Author Topic: Genetic Modifications  (Read 470 times)

netfreak

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Genetic Modifications
« on: February 11, 2017, 04:35:29 pm »
                            Genetic Modifications

by Anders Sandberg

It is an interesting fact that most proposals of improving the human body in
transhumanistic discussions are mainly based upon bionic and chemical
enhancements, while overlooking the potential of genetic engineering. In
part this may be due to the fact that most methods of changing the genome is
most efficient only on very small groups of cells or in the embryo. This
means that these methods will mainly work on our children, not on ourselves,
something which has made many transhumanists turn to other methods. However,
genetic engineering has obviously great potential to transform living
beings, it is already an viable technology (unlike bionics) and gene therapy
is advancing fast. Perhaps most important, and controversial, is the fact
that this method will not only change a single individual, but also affect
all of his/her/its offspring. This will give us the ability to once for all
eliminate certain genes or add new ones.

In the following I will mainly deal with modifications which are possible
according to what we know, and reasonable extrapolations of current
technology. This means that most of these enhancements will work only on the
molecular level and not in the lesser understood areas of morphogenesis or
other high-level functions.
------------------------------------------------------------------------

Simple Modifications

These modifications are mainly concerned with removing undesirable parts of
the genome and changes between different naturally occurring alleles.

Removal of genetic defects

Removal of genetic diseases

These two categories overlap to a great extent. They include mutations of
important genes, omissions or accidental overlaps in the genome. Many
diseases seem to have an genetic factor, for example Alzenheimer's disease,
glaucoma, certain forms of obesity, retinal detachment, diabetes II and
cancer, and there are many more geners that weaken the body or make some
diseases likelier.

Removal of undesirable traits

Of course, what is undesirable is often a highly individual matter, and many
negative traits are linked to positive traits in a complex manner. For
example, the "novelty gene", which induces "novelty-seeking behavior" (i.e.
adventureness) will under the right circumstances make a person a dynamic
neophile, but could also increase the risk for to drug addiction (Reward
Deficiency Syndrom); Dyslexia might be linked with visual thinking.

One solution to this is perhaps to inhibit the expression of the undesired
genes, but provide a mechanism to remove inhibition if the owner of the gene
so desires (this could possibly be accomplished through the creation of
artificial genetic switches, which could be controlled using artificial
hormones, although it is much more complex than simply removing the gene).
Unfortunately this will not have any effect on genes responsible for the
formation of organs or the body, since they are used only during development
and then lie dormant.

Also note that removal of a gene linked to an undesirable trait may not
completely prevent its expression, since many of these traits are linked
both to several genes and environmental factors. Some possible genetic
traits which could be removed (or added for some reason) are:

   * Alcoholism
   * Drug Abuse
   * Schizophrenia
   * Cancer
   * Diabetes
   * Mano-Depressivity
   * Extreme Aggression
   * Wisdom Teeth

Cosmetic Modifications

These include, but are certainly not limited to:

   * Hair colour, style and growth
   * Eye colour
   * Skin colour
   * Build

Other changes

There is no doubt that there are many other possible alterations in
appearance which could be developed. This is mainly dependent on culture and
social acceptance rather than technical details. The ideals of beauty are
very variable.
------------------------------------------------------------------------

More Complex Modifications

Removal of Unused or Undesirable Genome

This is partially speculative, because currently we have very little
understanding of the non-coding parts of the genome. Some parts (like
promoters and various markers) are important for the function of the cell,
while others are neutral or more or less destructive. Removed parts may need
to be replaced with random or specially developed "fill out" DNA.

Transposomes

Transposomes make up around 10% of the human genome. While most of them are
rather benign and have fulfilled an evolutionary function, they sometimes
cause cancer and damage to vital genes. Since they do not have any
biological function, the can probably be removed.

Oncogenes

There are several hereditary forms of cancer. One type is caused by
defective anti-oncogenes, which prevent oncogenes from causing cancer. These
can of course be corrected. Another type seems to be caused by already
highly promoted oncogenes, which only require a slight push top become
dangerous. These could perhaps be "tuned" to a more acceptable level.

Increase of Anti-Oxidant Enzyme Production

This could for example be done through promotion of superoxide-dismutase.
This might help slow down ageing and make the body more resistant to
environmental dangers and free radicals. However, increasing the amount too
much will probably interfere with normal biochemistry; further research is
needed. One possible solution would be to add some ways of controlling the
amounts, for example by linking them to the sleep cycle.

Improvements in Telomerase Activity

One of the more interesting theories about cell ageing is that the telomeres
are gradually broken at each cell-division, until coding genome is destroyed
after a certain number of divisions and the cell dies. If the activity of
telomerase, which protects the telomeres, could be increased this would
perhaps slow down cell-ageing.

One problem with this is however that it would increase the risk of cancer
(many varieties of cancer have greatly heightened telomerase activity and
are thus immortal). Improvements of telomerase activity must probably be
combined with improved error correction and other anti-cancer enhancements
to avoid increasing the risk of cancer too much.

