Newsletter - November 2012
A Genetic Counselor's Perspective on Cord Blood Banking
Cord blood banking offers all expectant families a rare opportunity to help patients with a number of devastating diseases, whether those patients are within or outside their family. In those families that have a history of medical conditions that may have a genetic component, genetic counseling can help the expectant parents to determine the potential therapeutic value of their baby's cord blood.
Of particular interest to a genetic counselor are the thousands of patients diagnosed each year with conditions that can be treated by stem cell transplant, either currently or in clinical trials. But over 70% of patients will not find a suitable matched adult stem cell donor within their own family. Umbilical cord blood is an alternative source of stem cells for these patients. The first cord blood transplant took place in 1988, and since then over 25,000 cord blood transplants have been performed world-wide for about 80 diagnoses.
Family genetics are important in stem cell transplantation, because patients fare better when their donor is related. Stem cell transplants from a close relative have the advantage in that the recipient is able to tolerate a less perfect match to the donor, experiences less graft-versus-host disease, have greater likelihood of survival than with an unrelated donor, and have the ability to go back to the donor for more matching blood or tissues if needed.
Families with histories of genetic disease or potential risk for genetic disease will likely have the greatest interest in cord blood banking. These families need to first understand the inheritance of genetic markers in their family. For example, if an expectant mother is offering to bank her baby's cord blood as therapy for a relative, is that baby a close enough match to be a donor for the prospective patient, and is that baby a carrier and/or at risk for the disease? A genetic counselor can review the genetics of any conditions of concern, in each family, so that this information can be factored into the decision to save or use cord blood for therapy.
Leukemia is one of the main diagnoses for which patients receive stem cell transplants, and a growing percentage of these patients will receive a transplant using cord blood. Altogether, there does not appear to be a strong genetic component to leukemia. However, we could do better at identifying the occasional families where leukemia may have a genetic component and/or be associated with an inherited cancer predisposition syndrome. At least 55 cancer syndromes are now characterized, each with their own causal genes, and at least a dozen of them list leukemia within their spectrum of possible cancers. Currently, the overall odds of a person in the US having a stem cell transplant are 1 in 217 over a lifetime (Nietfeld et al. 2008), but this could increase if at-risk individuals were better identified and entered into the treatment pipeline earlier.
Some inherited conditions are genetically heterogeneous, meaning that they may be inherited in multiple ways. Thus for the same condition, some families can use relatives as transplant donors and some families cannot. This is the case in dominantly inherited conditions or some chromosomal conditions such as DiGeorge Syndrome or Diamond-Blackfan anemia, where some carriers of the condition are only mildly affected. The genetic testing registry is a helpful resource for more information.
Those families that carry recessively inherited genetic diseases such as Fanconi anemia, thalassemia, sickle cell anemia, adenosine deaminase deficiency (ADA-SCID) and Hurler syndrome, face a complex set of possible options. For some of these conditions, such as ADA-SCID and Hurler syndrome, a stem cell transplant from a donor is the only hope of long-term survival. For other conditions, such as sickle cell and thalassemia, the benefits of stem cell transplants must be weighed against the risks, and at present transplantation is reserved for the most severely afflicted patients. However, ongoing clinical trials are attempting to help a wider range of these patients by delivering stem cell transplants with reduced intensity chemotherapy (see ClinicalTrials.gov). Finally, gene therapy is the newest therapy for inherited disorders, such as sickle cell anemia and Fanconi anemia.
Ironically, the advent of gene therapy changes the prevailing wisdom regarding the advisability of cord blood storage in families affected by genetic diseases. Before, treatment with a stem cell transplant required a donor who was a close match but did not have the disease. The patient's own cord blood was considered useless because it carried the disease, and instead cord blood donations were encouraged from healthy volunteers. Now that correction of the patient's own genome is becoming possible for more disorders, it is actually advisable to save the cord blood of children in affected families, for potential use in gene therapy.
