One Embryo – Three Parents?

The web is alive with reports that scientists at the Oregon Health & Science University have managed to make embryos that contained genetic material from two mothers and one father. There has been a certain amount of “creepiness” applied to this experiment, but there are various reasons why this experiment was done. I will fully admit that there is a degree of creepiness to this experiment and the destruction of these embryos is also deplorable. However, this is a strategy to cure some genuinely nasty genetic diseases. Therefore, the research is not for nothing.

Deoxyribonucleic acid or DNA is the molecule all living organisms use to store genetic information, with the exception of some RNA viruses, but there is a debate as to whether or not viruses are actually alive. DNA is housed within the nucleus and is organized into linear molecules of DNA known as chromosomes.

However, there is another compartment in human cells that also houses DNA. The power-generation structure of the cell is called the mitochondrion. Mitochondria are enclosed by two membranes; and inner and outer mitochondrial membrane. There is also an internal network of membranes called cristae. Embedded in the membranes of the cristae are the components of the electron transport chain that are used for energy production.

Directly inside the mitochondrion is a soluble region known as the mitochondrial matrix. Soluble enzymes are found in the matrix as are metabolites and other small molecules. Another large molecule found in the mitochondrial matrix is the mitochondrial genome, which consists of multiple copies of small, circular molecule of DNA.

The mitochondrial genome encodes several genes necessary for the energy production machinery of the mitochondrion. The vast majority of the energy production machinery components are encoded by the nuclear genome, but the small number of mitochondrial components encoded by the mitochondrial genome are crucial for energy production.

Replication of the mitochondrial DNA is accomplished by a DNA replication system that is specific to the mitochondrion.  Unfortunately, this DNA replication system is less accurate than that used in the nucleus.  Therefore, mutations in mitochondrial DNA are relatively common.  Loss of function mutations in mitochondrial genes can compromise the ability of the mitochondrion to make chemical energy, and such mutations have dire consequences for several different organ systems.

The list of genetic diseases causes by mutations in mitochondrial DNA is long.  Here is a short list:

1.  Kearns-Sayre Syndrome – weakness or paralysis of the eye muscles, impaired eye movement and  drooping eyelids, loss of vision, abnormalities of the electrical signals that control the heartbeat, coordination and balance problems, abnormally high levels of protein in the fluid that surrounds and protects the brain and spinal cord, muscle weakness in their limbs, deafness, kidney problems, or a deterioration of cognitive functions (dementia). Affected individuals often have short stature and suffer from diabetes mellitus.

2.  Leber hereditary optic neuropathy – first sign is blurring and clouding of vision, and over time, vision worsens with a severe loss of sharpness and color vision.

3.  Leigh Syndrome – first signs are seen in infancy and are usually vomiting, diarrhea, and difficulty swallowing, eating problem, an inability to grow and gain weight at the expected rate, severe muscle and movement problems, weak muscle tone, involuntary muscle contractions, and problems with movement and balance, loss of sensation and weakness in the limbs.

4. MELAS – mitochondrial encephalomyopathy lactic acidosis, stroke-like episodes – signs and symptoms appear in childhood and may include muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and seizures. Stroke-like episodes beginning before age 40, and often involve temporary muscle weakness on one side of the body, altered consciousness, vision abnormalities, seizures, and severe headaches resembling migraines.  Strokes can progressively damage the brain, leading to vision loss, problems with movement, and a loss of intellectual function.

5.  MERRF – myoclonus epilepsy and ragged-red fibers – characterized by muscle twitches (myoclonus), weakness (myopathy), and progressive stiffness (spasticity).

6.  MILS – maternally inherited Leigh syndrome – a progressive brain disorder that usually appears in infancy or early childhood.  Affected children may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement. Heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder.

7.  Pearson Syndrome – a fatal disorder of infants with anemia and exocrine pancreatic insufficiency.  It is now known to be a rare, multisystemic, mitochondrial genetic disease, with anemia (low red blood cell count), neutropenia (low white blood cell count), and thrombocytopenia (low platelet count), as well as variable liver, kidney, and endocrine failure. Death usually occurs early in life.

8.  Progressive external ophthalmoplegia – Weakness of the eye muscles, drooping eyelids (ptosis), weakness or paralysis of the muscles that move the eye.  Affected individuals may also have general weakness of the skeletal muscles particularly in the neck, arms, or legs that may be especially noticeable during exercise.

9.  NARP – neuropathy, ataxia, retinitis pigmentosa – Beginning in childhood or early adulthood, numbness, tingling, or pain in the arms and legs; muscle weakness; and problems with balance and coordination; also vision loss learning disabilities, developmental delay, seizures, dementia, hearing loss, and cardiac conduction defects.

