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2. THE ULTIMATE PHILOSOPHICAL PROBLEM:THE CHILD OF A MILLION PARENTS
What is a person (man/woman/ or any of the other more than a dozen sexes?). I once had
extended discussions with a friend now deceased, as to how we would define a human to
an alien race. What would be prohibited to an alien, what actually is human. This is going
to be covered in a future article, in detail.
The article here is one I wrote in 2011 but was rejected by publishers. At the time it
appeared to be science fiction, but science moves on. How many biological parents can a
person have? When this was written, an American doctor had tried to cure mitochondrial
disease in about a dozen children, by injecting the unfertilized egg with mitochondria from a
disease-free donor. This project stopped, though I believe some children have been born.
Progress continues, as the British government has now made this process legal. Also of
interest, is the enabling legislation specifically absolved any mitochondrial donor of
parental obligations. And of course very recently Chinese researchers have been
modifying genes in human embryos, for research.
So my article is, how many parents CAN one child have? 3, 30, 3000?
Is one gene inserted from another person enough to claim parenthood? Read the article;
there is so much going on so fast, that seems like science fiction, such as human/mouse
hybrids, etc etc.


The Ultimate Philosophical Problem: The Child of a Million Parents

By Gerald A. Krulik

DRAFT COMPLETED July 7, 2011


The most important questions facing the human race are those affecting its future. The
most direct influence on our future history is that of human reproduction, the continuance
of the race. People do not mate at random; politics, religion, ethics, and laws are extremely
important in determining who has offspring. The question of parentage is important to
society in many ways, especially economically in terms of child support and inheritance,
and in social status. Maternity is easily established. Paternity is the subject of less certainty.

Over most of the last few millennia, LEPR (=Legal Ethical Philosophical Religious) ideas,
have pretty much stayed in balance with social and political systems and the judicial
system of the moment. However, the new field of science has increasingly caused
problems for these older fields of thought. One example is the question of parentage of a
child. Laws and customs have evolved to handle the various circumstances regarding
children, such as lawful and unlawful parents, or parentage by a non-married person. We
have many specialized words and laws that cover the production of bastards, or love
children, wives and mistresses, children of rape or incest. Thus in many places, a man’s
lawful wife is assumed to be the bearer of his child, regardless of any other facts in the
case. Likewise, inheritance laws are pretty well thought out and are dependent on the
country and social structure. Some countries like England, espouse primogeniture, leaving
the bulk of an estate to the oldest, usually male, child. Other countries like India, tend to
divide property up equally among the children. Many countries or states hold that in the
absence of a specific will, all children will inherit equally.

The field of assisted parentage has challenged almost all old assumptions and laws. We
can easily trace the efforts of assisted parentage to circa 1600 BC in the Old Testament.
Sarai was unable to conceive a child with Abram, so offered her slave Hagar as a
surrogate wife and who bore the surrogate child, Ishmael. In an effect often seen in
modern assisted parentage efforts, Sarai then became pregnant and bore Isaac. The
biblical details and problems of this parentage conflict are little different than those of
modern times.

Progress was slow for millennia. In 1790, John Hunter reported the first case of artificial
insemination. By the early 1900s it had become common enough to attract the attention of
the Catholic Church, which objected to all forms of artificial insemination. The first child
from frozen sperm was reported in 1953, following improvements in cryopreservation and
antibiotic treatment of sperm. The sperm bank industry and the process of artificial
insemination became commercialized in the 1970s. While the use of artificial insemination
now seems widely accepted, this may be just be the calm before the perfect storm.

Apart from artificial insemination, the easy prediction and presumption of parentage began
to fall apart in the middle of the last century. Wiener and Landsteiner discovered the Rh
factor in 1937 when doing work on blood typing. With the rise of understanding of genetic
inheritance, even though DNA was still not discovered, the Rh factor could sometimes be
used legally to indicate or disprove parentage. The laws are still catching up with this old
science. Improvements in blood typing and knowledge of DNA inheritance led to analysis
for many more factors or enzymes, allowing for more precise determination, or more often,
denial of parentage. Now the question of parentage is increasingly being sought using
DNA matching techniques. These much more sophisticated tests can now show a level of
detail in inheritance that has never been contemplated. An example was the use of bone
DNA to conclusively prove the identity of the skeletal remains of the Romanovs, down to
each person’s sex. Whole genome DNA analysis can show broad strokes of ancestry too,
such as whether there are any recent African type genes, or in which continental area
ancestors lived. There are now commercial companies which will examine at least parts of
your genome and express opinions as to your ancestry. Biochemists can now look at
genetic samples of mother, father, and child, and definitely show that a certain man could
NOT be a father. As is true in life, it is less easy to prove actual parentage. A real life
example is the question of parentage of Thomas Jefferson’s Negro descendents. Testing
has shown that a group of people are indeed descendents of the Jeffersonian genetic line.
What science cannot yet prove, is whether Thomas Jefferson was the father as some
opine, or whether the actual ancestor was the brother of Thomas Jefferson. Science is now
far in advance of the judicial system, as many jurisdictions regard any such DNA-based
proof as irrelevant and not a factor in assigning child support or spousal support. Public
opinion, and evolving ideas of fairness, are increasingly challenging these laws.

Science is changing the ability not just to answer questions of child
parentage/ownership/financial support/inheritance very rapidly, but also to bring into
question the very ideas of parentage. Consider how assisted reproduction methods,
including artificial insemination, surrogate motherhood, sperm donation and sperm
banking, cryopreservation of sperm and eggs, fertilization in vivo, in-vitro (in-Petri dish),
and by intracytoplasmic sperm injection (microinjection of a sperm into the egg, when the
sperm is defective), egg  banks and egg donation, have challenged the ability of our
philosophers and ethicists to respond. Consider just two examples: accidental incest, and
time shifted reproduction by living or by dead people.

Accidental incest will occur when the donors of sperm and/or eggs are confidential.
Increasingly strong confidentiality laws suggest that this may become more common in the
future, though the probability may be low. One early article from 1960 actually addressed
this issue in a hypothetical way for Great Britain, but did not mention legal, ethical, or
philosophical problems. A more recent Taiwanese article from 2007 continues discussion
of this issue, but also mentions that donor anonymity is being removed. No laws seem to
protect the couples or children, in these cases. Take the related example of the Dutch
couple, who used the technique of ex-vitro (in-vivo or Petri dish) fertilization of multiple
eggs from the wife, with donor sperm. They had twins, one white and one black, due to
mistakes and contamination at the fertilization clinic. However, this problem has been
discussed and is changing in many countries. Now that artificially inseminated children
have become adults, they have demanded the right to know their actual parents. Courts
have sided with this view to the extent that now in many jurisdictions the identity of the
sperm donor must be disclosed, despite assurances at the time of donation that they would
never be identified. One recent case on US television covered a young man who gave
donations to a sperm bank when in college. Some of his adult children have now
demanded that they find out, not only his identity, but also the identity of their half-siblings.
This specific man has 51 identified children and two of them were brought together on the
TV show for the first time. Imagine all the possible legal ramifications of this disclosure, the
ethics of determining whose rights are paramount or are being violated, and you begin to
have sympathy for religious views that say such incidents should never have occurred at
all. Still, these are well-known legal and ethical issues when they occur within polygynous
relationships, to men with dozens or more wives. Any difficulties can probably be
accommodated within known historical and judicial frameworks.  

