Mechanism that Prevents Stem Cell Aging

A research group at the University of Valencia, Spain, led by Isabel Fariñas Gómez, at the Molecular Neurobiology Unit, has discovered a mechanism that maintains stem cell populations in the brain and prevents these stem cells from overproliferating early in life and burning out.

Gómez’s group has discovered that the product of the CDKn1a/p21 gene is essential for maintaining brain stem cells.  By keeping these stem cells active and functional, the brain dynamically changes as it learns and remembers, and maintains its good state of health.  In the absence of p21, brain stem cell populations deplete and this prevents the formation of new neurons toward the end of life.

Stem cells require p21 to replicate themselves in a controlled fashion.  In other cell types, p21 acts as a “tumor suppressor” gene.  Tumor suppressor genes encode proteins that tend to put the brakes on cell proliferation.  Loss-of-function mutations in tumor suppressor genes causes uncontrolled group and predisposes that cell and its descendants to become cancer cells.

p21 function

However, in neural stem cells, p21 functions differently.  Depletion of p21 from neural stem cells causes their depletion rather than their overgrowth.  In short, an absence of p21 causes these cells to age.

This research, conducted in collaboration with Anxo Vidal from the University of Santiago de Compostela, shows that p21 in neural stem cells restrains the production of molecules that induce the depletion of these this stem cell population.  Thus p21 restricts aging.  According to Fariñas Gómez, “The research allows us to understand better how stem cells get lost in our brains as we age, and opens the possibility to try to alleviate this deterioration.”

Tumor Suppressor Gene is Required For Neural Stem Cells to Differentiate into Mature Neurons

Cancer cells form when healthy cells accumulate mutations that either inactivate tumor suppressor genes or activate proto-oncogenes. Tumor suppressor genes work inside cells to put the brakes on cell proliferation. Proto-oncogenes work to drive cell proliferation. Loss-of-function mutations in tumor suppressor genes remove controls on cell proliferation, which causes cells to divide uncontrollably. Conversely activating mutations in proto-oncogenes removes the controls on the activity of proto-oncogenes, converting them into oncogenes and driving the cell to divide uncontrollably. If a cell accumulates enough of these mutations, they can grow in such an uncontrollable fashion that they start to gain extra chromosomes or pieces of chromosomes, which contributes to the genetic abnormality of the cell. Accumulation of more mutations allows the cell to break free from the original tumorous mass and spread to other tissues.

There are over 35 identified tumor suppressor genes and one of these, CHD5, has another role besides controlling cell proliferation. Researchers at Karolinska Institutet in Stockholm, Swede, in collaboration with other laboratories at Trinity College in Dublin and BRIC in Copenhagen has established a vital role for CHD5 in normal nervous development.

Once stem cells approach the final phase of differentiation into neurons, the CHD5 protein is made at high levels. CHD5 reshapes the chromatin structure into which DNA is packaged in cells, and in doing so, it facilitates or obstructs the expression of other genes.

Ulrika Nyman, postdoc researcher in Johan Holmberg’s laboratory, said that when they switched of CHD5 expression in stem cells from mouse embryos at the time when the brain develops, the CHD5-less stem cells were unable to turn off those genes that are usually expressed in other tissues, and equally unable to turn on those genes necessary for making mature neurons. Thus these CHD5-less stem cells were trapped in a nether-state between stem cells and neurons.

CHD5 function in stem cell differentiationretinoic

The gene that encodes the CHD5 protein is found on chromosome 1 (1p36) and it is lost in several different cancers, in particular neuroblastomas, a disease found mainly in children and is thought to arise during the development of the peripheral nervous system.

Neuroblastomas that lack this part of chromosome 1 that contains the CHD5 gene are usually more aggressive and more rapidly fatal.

Treatment with retinoic acid forces immature nerve cells and some neuroblastomas to mature into specialized nerve cells. However, when workers from Holmberg’s laboratory prevented neuroblastomas from turning up their expression of CHD5, they no longer responded to retinoic acid treatment.

Holmberg explained, “In the absence of CHD5, neural tumor cells cannot mature into harmless neurons, but continue to divide, making the tumor more malignant and much harder to treat. We now hope to be able to restore the ability to upregulate CHD5 in aggressive tumor cells and make them mature into harmless nerve cells.”

Myriad Genetics Hordes Breast Cancer Data

Kathleen Sloan the president of the National Organization of Women has a troubling article at the Center for Bioethics and Culture website. It tells the story of a biotechnology company called Myriad Genetics and it BRCA1 & 2 test.

What the heck is BRCA1 & 2?  BRCA stands for “breast cancer” and mutations in BRCA 1 or 2 predispose females to breast and ovarian cancer. Mutations in BRCA genes also increase the risk of colon, prostate and pancreatic cancer.  Approximately 7% of breast cancer and 11 – 15% of ovarian cancer cases are caused by mutations in the BRCA genes.  If someone carries a mutation in either BRCA 1 or 2, they have a syndrome called Hereditary Breast and Ovarian Cancer (HBOC) syndrome.

The BRCA genes encode proteins that help repair DNA when it is damaged. Even though BRCA 1 & 2 work with several other proteins to accomplish this repair, mutations in the BRCA genes that compromise the quality of the proteins they encode can diminish the ability of cells to repair their DNA. Loss of efficient DNA repair systems leads to greater numbers of mutations in cells, some of which cause either loss of tumor suppress genes that normally put the brakes of cell proliferation, or activation of proto-oncogenes, which encode proteins that promote cell proliferation. Loss of tumor suppressor genes and activation of proto-oncogenes produces a cancer cell, and mutations in BRCA 1 or 2 and accelerate the onset of cancer cell formation (this is a highly simplified explanation and I apologize to the aficionados out there, but I am trying put the cookies on a nice low shelf).

