Wednesday, September 12, 2007

Yvonne Perry - Right to Recover

I have a treat for you today -- two excerpts from two great authors and two very different books. I submit both chapters for your reading enjoyment and remember to post a comment to each author for a chance to win a copy of their books.


Stem cell research is being actively conducted around the world for both scientific and medical reasons. Scientifically, stem cell biology provides excellent information about what is normal and abnormal regarding how cells develop. Understanding what causes cells to become diseased helps scientists find ways to prevent genes from becoming dysfunctional. It also helps them produce drugs and treatments to cure illnesses. Medically, adult stem cells from bone marrow and human umbilical cord blood have been proven to repair and regenerate diseased cells when transplanted into animals and humans. Never in history has one technology held such strong potential to help a majority of people live a healthier life as does the science of stem cell biology. Likewise, never in history has such a remarkable science been so ethically debated.

There are two categories of stem cells: adult and embryonic. For clarification in this book, the term “adult stem cells” refers to stem cells harvested from umbilical cord blood, the placenta, amniotic fluid drawn during pregnancy, and bone marrow of a child or fully-grown adult. The term “embryonic stem cells” refers to stem cells harvested from fertilized eggs created in vitro (outside the body).

What is a Stem Cell?

Stem cells are an undifferentiated group of cells which, depending on their surrounding conditions, are capable of developing into other types of cells such as liver cells, kidney cells, brain cells, or any of the other 260 different types of cells that make up the human body.

There are three types of stem cells: totipotent, which can develop into an entire embryo; pluripotent, which undergo a process of differentiation that changes them into multipotent cells (also called unipotent); and multipotent, which give rise to cells that have a particular function. Multipotent cells (adult stem cells) are permanently differentiated or fixed. For example, multipotent blood stem cells give rise to red blood cells, white blood cells, and platelets, but they cannot functionally develop into other non-blood cells such as liver cells, nerve cells, or heart muscle cells. These unique cells are with us throughout our lives and are used by the body to repair unhealthy or disabled cells of like kind.

Stem cells respond to the other cells around them, and a cell’s fate is determined by the other cells and chemicals in its environment. In their natural state, both totipotent and pluripotent stem cells are not yet any type of cell; instead, they are unassigned or blank. These “undifferentiated” cells have no specific purpose assigned to them other than to reproduce like cells while waiting for a genetic signal to tell them to develop into another type of cell. These signals are found within the environment of the body. Biologists are learning about these signals in hopes of determining the molecular method these stem cells use to differentiate and become tissues, nerves, vessels, and organs. It is believed that organs and tissues may one day be grown from pluripotent cells in laboratories to be used in lieu of, or in addition to, human organ donation. However, the main reason scientists study totipotent and pluripotent cells is to learn more about the cells’ behavior. Understanding what causes cells to become diseased will help researchers know how to produce drugs and treatments to combat or even prevent disease.

When a sperm and ovum are united (whether in vitro or inside the female body) fertilization occurs, and the two parts become a single totipotent cell. A fertilized egg is also known as a zygote. Within hours after fertilization this cell divides into two identical cells, which also divide thus forming pluripotent stem cells. By the fourth day the cell cluster has divided to reach approximately 16 cells, and it is called a morula. The division/multiplication process continues for about five days until a hollow sphere of about 32 cells is formed along with a fluid filled cavity. This sphere or cluster of primordial cells is then called a blastocyst. If the blastocyst cells are inside the womb, development continues as these stem cells begin to differentiate and form all the cells needed to make an entire human being. However, in an artificial environment outside the body (in vitro), the pluripotent stem cells from a fertilized egg will only reproduce more undifferentiated cells. They cannot produce a fully developed embryo.

Figure 1: Morula

Figure 2: Blastocyst

A blastocyst has an inner and outer layer of cells. The outer layer (called the trophectoderm) will form the placenta and other tissue needed to support development in the uterus. The inner cells are undifferentiated or unspecific in what they will become, but they are able to form any type of cell found in a human body. If the entire blastocyst is inserted into the uterus, it must implant itself and begin to draw nourishment from the mother in order to move to the next stage of development. If implantation (conception) occurs, the resulting embryo will become a fetus at eight weeks, which will develop into a human baby within nine months.

