Scientists sporting white coats and safety gloves are working in a bright Food and Drug Administration (FDA) lab on an incredible project.
They are part of FDA’s MSC Consortium, a large team of FDA scientists studying adult mesenchymal stem cells (MSCs)—cells that could eventually be used to repair, replace, restore or regenerate cells in the body, including those needed for heart and bone repair.
The scientists’ investigational work is unprecedented: Seven labs at FDA’s Center for Biologics Evaluation and Research formed the consortium to fill in gaps in knowledge about how stem cells function.
“This research aims to facilitate development of this important class of innovative medical products,” explains Carolyn A. Wilson, Ph.D., associate director for research at the center. “It’s the first time we’ve done anything like this, and it’s proven to be a very useful approach. It’s worked so well because this is a huge, complicated project that requires expertise in many different technologies and methods.”
The research could ultimately be key to the advancement of personalized medicine, the practice in which medical treatment is tailored to the needs of an individual patient. “It’s not science fiction,” says Steven R. Bauer, Ph.D., chief of the Cellular and Tissue Therapy Branch in FDA’s Office of Cellular Tissue and Gene Therapies. “For me, regenerative medicine is the most exciting part of what we regulate in our office.”
So What Are Stem Cells?
There are two basic kinds of stem cells that are currently useful in the field of regenerative medicine: multipotent and pluripotent stem cells. Multipotent stem cells are generally taken from adults and can divide and develop into many different cell types. Pluripotent stem cells can develop into any type of cell in the body. Both types could divide to replenish cells damaged by injury, illness or normal wear. When stem cells divide, the new cells can either remain stem cells or develop into a new type of cell with a more specific function.
Two types of pluripotent stem cells exist: human embryonic stem cells and induced pluripotent stem cells, which are created by reprogramming adult cells that had already changed into a mature type of cell.
FDA’s MSC Consortium is not studying stem cells taken from embryos. “We’re looking at a particular kind of multipotent adult stem cell—the MSC—which is being used in a lot of regenerative medicine clinical trials,” adds Bauer.
The group is currently studying eight unique cell lines, each acquired from commercial sources and sourced to one of eight distinct, adult donors. (Males and females age 22 to 47 donated stem cells from bone marrow.)
The cells under study are multipotent: “They can differentiate (mature into) at least three cell types: bone, fat and cartilage, primarily,” Bauer explains. “They can also differentiate into nerve cells, liver cells and a kind of cell called ‘stroma’ that is in the bone marrow and supports blood forming cells. Then, for investigational clinical uses, they’ve been used for repairing hearts, repairing bone and repairing cartilage.”
Why Is FDA Studying These Cells?
In addition to differentiating into a variety of replacement cell types, MSCs can limit a patient’s immune response. So they can potentially be taken from one human donor and placed into a different recipient with less possibility of rejection.
But growing stem cells and making sure they are safe and effective is challenging, which is one reason why stem-cell based clinical trials have not yet resulted in a marketed product.
“The major challenge is that cells are much more complex than traditional products that FDA regulates. And they have the ability to respond to their environment,” Bauer explains. “Taking them out of the body and manufacturing them—that is, growing large numbers of them—or isolating them can change their biology. And it can change the way they behave if they are put back into the patient.”
For instance, if cells are manufactured in large quantities outside their natural environment, they may become ineffective or develop harmful characteristics. For example, they can produce tumors, severe immune reactions or growth of unwanted tissue. So FDA is trying to develop methods that would predict with more certainty how manufactured or isolated adult stem cells will behave in patients.
What’s Being Done?
In the labs, cells are suspended in a nutrient liquid solution and grown in sterile containers called tissue culture flasks. Cells then multiply and go through three, five or seven generations of growth.
FDA scientists are using a variety of cutting-edge methods to characterize cells and then determine if any of these characteristics can predict the behavior of the cells in biological assays or in animal models. The next step will be to determine if any characteristics they measure will predict the safety or effectiveness of stem-cell based products in patients.
Specifically, scientists will continue studying whether factors such as different methods of growing the cells, donor age or gender affects the cells’ quality and performance. This research will ultimately provide new tools to the community of academic and private industry scientists who are interested in evaluating and developing stem cells into new clinical treatments.
