Genetic Engineering

Stem Cells

By the time you finish reading this article quite a lot of the information could well be out of date. The world of Stem Cell research is fast changing and every day there are new developments and new research findings published.

What you read here is as an overview of what is commonly held to be true as of May 2005, a month in which major advancements in the field have been announced.

This month a team of scientists from Seoul National University in South Korea led by Professor Woo Suk Hwang published a paper about their latest trails using human embryonic stem cells. The team took skin cells from patients with specific diseases, which they then transplanted into donated eggs that had had their own genetic material removed. The eggs where then grown to an early stage at which time the stem cells where removed and found to match the DNA of the cell donor, making them 'pateint specific stem cells'.

This announcement has caused huge ripples around the world not least in the USA where President Bush immediately reacted by proclaiming he would veto pending legislation if it allowed for stem cell research using embryonic stem cells. On May 23 2005 the legislation that concerned Bush was approved by the House of Representatives. But we are getting ahead of ourselves. First lets look at some of the basics.

WHAT ARE STEMS CELLS?

There are a number of different kinds of stem cells.

After sperm fertilises an egg a single celled zygote is formed. This cell is a Totipotent stem cell which means that it can become any kind of human cell. This includes the cells needed for the formation of the placenta, the formation of the embryo and the development of all other fetal tissue and organs. Totipotent stem cells divide to make more totipotent stem cells which can themselves become fetuses; which is where identical twins come from.

4 days after the formation of the zygote the totipotent stem cells stop dividing and begin to form the Blastocyst. A Blastocyst is a mass of cells consisting of three parts; an outer layer of stem cells called the trophoblast or trophectoderm, which form the cells of the placenta and other tissue needed to support the fetus, a hollow area and Inner Mass stem cells which form the cells that become the fetus. These stem cells are Pluripotent meaning they can become almost any kind of cell. Inner Mass stem cells are not totipotent because they cannot make trophoblast cells but they can make any other kind of human tissue cell.

Embryonic Stem Cell.jpg The Pluripotent stem cells of the Inner mass then begin to specialize into Multipotent stem cells which can become different kinds of cell depending on their specialism, for example blood stem cells can become red or white blood cells or platelets. This process is known as stem cell differentiation

Multipotent stem cells are also found in the formed human and are commonly known as Adult Stem Cells. Whereas the role of pre-birth multipotent stem cells is to form, build and develop the new human, the role of the adult stem cell is one of repair and renewal.

Adult stem cells are know to exist in a several areas of the bodies organs and tissues. Some of the earliest stem cells to be discovered, in the 1960's, were those in bone marrow. Bone marrow contains at least two types of stem cell, those for the formation of blood related cells and those for the formation of bone, cartilage, fat, and fibrous connective tissue.

The body is known to hold stocks of stem cells in various other places including; the brain, the skin, skeletal muscle and liver.

Until relatively recently it was thought that multipotent stem cells were only capable of differentiating into cells for use within their specialism. The stem cells multipotency had led scientist to believe that this meant that stem cells which live in a specific place could only differentiate into cells related to that organ or tissue, it seems that this may not be true. Recent experimentation suggests that certain adult stem cells may be pluripotent and capable of Transdifferentiation, the ability to differentiate into other cell types outside of their specialism. It has been shown that already differentiated cells can transdifferentiate and more particularly can be induced to transdifferentiate. Whilst some evidence seems to exist for transdifferentiation there is a big debate regarding how exactly it happens, some scientists have suggested that a process of fusion occurs that gives the appearance of transdifferentiation. At this time there is no accepted conclusive proof either way.

Finally stem cells are found in one other place, the umbilical cord. These stem cells are also multipotent and more specifically only make blood cells.

LIFE CYCLE OF A CELL:

While we bear in mind the debate about transdifferentiation and the nature of adult stem cells, certain aspects of stem cell morphology are held to be true. This is a basic overview of these 'knows'.

From Stem to Death.

Stem cells sit around in the zygote, embryo, fetus or the birthed human, dividing. The division of stem cells into new stem cells is known as self-renewal, the division of a stem cell into a new, specialist cell is know as differentiation. The stem cells are waiting for a signal to start to differentiate. Differentiation is the process of becoming a specialist cell.

The stem cell receives the signal telling it to turn on certain genes and make the required proteins. Part of this process is the continuing division of the cell. The differentiation process is complete once the cell stops dividing. It is now a specialist cell. This cell then makes its way to the required spot where it continues to function until death. The point of death varies from cell type to cell type

DIFFERENT KINDS OF STEM CELLS:

Type

Behaviour

Found In

Early Embryonic

Totipotent

Zygote

Blastocyst Embryonic

Pluripotent

Inner Mass of Blastocyst

Fetal

Pluripotent

Fetus

Umbilical Cord

Multipotent

Umbilical Cord

Adult

Multipotent

Babies, Infants, Children, Adults

Scientist mainly use two types of stem cells, blastocyst embryonic and adult which they obtain from either animals or humans. In the main scientist steer clear of using totipotent embryonic stem cells because of the controversy caused by their use. A totipotent stem cell has the total ability to become a human, i.e. it cannot only make the tissue required for human life but also the tissue necessary for the placenta. As the embryo develops the stem cells become less pluripotent so fetal stem cells are less versatile. Umbilical cord stem cells have so far only been found to hold blood stem cells. Adult stem cells were thought to have formed their specialism and therefore only be able to produce cells that fit the specialism; evidence is beginning to suggest that this may not be so. And lets not forget the transdifferentiation experimentation here.

The Variety of Life:

There are a lot of different kinds of cells that go to make up the body. The different kinds of cells have hugely differing life cycles.