Time shifted reproduction is even more fraught with unintended possibilities. There have
been court cases involving a deceased donor’s sperm to produce a child long after the
donor’s death. Now that eggs are routinely being frozen also, it will become more common
to have children born of surrogate mothers, long after their biological mother and father
are dead, or the mother is past what is considered normal child-bearing age. Note that this
whole idea of child bearing age itself is becoming irrelevant, as women over 60 years of
age, well past menopause, have given birth from implanted eggs. Are any such children
entitled to an inheritance from their possibly long-deceased parents estates? Or will they
be considered to be orphans or abandoned children, or even emancipated children,
perhaps with coverage under current laws, though the ethics may be questionable in some
of these interpretations? Another related question is the responsibility of storage facilities
and donors as to whether frozen eggs and sperm may just be thawed out and disposed of.
Ownership of eggs and sperm from deceased persons has already been tested in court,
showing that they are indeed property and fall under inheritance and divorce laws
themselves.
This is not a small issue. The first ‘test tube’ baby, born using eggs fertilized with sperm,
outside the womb, was born in 1978. Now it is estimated than in excess of 3 million such
births have occurred worldwide. Multiple births are far more common with this technique
than with standard reproduction, as multiple eggs are often inseminated and put into the
mother to raise the chances of having at least one success. Now at least 40% of triplets
are thought to be from artificial insemination, despite the relatively tiny number of such
pregnancies. Controversies have erupted over the use or overuse of multiple eggs, as was
seen in the case of the ‘octomom’ in California, who bore 8 healthy children despite ethical
and medical guidelines against this practice.
Legal issues, particularly in artificial insemination cases with donor sperm, have raised
debate over the parental rights of sperm donors, privacy rights and the ethics in sperm
donor banks for artificial insemination. Some European countries have regulations that
deem artificial insemination babies as legitimate offspring of the mother's husband but
most other countries have not addressed the issue in the law. Relatively little debate
seems to have occurred on the philosophy and ethics of a system which promotes the birth
of children by parents who are not genetically capable of have children. There is little
problem with artificial insemination for parents who have physical problems, such as age or
inheritance or scar tissue or accidents, which keep them from conceiving. But what about
the children of parents who have very low sperm counts, or high levels of defective sperm,
for example? Are we causing problems for the future of the human race, by propagating
highly defective, but not immediately fatal, genes? The opposite side of the issue is more
clear-cut. We now have the technology to almost eliminate some genetic based diseases
such as hemophilia or Tay-Sachs disease, by selective abortion and other techniques, but
this is also a matter of religious, ethical, and philosophical debate. However, the success
against the usually fatal or debilitating Tay-Sachs disease is clear-cut. The incidence of
Tay-Sachs disease has dropped more than 90% thru prenatal diagnosis, pre-implantation
genetic diagnosis of fertilized eggs used for implantation, and prospective parental/spousal
screening methods. The success of this screening program led Israel to become the first
country to offer all couples free genetic screening and counseling, and is now a leader in
this area.
Parentage used to be a very clear issue. One had 2 parents, who were married to each
other, or not, as the case may be. The only questions were of the identity of the legal
parentage of the father and mother, which were important for property inheritance and
social standing, or religiosity, as in the Jewish religion where only Jewish motherhood
controls the identity of being Jewish. Then it became a question of sperm donor, father,
egg donor, mother, surrogate mother, and the conflicting rights and obligations of each.
Currently it is easy to have at least 5 parents, with conflicting claims, for each child. For
example, an infertile man may contact a sperm bank for a donation. If the wife is also
infertile for whatever reason, they may acquire an unfertilized egg from a donor. After
fertilization, the egg can now be implanted in another woman who agrees to be a surrogate
mother to carry the baby to term. Thus we have five ‘legal?’ parents of the child. Are the
parents of the surrogate mother entitled to Grandparents Rights, even if the surrogate
gives up the child?

Now many of the old common-sense LEPR laws on inheritance, support, parentage,
citizenship, and responsibility have to be re-thought and re-written. But, this is only the
very beginning of the changes that are coming. The rapidly evolving field of biotechnology
is going to open up possibilities that even science fiction writers have not considered.

The First Man-Made Organism

It has been little more than a year, since May 2010, that the first synthetic microbe was
fabricated. Mycoplasma mycoides, or more properly Mycoplasma mycoides JCVI-syn1.0, is
a new form of life. This organism is nearly, though not completely, identical to the parent M.
mycoides. A distinct but related organism, Mycoplasma capricolum, was used as the
disposable starting template. This cell, had all the chemical ingredients and expressed
organelles needed for life. The genome (its chromosomes) were  removed and replaced
with a totally chemically synthesized genetic code of the related species, M. mycoides. This
event was totally successful. The composite organism has been successfully cultured
through many generations, so the resultant microbe can be considered man-made, even
though it is just a copy of an existing microbe. Earlier work by many teams of scientists
produced techniques to read the genetic DNA code, and to synthesize exact copies of
fragments of it. The further work by Venter and co-workers has shown how to successfully
assemble these fragments into working genes, how to handle and move them, and how to
insert them into an enucleated cell, without degradation of the DNA.

Perhaps a more understandable analogy is the strangler fig-support tree relationship. A
strangler fig seed germinates, usually as an epiphyte on the trunk or branches of a tree.
As it grows, it stretches its branches skyward while roots grow downwards into the soil.
Eventually the roots cover the trunk of the support tree while the strangler fig’s leaves and
branches emerge above the crown of the support tree. The support tree finally dies from
light and nutrients starvation. The rotting support tree is often encased within the
encapsulating strangler fig. The old tree has been replaced with a new tree in exactly the
same spot and with largely the same shape. For the new organism, once the chromosomes
were implanted in the cell of M. capricolum, the new chromosomes took over the operation,
maintenance, and replacement functions of the cell, so in a short time none of the original
cellular contents were left. It is almost like changing a VW into a Mercedes, while the car is
operating.

Details of the Synthetic Bacterium Assembly

Of course, it is still WAY beyond our conceivable ability, to make a living cell from scratch.
Scientific successes have been in finding ways to remove the master blueprint of the cell,
the DNA chromosomes, while leaving the rest of the living cell in a state of suspended
animation. Chromosomes are constantly active, forming new proteins and directing their
use, like an operating computer program. Without the chromosomes, the cell will die soon
as the residual protein instruction flow stops. SO there is a brief window of time in which we
can deftly insert new chromosomal material, and resume cellular life using a new set of
operating instructions.

This is a clarification of how Venter and his associates made the first synthetic cell. The
‘cell’ referred to is actually a man-made copy of the genetic code, the single chromosome
found in this bacterium. First the genetic code of the target cell was analyzed. This was
about 1.2 million DNA bases long. Then the genetic code was chemically synthesized in
various laboratories. Venter’s group assembled it into an intact DNA chromosome (there is
only one in most bacterial cells). This was a major challenge that had never been done
before, necessitating the invention of new techniques. DNA molecules are very long when
uncoiled, and very thin relative to their length, thus are very very fragile. The basic DNA
molecule is around 2.4 billionths of a meter wide; the length varies with the number of DNA
bases on the chromosome. Human DNA has roughly 3.2 billion bases in one set of 23
chromosomes. An average chromosome has a length of around 100 cm if completely
uncoiled, but with a thickness of only 0.00000024 cm so can break even under gentle
pressure. They made the synthetic chromosome in small segments, combined smaller
segments into larger pieces, and finally assembled all of the pieces, in the correct order,
into one chromosome.

Next Venter’s group took a closely related, but different, bacterium in the same genus.
They can easily be told apart by genetic analysis. The DNA was removed from this
bacterium, but the rest of the cytoplasm—the liquid mass inside a cell, which contains all
the working chemistry plus all the organelles or specialized cellular organs—remained. Now
they inserted the new, synthetic DNA of the different bacterium. The DNA soon began to
work as it does in a normal cell, and the cell soon started dividing. Genetic analysis
showed that the new cell, after multiple generations of division, was identical to the original
bacterium, and the DNA was same as the synthetic and the natural DNA. But what about
mitochondria, you may ask? In this case it is easy to answer. Bacteria do not contain
mitochondria. Mitochondria are the highly modified and degenerate remnants of an
originally free living bacterium that went from living inside an ancient proto-eukaryote as an
invader, then as a progressively modified symbiote. Mitochondria are basically the energy
production centers of the cell, though we are learning that they do some other things as
well. While some of its DNA actually did migrate into and become integrated with the host
eukaryote DNA, some remained inside the degenerate cells that are the mitochondria. This
is the reason that all eukaryotic cells, including all visible macroscopic life on earth, contain
mitochondria, and thus two separate sets of genetic codes. Bacteria are prokaryotes, thus
lack mitochondria; animals and plants are eukaryotes, and thus have mitochondria.