Within the womb a blastocyst automatically stops producing undifferentiated stem cells once the body parts have formed. Otherwise, a human would have multiple heads, hearts, legs, etc. However, the inner cells of the blastocyst, if separated from the trophectoderm outside the uterus, cannot form an entire organism. These inner cells can continue to make more undifferentiated stem cells if properly tended to in a lab. The blastocysts used for stem cell research are cultured in lab containers outside the human body where a single cell may continue to divide up to 100 times. These newly developed undifferentiated cells are what researchers are studying.

Scientists do not know how long a cultured line of stem cells can continue to divide or live outside the uterus. The newly divided cells are used to study what causes undifferentiated stem cells to develop into particular cells. There is great hope of being able to cause these undifferentiated stem cells to form tissue, nerve cells, and organs that can be used for patients needing heart, lung, liver, and kidney transplants. Unlike human organ donors, who must die before their parts can be used by another human, the inner cells of the blastocyst may continue to create new living cells that might be used to make new organs, nerves, and tissues. By taking only one cell from the inner mass of the blastocyst, a new cell line can be created. The remaining cells are not harmed. The blastocyst with one cell removed could theoretically be implanted into a uterus and brought to full term.

Stem Cell Technology Currently in Use

In my hope to have you accept all types of stem cell research, I’d like to show some ways that stem cell research is already benefiting society. At the top of the list are bone marrow transplants and umbilical cord blood infusions.

Bone Marrow Transplants

While its use is still in the developing stages, there are technologies available using adult stem cells to help people with heart conditions, spinal cord injuries, and orthopedic repair of bone and cartilage. Known as regenerative medicine, these techniques harness the body’s natural ability to renew and heal itself. Here are a few examples:

Here in the state of Tennessee, doctors at Vanderbilt University Medical Center commonly use bone marrow transplants in the treatment of cancer patients. More about that in just a moment.

In Germany, heart attack victims have made a rapid and remarkable recovery after receiving implants of their own bone marrow stem cells during heart surgery.
Mesoblast Limited is an Australian biotechnology company known for developing treatments through adult stem cell technology aimed at the regeneration and repair of bone and cartilage. In a pilot clinical trial at the Royal Melbourne Hospital, Mesoblast’s technology was used on a patient with a 5cm fracture of the femur that had failed to heal after nine months. Three months after specialized stem cell treatment, the gap had been filled by new bone and the patient had regained use of his leg and was walking unaided.

Vanderbilt University Medical Center in Nashville specializes in adult stem cell transplant using either a patient’s own stem cells, the stem cells of a related or unrelated donor, or cord blood stem cells to assist patients. The donor in sixty percent of all cases is a brother, sister, or adequately matched donor; however, there are cases where stem cells from an unrelated donor are used. There are “cell banks” in the U.S. where hospitals may conduct a computerized search to locate the appropriate units and have them transported to the hospital where a patient is to receive treatment.
The blood-forming (hematopoietic) stem cells of bone marrow change into red, white, and other blood cells throughout life. The standard procedure for cancer treatment takes stem cells from the bone marrow of a patient. One way to retrieve them is to sedate the donor and stick needles in the hip bone and draw out the bone marrow. This method removes plasma, blood, and other cells, but a small population will be stem cells.

Because stem cells in the bone marrow are very small in quantity, recent technology gives the donor an injection prior to harvesting, to increase stem cell production so that it fills the marrow and spills into the blood. The blood is then drawn from a vein in one arm and pumped into a filter very much like a dialysis machine where the stem cells are spun at a certain speed causing the blood cells to separate into their components. Plasma will rise to the top, red cells will stick to the bottom, and the frothy looking layer in between is where the white cells and stem cells are trapped. The machine siphons off the stem cells and collects them before returning the rest of the blood to the vein in the donor’s other arm. The entire closed-circuit cycle takes four to five hours and does no harm to the patient. Once the stem cells are obtained, they are frozen at 220 degrees below zero Fahrenheit until time to reintroduce them to the patient once chemotherapy is complete.