Two examples:

Skin Cells

The Skin needs Keratinocyte cells for repair and renewal. The stem cells recieve the signal to start to differentiate into a Keratinocyte cell deep within the skin layers. As it differentiates it moves towards the surface of the skin.Before the cell reaches the surface it loses it nucleus and dies. As a dead cell on the outer layer its job is to protect the living cells underneath until it finally flakes off to become dust. As you can see this process requires a lot of stem cells to be available for differentiation as the skin is continuously repairing and renewing itself.

Nerve Cells

Image courtesy of National Institute of Neurological Disorders and Stroke (NINDS) Nerve cells come in two basic forms, Neurons and Glia. Neurons transmit information and are supported by the glia cells. They are mostly created during the embryonic and fetal stages ergo they are from embryonic or fetal stem cells. When a stem cell starts to differentiate for use within the nervous system it can do one of three things; it can self-renew, it can become an astrocyte, a type of glia cell, or it will produce neurons or oligodendrocytes. By the time we are born most of our neural stem cell activity has finished. As children we probably grow a few more neurons that are used to create neural circuits. The jury is still out on how much activity happens after birth, there is evidence to suggest that the brain can and does make new neural cells from adult stem cells. The death of a neural cell is infrequent and happens after a long and active life.

WHY DO SCIENTISTS LIKE STEM CELLS?

Stem cells are some of the most interesting cells in the human makeup. They possess three key features that make them eminently useful and fascinating for scientists.

1. Stem cells are cells that have yet to have their specific role in the formation of tissue determined.

2. Stem cells can become almost any other kind of cell. They are waiting for a signal that will tell them what kind of tissue cell to become.

3. Stem cells have the ability to divide - proliferate over long periods of time.

The pluripotent nature of embryonic stem cells - the ability to become almost any other kind of cell makes it one of the favourites with scientist. Also embryonic stem cells are more easily grown in the laboratory and are generally more abundant. But this is the stem cell that causes most controversy. The argument is fundamentally about when human life begins; at birth or at conception, and the right to life. Using adult stem cells is basically uncontroversial but at present adult stem cells are seen as less versatile; they are rarer and they proliferate less readily.

HOW ARE STEM CELLS GROWN?

Embryonic Stem Cells

Firstly the scientist needs to have a blastocyst from which to extract the Inner Mass Stem Cells. The Inner cell mass is then transferred into a plastic dish that has been coated with, most commonly, mouse embryonic skin cells and contains a soup of nutrients and growth factors. These initial stem cells divide over a period of a few days to fill the dish. Once the dish is full the stem cells are removed from the dish and transferred into new dishes where they continue to divide. This process is repeated for about six months. After 6 months the initial batch of 30 stem cells has become several million. These cells are all still pluripotent. During this six month process periodic tests are made to ensure that the stem cells are still healthy, genetically normal and have not started to differentiate.

If the batch passes all the test then it can be called an embryonic stem cell line. There is no accepted standard for these test and scientist admit that the tests do not in fact give a clear indication of the stem cell lines fundamental properties and functions.

The scientists keep the stem cell lines from spontaneously differentiating by controlling the conditions under which the stem cells are grown. When they need to start the differentiation the conditions are changed. To produce a stem cell line for the creation of specific types of cell the scientist adjusts the chemical composition of the culture or the surface medium or inserts some specific genes. At present this process is not that reliable.

Adult Stem Cells

Adult stem cells are already specialists, but specialist waiting for their signal to start to work - differentiate. There are some important aspects of adult stem cells that need to be borne in mind; they do not exist in large quantities and they do not divide until they are activated by disease or injury and are required for a repair or renewal job.

The biggest challenge to scientist in the field of adult stem cell research has been how exactly to produce enough adult stem cells to make it viable as a therapeutic option. So far there has been limited success in the field of stem cell proliferation and control. A regular check on the news will show monthly if not weekly hopeful articles describing 'promising' new discoveries.

WHAT DO SCIENTISTS WANT TO DO WITH STEM CELLS?

Disease Elimination and Cure

Most of the more lethal diseases such as cancer are caused by faulty cell differentiation and division, as are birth defects. If scientist can understand, unravel and control the complex processes of differentiation it will be a huge step towards finding ways to eliminate and cure such diseases, birth defects and genetic disorders.

Drug Testing

Rather than rely on animals for testing new drugs and therapies scientist are attempting to create stem cells line that can be used to produce cells for testing drugs and therapies. Cancer cell lines are already used to test anti-tumour drugs. To be able to test drugs on different kinds of tissue requires the scientist to be able to produce consistent stem cell lines and have them differentiate to exactly match so that each drug type has 'level playing field' for comparison.

Tissue and Organ Replacement and Renewal

Experimentation has shown that it may be possible to use stem cells to create new cells that can be used to repair damaged tissue or even eventually to grow new organs. Some of the injuries and diseases that scientists are concentrating on are; Parkinson's and Alzheimer's diseases, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis. The idea is that healthy cells are generated in the laboratory and then transplanted into the patient where they will replace and renew the damaged tissue.

FUTURE HUMAN EVOLUTION

It is highly likely that stem cell research will be a major player in the future. The possibilities for the manipulation of the human form, making the adjustments that might prove necessary, are likely to be achieved using stem cell engineering. Taking stem cells and manipulating them for alternative cell production could hold possibilities for changing organ or tissue function. Growing genetically manipulated organs could also be a possibility. Who knows what kind of new organ might be feasible this way?.

ISSUES AND ETHICS

This article scratches only the very surface of the subject of stem cell research. There are many hurdles for the scientists to overcome and many ethical issues to be debated and resolved. These issues are discussed more fully in other sections of this site.

If you would like more in depth information on the subject of stem cells a good starting point is the National Institutes of Health (USA) stem cell site.

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