To complete the answer, the cytoplasm of the related species IS different from the
cytoplasm of the synthetic DNA species. But the old set of DNA maintenance and
construction instructions were replaced by the new DNA sequence in the cell. As cell
division and multiplication took place, the original cytoplasmic material was diluted by newly
synthesized material of the new, related species, and removed by processes that eliminate
aged and degraded cellular contents. Soon both the cytoplasm and the DNA of the new
cell, became identical to the original natural species. However, there are a number of
genetic differences between M. mycoides and Mycoplasma mycoides JCVI-syn1.0. First,
they deleted 14 genes thought to be unnecessary for life, from the genome of M.
mycoides, leaving hundreds of genes behind. Then they put in 9 SNPs (single nucleotide
polymorphisms—more on this later) by changing single nucleotides (DNA bases) in parts of
the approximately one million DNA-base genome. Finally they watermarked the organism to
show it is synthetic, by putting in new genes which can be transcribed to English language
messages. They made four new genes, for the 4 watermarks they attached to the bacterial
chromosome.

The first watermark is an HTML script. A standard browser reads this as a text message,
congratulating the decoder and giving an email link (mroqstiz@jcvi.org) to verify the
decoded message. The second watermark contains a list of authors (or builders) of the
organism. (Note to me, if they are authors, then the organism falls under US copyright laws
with exclusivity of 75 years plus the lifetime of the oldest author, rather than patent law of a
short term.) The second watermark has a James Joyce quotation: "To live to err, to fall, to
triumph, to recreate life out of life". The third watermark contains more authors plus a
quotation from Robert Oppenheimer: "See things not as they are, but as they might be".
The fourth watermark contains even more authors (this was a big cooperative project) plus
a very relevant quotation from Richard Feynman: "What I cannot build, I cannot
understand".

MORE BACKGROUND MATERIAL

Ethicists have to wrestle with the use and mis-use of molecular biology, but I fear they are
falling fast behind. Most people have some awareness of the controversies surrounding
embryonic stem cell research. These special stem cells must be isolated from an embryo,
so even if there would be no chance of a potential child being born, one is potentially
destroyed to get the stem cells. There are also a lot of current discussions considering the
wrongful use of prenatal sex determination to eliminate one sex of child. This is such a
highly used and mostly illegal procedure that it is already impacting national sex ratios.
Some areas of India and China, where males are more highly valued than females, are
showing up to 3 live male births for every 2 female births. Other work is progressing on the
ethics and laws for prenatal screening for fatal or chronic diseases. Debate is heating up
on whether all mothers must get such screening, what ailments should be screened for,
whether certain children should be aborted, and what the financial and legal
responsibilities should be for parents who knowingly give birth to a defective child.
Obviously, with the US legal system, it will soon be common for genetically defective
children to sue their parents for giving them birth at all.

Parthenogenesis
Parthenogenesis, production of live young from unfertilized eggs, is common in nature.
Chickens are known to occasionally produce chicks from unfertilized eggs. Male ants are
all born from unfertilized eggs, so male ants never have sons. Many lizards including the
Komodo dragon, and fish, worms, and other creatures, can at least sometimes produce
offspring without a male parent. Hermaphroditic fish—those who start as male, or as
female, then switch to the other sex when needed—have no sex chromosomes. And some
animals such as turtles and crocodilians have their adult sex determined by the
temperature at which the egg is incubated.

In most mammals, a parthenogenetic offspring can only be female, as the parent only has
the X gene for sex determination. A female is XX and a male is XY. (I deliberately ignore
things like the platypus, with 5 pairs of sex determining genes!) Birds have a different sex
determination system, with females ZW and males ZZ. Thus fatherless chickens are always
male, as WW eggs are not viable. Science has now made this observation obsolete.
Parthenogenetic mice with one mother have been produced, by using special techniques.

Mice with 3 Parents, Male Mice with only 2 Male Parents, and Male Mice with NO Male
Parents
However, no natural example exists of male parents reproducing together without females,
as an egg cell is needed to start. Mice are easy to manipulate in the lab, so can be used
for all kinds of procedures. Mice have now been produced who have two male parents, and
no female parents. Scientists started with an egg cell, removed the nucleus, and replaced
it with the fusion of two sperm cells. Remember that the nucleus of a sperm cell, the only
part that enters the eggs, is one half of a pair of chromosomes. If you join two sperm cell
DNAs, you get the equivalent of a normal egg-sperm fusion, with one exception. The mice
are YY, or have a double male chromosome, instead of the normal XY sex chromosomes.
In female mice one of the XX sex chromosomes is randomly deactivated. Perhaps that
occurred with these YY mice, as they seem normal. To be more accurate, they were
started from an egg cell having mitochondria, so they still have a mitochondrial female
parent. All the rest of the genes are from the two male parents—or it could be one male
parent, with two of its own genes. This really sounds strange even to me, but when you
analyze it, it is really just the male equivalent of the well-known female parthenogenesis.
Remember that these mice have THREE genetic parents, if sperm from two different males
were fused, or TWO genetic parents if only one male’s sperm was fused. These mice show
how parentage in the normal old-fashioned sense of the word, is becoming fuzzy and
outdated.

Scientists have also produced male mice from an originally XX female egg. This did not
have a Y chromosome, so they were able to induce the egg to develop and divide by
activating another part of a chromosome which functioned as a Y chromosome sex
determination factor. It is interesting that the mice appeared to be normal.

Humans with Multiple (or Less than 2) Sex Determination Chromosomes
A related human disability concerns the people with three or more sex determination
genes. These syndromes occur due to defects during sperm formation. The two sets of
chromosomes are supposed to separate cleanly during sperm production, with one set of
genes and one sex determination gene in each sperm. When the chromosome separation
is incomplete, one sperm can have both sex determining genes, so the sperm may be XX
or XY. Thus the egg cell will have two sets of standard genes plus 3 sex determination
genes. People with XXY, XYY, and further multiples of sex determination genes, exhibit
Klinefelter Syndrome and other abnormalities. Women can have an additional sex
determination disorder. A few women have only one sex chromosome, so are XO. They are
sterile, short, and do not mature their sex organs. Others have an extra X, so are XXX.
They are fertile, though not fully so, are tall, and may have learning disorders. Many other
variants on the sex chromosome and its expression are known. Most have only been
identified in recent decades, and more are still being identified. All of these variants are
considered to be abnormal and are the result of two parent reproduction. They all fit with
little trouble into the standard LEPR (legal, ethical, philosophical and religious) systems,
since there have always been abnormal appearing children that have to be accommodated
within our social systems.

Mitochondrial Genes and Diseases
Here is another example of genetic mischief. It is now known that certain diseases are
transmitted only through the female line, from mutations in the maternal mitochondria. This
is a totally different genetic system than what is transmitted during sexual reproduction.
Mitochondria do NOT reproduce sexually, only asexually by simple division within each
female cell.  Y-linked male diseases are only transmitted because they appear on the Y-
chromosome; other X-linked diseases like hemophilia are only transmitted through the X-
chromosome. Both Y- and X-chromosome linked diseases are transmitted through sexual
reproduction.