“The consortium has shown that widely accepted ways to identify and characterize MSCs do not reveal some important biological differences between batches of these cells,” Bauer says. So the consortium seeks to demonstrate ways to better characterize MSCs that will be used in clinical trials. That’s important because, if investigators can improve the tools used to characterize MSCs used for clinical trials, the data generated from their studies could also improve because their MSC products will be more predictable, he adds.
And the improved predictability of their products will, in turn, allow FDA scientists to more easily evaluate the safety and effectiveness of new stem cell technologies—a key part of the regulatory science that is the foundation of FDA decisions.
Agency scientists already have published six papers in scientific journals such as Tissue Engineering and Cytotherapy. “We’re hoping this project will inspire people to do more research in this area,” Bauer says.
Stem cells, like other medical products intended to treat, cure or prevent disease, require FDA approval before they can be marketed. “It is important for FDA to maintain a sound regulatory science research program to promote the development of safe and effective products in emerging areas that hold great promise,” Bauer says.
“My colleagues and I hope our scientific findings will be helpful in the field of regenerative medicine, including the ability to repair or even replace organs and tissues more safely and effectively than traditional means,” he adds. “Although there are many scientific hurdles to overcome before the use of stem cells reaches its full potential, I think this medicine will eventually have the capacity to do that.”
This article appears on FDA’s Consumer Updates page, which features the latest on all FDA-regulated products.
Mice crippled by an autoimmune disease similar to multiple sclerosis (MS) regained the ability to walk and run after a team of researchers led by scientists at The Scripps Research Institute (TSRI), University of Utah and University of California (UC), Irvine implanted human stem cells into their injured spinal cords.
Remarkably, the mice recovered even after their bodies rejected the human stem cells. “When we implanted the human cells into mice that were paralyzed, they got up and started walking a couple of weeks later, and they completely recovered over the next several months,” said study co-leader Jeanne Loring, a professor of developmental neurobiology at TSRI.
Thomas Lane, an immunologist at the University of Utah who co-led the study with Loring, said he had never seen anything like it. “We’ve been studying mouse stem cells for a long time, but we never saw the clinical improvement that occurred with the human cells that Dr. Loring’s lab provided,” said Lane, who began the study at UC Irvine.
The mice’s dramatic recovery, which is reported online ahead of print by the journal Stem Cell Reports, could lead to new ways to treat multiple sclerosis in humans.
“This is a great step forward in the development of new therapies for stopping disease progression and promoting repair for MS patients,” said co-author Craig Walsh, a UC Irvine immunologist.
MS is an autoimmune disease of the brain and spinal cord that affects more than a half-million people in North America and Europe, and more than two million worldwide. In MS, immune cells known as T cells invade the upper spinal cord and brain, causing inflammation and ultimately the loss of an insulating coating on nerve fibers called myelin. Affected nerve fibers lose their ability to transmit electrical signals efficiently, and this can eventually lead to symptoms such as limb weakness, numbness and tingling, fatigue, vision problems, slurred speech, memory difficulties and depression.
Current therapies, such as interferon beta, aim to suppress the immune attack that strips the myelin from nerve fibers. But they are only partially effective and often have significant adverse side effects. Loring’s group at TSRI has been searching for another way to treat MS using human pluripotent stem cells, which are cells that have the potential to transform into any of the cell types in the body.
Loring’s group has been focused on turning human stem cells into neural precursor cells, which are an intermediate cell type that can eventually develop into neurons and other kinds of cells in the nervous system. In collaboration with Lane’s group, Loring’s team has been testing the effects of implanting human neural precursor cells into the spinal cords of mice that have been infected with a virus that induces symptoms of MS.
The transformation that took place in the largely immobilized mice after the human neural precursor cells were injected into the animals’ damaged spinal cords was dramatic. “Tom called me up and said, ‘You’re not going to believe this,’” Loring said. “He sent me a video, and it showed the mice running around the cages. I said, ‘Are you sure these are the same mice?’”
Even more remarkable, the animals continued walking even after the human cells were rejected, which occurred about a week after implantation. This suggests that the human stem cells were secreting a protein or proteins that had a long-lasting effect on preventing or impeding the progression of MS in the mice, said Ron Coleman, a TSRI graduate student in Loring’s lab who was first author of the paper with Lu Chen of UC Irvine. “Once the human stem cells kick that first domino, the cells can be removed and the process will go on because they’ve initiated a cascade of events,” said Coleman.