Cord blood banking is particularly valuable in cultures where intermarriage between relatives is practiced. The more families practice consanguineous marriage, the more likely their offspring will have common disease genes, conferring greater risk for birth defects, mental retardation, leukemias, any inherited diseases and especially those inherited diseases prevalent in that ethnic group. Some examples of well-known genetic diseases which have higher prevalence in certain ethnic groups are sickle cell anemia, thalassemia, Tay Sachs, and cystic fibrosis. The rate of consanguinity is 20-50% in about one billion of the world's population. One consequence is that the prevention and treatment of thalassemia has been declared a public health priority by the World Health Organization.
To summarize, directed donation or private storage of cord blood may provide the only opportunity for a biological life-saving link for individuals who know there is a history of disease in their family. I only hope that more medical providers besides myself will be questioned on the matter of cord blood banking and will bring this topic to light in their practices and when called upon to educate their communities.
BMT-Talk: A forum for transplant patients
BMT-Talk is an un-moderated mailing list or listserv (TM) hosted by the Association of Cancer Online Resources (ACOR). BMT-Talk functions as a virtual community for stem cell transplant patients and their caregivers. Its members are largely patients who are about to undergo or have undergone a bone marrow transplant (BMT), peripheral blood stem cell transplant (PBSCT), or cord blood transplant (CBT). There are also a number of spouses, partners, parents and other family and friends of patients undergoing a transplant. Many members have transplants for leukemia, although there are members who have transplants for Hodgkin's Lymphoma, Non Hodgkin's Lymphoma, Myelodysplastic Syndromes as well as other non-malignant conditions, such as Aplastic Anemia.
BMT-Talk was started in 1994 by Laurel Simmons, who had had a transplant in 1987 for chronic myelogenous leukemia. Initially it was hosted by the Massachusetts Institute of Technology, where Laurel worked at the time. Around 1997, BMT-Talk joined the growing list of cancer related mailing lists hosted on ACOR. There are currently about 1000 members of BMT-Talk, and new members are always welcome.
Discussions on BMT-Talk are initiated by the members, and almost any topic related to a transplant is fair game. When a member sends an Email to the listserv, messages are sent to all the other members of the list. There is no moderator to approve or edit a posting. BMT-Talk has two other list managers besides myself: Elaine Kemp, who is a Hodgkin's disease survivor and has had two autologous transplants; and Lorraine Johnston, whose husband is also a Hodgkin's survivor. The list managers help members subscribe to or unsubscribe from the list and with any other problems associated with using the list. On very rare occasions they step in to get discussions back on topic.
BMT-Talk members help each other to navigate the process of stem cell transplant and survival. New members are often interested in what to take with them to the hospital, where to stay at a transplant center (if they are coming from out of town), and how to get through the transplant, among other things. In the last few months there have been a number of conversations on how to convince insurance companies to pay for cancer procedures or drugs, as well as how to get coverage at a particular transplant center. Medical questions are also quite common. A recent question was on how to decide between two significantly different conditioning regimens offered at two different transplant centers. Although the members of BMT-Talk cannot give medical advice, they can provide suggestions on what questions to ask the different centers, based on their individual experiences.
BMT-Talk members join to ask questions and stay because they have made friends. BMT-Talk provides members with experienced support and advice at a critical time in their lives.
The "Paracrine Effect" is the best thing about Stem Cells
Regenerative medicine is the science of repairing diseased and damaged cells or tissues. This can be accomplished in two ways. First, stem cells can directly replace the diseased cells by engrafting and differentiating into the required cell type. This is what happens during a bone marrow transplant, where the donor stem cells replace the patient's blood and immune system.
The second method of regenerative medicine is the paracrine effect. In this mechanism some of specialized donor cells act to stimulate the patient's cells to repair the diseased tissue, without the donor cells contributing directly to the new tissue. This happens because the donor cells secrete factors that signal the patient's cells to change their behavior, and this signaling from one cell to another is called the paracrine effect.
In many pre-clinical studies of stem cell transplants, investigators observed that damaged patient tissue was repaired after the transplant, but when the new tissue was analyzed there was a noticeable absence of donor cells. Upon further investigation, scientists were able to demonstrate that the donor stem cells were secreting factors that triggered the patient's cells to repair the tissue themselves. Mammals have a wound repair mechanism that on its own can only deal with small wounds, and is incapable of repairing large wounds or of regenerating new functioning tissue instead of just scar tissue. But, studies of the paracrine effect have demonstrated that mammalian tissue does contain cells capable of regeneration, they just need to receive the appropriate signals to initiate the regeneration and repair.