The mitochondria are an ancient form of symbiosis which led to the evolution of eukaryotic
single celled life (bacteria and archaea are called prokaryotes), followed by multi-cellular
and macroscopic life forms. Mitochondria are the remains of separate organisms, floating
in the cytoplasm, and have their own membrane separating themselves and their genes
from the rest of the organism. Over the eons of time that they have been inside of
eukaryotic cells, they have partially transferred and integrated their genetic code with the
host DNA. Some originally mitochondrial genes have transferred to what we think of as
standard DNA, but a small number of genes remain within the mitochondria. Mitochondria
are now found only within living cells, as they have totally lost the capacity for independent
living. Mitochondria have many essential functions, but especially the production of ATP
(adenosine triphosphate), the chemical driving force for most aspects of respiration,
chemical synthesis, and growth of cells. They have their own residual genetic code, the
Mitochondrial Genome, separate from what is called the Human Genome, which allows
them to reproduce within the cell. This is a circular DNA of only 16 kilobases, much smaller
than in bacteria, since it is only the symbiotic remnant of the original DNA. There are only
37 known genes in the mitochondrial DNA, whereas the smallest bacterial genome known
has about 400 genes. The mitochondrion is also different from most bacteria in that each
mitochondrion has 2 to 10 copies of its DNA, while most bacteria have only one copy. Men
contribute no mitochondria to their offspring, since mostly only the DNA package in the
head of the sperm penetrates the egg cell. The male mitochondria in the rest of the sperm
cell, drop off and disintegrate. A few mitochondria from the male sperm do enter the egg
cell, but are chemically marked for destruction by the egg and do not persist. Different cells
have different numbers of mitochondria, with human liver cells having up to 2000 per cell.

Remember though all these discussions, that people all have two parents but three
separate DNA contributions to two separate genetic codes. Everyone has a mother and a
father, so the standard DNA is the product of two parents. Mothers also contribute another
DNA code, kept separately in the mitochondria of their cells, which never meets or reacts
with the father’s mitochondrial DNA. Thus everyone (thus far, almost!) has two genomic
parents with only one maternal mitochondrial parent.

USE and MISUSE of TECHNOLOGIES

Once some procedure is possible in biotechnology, it will be used, and not necessarily for
the original purpose. Some skeptics may argue that ‘society’ or ‘the laws’ will not allow the
actual implementation of any such technique that I will hypothesize here. I will argue that
such people assume an American (or at least a Western civilization, Christianity-biased)
social, legal, ethical, and philosophical structure will be imposed on the whole world. The
widespread third world use of purchased donor organs or forcible blood collections should
give pause for this idea. The selective abortion of identified female babies in several
countries is beginning to impact their social structures. A recent event in Nigeria exposed
the use of kidnapped girls, to bear children later sold for adoption or for use in magical
ceremonies. Even in America, people have no control over autopsies, or removal of
corneas, bones, and other parts from their own or from relative’s corpses for transplant
use. And in China, and perhaps other countries, executed criminals are used for organ
donation. In summary, Western Christian ethics are not the same as Buddhist, Hindu,
Muslim, animist, oriental, African, and other ethical systems.

It is now necessary to think about very new and unusual topics and ideas—to Think
Outside the Box, or OB2, as convenient shorthand for mind-blowing ideas. Each discussion
step will consider a new and novel level of parentage, from children born of 3 biological
parents, to children born of one million parents, or more.

OB2  One: The child having Three biological parents.

Women who have fatal or debilitating mitochondrial diseases will pass them on to all of
their children. No DNA base pair matching can occur, as standard sexual reproduction, so
there is no way to compensate for defective mitochondrial genes. Assisted reproduction
specialists have suggested that women with mitochondrial disease can still bear disease-
free children. Their proposal is to remove just the nucleus from a woman’s egg, fertilized or
not, and insert it into an enucleated donor egg. The egg would then be allowed to develop
normally inside the woman or a surrogate mother. Simplistically, such a child would have 3
genetic sets of parents: half of the genetic code DNA from the father, half from the mother,
and the tiny amount of mitochondrial DNA from a second woman. Who is the mother(s) for
legal purposes? Will future laws follow the lead of laws on step-parenting, adoption, and
joint custody, or will new law need to be made?

This first idea is NOT science fiction as it is an accomplished fact. First tests were done
using mice, as is usual. This procedure has now been done in humans, but in a ham-fisted
way. Maybe 30 babies around the world already have one male parent and 2 female
parents. This is because they are not produced with one set of mitochondria. Instead, the
fertilized nucleus and any attached mitochondria from one woman, is inserted into the
enucleated egg cell of a second woman. I have not seen any reports that show that the
extra mitochondria are destroyed, so it is likely that the child has two mothers and one
father, either by accident of the procedure used, or by the current inability to destroy
unwanted mitochondria selectively in the enucleated donor egg.   

OB2 OneA: The Three parent child with only one sex chromosome.

Thinking OB2, there seems to be no need for two sex chromosomes, except that it makes
sexual recombination of genes easier. The male sex chromosome is dominant in all XY
children, as far as is known (though there are a lot of strange but natural people around,
androgynes who can have functional male and female parts, and ‘intersexes’ who have
variable combinations of male and female characteristics). The extra X sex chromosome is
supposed to be inactivated in women. However new discoveries continue to be made, and
it may be that there is blending of the expression of the genes on the two X chromosomes,
with only some genes on each X chromosome (de-)activated. There are also rare XO
women, who have only one X chromosome. These are the only natural two parent children
(father, mother, and mitochondrial mother) with one sex parent chromosome.

So we are discussing UN-natural reproduction, not Natural reproduction. If the egg is
manipulated in the lab to introduce a second mitochondrial genome from a second female
donor, we can consider if we really need two sex chromosomes? Or can one of them be
discarded, or replaced with the sex chromosome of someone else? I am not sure why
someone would want to do this, but can consider more science fiction type scenarios
involving radical social or religious or gender groups.


Think outside (outside the box) or OB3.

One female or one male sex chromosome (X or Y chromosome) is all that is needed, since
the other X or Y is inactivated. We know that XO women, though rare, do exist. This proves
that only one sex determination chromosome is really necessary even though it may be
highly desirable. It should be possible to make a YO child by inactivating or destroying the
X chromosome in the donor egg.

The male chromosome is the smallest human chromosome, at about 58 million base pairs.
The number of active genes is somewhere between 70 and 200, so most of the Y
chromosome is not known to be used. Remember that the first synthetic organism,
Mycoplasma mycoides JCVI-syn1.0, has around 400 genes packed into a chromosome of
1.08 million base pairs.

It now seems almost a trivial exercise, to make an artificial Y chromosome purely from
chemicals. The actual number of genes is less than that found in the synthetic bacterium.
Perhaps for a first try, limit the size of the Y chromosome to about one million base pairs,
with the 70-200 genes arranged in sequence. Certainly some lab, somewhere, can make
each individual gene and save them until the time is right to use them. I can envision that
with this small a number of genes, each can be separately examined and expressed, to
see if there are any defects. Those defects would be removed or replaced, in the artificial
set of genes.

I can envision commercial labs whose function would be to synthesize and supply each and
every one of the approximately 23,000 human genes. What if consumers could use custom
modified male chromosomes for their offspring? Or, how about duplicating and replacing
existing Y chromosomes with ones from athletes, movie stars, and so on. How do you price
your mitochondria—it is probably illegal in the US, though the labs can make lots of money
from you. When will this restrictive law regarding organ transplants be changed or
modified? It is strange that eggs and sperm can be sold by a person, and even blood, but
not kidneys, skin, or other organs. Mitochondria are an odd case—are they an organ,
since organelles are just tiny organs; or are they reproductive items like non-regulated
sperm and eggs?

