Genetics and Stem Cells

"What if the baby that the stem cells come from has a genetic defect?"

First of all, the parents of our stem cell donor infants are screened for genetic diseases in them and in their families.  In most cases, when a child develops a genetic disease, it is a recessive trait.  This means that the child gets the disease because that child has two coinciding copies of a bad gene.  Genetic diseases are rare.  Recessive genetic defects being active in a baby are many times more rare.

It is very likely that any family genetic defect that would be active in the baby would be uncovered in the screening process.  It is also very likely that any hidden genetic defects would not be active in the baby, or in his stem cells.  It is extremely unlikely that any genetic defect in the baby’s cells would cause any problems in a transplant recipient.  If there were any effect at all, it would likely be that the cells were not as helpful as they otherwise might have been.  Even this is very unlikely.  Read on for a more detailed explanation.

Sickle cell

As you know, genetic traits are encoded on DNA strings, called chromosomes.  Portions of DNA called genes are strung along the chromosomes in the thousands.  Each parent contributes half of the 46 chromosomes in the infant’s cells.  The chromosomes are in pairs, so the baby gets two copies of each chromosome, and on the chromosome, each gene, each string of genetic material.

Genes generally code for a protein.  Often, this is a special type of protein called an enzyme.  Enzymes act as catalysts in most of the chemical reactions in the body, making the reactions proceed more rapidly.  When an enzyme is defective, it may not be able to effectively act as a catalyst in a particular reaction.  Instead of the intended product of the reaction being made, the substrates, or the chemicals that the enzyme acts on, accumulate.  It is like if a tuna fish canning machine were broken down, you would not get cans of tuna.  Instead, you would get piles of cans, and piles of unpacked tuna.  And the tuna can box packer would not have canned tuna to box.

Sometimes, the lack of the reaction product causes the disease condition (no canned tuna).  In other cases, it is the accumulation of unprocessed substrate material that causes the disease problem (piles of unpacked tuna, and piles of empty tuna cans).  As long as there is one good enzyme produced by one of the chromosomes, there is usually enough enzyme activity to produce the desired product, and to prevent accumulation of the substrate material (one tuna canning machine can usually keep up, even though you usually use two).

When there is a genetic problem, it is usually due to a defect in the DNA coding for a specific protein or enzyme.  Sometimes, though, a longer piece of a chromosome is broken off or deleted, or sometimes even an extra copy is included.  Since this usually causes significant anomalies in the newborn baby, these defects are usually identified by the physician or midwife examining the newborn. 

A defective gene produces a defective version of the protein or enzyme. As long as at least one good gene is present, most cells are able to make enough of the protein or enzyme to function adequately.  In this case, no disease results, even though the abnormal gene is present.  This kind of genetic problem is called a recessive trait.  Recessive traits are not extremely uncommon, but they rarely result in disease.  Only when there are similar recessive defects on the same gene of the same chromosome, coming from hidden genetic defects on both the mothers side and the fathers side, does the genetic defect cause disease.

 Most hidden genetic defects are recessive traits.  This means that both the father’s family and the mother’s family can have a hidden copy of the bad gene on their paired chromosomes, but as long as there is a good copy on the other chromosome, no disease is expressed.  The members of the family with a copy of the defective gene are called “carriers” of the genetic “trait”.  They do not have the genetic disease, but carry the possibility of the disease in their genes. If a woman from a family with a hidden genetic defect (a carrier) marries a man from a family with the same defect (another carrier), then it becomes possible that the genetic defect will cause disease in their child.  That is why most societies prohibit marriage of close relatives.  An egg from such a mother has a 50:50 chance of having this trait, as does a sperm from her husband.  Only when an egg with the trait is fertilized by a sperm with the same trait does that disease become expressed.

Since an egg from a mother who is a carrier of this trait has a 50:50 chance of having the trait, and so does the sperm from a man with the trait (but not the disease), when an egg from a carrier is fertilized by a sperm from a carrier of this trait, it receives one copy of each chromosome from the father and another from the mother, and there is a 1 in 4 chance that this child will end up with two bad gene copies.
 
With two bad genes and no normal ones, there is no chance of a functional enzyme in the cell.  The combined enzyme defects prevent the normal processing of enzyme substrate materials into enzyme products, and the condition eventually makes itself known.  

In those genetic disorders where a single bad gene out of the pair causes a problem, this is a “dominant trait” (or possibly an incompletely dominant trait), and is readily apparent as a family disease pattern.  There are no hidden “carriers” of these genes in a family—if someone has the gene, then it is apparent in his or her own health.  Dominant genetic defects are therefore easy to identify and screen out.

When the mothers and fathers are screened for family genetic disorders, dominant genetic defects are easy to detect.  They affect everyone in the family (mother’s family, father’s family, these parents, and all of their children).  These donors are easily rejected from our collection program.