None of these diseases sounds terribly pleasant, and there are no known cures or effective treatments for them.

The severity of these diseases depends upon the proportion of the mitochondria that possess the mutated version of the mitochondrial genes.  Typically, mitochondria contain multiple copies of their genomes, and mutant versions of these genomes are mixed with normal copies.  When mitochondria divide, the copies of the genomes are randomly distributed between the two daughter mitochondria.  Therefore, some mitochondria will have mainly copies of the mutant version of the genome while others will have mainly copies of the normal version of the genome.  This condition is called heteroplasmy, and how widely these mutant versions are distributed throughout the body determines the severity of the mitochondrial genetic disease.

Mitochondria are inherited from the mother.  This is due to the fact that the egg, which is supplied by the mother, contains a large quantity of mitochondria, whereas the sperm that fertilizes the egg, only has relatively a few mitochondria.  Therefore, mitochondrial genetic diseases will only be transmitted through the mother, and if a mother is known to have a mitochondrial genetic disease, she will pass that disease onto her children, regardless of the health of the father.

This is the main reason for the technology tested in this paper: Masahito Tachibana, et al., Towards germline gene therapy of inherited mitochondrial diseases, Nature (2012) doi:10.1038/nature11647.  In this paper, scientists from the Division of Reproductive & Developmental Sciences at the Oregon National Primate Research Center in Oregon Health & Science University, used a technique that extracts the nuclear genome from the egg and transplants it into the egg of a donor, after which the egg is fertilized with normal sperm.  This technique would bypass the mitochondrial mutations in the mother’s eggs and replace that genome with a new genome that does not carry such a mutation.

The technique used in this paper is called “spindle transfer.”  This technique takes an oocyte donated by a woman who carries and suffers from a mitochondrial genetic disease and isolates and transplants the chromosomes (nuclear genetic material) from the patient’s unfertilized oocyte into the cytoplasm of another donated, enucleated egg, that contains healthy mtDNA as well as other organelles, RNA and proteins.  Such a child born a result of this spindle transfer procedure will be the genetic child of the patient but will carry healthy mitochondrial genes from the egg of the donor. Prior studies in a monkey model showed not only the feasibility of the spindle transfer (ST) procedure but also that ST is highly effective and completely compatible with normal fertilization and birth of healthy offspring (see Tachibana, M. et al. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 461, 367–372 (2009)).  This strategy might have an important future as a therapy to avoid transmission of serious mitochondrial diseases.

In this paper, seven volunteers (aged 21–32 years) donated a total of 106 mature eggs, and 65 eggs were used for the ST procedure and 33 served as non-manipulated controls.  Of the 64 ST eggs, 60 of them survived intracytoplasmic sperm injection (ICSI; 94%) and 44 formed showed the early signs of successful fertilization (73%).  These results were comparable to those found in the non-manipulated eggs; 32 oocytes survived ICSI (97%) and 24 (75%) formed pronuclei .  However, when these embryos were further observed, 48% (21/44) of the ST eggs were normal, but 87% of the non-manipulated embryos were normal.  Therefore, these manipulations can decrease the efficiency of fertilization.

If fertilization occurs normally, the ST embryos seem to be able to form blastocysts as well as the normal controls.  Blastocyst formation rate in the normally fertilized ST group (13/21, 62%) was statistically similar to controls (16/21, 76%).  Embryonic stem cell derivation rates were higher in the normal embryos (56%)  than in the ST group embryos (32%).

This paper uses an ingenious technique to potentially help women with a genetic disease.  That should give us some hope.  However, what I find reprehensible in this paper is the destruction of all these embryos.  These were young human lives that were snuffed out for the sake of convenience.

Wesley Smith at the Human Exceptionalism Blog has a different take on this technique.  Here are his words:  “Also note, that preventing illness is just the key that opens the door to many of these Brave New World technologies. Eventually–given the way things go these days–if the procedure ever becomes doable, it will go quickly from the “medical” to the “consumerist,” e.g., facilitating lifestyle choices and personal preferences.  That’s what happened with IVF, after all, which is no longer restricted to treating the infertile. Indeed, if we ever normalize polyamory, one could see the technique as a way for three partners to have biologially related children.”

Smith has a good point.  However, given the devastating nature of these mitochondrial genetic diseases, it seems to me that using this technique to prevent such horrific diseases from being passed on is a good thing.  However, we should certainly not let this technique be a license into another foray into experimental lifestyles.  Could we use this technique for medical purposes only?  Smith seems to think that the answer to this question is “No.”  I am certainly sympathetic to his caution, but I am also unwilling, at this point, to prevent mothers with these diseases from using this technology to have healthy babies that do not die at a young age.  If there is another way to purge such diseases from the mother’s eggs, then I am all ears, but for now this seems to be the best and only way.