There is a possible very positive application here. Instead of selectively aborting female
fetuses as is done illegally in many countries, why not change the sex of the existing fetus
by biochemically targeting one of the sex determining X-chromosomes? If eggs are being
implanted in a woman, it should be possible to remove one of the X-chromosomes,
perhaps with light tweezers and laser pulses, and insert the Y-chromosome from the father.
This would be an instant sex change operation.


Step Two: The 500+ parent child.

Let us follow this line of questioning a bit further. We have seen that there are already a
fair number of children born through mitochondrial manipulation. These children have
three genetic parents, just like normal people. But normal people are ((male DNA +(female
DNA + female mitochondrial DNA)). The children who have extra mitochondria in their cells
still have three genetic parents, but are different: ((male DNA +(female DNA + (female
mitochondrial DNA +female donor mitochondrial DNA))). Do we need a separate legal term
for these three parent children? This is certainly more basic than plastic surgery, blood
transfusions, or organ transplants, all of which leave the genetic legacy of the person
unchanged. Does the mitochondrial female donor even qualify as a parent under existing
laws and ethics?  

What if this is only the beginning? The ethical question being pondered in the literature I
have seen, seems to consider or assume the use of only one mitochondrial donor for the
replacement of defective mitochondria. Cells contain many mitochondria, depending on
their function in the body. Liver cells seem to have the most, around 2000 per cell. Let us
assume that a human egg cell contains 500 mitochondria, since I could not confirm an
actual figure. It should soon be possible to remove all of these and replace them with 500
new mitochondria. In the most extreme case, they would all be from different women. This
child would then have 502 identifiable parents.

Under many current inheritance laws, this child may have the potential  right to inherit from
each and every parent, even without a will which identifies or accepts such a child. And if
both husband and wife died in an accident, who of the 500 women gets custody? Or pays
support? Will current laws assume that only the two married parents are the parents, with
the other 500 falling under some sort of unmarried parent definition?  Do we need a
different definition of parentage that legalizes partial parents and defines their rights, either
absolutely or on a percentage of parental contribution basis?

OB2 TwoA: Whose mitochondria do you use?

Let’s stop being sexist (if you can by now determine what that means). Why assume that
the donor mitochondria have to be from women. Why not take all the replacement
mitochondria from a man? Or from 500 different men? Or any possible combination of men
and women? This is not as shocking as it could be, since men have nothing to do with their
mitochondria anyways. They only inherit them, solely from the female line only, directly
through the female parent. So men are men because they have a Y chromosome, not
because they contribute any genetic mitochondrial heritage. Since men never contribute
the mitochondria at all, the child strictly speaking, should have 500 grandmothers, not
fathers. Also, the existing technology produces children by using donor mitochondria from
a separate female donor. Why not take the mitochondria from the FATHER, so the child will
be genetically ---using my clumsy terminology---((male DNA + male mitochondrial DNA)+
female DNA ), or MMmF,  instead of the natural ((male DNA +(female DNA + female
mitochondrial DNA)), or MFFm. Are the male donors’ mothers going to file for grandparents
rights in the offspring because of the MMmF parentage? Why not?


Think outside (outside the box) or OB3 !

As long as you are putting in new mitochondria, why stop with the piddling little examples
already described? A whole industry could be formed, to supply mitochondria to any
specification and any final donor egg mosaic. Want 500 movie star mitochondria, or just
those of Elvis or Marilyn? Male or female mitochondrial donors or both? Nobel prize
winners? Beauty contest winners?  Future galactic warriors, with 500 Olympic winner
mitochondria? The mitochondria do directly impact endurance and power since they are
the energy cells within the cells. How about 500 of your extended family—is this an
example of future incest? Don’t cringe and say it is impossible—the fact is that responsible
reproduction scientists are now replacing or supplementing defective mitochondria with
new healthy ones. It does not appear that anyone even came close to considering the
ramifications of this new idea, so there are no legal, ethical, or religious boundaries in
place to restrict its implementation. Philosophers, religionists, ethicists, the judiciary and
legislatures, all will have their mental boundaries stretched to accommodate (or prohibit, in
their jurisdiction) these concepts.

When you put mitochondria of men put into eggs, is it fathering, or grandmothering? All
mitochondria arose and are inherited solely thru each female line; they don’t fuse
genetically to swap genes and rarely change. If you give 500 childless men a chance to
become fathers by donating one mitochondrion each, will they take advantage of it just to
become a 0.02% father and get a present or card on fathers’ day? This is a really complex
question, perhaps being a cross between being a parent or an organ donor (mitochondria
are mini organs or organelles).

OB2 Three: The 46+ parent child

Dividing cells undergo mitosis, or the separation of the DNA into pairs of chromosomes.
These chromosomes then undergo duplication, followed by meiosis, or duplication of the
cell itself, each with its own chromosomes. Humans have 23 pairs of chromosomes. Thus
each chromosome, 23 from the male, and 23 from the female line, could be separated.
These chromosomes are easily identified even with a light microscope. The procedure
would be to take 46 separate parents, one for each chromosome, and combine them
together into one set of human DNA. This works to give any combination of types of
parents for the children, up to 46 different parents.

Remember that karyotyping (analysis of the number of chromosome pairs in a cell) is done
routinely. Karyotyping can help indicate the presence of certain diseases and
abnormalities. The chromosomes are large enough to see with a light microscope. They
are often fluorescently labeled to help with identifications. Chromosomes are not really
living organisms, which is why they can be fairly easily moved from cell to cell without
regard for maintaining any particular metabolic activity. The biggest problem with
chromosomal separations may be due more to the physical and chemical fragility of the
structures. A problem during karyotyping, is that you are looking at the pairs of
chromosomes, which are linked together by a chemical bridge called a centromere. These
centromeres would need to be broken so the individual chromosomes can be used. In
addition, the process of chromosome separation, duplication, and reassembly followed by
cell division, is very complex and is mediated by complex structures within the cell that are
not currently easily amenable to modification. It might be easier to start with sperm and
unfertilized egg cells, as they only have one set of chromosomes.

Much work has been done with gene therapy to overcome problems with defective genes.
Techniques are routinely used in lab animals, and in humans, to insert new genes into
existing chromosomes. The new gene is usually, at this stage of technological
development, put inside of a virus that will insert itself into a cell, and integrate the new
gene with the cell DNA. This works because there are viruses which actually break into
genes as part of their lifestyle. Most animals and plants, including humans, have
endogenous viral DNA. This viral DNA actually is part of our genome, and can be
transmitted to our offspring. Sometimes, the endogenous DNA is activated and released
from the genome during cell division and growth. This can lead to cancers or other
problems.

These techniques are a long way from working with the whole chromosome full of genes,
but techniques have been developed to insert working genes into an adult organism to
cure the faulty gene, especially using stem cells. It is reasonable to expect that further
development and scale-up work will make whole chromosome replacement possible, at
least in embryos. Then it is just another developmental step to replace multiple
chromosomes, until the complete genome is replaced stepwise. Remember that single
chromosome replacement is just a further modification of what is done now using what we
call standard techniques for assisted reproduction, where the whole set of chromosomes
(male sperm or female egg) are replaced at one time. Doing it one chromosome at a time
is actually harder to accomplish.

This type of parentage is one of the easiest for people to understand, since we are just
using a chromosome replacement from up to 46 people. Would people pull out photos to
show off their offspring, bragging that their 11th female chromosome child is a genius?
Christmas and birthday parties could be fun, at least for the child, with up to 46 sets of
presents.



  OB2 ThreeA: The One parent child

  As a further LEPR complication, you do not necessarily have to start with chromosomes
from a male or a female. All you need is two separate X sex chromosomes to give a female
child, and one X and one Y sex chromosome to give a male child. ALL  OF THE
CHROMOSOMES EXCEPT THE SINGLE Y CAN COME FROM EITHER ORIGINAL SEX.
Thus you can imagine a female child having only female or only male chromosomes. Her
sex chromosomes can come from either female or from male ancestors. A male child does
need (at present) one male ancestor, for the Y chromosome. Otherwise, all her/his/thems
(?) chromosomes can come from either male or female ancestors, or any combination of
ancestors desired. So it should be easy to make a female child using only one set of
genes, duplicated, from a female.