The paracrine mechanism has turned out to be very beneficial. At first, most scientists were disappointed that transplanted donor cells often did not contribute directly to new tissue, but the advantages of having a paracrine effect soon became apparent. The most important observation was that even though the donor cells were short lived, they had a long term effect on tissue regeneration. It seems that they are important for initiating tissue repair but are dispensable once the patient's cells are activated.
The fact that donor cells do not have to persist in order to achieve a cure via the paracrine effect has the implication
Many different cell types can invoke a paracrine response. Paracrine effect cells include mesenchymal cells and blood cells that can be isolated from donor bone marrow, adipose (fat) tissue, umbilical cord blood, and umbilical cord tissue.
In addition, studies have indicated that the paracrine effect is amplified because the donor cells are attracted to the damaged tissues that need their help. The damaged patient cells are secreting cytokines, regulatory proteins that act as mediators to generate an immune response that attract the donor cells. In turn, the donor cells secrete their own cocktail of proteins that stimulate the patient's stem cells and help to reduce inflammation, promote cell proliferation, and increase vascularization and blood flow into the areas that need to heal. Paracrine effect cells can also secrete factors that inhibit the death of patient cells due to injury or disease.
An important third paracrine effect is their ability to 'dampen' the immune response that occurs during transplant rejection or during autoimmune disease (1). In this case the cells can be used directly or in conjuction with other stem cells for therapeutic purposes. For example, the application of mesenchymal cells along with blood stem cells during a bone marrow transplant seems to reduce graft versus host disease (2).
An advantage of using cells, versus medication, to promote regeneration is that transplanted cells will respond to their environment and secrete the factors as they are needed and in the appropriate concentration. The cells can be thought of as 'drug factories' that adapt as the tissue is repaired. Preclinical studies have demonstrated the efficacy of mesenchymal cells and cord blood cells for the treatment of neural, heart, kidney and muscle based diseases. There have been some convincing studies on the neuroprotective effect of cord blood cells. In one study, cord blood cells were used to treat spinal cord injury. The transplanted cells were only present for 7-10 days, but were able to reduce the wound lesion and significantly improved mobility in the hind limb of spinal cord injured rats when compared to injured animals that did not receive cord blood cells (3). Recently a study showed that cord blood could reduce diabetes-related kidney damage. The improvement was significant although very few cord blood cells engrafted, indicating that the mechanism of action was via the paracrine effect (4). Myocardial damage has also been reported to be repaired by the paracrine effect of cord blood (5).
The paracrine effect was an unexpected mechanism for tissue regeneration from stem cells but has led to new possibilities for the treatment of different diseases. The ability of umbilical cord blood and tissue-derived stem cells to promote tissue regeneration by both contributing directly to new tissue as well as by the paracrine effect of stimulating endogenous repair will lead to novel cell therapies.
- Najar, M., et al. Adipose-tissue-derived and Wharton's jelly-derived mesenchymal stromal cells suppress lymphocyte responses by secreting leukemia inhibitory factor. Tissue engineering. Part A 16, 3537-3546 (2010).
- Lazarus, H.M. Acute leukemia in adults: novel allogeneic transplant strategies. Hematology 17 Suppl 1, S47-51 (2012).
- Chua, S.J., et al. The effect of umbilical cord blood cells on outcomes after experimental traumatic spinal cord injury. Spine (Phila Pa 1976) 35, 1520-1526 (2010).
- Park, J.H., Park, J., Hwang, S.H., Han, H. & Ha, H. Delayed treatment with human umbilical cord blood-derived stem cells attenuates diabetic renal injury. Transplantation proceedings 44, 1123-1126 (2012).
- Greco, N. & Laughlin, M.J. Umbilical cord blood stem cells for myocardial repair and regeneration. Methods Mol Biol 660, 29-52 (2010).