The scientists showed in the new study that the implanted human stem cells triggered the creation of white blood cells known as regulatory T cells, which are responsible for shutting down the autoimmune response at the end of an inflammation. In addition, the implanted cells released proteins that signaled cells to re-myelinate the nerve cells that had been stripped of their protective sheaths.
The particular line of human neural precursor cells used to heal the mice was the result of a lucky break. Coleman was using a common technique for coaxing human stem cells into neural precursor cells, but decided partway through the process to deviate from the standard protocol. In particular, he transferred the developing cells to another Petri dish.
“I wanted the cells to all have similar properties, and they looked really different when I didn’t transfer them,” said Coleman, who was motivated to study MS after his mother died from the disease. This step, called “passaging,” proved key. “It turns out that passaging alters the types of proteins that the cells express,” he said.
Loring called the creation of the successful neural precursor cell line a “happy accident.” “If we had used common techniques to create the cells, they wouldn’t have worked,” she said. “We’ve shown that now. There are a dozen different ways to make neural precursor cells, and only this one has worked so far. We now know that it is incredibly important to make the cells the same way every time.”
The team is now working to discover the particular proteins that its unique line of human precursor cells release. One promising candidate is a class of proteins known as transforming growth factor beta, or TGF-B, which other studies have shown is involved the creation of regulatory T cells. Experiments by the scientists showed that the human neural precursor cells released TGF-B proteins while they were inside the spinal cords of the impaired mice. However, it’s also likely that other, as yet unidentified, protein factors may also be involved in the mice’s healing.
If the team can pinpoint which proteins released by the neural precursor cells are responsible for the animals’ recovery, it may be possible to devise MS treatments that don’t involve the use of human stem cells. “Once we identify the factors that are responsible for healing, we could make a drug out of them,” said Lane. Another possibility, Loring said, might be to infuse the spinal cords of humans affected by MS with the protein factors that promote healing.
A better understanding of what makes these human neural precursor cells effective in mice will be key to developing either of these therapies for humans. “We’re on the trail now of what these cells do and how they work,” Loring said.
In addition to Loring, Lane, Walsh, Coleman and Chen, authors of the study, “Human neural precursor cells promote neurologic recovery in a viral model of multiple sclerosis,” are Ronika Leang, Alexandra Kopf, Ilse Sears-Kraxberger and Oswald Steward of UC Irvine, Ha Tran of TSRI and Wendy B. Macklin of the University of Colorado School of Medicine.
The Scripps Research Institute (TSRI) is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases.
The ‘National Guidelines for Stem Cell Research‘, issued recently by the Union health ministry, has fixed the responsibility for investigators, institutions and sponsors in the conduct of stem cell research in the country.
According to the Guidelines, the investigators and institutions where stem cell research is being conducted bear the ultimate responsibility of ensuring that research activities are in accordance with the national regulations and guidelines. In particular, scientists whose research involves human ES cells should work closely with monitoring/regulatory bodies, demonstrate respect for autonomy and privacy of those who donate gametes, blastocysts, embryos or somatic cells for stem cell research, and be sensitive to public concerns about research that involves human embryos.
Those working with human iPS cells shall be particularly careful with the vectors and genes used for induction of stemness against malignant transformation. Sponsors shall also take note of their responsibilities and liabilities under various statutes, regulations and guidelines governing research and development in this field in the country.
As per the guidelines, each institution shall maintain a register of its investigators conducting stem cell research and ensure that all registered users are kept up to date with existing guidelines and regulations regarding the use of these cells. It shall also be the responsibility of the institution to ensure that most current standards are applied. Each institution shall constitute an IC-SCR as provided in these guidelines and provide adequate support for its functioning. All records pertaining to clinical adult stem cell research must be maintained for a period of at least five years and those for ES/iPS cell research for atleast10 years.