The easiest way may be to just take the egg DNA and replicate it, then combine it. The
harder way would be to separate the chromosomal strands from a mitotic diving cell, and
add them to the same woman’s DNA. DNA silencing using selective methylation is now
known as the reason why only half of any set of genes work, and why even identical twins,
which are natural clones, are not truly identical in all aspects. This would mean that the
woman child is, and is not, an identical twin of the mother. Or you could take separate
chromosomes, at random, from each of the two chromosomes in the mother, randomly
methlyate the genes, and have a child with the same total ancestry, but who looks very
different due to the difference in gene activation. A woman can have a male child using
only her genes, if a small male Y gene is substituted for one of the X genes. Of course, the
Y gene is the smallest in the body outside of mitochondrial genes, so would be easiest to
make synthetically. The mother could easily have a son whose father is a laboratory. (Is
this the Rocky Horror or the Frankenstein version?)

What is the difference between a One Parent Child, and parthenogenesis?
Parthenogenesis  involves inducing an egg to duplicate its single set of chromosomes, or
to form a developable egg directly with a double set of chromosomes. This seems to be a
prohibited lifestyle in mammals, though not in lower vertebrates. Scientists have produced
rabbits, mice, monkeys, and other mammals using induced parthenogenesis but the
offspring are often abnormal. It appears that mammals have a form of development where
certain regions of a paternal or maternal chromosome are inactivated, with the
corresponding region in the opposite chromosome activated. A mammal created by
parthenogenesis has double doses of maternally imprinted genes and lacks paternally
imprinted genes. Thus natural parthenogenesis is not known to occur in any mammal.

Like many ideas discussed here, the One Parent Child is not just a hypothetical possibility.
Many mammals including our favorite test animal, mice, have been induced to form one
parent offspring by a variety of tricky techniques. These are females only, thus far. The
male mice produced by fusion of two sperm, are not from identical DNA but from 2 different
DNAs, so they are two-male-parent mice. Male mice have been made from female mice, by
activating a portion of the female genome to mimic male sex determining activity. These
again have two parents, but it is only a matter of time before one parent male mice are
formed.

You say mice are not humans? You have a point, but nowadays not much of one. A
Korean research team led by Hwang Woo-Suk made the first parthenogenetic human
embryos in 2004. Other investigators have since duplicated his success. These embryos
were used to generate embryonic stem cells, not offspring. To my knowledge, no one has
yet claimed to have implanted such a one parent embryo into a surrogate mother to
produce a child. But, the process has been proven, at least up to the stage of a few
HUMAN cell doublings of development. It remains to be seen, and it eventually will, whether
such single parent children are developmentally normal.

OB3 Four: The 546 parent child.

There are only 37 known genes in the mitochondrial genome. This means that we have
large multiples of possible genetically distinct mitochondria to choose from. We can have
mitochondria that are identical in 36 of the 37 genes, or have 2, 3, or more differences.
But, we still have only 500 parents since the number of mitochondria will be the same as
for the 500+ parent child. (For simplicity I am ignoring the fact that each mitochrondrion
contains more than one copy of its gene). Now we add the 46 different chromosomes taken
from 46 different people, to the enucleated egg cell containing 500 different mitochondria,
and get a child with truly complex parentage. To be trivial, think of the number of mother’s
and father’s day cards that the child would need. And every birthday party would need a
ballroom rental, with rented trucks to take home all of the presents. Possibly the child will
also need her/his/shims/??? bookkeeper to keep track of presents and thank you cards,
monetary contributions and lists of living and dead parents with condolences, addresses
and email addresses, social life accounts on the web, lists of parents versus friends on
social networking sites, etc.

Do we need new names for partial parents, such as chromosome-17 father (or mother), or
mitochondrial momma-137? How does one define visitation, support, and inheritance
rights, if any? These questions are not at all trivial. The adult child will surely want to know
its immediate ancestry, and will apply to the courts to remove any secrecy shield, leading
to additional complications. It is up to the philosophers and ethicists to help guide us
through such a social, legal, and religious maze. Imagine trying to decide how much of a
person’s genes are relevant to these questions of parentage. Does contributing even
0.05% of a child’s genes count as parentage? If not, why not? If an X sex chromosome
from a Jewish woman is used, will the child automatically be of the Jewish religion? The
child must have parents to be born (so far). Why should a chromosome parent be superior
to a mitochondrial parent? Adopted parents assume most or all of the rights of the original
parents, so perhaps the various laws relating to adoption could be expanded to
accommodate the 546 possible parents of a genetic mosaic child.

Note that in all of these scenarios I have not treated the donor of the egg cell or the donors
of the cytoplasm that will accompany any mitochondrial injections as any type of parent.
The reason is that the egg cell contains many different types of subcellular components.
Even though the original haploid DNA is removed from the donor egg cell, all of these
structures remain. But, they will not persist. Once the new nuclear DNA is implanted into
the egg cell, it will now control the parentage and manufacture of all these subcellular
components in the cytoplasm of the egg. For a time, there will be a complex mixture of
original and new structures, with different parentages. However, all the structures from the
original parentage will age and be destroyed, as the egg cell divides and grows and ages.
After a certain number of divisions, none of the original subcellular components will persist.
The same holds true for any subcellular structures encoded by the mitochondrial DNA.
This is why we do not have to take the original parentage of the egg cytoplasm and
substructures into account in our bookkeeping, as it zeroes out of the equation.


Step Five: The 46500+ parent child

There are somewhere in the vicinity of 23,000 working genes in the human genome, and
another 23,000 that are inactive. Inactivation seems to be largely random between the
male and female genetic contribution. Large scale screening experiments could determine
which versions of each gene are optimum. Then one optimum gene would be taken from
each of 46000 parents, and assembled into the DNA scaffolding. We would also
incorporate the by now routine use of 500 different mitochondrial donors.

Just how do you determine which gene is optimum? We cannot and hopefully will not do to
humans, what is being done now with mice! There is an international project to determine
the function, in the living animal, of each and every single gene in the laboratory mouse.
Technology now exists to target every single gene in a living animal. The targeted gene
can be removed, inactivated, or chemically modified for later inactivation. These tags are
passed on to their offspring. At any point in the life of the mice offspring, the specific gene
can be turned off, or inactivated. This allows researchers to see which genes are strictly
necessary for life, and what effect each gene has. Earlier technology only inactivated the
gene on the chromosome immediately, so many embryos died immediately. Furthermore,
each and every modified mouse, approximately 30,000 different mouse genomes, is being
stored in liquid nitrogen and made available for propagation for distribution and testing.

Many genes are very similar between mice and humans. This experimental data will help
determine the function, the expression, and the absolute or relative necessity, of the
majority of human genes. No humans need be sacrificed for this work. Yet it should take
only a short time to assemble all of the human genes separately, once the mouse
technology is perfected further.

Once each separate gene is identified, technology now exists to duplicate it from the
existing gene, or even to make the gene from scratch. I am not very sure if there is any
meaningful distinction anymore, between assembling a gene DNA base by DNA base using
only synthetic chemicals; or copying a gene inside of a living yeast cell; or in a test tube
using enzymes and DNA bases. And once the gene is made or isolated, it can be stored,
frozen, and used at any future time. Or just kept in a database and made as needed. The
technology today is hundreds of times faster than that of only ten years ago. Biochemical
techniques will continue to improve quickly, just as computers have.  