Each cancer disorder has its own stem cell. Some are so resilient they survive certain types of chemotherapy. There may be a pseudo cure or remission between times, but within a few years these cells may grow back and give rise to cancer again. In order to completely destroy the cancer stem cells the patient needs super high doses of chemotherapy. This concentrated dosage not only destroys cancer cells, it also destroys vital bone marrow cells in the process. It also destroys brain cells according to Dr. Mark Noble, Ph.D., an advocate in the field of stem cell research at University of Rochester Medical Center. Since this would result in death, high dosages cannot be used unless the patient’s bone marrow cells are replaced afterward. Once chemotherapy is complete, the patient’s own stem cells are reintroduced into the body where they regenerate perfectly healthy bone marrow cells and long-term health is restored to the patient. In my interview with Dr. Madan Jagasia, Assistant Professor of Medicine at Vanderbilt University Medical Center, he remarked, “We are basically rescuing patients using their own stem cells.”

Another case where stem cells might be used is to restore a patient’s heart muscle. When a patient has a heart attack, heart muscle is lost. You can balloon or stint the arteries, or do a by-pass operation, but once the heart muscle is lost it does not have the capacity to regenerate. Studies in Europe have been done where the patient’s own stem cells are collected within two or three days after a heart attack and then purified and injected directly into the heart through catheters. The data from early animal and human studies show that these stem cells in the environment of the heart should be able to turn into heart muscle cells to repair or replace damaged cells.

Vanderbilt University Medical Center was the first hospital in the state of Tennessee to perform a new therapy using bone marrow stem cells to stimulate regeneration of the heart muscle after a heart attack. Douglas Vaughan, M.D., chief of the Division of Cardiovascular Medicine, reported that John Plummer, 63, underwent the stem cell regeneration therapy on March 11, 2007, after experiencing a heart attack one week prior. More randomized-controlled trials to study the effects of cell therapy in treating cardiac disease are scheduled.

Cord Blood

An Illinois mother Mary Schneider banked her son’s cord blood when he was born. Within a year or so Ryan was showing moderate signs of cerebral palsy. By age two, the child only weighed 25 pounds and was unable to eat. His upper body strength was severely decreased, and he had only a two-word vocabulary. After nine months of speech therapy, his vocabulary consisted of 40 words, but he still had no sentence structure. Only close family members could understand him. Mary worried that her son’s condition would only get worse. Hoping that regenerative stem cells would help him, Mary began the search for a doctor or biologists who could administer her son’s cord blood CD34 stem cells back to him. Since the blood contained Ryan’s own unaltered DNA and no drugs, the infusion process does not require FDA approval. It is an intravenous procedure. It should be simple, right?

Wrong. The search proved more difficult than Mary expected because the treatment using cord blood was so new it hadn’t been tested, and many doctors were unwilling to take the risk without the support of clinical trials. After weeks of searching the Internet and making phone calls to leading stem cell researchers nationwide, Mary found little hope or information but a lot of refusals to do the transfusion. In an age when a patient can get donated blood from a stranger during surgery, no one would give this child his own cord blood! One doctor told Mary that he could give him Botox injections if Ryan’s hands got too spastic!

Mary talked with Dr. Evan Snyder who deals mostly with research using fetal and in vitro blastocyst stem cells. At the time (2005) Snyder’s research was about five years away from human clinical trials. Mary couldn’t wait that long. Upon Dr. Snyder’s advice, she arranged for a metabolic study, a chromosome work up to conclude that Ryan did indeed have mild cerebral palsy and to establish a base-line study for comparison after the infusion. Pre- and post-infusion evaluations and progress monitoring with neural behavior experts and therapists were conducted through Easter Seals Dupage County, Illinois.