The guidelines further explain that the physician/scientist engaged in stem cell research shall endeavour to avoid any activity that leads to unnecessary hype, or unrealistic expectations in the minds of study subjects or public at large regarding stem cell therapy. The study subject and other responsible family members must be given adequate and unbiased information about the trial protocol, its limitations and potential adverse effects. They must also be informed about the given indication for therapy. The investigator’s responsibility is to generate robust scientific evidence through good clinical trials which may then be applied for the benefit of the patients.
According to the Guidelines, the institutions conducting stem cell research shall establish suitable mechanisms for creating awareness and communicating scientific evidences to the public. The basic scientists engaged in human stem cell research shall be vigilant to safeguard rights and dignity of human donors and aborted foetuses from whom samples for research have been obtained. The biological material should be treated with utmost respect and care in all experiments. The use of human embryos shall be restricted as much as possible, and shall be resorted to where there are no other alternatives. Also, special care should be taken in introducing human cells in animals, particularly in early developmental stages, which may lead to development of chimeras or incorporation into brain/gonads.
The ‘National Guidelines for Stem Cell Research’, issued recently by the Union health ministry, has elaborated about the functions and composition of the National Apex Committee for Stem Cell Research and Therapy (NAC-SCRT) and the Institutional Committee for Stem Cell Research (IC-SCR).
According to the Guidelines, the NAC-SCRT will be a multidisciplinary committee with a secretariat. It will have two main functions of general oversight of the field of stem cell research and therapy in India and formulation of policy related to it; and review of specific controversial or ethically sensitive research and proposals for therapeutic use of stem cells/differentiated derivatives.
There should be at least 15 members in the committee. The committee composition will include chairman, alternative chairman, member secretary, nominees from DBT, DST, CSIR, DSIR, ICMR, DCGI, DAE, MCI, DGHS and biomedical experts drawn from appropriate disciplines such as haematology, pharmacology, immunology, cell biology, microbiology, genetics, developmental biology, clinical medicine and nursing. Other members would include a legal expert, social scientist, and women’s representative. In addition consultants/experts could be consulted / invited for specific topics and advice.
The committee has the responsibility to examine scientific, technical, ethical, legal and social issues in the area of stem cell or their derivatives based research and therapy. It has to maintain a register of all institutions involved in any type of stem cell research and therapy including details of their IC-SCR. Besides, it has to review annual reports of these IC-SCRs for compliance with national guidelines and ethical practices. Use of chimeric tissue for research shall be reviewed by it and will review and update the national guidelines for stem cell research and therapy periodically, considering scientific developments at the national or
The NAC-SCRT has to respond to queries/representations from all the stakeholders in the community (investigators, industry, R&D institutions, entrepreneurs, media, patient groups, govt agencies etc). It also has to respond to controversial issues raised /received from NGOs, patients, individuals etc., and diverted to NAC-SCRT by other agencies like ICMR, DBT, DST, MCI, DCGI, etc.
Moreover, the committee has to monitor any unethical practices related to stem cell research and/or therapy being followed at any organization or any individual and bring them to the notice
of relevant authorities.
The IC-SCR will be a multidisciplinary body at the institutional level. Institutions involved in stem cell research are required to set-up a special review board to oversee research (basic science and clinical) in this field. It should be registered with the NAC-SCRT and should provide overview of all issues related to stem cell research at the institutional level.
The IC-SCR has to review and approve the scientific merit of research protocols and will function in compliance with all relevant regulations and guidelines. It should maintain a register of hES cell research conducted at the institution and hES cell lines derived or imported by institutional investigators and notify NAC-SCRT. It has to facilitate training of investigators involved in stem cell research and submit annual report to NAC-SCRT.
There should be at least seven members in the committee and it should include representatives of the public and persons with expertise in clinical medicine, developmental biology, stem cell research, molecular biology, assisted reproduction technology, and ethical and legal issues in stem cell research. It should have the resources to coordinate reviews of various protocols.
The chairman of the IC-SCR must have relevant medical/scientific background and be from outside the institute with no conflict of interest (COI). Members from law, ethics and social sciences must be from outside the institute and with no COI. Stem cell experts, if possible from outside the institute, can be the scientific/technical members. Member Secretary can be from the same institute and must not have any COI. Any member having COI with a particular proposal must abstain from the discussion and decision making process of that proposal.
IC-SCR members must be familiar with the current bioethical guidelines and guidelines for stem cell research.