Perhaps some of the commercial gene sequencing labs today will evolve into the
equivalent of a lending library, or better, a copy on demand purchase library. They will hold
reference copies of one or more ‘standard’ sequences of all human genes. Plus they will
accumulate copies of supposedly more optimum genes, perhaps often optimized for
different purposes. I can just envision the commercial competitive advertising! And why not
add a few extra genes? Just by adding the Vitamin C synthesis sequence, found in almost
all animals except great apes and humans, bats, guinea pigs, Dalmatian dogs, and a few
other animals, would benefit their health and make them immune to scurvy. I would love the
ability to re-grow lost digits and to be able to regenerate limbs and skin perfectly without
scar tissue, like salamanders. There is plenty of room on the human genome, so possibly
thousands of desirable extra genes could be added.

Now the birthday child—I am going to assume that by this time, artificial wombs have not
been perfected so shim (?) will not be decanted—will need a big place for the party. A
soccer stadium sounds about right, with the playing field heaped high with presents. I
would hope that the child would be sufficiently altruistic, given the shared circumstances of
its eventual birth, to donate the presents or money to those less fortunate children. For
example, I would recommend that they donate the presents to those poor children of only
two parents, who suffer from acne, poor eyesight, memory deficiency, metabolic diseases,
overweight, hair loss, lack of absolute pitch discrimination, skin cancer and other cancer
susceptibilities, inability to run a 3 minute mile or hold their breath for 10 minutes, diabetes
susceptibility, potential lifespan of less than 120 years, only 2 sets of teeth in their lifetime,
cavity prone teeth, non-self cleaning arteries, an appendix, lack of a perfect six pack of
muscles or an optimal breast to waist to hips ratio, non-immunity to Alzheimer’s disease
and AIDS, a generally substandard immune system, etc.

There will be many children whose parents were too poor, or hindered by religious,
intellectual, or societal beliefs and barriers, to afford to give ‘birth’ to a prime child. After all,
you don’t have to replace every gene. Natural parents could start with their own genes,
and just have them selectively modified. This aspect has been extensively discussed in
science fiction stories and mainstream ethics discussions. I have seen nothing on the total
optimization and multiple parent replacement of all genes in the human chromosome.
Probably whole legal firms will grow to handle pro and con lawsuits on natural versus
artificial parentage, with children on both sides of the technology joining in lawsuits.  

This is pretty severe parental fragmentation though. I don’t know if people will take great
pride in their contribution to such children, unless their contribution is a gene conferring,
for example, super strength or ultra fast reflexes or eidetic memory. After all, a parental
contribution of 1/(46,500) or so is only 0.00215% parentage more or less, depending on
whether you are counting only the number of genes, or the size of each gene, in the child.
And it might be hard to be really proud of contributing only, say, a muscle mass gene or
one of twenty genes to determine eye or skin color.

I am pretty sure that if parents are recognized on the basis of such tiny contributions
(though each and every one is needed to give a child!), then the laws and social customs
on incest and inbreeding will need to be overhauled. If you and the child share only one
gene, could that be the basis of  parent-child incest? Or, how many genes in common,
does it take before two children are too closely related to marry? Is it half the genes, as in
prohibited brother-sister marriage, or is it ten, 100, 1000, or 10,000 common genes when
two children of the same laboratory purchased genes want to marry? Maybe common
sense will prevail (It could happen!) and the new laws will parallel the actual genetic
contribution of existing laws, for first and second cousin marriages, for example. Although
the subject of prohibited relatedness, when we are considering taboo relationships based
on village or clan membership, may go in entirely different directions based on the desires
of the local peoples.

OB3 FiveA: Whose lab-created genes do you use?

SO what happens if each gene including the mitochondrial genes, are made synthetically,
like Venter and co-workers have done with their novel bacterium Mycoplasma mycoides
JCVI-syn1.0 ? Does the child have NO legal parents? Does each gene laboratory
supplying genes, or on-line database of the original genetic code, share in the
ownership/parentage? Or does the synthesis team become its parents by default of actual
manufacture? Or will this be considered an emancipated, or better, an orphan parentless
child in the truest sense of the word? Will the state take ownership of parentless children?
Or does each gene parent have a trademark or engineering design claim on their separate
genes, thus giving partial ownership in the child instead of parentage rights? Perhaps
existing laws against slavery and human ownership would be used as starting points for
discussion.

Does each and every parent of the original gene/gene sequence have to sign an informed
consent form? And sign another form if their gene is actually used to create a child? How
does informed consent work, with an unborn child without actual parents? Are these
children bound by such agreements, including any limiting their right to sue or get
compensation?

If natural genes are used to produce a child and the child is given inheritance rights, does
a child of the synthetic version of the same genes have any inheritance rights? I would at
the very least consider purchasing a very good blanket coverage insurance policy, if I was
involved in such genetic distribution labs. I am not sure how the insurance company
actually would go about setting the premiums. Could a totally synthetic gene child sue the
lab for loss of parental care and affection, or loss of other as undefined biological and
societal rights? What if the synthetic version of the gene, as may be very likely, have
millions of exact copies walking around in totally natural genomes? Does where the gene
come from, such as a given lab, count differently than it just being a common natural
gene? Do we regard all these millions of natural people as, say, cousins, because their
gene is the same as the synthetic one?

Maybe each synthetic gene will need a watermark, like Venter’s lab put into the
Mycoplasma mycoides JCVI-syn1.0 bacterium gene. This could be used to establish
parentage, lab parentage, gene parentage, copyright ownership, citizenship, inheritance,
legal liabilities. Thinking farther out, what happens to these watermarks when the children
have children, multiple generations, with each other or with natural children and the
watermarks combine and segregate in the new children?



Step Six: The Million Parent Child

We are still just at the beginning stages of understanding the structure and rules
governing the actual use of genetic DNA. This statement is made because over 99% of the
human genome does not appear to code for traditional proteins, the structural and
regulatory units of the human body. This extra DNA has been called ‘junk’ DNA. The
implied implication would be that this excess DNA could be removed from the genome,
leaving a much slimmed-down and perhaps more efficient and effective genetic legacy. As
more data accumulates, it seems that this so-called ‘junk’ DNA actually serves important
functions. Many of these functions are related to how proteins interact with the whole
genomic expression, during development of structures. If this junk DNA actually was junk, it
would decay and change and eventually disappear. This is what happens during those
rare events, when the whole genome duplicates and remains intact in a cell. This is called
polyploidy, and is found in both animals and plants, though much more commonly in plants.

The polyploidy cell thus contains two identical copies of each gene from each original
parent, so has two sets of two copies of each gene. If a human were identified as polyploid,
he or she would have (46+46=92) chromosomes, with twice the normal number of genes,
or about 52,000. Human polyploids (1.5 copies are called triploidy and 2 total copies of the
genome are called tetraploidy) have been identified, but they are extremely rare and most
such children die before or soon after birth.

These extra genes are fertile grounds for evolution, since the extra genes are now
available for modification and use for other purposes and structures. At the same time,
genes that are actually unused rapidly decay (we are talking a time scale of millions of
years), accumulating changes affecting coding, size, and assembly, until unused
duplicated genes disappear or remain as genetic ghosts of functions past. This is shown in
the genes of the first plant sequenced, Arabidopsis thaliana. About ten to twenty million
years ago it went through a whole genome duplication event. Many of the extra genes are
decaying or have totally disappeared. Ancient duplicated genes can show up as so called
‘junk DNA’, when the genes lose starting and ending regions, cannot be expressed, or
even recognized in comparison to any working genes. But junk DNA cannot be arbitrarily
ignored. Some ‘junk’ DNA has been shown to be stable to changes in coding over periods
of hundreds of millions of years, showing that it is extremely important to the organism. A
primary goal right now is trying to find rules and explanations for the differences in
behavior between standard genes (protein coding genes) and parts of the ‘junk’ genome
that may have regulatory or developmental functions quite apart from our standard
theories that genes must code for proteins.