Dr. Harris, head of the Cord Blood Registry bank where Ryan’s stem cells were stored, suggested Mary contact Dr. Joanne Kurtzberg, a pediatric oncologist in the Blood and Marrow Transplantation Division at Duke University, to see if she would do the infusion. Dr. Kurtzberg was willing to give the procedure a try, but she knew that, regardless of whether the treatment was successful or not, it would open the doors to a whole new dimension of the medical world, and she would be bombarded by the media and other researchers. In October 2005, just weeks prior to his third birthday, Dr. Kurtzberg introduced stem cells from Ryan’s own cord blood to his body through a 20-minute intravenous drip of stem cells in the back of his hand. This was followed by two hours of saline drip to nudge the cells through his system. The cells then instinctively knew how to find their place and begin repair and regeneration. Within a week Ryan was showing progress and continued to improve in the weeks and months afterward. Eight months after the infusion, the dexterity in Ryan’s hands and arms returned. Today the 4-year-old boy speaks clearly in coherent sentences and is at normal weight for his age group. He is testing at normal or even above average levels in motor skill tests.

Since there are so few studies on cord blood infusion, it can’t be considered a proven treatment; therefore, insurance companies typically refuse to pay for the procedure. Mary Schneider went all the way to Capitol Hill to make sure other parents could access the treatment for their own children. She volunteers her time to train parents about what to expect during the procedure and the following months. She lobbied for federal funding for all types of stem cell research, hoping to receive grant money for parents who cannot afford the infusion their children need. Making speeches with Senator Brownback, Mary was in the East Room when Bush vetoed H.R. 810. Five minutes before his announcement she had urged him not to veto the bill that would have expanded funding for blastocystic stem cell research. Then she sat in silent protest as the president vetoed the bill.

If you want to bank your child’s cord blood, you have a choice of private or public banking options. Private banks will insure (for a fee) that your child’s cord blood will be available whenever it is called for. Public banks do not charge for cord blood, but it is considered a donation to society and may be used by others who need it. Therefore, your child’s stem cells may not be available after the first year or two. Since a typical pregnancy produces more stem cells than are typically taken by private banks, some families are donating cord blood to both private and public banks. Consult your doctor to help you with this decision.

Embryonic (Blastocyst) Stem Cells

Adult stem cells contain more DNA abnormalities caused by sunlight and environmental and other toxins. Because there is a greater margin for errors when making DNA copies of adult stem cells, scientists have looked to another source of stem cells—those created in vitro (outside the body). We’ll see in a moment why the term “human embryonic stem cells” (hESC) used by the media is misleading when referring to these in vitro cultured cells.

The in vitro process is used to assist couples who have difficulty becoming pregnant through the natural method. Let’s suppose a couple goes to a lab for fertility assistance. Both partners would donate their reproductive seeds (sperm and ova). The male donates ejaculate material. The female must be heavily sedated while a needle is inserted vaginally to extract eggs from the ovary. The lab successfully fertilizes three eggs for the couple. We now have three zygotes that begin to develop into a morula, then a blastocyst.

A few days after fertilization, the blastocyst is introduced into the woman’s uterus and the other two are frozen while the couple waits to see if conception will occur. You may be wondering why the sperm and egg are not frozen separately instead of being united first. A fertilized egg has a much better chance of surviving the freezing process than an unfertilized egg.

The success rate for implantation is about 40% nationwide for women under age thirty-five. If a pregnancy is not achieved, the couple may try again at the appropriate time of the woman’s menstrual cycle using another blastocyst they have deposited. Each attempt costs approximately $10,000 to $15,000. Let’s say the couple conceives after one try and there are two blastocysts remaining in the lab. Now comes the question, “What would you like the lab to do with the leftover blastocysts?”

The couple presently has four choices:

Pay to have the cells preserved for another attempt at pregnancy a few years down the road (although the shelf life of a frozen blastocyst is not eternal).
Simply throw them away if they do not plan to have any more children.
Let them be used for research in privately-funded labs.
Give them up for surrogate adoption. A couple with a low sperm count may have the donated blastocyst implanted into their fertile womb and raise the baby as their own.
Many couples actually abandon their leftover blastocysts and leave them at the fertility clinic. In such cases the clinic has no choice but to discard the leftovers.

