. Additionally it also raises the possibility that other cell types, like neurons to repair brains damaged by disease or injury, could also be directly induced and grown in the lab using a mere scrap of a person’s own skin. The principal investigator, Mick Bhatia, the scientific director of McMaster’s Stem Cell and Cancer Research Institute, said his team was able to produce oxygen-carrying red blood cells, two kinds of immune cells and megakarocytes, the cells that generate platelets which are required for blood clotting.
This research has an additional significance in that these scientists were able to coax mature blood cells from skin without passing them through the intermediate step of producing stem cells that would then need to be differentiated into the various blood cell types. While blood cells can be made from either embryonic stem cells or induced pluripotent stem (iPS) cells, the process is far more complicated and time-consuming, as well as being fraught with potential safety problems. Such blood cells would also be “fetal” in nature, and not mature adult cells. These fetal blood cells would have properties that make them unsuitable for transfusion.
Bhatia said: “Because we were starting out with adult fibroblasts (skin cells), we actually made adult blood, which we are predicting is going to be far more useful.”
Skin cells used to generate blood cells came from six individuals who ranged in age from newborn to 65-plus. Apparently, the age of the donor did not matter. Scientists were able to convert all of the human skin cells to blood no matter how the age of the patient. When they transplanted these blood cells into lab-bred mice, they did not cause tumors, and behaved as normal red blood cells.
Dr. Cynthia Dunbar of the U.S. National Heart, Lung and Blood Institute said no one has been able to produce mature adult blood cells from embryonic or iPS stem cells, so the McMaster team’s ability to beget them — while detouring around stem cells — is an extremely exciting achievement. “The ability to do this is going to open a lot of doors in terms of being able to study biology,” Dunbar said from Bethesda, Md. “In terms of whether it’s going to be put into patients in the next five years, I think that’s very unlikely. But that doesn’t take away from how important it is scientifically and how important it is conceivably for eventual clinical applications.”
Cancer treatment is one area in which a supply of healthy blood cells is critical. This technique could potentially provide a new source of non-cancerous blood replacement for people with leukemia, who now rely on bone marrow transplants. For patients with solid organ tumors who are taking high doses or a prolonged regimen of chemotherapy, being able to generate new blood cells from a patient’s own skin would mean not having to interrupt treatment when the drugs begin destroying the blood system.
Pauses in anti-cancer treatment in order to give the patient time to recover and make new red blood cells can give the tumor time to grow out and spread throughout the body. Therefore another major advantage of this discovery is that physicians can provide the patient with new blood cell progenitors while continually treating the patient with chemotherapy.”
It might even be possible to freeze red blood cells and those that produce platelets created from the skin of people with rare blood types, not only for personal use but also for others with the same blood signature who need a transfusion. The McMaster team also plans to use the cells for testing experimental drugs, in what he calls “a clinical trial in a dish.”
There are, of course, a number of hurdles to overcome: finding a way to produce large quantities of the cells, ensuring their safety and seeking regulatory approval for their use. The team also has to determine the proper recipes for pulling out other cells that make up blood, including key disease-fighting white cells.
Still, Bhatia and his colleagues are already moving ahead — determining what other cellular building blocks of the human body they can draw from skin. “So we’re hoping this is not just limited to blood,” he said. “We’re hoping we can also get other cell types (and) we already have encouraging evidence.”

Harvard stem cell researcher retracts two papers

Harvard Medical School stem researcher Amy Wagers, who works at the Joslin Diabetes Center has issued a retraction notice for a 2010 paper, and has also issued a “statement of concern” in which she intends to review a second paper from 2008. One of her former postdoctoral fellows, Shane Mayack, was the first author on both of these papers, and she maintains the validity of the results reported in these papers.

On October 13, 2010, Wagers and two other authors retracted their January 2010 paper “Systemic signals regulate ageing and rejuvenation of blood stem cell niches.” This paper reported data that they interpreted to mean that stem cell aging processes might be reversible but the notice references “serious concerns” with the data that led to that hypothesis, which prompted the retraction.  Wagers has even issued a statement that upon reviewing the data from the Nature paper, she immediately notified Nature, JDC, and HMS that she and her colleagues have begun to repeat the experiments to test their validity.

A point of concern for Wager is the appearance of very similar figures in both papers; Figure S3b from the Nature paper and Figure 6c from the Blood paper chart the frequency of blood stem cells but result from very different protocols.  A day later, Wagers published a notice of concern in the journal Blood that stated that a 2008 paper that she coauthored with Mayack is also under review for possible misreporting of the data.  No further information has yet been published concerning the study, “Osteolineage niche cells initiate hematopoietic stem cell mobilization,” which features a figure that is strikingly similar to one published in the retracted Nature paper.

Although Mayack has not personally commented on the retractions, her lawyer issued a statement saying that although Mayack realizes the data presentation was improperly handled, she believes the underlying research remains conclusive. Accordingly, Mayack did not sign the retraction notice. Further examination is ongoing to determine if the conclusions presented in either paper are still viable.

At this point it is hard to say, but it seems possible that this is just a mix-up.  Hopefully, work from Wager’s lab will determine if the conclusions are justified.  Academic misconduct is a problem is science these days.  The most notorious case is that of South Korean researcher Professor Woo Suk Hwang,  However it is exceedingly hard to say if this case falls under this category.  My feeling is that the jury is still out on this one.  It is better to give the researchers the benefit of the doubt, given the information in hand.  As things develop, there will be more to say.