Recessive genetic defects are more difficult to screen out.  If there are no cases in which the same abnormal gene is in both parents of any individuals in this family, there will be no cases where the disorder has expressed itself.  It will therefore be impossible, without extensive genetic testing, to find any of these hidden gene defects. If there is only one copy of the gene in the family chromosomes, there will be at most one copy of the gene in the baby, and so the disorder will not be expressed in the baby, or its stem cells.

Suppose that the unlikely case occurs that there is a recessive genetic defect present on one of the chromosomes in the stem cells.  These cells would still be able to do all of the functions of any other stem cell, since they have a normal copy of the gene on the other paired chromosome.
  
In the extremely unlikely (millions or billions to one) chance that the hidden genetic defect is matched by another hidden defect in exactly the same gene, out of the thousands of genes on that particular chromosome, then the stem cells produced by that baby would be unable to make one protein or enzyme.  The chances of that particular protein being one needed in the activities of the stem cell are slim.  Even if the defective enzyme were needed for some chemical reaction by the stem cells, your own cells would still be able to make that chemical, and it is possible that the stem cells would be able to take it in, and use it.  In the even more unlikely (billions or trillions to one) chance that the stem cells were made unable to function by the defect, then they would not have been able to function in the baby either, so the baby would not have been born!
 
We cannot rule out the possibility that some genetic defect in a baby might make its stem cells not work right in your body, even though they worked just fine in making a baby!  What then would be the effect of transplanting these defective stem cells into you?  Basically, nothing.  If they didn’t work, they still would not harm you.  You would not get the benefits of the stem cells, but neither would you be harmed.

Let’s look at the example of one genetic disease: 

Sickle cell disease is a genetic disease which causes a defect in the hemoglobin protein in the red blood cells. The abnormal hemoglobin causes the red blood cells to deform.  In Africa, where the disorder originated, having one abnormal sickle cell gene, or in other words, being a sickle cell carrier, protects against malaria.  As a recessive defect, full-blown sickle-cell disease is only present when two copies of the sickle cell trait coincide in the same person.  This defect in hemoglobin makes the red cells deformed, especially when stressed by low oxygen conditions.  The mass deformations of red cells that occur in a “sickle cell crisis” cause severe pain, blocked blood flow, and organ damage. Sickle cell disease is likely to be well known in a family.  The presence of a case of sickle cell disease in a family line would cause rejection of a mother as a donor of her child’s stem cells.

If a family were sickle cell carriers, this could be detected by special blood tests, but if the family had never intermarried with another family of carriers, there would be no cases of full-blown sickle cell disease, so it would be unlikely that such tests were ever done on this family. 

The presence of sickle cell trait in transplanted stem cells would NOT cause the disease in the recipient. 

If the transplantation were being given to replace bone marrow in a cancer patient, it would be important to use blood stem cells from a person who had been tested for abnormal hemoglobin, because these stem cells are going to replace all of the blood-producing cells for that person.  Even if the recipient did have bone marrow problems, the stem cells would likely help him.  These stem cell trait stem cells would even be fine for producing red blood cells, even though there would be some abnormal hemoglobin present.  But in general, such abnormal stem cells would work just fine.  And for most people, the presence of stem cell trait would cause no problems, and the stem cells would seek out and repair the other defects in the body.

If the screening process totally failed, and stem cells were transplanted from a baby which was going to go on and develop full-blown sickle cell disease (the same bad genes on two chromosomes), this could cause sickle cell disease only if there were a pre-existing defect in the bone marrow which caused the stem cells to migrate there and start producing red blood cells.  So, the presence of these abnormal genes would only be important if the stem cells were being given to replace blood producing cells in the bone marrow, for example, in a patient who had some blood disease, or perhaps a bone marrow transplant recipient.  In the presence of normal bone marrow and a normal blood system, the stem cells would not have a reason to seek out this niche to set up housekeeping, and would be unlikely to be activated to produce blood-producing cells.  These stem cells would be quite able to do any other function desired of stem cells, including replacement of immune system stem cells, platelet-precursor stem cells, or white blood cell (leukocyte) precursor stem cells. 

So, we see that it is very unlikely that a genetic disorder be present in donated stem cells.  Dominant genetic disorders are easy to screen out, based on family history.  Recessive genetic disorders are also likely to be screened out.  Hidden recessive genes in carriers could possibly get through the screening process, but would not affect the function of the stem cells, and would not adversely affect your body.  Double recessive gene defects that would cause stem cell dysfunction would likely be fatal to the developing embryo, so would not result in a healthy childbirth, and would not pass our screening process.  In the extremely remote event that a double recessive gene existed which would affect the stem cells, it would also affect the newborn soon in its life.  But it would be very unlikely to cause any adverse effect in the transplant recipient.  Much more likely would be the chance that the transplant of these cells would not do anything at all.

"What types of genetic diseases might be helped by stem cell therapy?"