The field of blastocyst stem cell research is yet to be fully explored due to U.S. government restrictions and the fact that it receives very little public funding due to controversy. Many believe this type of research holds even greater promise than adult stem cells due to the plasticity of the undifferentiated cells.

Ruth R. Faden, Wagley professor of biomedical ethics at Johns Hopkins University, co-wrote an essay with John D. Gearhart, C. Michael Armstrong professor at Johns Hopkins Medicine. Together they report:

As much as we might wish it to be otherwise, no non-embryonic sources of stem cells—not stem cells from cord blood or from any “adult” sources—have been shown to have anything like the potential to lead us to viable treatments for such diseases as juvenile diabetes, Parkinson’s and spinal cord injury that stem cells derived from very early embryos do. The science here is unequivocal: Access to embryonic stem cell lines is essential to rapid progress in stem cell research.1

Most scientists believe that research on these stem cells offers the most promise because these stem cells are totipotent, which means they are able to replicate themselves and become any type of cell in the body. Mouse and baboon models prove the concept of “trans-differentiation” or “plasticity” of stem cells—the ability to differentiate into multiple cell types. This is what enables stem cells to replenish themselves and repair tissues in the body. Adult stem cells do not offer the same promise because they are somatic or limited and can only develop into the type of cells found in the organ from which they are taken. Additionally, not all adult organs contain stem cells; therefore not all organs can be regenerated by using adult stem cells. Recent reports show that adult stem cells lose plasticity or shut down to avoid becoming cancerous during the aging process. The mechanisms by which older stem cells shut themselves down was better understood when a gene called ink4a was discovered. Ink4a has been found to interfere with the ability of older stem cells to transform into several different types of tissue. This explains why adult stem cells are not adequate to regenerate the parts of the body damaged by Parkinson’s or diabetes.

Science does not yet understand how individual parts form during embryogeny. For example, at a certain stage, the eye looks like a glob of skin cells, but when the tissue behind the eye comes in contact with the skin layer where the eye is going to be, there is an interaction that causes the skin cells to become an eye. We have to understand the chemical conditions, creative signals, and the precise interaction of each and every organ before we can determine why a liver becomes a liver and why a pancreas becomes a pancreas in the embryonic stages of development. There is a huge division of embryology at Vanderbilt University Medical Center that is studying this entire field because it has very important therapeutic implications. Dr. Jagasia states:

“You can’t just take a stem cell and unite it with a liver cell or kidney cell and expect it to automatically grow into a new liver. You have to study the conditions and come up with a cocktail of chemicals that are prevalent in the liver or kidney cell and make it look and act like a liver or kidney cell. That will take years and years of research to figure out. Most of the cocktails are available to make a stem cell into a nerve cell or bone marrow cell or a skin cell, but the question is, is that skin cell going to match up with the rest of the skin on the patient’s body? Is it going to form a glob or is it going to be smooth, flat skin? With precise technology, we can make a stem cell become a liver cell, but we cannot guarantee that the new liver cell will connect perfectly with the liver cell next to it. What we don’t want is a glob of liver cells because that is what we call a tumor. We want a perfectly normal organ. The making of a brain cell from a stem cell has to work in symphony with the cells around it. You can’t have a brain cell doing whatever it wants to in one part of the brain or you will have the part of the brain that controls movement, telling an arm or other part of the body to talk.

“Scientists can make frogs with three eyes by manipulating the gene so it receives a signal that cells in a certain place should become an eye. It is not the tissues or mass of cells which will become an eye; it is the interaction of the cells with the skin that will force it to become an eye. The mesoderm is the middle of the three cell layers in an embryo. The visceral organs—the liver, spleen, pancreas, intestines—as well as connective tissue, muscle, blood vessels, bone, muscle and the heart develop from this group of cells. If you look at the vascular system in its early stages, it is just one tube. Why does the tube double up and triple up to become the heart here and stay a tube elsewhere? These are fascinating questions we must be able to answer before we can do embryonic implants on humans. Since we haven’t been able to start doing human research, we don’t know what the obstacles are. We just don’t know what will happen when a manipulated cell is introduced into the human body, and we don’t have the funds for the research needed to find out. Even if stem cell research were unlimited today, it would be a couple of decades before we could reach our dream of being able to make a stem cell into a liver and insure that an organized and predictable outcome will be achieved.