All of this material is subject to future analysis and optimizations. And then there are the
SNPs. SNPs are Single Nucleotide Polymorphisms. No two people have exactly the same
DNA sequence. There are insertions, deletions, inversions, duplications, in part or in
whole, for all protein coding sequences. For the main protein-coding DNA, they are almost
a non-issue for the million parent child. After all, we are going to select one person to be
the donor for each of the approximately 23,000 genes on each of the two chromosomes.
The best, most functional SNPs will be selected already on these genes. The Million Parent
Child may actually have more genes than 30,000. Some genes may be found to give 2 or
more types of favorably acting proteins, or some proteins may be under-expressed unless
extra copies of the genes are present. Other genes may be added in order to get more
activity, such as for improved immune function. However, we are still a long way from the
Million Parent Child.

More than 10 million SNPs have already been identified from human subjects~! This is a lot
of variation, for only 46,000 genes. Most gene-based SNPs seem to only come in two
variations, though as research continues many more SNPs will be found at lower and lower
frequencies. If most genes only have 2 variations, why are there so many? Part of the
answer is that there are usually many more than one SNPs for each protein coding gene.
SNPs are also found in the over 98% of the human genome, that does not code for
proteins. This originally was classed as ‘junk’ DNA, since it was thought to be useless.
Further work has now shown that some stretches of this ‘junk’ or better, non-protein coding
DNA, have been conserved over many tens of millions of years of evolution. This alone
shows that it must have very important functions.  SNPs are so common that they appear
to occur every 100 to 300 bases along the 3 billion base human genome. Only about 1.5%
of the genome actually codes for proteins. Therefore most SNPs are actually found in the
non-protein coding sections of the DNA. Many of these regions are now known to code for
short stretches of RNA. These RNA segments have been shown to be important in
development and regulation of development, feedback loops for expression of proteins
from genes, gene splicing, transcription factor binding, and other functions.

It appears that it will be simple to identify 1,000,000 unique genomic genes, mitochondrial
variant genes, and SNP delimited segments of the non-coding DNA regions. The hard part
will be to determine which ones to select, from which individuals, to assemble into the
million parent-child fertilized egg. This would be only an assembly program, using perhaps
randomly selected genetic segments from different people, with checks to keep out know
variations leading to genetic diseases. Much farther into the future would be an
optimization program, to determine which of the many variants would give the best range of
possible non-protein coding genomes. This would be a much more demanding type of
work, with first-order, second-order, and further effects and interferences needing to be
identified. SNP-based diseases will undoubtedly be described, along optimal and sub-
optimal SNP sequences.

Some will object that this is too much technological work to duplicate all of these genes, to
isolate them from natural humans, or to make them synthetically. Progress in this field is so
rapid that it has left such skeptics behind. An international project to make a complete set
of knock-out gene mice is nearing completion in the next year or so. Mice have about the
same number of genes as humans. Special strands of DNA are used to bind to only one
gene at a time, with a different strand for each of the thousands of genes. Thus each gene
can be chemically identified, tagged and marked, and ultimately removed and manipulated.
And the duplication of such individual genes gets easier every year. Current technology
has moved beyond the TAQ polymerase techniques, to using bacterial plasmid duplication,
bacterial chromosome duplication, and yeast chromosome synthesis and assembly
techniques.

One advantage to working with genes, rather than complete organisms, is that they are
NOT alive. Genes are almost the same as viruses, which is why viruses can insert into
chromosomes and become part of the target’s DNA. Viruses are genes enclosed in a shell
with usually some way to promote entrance into a living cell. Viruses do not live—
metabolize, grow, reproduce—on their own, but only by conscripting the existing living cell
network by changing the instruction codes. Bacterial cultures for example, keep changing
randomly due to genetic drift and to adaptation to the exact culture conditions used in
captivity. That is why an original culture is frozen for storage. A very small subset can then
be thawed to give the original, unmodified organism. Living things constantly change,
whether we want them to or not. Viruses have been shown to be more similar to crystals,
since the work on tobacco mosaic virus (TMV) many decades ago. The TMV consists of a
coat, to protect the genetic material and to help infect tobacco cells, and the interior, which
contains the genes that take over the cell’s protein synthesis mechanisms. The TMV was
chemically separated in the shell, and the interior. Each was shown to be non-infective.
Each was stored separately in a dry state. Eventually they were mixed together, the shell
and interior re-assembled, and the dead chemicals became infectious again.

Once any gene is sequenced, it can be isolated, duplicated, and saved indefinitely for
future assembly or modification. Genes can even just be kept as information in a data
bank, to be made as needed. Taxonomic work, the study of genetic relationships of living
animals and plants, used to be done by dissection, microscopic studies, and detailed
physical, physiological, and even hybridization tests. Taxonomic work now is quickly
migrating to the gene sequencing lab, the storage and comparison of the different genetic
codes via mathematical techniques, with little apparent concern for the actual living
organism. The smallpox virus now exists only in silicon memory, except for two high security
labs which still have some of the actual virus. Rinderpest has now been exterminated from
the wild, and polio may soon follow. But the sequences will be with us forever; these
species, if non-living viruses can really be considered species, can be resurrected from the
dead at any future time.

Here is where it again gets complicated. Chemically and biologically, there is no difference
between an isolated natural gene and the same gene that is chemically synthesized.
Legally, ethically, and philosophically, there may be a great difference. Back to the
question of inheritance: if a gene is isolated from a person and used to help make a child,
even if that gene is chemically and sequentially identical to millions of other people, only
that one person is the parent for that gene. This is standard law; think of brown eye color,
where most of the people in the world have brown eyes but different parents. If the same
gene sequence is chemically synthesized from scratch, there is NO legal parent for that
gene, even though millions of people have that gene. Can the original donor of the tissue
which is subsequently sequenced, be liable for the use of that gene in producing a child?

Now consider the hybrid consequence. A gene is isolated from a person and sequenced.
The same gene is isolated again, and used as a template to chemically produce multiple
copies of the gene by any given technology. Or we make the gene de novo, from the
sequence data. We then use this chemically produced gene to produce multiple copies for
further use. What is the LEPR (=Legal Ethical Philosophical Religious) status of each of
the THREE children: made from isolated genes from actual humans; made from synthetic
chemical templates of the isolated gene; or made totally synthetically, using only the
information content of the original gene?

Regardless of the method, once each of the approximately 23000 genes is synthesized, it
can be duplicated, stored, modified, and used. The work needs to be done only once, so
what looks like an impossible task can now be broken down into tiny segments, to be
utilized at any future time.

Here is how a million-parent child could be produced:

46,000 different genes, in two sets of 23,000 genes, each from a different parent
500 or more mitochondrial genome parents
950,000+ different SNPs, selected from the best of the ‘junk’ DNA sections.

Of course, there is an enormous amount of work still to be done before any such children
can be born. And very possibly they will never be born—LEPR reasoning may prohibit any
such attempt world-wide. But we have seen that technology now exists to make, either in
animals or in children or both,

EXISTING TECHNOLOGY
One parent children from a female
Two parent children from two males (plus the mitochondrial parent)
Male children from a female
Children with multiple, or with only one, sex chromosome
Children with four parents, from mitochondrial transfer
Replacing single genes from a different parent
Cloning of single genes
Chemical synthesis of single genes
Cloning of whole chromosomes
Chemical synthesis of whole chromosomes
Replacement of existing natural chromosomes by synthetic chromosomes in bacteria

ON THE HORIZON
Replacing multiple genes from different parents
Multiple, up to 500, parent children from mitochondrial transfer
Replacing single chromosomes in multiple chromosome organisms
Replacing multiple chromosomes using different parents
Replacing SNP sequences
Synthesis of whole chromosomes
Synthesis of whole chromosomes with improved SNPs
Combining natural and synthesized genes into living childreN



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