Myriad Genetics came along and developed a genetic test for cancer-causing mutations in BRCA 1 & 2. This is good news, but Myriad Genetics is presently with holding their data from patients. This is not good news. Myriad Genetics wants to generate a database of mutations found in BRCA 1 and 2 genes from women all over the world. Some of these mutations do not affect the function of the encoded protein and do not predispose the patient to breast cancer, but some do. Which ones are harmful and which ones are not?

At this point things get sticky. Myriad has complied its sequence data on BRCA in order to construct a “variants of unknown significance” or VUS. Such a compilation would be invaluable, since it would help physicians correctly interpret the results of a breast cancer test. According to its present data archive, Myriad Genetics claims that only 3% of its tests fall into the VUS unknown category. However, other testing services report a 20% VUS rate. Who’s right? hard to say, given that Myriad Genetics will not release its data. Apparently they feel that their data has commercial value.

The problem is that lots of outfits that provided data to Myriad Genetics free of charge in order for them to develop their test. These other outfits have all their data available on public databases. What about Myriad Genetics – nope.

According to Ms. Sloan, “Myriad Genetics, producer of the world’s biggest-selling gene test for breast and ovarian cancers, has become synonymous with corporate greed. In an egregious breach of bioethics, the company refuses to share groundbreaking knowledge that could benefit cancer patients.”

Myriad worked hard to develop this test – I do not think anyone is contesting that. Myriad Genetics has every right to make money off their test, but when they start hoarding potentially life-saving data, I think Ms. Sloan is right that they have crossed the line.

Myriad Genetics is also being sued because of their attempts to patent the BRCA genes. An impressive consortium of researchers, genetic counselors, women patients, cancer survivors, breast cancer and women’s health groups, and scientific associations representing 150,000 geneticists, pathologists and laboratory professionals are all plaintiffs in this lawsuit against the U.S. Patent Office, Myriad Genetics and the University of Utah Research Foundation, which hold the patents on the genes.

The lawsuit avers that patents on human genes violate the First Amendment because genes are “products of nature.” Therefore, such things cannot be patented. Such an argument has a strong intuitive appeal, and is almost certainly correct.

Read Ms. Sloan’s article here and see what you think.

New York Researchers Find Signaling Link Between Pluripotent Stem Cells and Cancer

Stem cell researchers at Mount Sinai School of Medicine, the University of Manchester and the MD Anderson Cancer Center have discovered a new role for signaling pathways usually associated with cancer cells in embryonic stem cell self-renewal and in adult cells that are in the process of being reprogrammed into induced pluripotent stem cells (iPSCs).

Normal cells have several genes known as “proto-oncogenes” that stimulate cell growth and cell proliferation. When expressed, proto-oncogenes drive cells to grow, and mutations in proto-oncogenes that disrupt their regulation convert them into “oncogenes” that drive cells to grow uncontrollably. Oncogenes are commonly found in tumors and the accumulation of oncogenic mutations in cancer cells drive them to grow faster and faster and with less and less controls.

In this publication, a proto-oncogene called Aurka and its role in embryonic stem cell self-renewal was examined. Aurka is commonly amplified in several human cancers, which underscores its importance in driving growth.

By utilizing a functional genomics strategy, the research group identified the protein kinase Aurora A or Aurka as a vital component of embryonic stem cell function. Aurka is a protein kinase, which is a biochemical way of saying that it is an enzyme that places phosphate groups on proteins. By placing phosphate groups on proteins, Aurka regulates their function. One of the main targets is a well-known tumor suppressor gene product called p53. Tumor suppressor genes encode proteins that put the brakes on cell proliferation. Tumors tend to accumulate loss-of-function mutations in tumor suppressor genes and these mutations decrease the controls on cell proliferation. The p53 tumor suppressor protein is known as the “guardian of the genome.” Mutations in p53 are found in a very wide range of tumors and many oncologists think that inactivating mutations in the p53 gene are mandatory for the evolution of cancer.

In the absence of Aurka, p53 activity is up-regulated and up-regulation of p53 in embryonic stem cells causes them to differentiate and lose their undifferentiated state. However, If Aurka is active, it attaches a phosphate group to p53 and inhibits it, thus shifting the embryonic stem cell to a self-renewal state.

Ihor R. Lemischka, the Lillian and Henry M. Stratton Professor of Gene and Cell Medicine and Director of the Black Family Stem Cell Institute at Mount Sinai Medical Center in New York City, said: “These studies are exiting not only from a basic science point-of-view, but also because they suggest that stem cell research may impact the development of novel treatments for cancer. Conversely, cancer research may facilitate the realization of the biomedical potential of stem cells.”

Mature cells have low levels of p53, but embryonic stem cells and iPSCs show high levels of p53. The p53 protein also has a limited role in promoting programmed cell death. They also inhibit the cell cycle in pluripotent cells and these recent findings provide a possible explanation to my pluripotent stem cells have so much of this protein even though it is relatively inactive.

By developing Aurka inhibitors, these researchers hope to treat cancers more effectively, and also manipulate pluripotent stem cells more successfully.

See “Regulation of Embryonic and Induced Pluripotency by Aurora Kinase-p53 Signaling,” Dung-Fang Lee et al., Cell Stem Cell, Volume 11, Issue 2, 179-194, 3 August 2012 DOI:10.1016/j.stem.2012.05.020.