“Stem cells are a fascinating group of cells. We can take a patient and blast them with marrow stem cells from a donor at age twenty and have it last a lifetime. If we have been able to perfect that technology using cord blood and bone marrow stem cells to cure cancer and other disorders, there is even more potential with embryonic stem cells that needs to be explored. The hypothesis needs to be tested and it’s very likely that if we start testing thirty things, we may get lucky in one.

“Stem cells are very robust and it’s tough to manipulate them. They don’t like to be poked on or injected and they like certain temperatures and conditions. On one hand they are finicky but on the other they are very strong. When we inject stem cells via bone marrow transplants after using chemo, the patients who survive recover to live normal lives with normal blood counts for the rest of their lives. If we have this type of success using our present technology, you have to believe that using stem cells from blastocysts or embryos would have an even greater potential to expand our ability to cure disease.

“Bone marrow transplant technology was discovered and started being used almost three decades ago. The problem with donor match and recipient rejection remains a problem today, so we are still not 100 percent successful in this technology. If we hadn’t had laboratory mice and the ability to play with stem cells thirty or forty years ago, we would not have this technology today. With embryonic stem cells, we’ve not even reached the starting block.

“If embryonic stem cell research were funded today, it would still need to be in a very controlled environment with ethical, moral, and social investigators with good oversight from protective committees involved. Since there are so many unknowns about this technology, we don’t know what to expect. We should start with larger animals. A larger animal is much more similar to a human that a rat is.”

Some people believe adult stem cells can be used in the same way as embryonic stem cells, but, as I mentioned earlier, this is not true due to the lack of plasticity of adult cells. Adult stem cells are “fixed” in what they will become and cannot develop into another type of cell. The research done on blastocyst stem cells may very well provide the solution for the shortage of organs needed for those on transplant waiting lists. And the great part is that no one has to die in the process! However, the science is still young and trials on humans have not been completed in every area.

There are still many uncertainties with blastocystic stem cell research that need to be practiced on animals before being introduced to humans. The doors for blastocystic stem cell research in the U.S. are unlocked, but the American government still has its hand on the doorknob. Without federal funds, this area of biological study will not open as quickly or as easily as the research on adult stem cells.

In no way do I suggest we abandon the research and technology for adult stem cells. Instead, the study of blastocyst stem cells should be added to the viable and advanced adult stem cell therapies, which have already proven useful in drug development and for treatment of leukemia, osteopetrosis, heart muscle restoration, and other ailments.


Yvonne Perry said...

Wow! The first chapter really looks lengthy on a blog! I think I'll link my blog to this post so my readers can easily find the entire first chapter. Thanks, Nikki.

Yvonne Perry

wendy said...

Ms. Perry:

I read this posting with interest and offer the following information for the book’s “Stem Cell Technology” section:

As the adult body’s richest source of stem cells, adipose (fat) fuels the Celution™ System, an investigational device designed to enable surgeons to restore the natural volume and contour lost in a partial mastectomy. With this breakthrough stem cell technology, a bedside device separates and concentrates a patient's own stem and regenerative cells within fat tissue so they may be re-administered in the same procedure in a “cell enhanced tissue transfer.” The Celution™ system, developed by Cytori Therapeutics in San Diego, will be introduced to a limited number of European hospitals in the first quarter of 2008. This technology also is in evaluation for the treatment of acute heart attack and chronic heart disease. More broadly, scientists have recently found adipose-derived stem cells aid in treating orthopedic conditions, cartilage damage, liver repair, spinal disc regeneration, wound healing, and gastrointestinal disorders.

I can forward the first scientific paper reporting on the presence of stem cells within adipose tissue, which was the foundation for Cytori’s development of its Celution™ System. I also would be pleased to connect you with researchers at Cytori who would be pleased to provide further information.

Best regards,
Wendy Emanuel (