See the FAQ above for more discussion about genetics.

The National Blood Donor Program lists many genetic disorders as possibly or definitely benefiting from stem cell transplants.  Many of these disorders listed are genetic problems with blood cell formation, and are helped by the hematopoietic (blood forming) stem cells found in umbilical cord blood. 

Here is a list of some of these genetic disorders of blood cells or blood formation:

Myelodysplastic Syndromes (bone marrow disorders)
Inherited Erythrocyte Abnormalities
Beta Thalassemia Major
Pure Red Cell Aplasia
Sickle Cell Disease
Histiocytic Disorders
Familial Erythrophagocytic Lymphohistiocytosis
Histiocytosis-X
Hemophagocytosis
Phagocyte Disorders
Chediak-Higashi Syndrome
Neutrophil Actin Deficiency
Reticular Dysgenesis
Inherited Platelet Abnormalities
Amegakaryocytosis/Congenital
Thrombocytopenia
Congenital Immune System Disorders
Ataxia-Telangiectasia
Kostmann Syndrome
Leukocyte Adhesion Deficiency
DiGeorge Syndrome
Bare Lymphocyte Syndrome
Omenn's Syndrome
Severe Combined Immunodeficiency (SCID)
SCID with Adenosine Deaminase Deficiency
Absence of T & B Cells SCID
Absence of T Cells, Normal B Cell SCID
Common Variable Immunodeficiency
X-Linked Lymphoproliferative Disorder
           
Other genetic diseases are called metabolic diseases, because they are characterized by defects in some metabolic, or biochemical, process.  Usually this is due to a defect in one gene on a chromosome.  See the above explanation for more information on genetics.  These diseases are also called “Liposomal Storage Diseases”, because they result in an over-abundance of metabolic substrate materials stored in the liposomes of a cell. Here is a list of some of these disorders:

Mucopolysaccharidoses (MPS)
Hurler's Syndrome (MPS-IH)
Scheie Syndrome (MPS-IS)
Hunter's Syndrome (MPS-II)
Sanfilippo Syndrome (MPS-III)
Morquio Syndrome (MPS-IV)
Maroteaux-Lamy Syndrome (MPS-VI)
Sly Syndrome, Beta-Glucuronidase Deficiency (MPS-VII)
Adrenoleukodystrophy
Mucolipidosis II (I-cell Disease)
Krabbe Disease
Gaucher's Disease
Niemann-Pick Disease
Wolman Disease
Metachromatic Leukodystrophy

Some of the diseases that stem cells may help include genetic metabolic disorders like these, in which fats or carbohydrate materials accumulate in the cells.  If it is a liver cell that is causing a problem because it doesn’t have the right enzyme (liver cells need more enzymes than most cells, because they are responsible for so many chemical reactions), then the liver cells may swell with accumulated substrate materials.  This can lead to liver failure and death.  Sometimes the accumulated materials themselves are toxic, and cause damage to other cells.

In disorders such as Maple Sugar Urine Disease (MSUD) and Phenylketonuria, or PKU (you have seen it on all of the Aspartame packages), there is an inability to process certain amino acids.  Maple Sugar Urine Disease and PKU cause a build up of toxic products in the blood.  These toxic products cause nerve and brain damage.

Other metabolic disorders involve the nerve cells themselves.  As the nerve cells swell with the abnormal materials, it causes cell dysfunction, which often leads to blindness, neurological impairment, and early death.

Sometimes, as in PKU and MSUD, the accumulated chemicals are able to leak out of the processing cells into the surrounding tissues, other cells, and the blood.  While this can affect the other cells if the chemicals are toxic, it also provides a way in which stem cells can be helpful.  Providing multipotent mesenchymal stem cells which then convert into liver cells, the liver begins to repair itself.  Since these new liver cells have normal enzyme function, they can begin to remove the accumulate substrate chemicals in the bloodstream.  Often, they are able to completely remove the accumulation of abnormal chemicals, so that the original liver cells are able to do most of their other work.
 
In other cases of this type of genetic disorders, the swollen, damaged liver cells are unable to get rid of the accumulated substrate material. These cells continue to be dysfunctional, but the new liver cells may be able to take over their function.

Sometimes, these original liver cells, which are unable to rid themselves of accumulated materials, continue to deteriorate, and they die.  In that case, the new, normal liver cells may be able to multiply, and essentially build a new liver.
 
In the case of nerve damage, again, if the accumulated materials are able to leak out and be processed elsewhere, the damage may be reversible.  It is also possible that new nerve cells, or new nerve helper cells (glial cells) produced from mesenchymal stem cells are able to replace the dysfunctioning nerve and glial cells.

There are other inherited diseases that do not fall into this category, but are considered likely to be helped by stem cell transplants. Some of these are:

Lesch-Myhan Syndrome
Cartilage-Hair Hypoplasia
Glanzmann Thrombasthemia
Osteopetrosis

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