Increase of DNA Error Correction

Some bacteria can survive very hard radiation, mainly through over-active
error correcting enzymes. By increasing the amount and activity of similar
enzymes (like DNA repair nucleases, AP endonuclease, DNA glyckosylases) in
our genome, we would become much more safe from mutagens and radiation. In
bacteria there are known enzyme complexes, known as the SOS response, which
activate when the genome has been damaged. Unfortunately they increase the
mutation rate, which is beneficial for bacterial survival but probably
undesirable for multicellular animals, since they would increase the risk
for cancer. Note that although evolution apparently can develop rather
efficient protections against radiation and other mutagenic factors, it is
normally not used more than at a rudimentary level in most living beings.
There is no evolutionary advantage in being resistant against radiation in
the low- energy environment on Earth, and the extra energy demands lower the
fitness of most living beings. However, we humans have no problem increasing
our energy intake as needed, and may have great use for better protection
from radiation in space. Of course, no amount of error correction will
remove mutations altogether, and it is probable that errors can be made in
replication which are transmitted to the daughter cells.

Other Anti-ageing Modifications

Beside the above mentioned possibilities (increased production of superoxide
dismutase, error correction and telomerase), there are doubtless many other
genes which could be optimised to improve the life span of the body. For
example, certain forms of the APO-E protein seems to be linked with
arteriosclerosis and Alzheimer's disease. If these are replaced with more
efficient forms, this risk will be greatly reduced. It is probably hard to
distinguish between removing damaged or disease-linked genes and prolonging
the life span.

Production of New Substances

Genes can be added for production of different substances (like vitamins,
antibiotics or drugs), which could be activated by artificial hormones,
special signals or chemical changes. In this case it might not even be
necessary to modify the genome of all cells, just some suitable (like a
patch of skin or the intestine) by a retroviral vector.

Resistance Against Poisons

It is also possible to add genes coding for enzymes breaking down or
protecting against various poisons or irritants. Whether this is useful or
not depends a bit on how paranoid one is about the chances of being
poisoned. One application could be the production of chemicals binding
enviromental hazards such as heavy metals or cancerogenic substances. It
might also decrease the risks of alcohol or drug abuse.
------------------------------------------------------------------------

Complex Modifications

These modifications require quite extensive additions to the genome, deal
with high level phenomena or require control systems.

Bacteriophage Genes

It might be desirable to attempt to add symbiotic bacteriophages to the
genome. When activated by an artificial hormone or a bacterial toxin, the
genes are expressed and the bacteriopages are produced. They will be used to
seek out certain types of bacteria within the body or its cavities, and then
attack them. This strategy might also include "tags" which makes the
bacteriophages or the waste products of their attacks on intruders attract
the attention of the immune system (the immune system will most probably
limit the usability of phages to systems outside its reach, since it will
regard the bacteriophages as an intruder). Care has to be taken to make sure
the page genes do not turn "rouge" within the genome or attack the cells
unnecessary.

Genome Commenting and Marking

In order to improve the "legibility" of the genome, tags or markings could
be placed in regular intervals or near important genes, so that they can be
easily identified or changed. This will also reduce the risk for erroneous
inserts.

Introduction of a Techno-Chromosome

Instead of placing new genes on the old chromosomes, it might be a good idea
to introduce a new chromosome for this purpose only. This would decrease the
risk that modifications cause undesirable changes to the rest of the system.
The Human Genome Project already uses similar techniques to keep human
genome libraries in yeast cells (so called YACs). The new chromosome would
initially be filled with a noncoding pattern, with regular markers to
simplify access or modification. One problem/possibility with adding another
chromosome is procreation; unless the partner also has an extra chromosome
fertilisation will not work correctly. This will literally make the bearers
of the chromosome a different species than Homo Sapiens. This could either
be overcome by somehow designing the system so that the extra chromosome is
not added to germ-line cells, or by using in vitro fertilisation (which
would probably be much more common at this time, since the parents will most
certainly want to determine what new genes to add and what to change). Some
current research seems to imply that extra chromosomes can be turned on and
off.

Additions to the senses

Several of our senses use chemical receptors to detect stimuli. These could
probably be changed or expanded.

Sight

Currently the human eye uses three slightly different types of rhodopsin for
colour vision. Other varieties are known among other animals, and could
perhaps conceivably be added to expand the human perceptive range (in order
to do this, the synthesis pathways must be added and placed near the other
genes coding for rhodopsin synthesis and somehow linked to the cone-cell
differentiation signals. Not exactly easy, but hardly impossible). This
could expand the range of colours from the near ultraviolet (based on insect
rhodopsin) to the near infrared. This would unfortunately work best on the
embryonic level, since then the brain will naturally integrate the new type
of cone to the visual system. Changes in adults would be much more
unpredictable.

Smell

It is know that there are many chemical receptors used by the olfactory
system, able to distinguish between several thousands types of compounds. It
is probably rather easy to add new receptors, to recognise certain chemicals
(like heavy metals) or perhaps other stimuli (long, unstable molecules could
react to ionising radiation, which would be felt as a certain smell).
However, it is probably harder to train the human brain to handle smell than
improving the sense organ itself, since we do not use our olfactory cortex
to its full capacity, being very much visually and auditory oriented.

Taste

There are four known groups of taste receptors with several subgroups (It is
interesting to notice their evolutionary value: salt signifies changes to
the osmotic balance, sour the acidity balance, sweet is usually linked to
high carbohydrate/energy content and bitter reacts to alkaloids/possible
poison). Adding another group might present some differentiation problems
like in the case of sight, and would probably be easier to do with additions
to olfaction instead.

Artificial Symptoms

As Alexander Chislenko has pointed out in his essay about Enchanced Reality,
many potentially life-threatening diseases lack easily noticed symptoms.
These could perhaps be added, so that the patient will notice something is
wrong on an early stage before it is too late.

A simple solution might be to add genes coding for enzymes producing a
strongly coloured compound, which colours the urine. These genes are
normally repressed by a repressor which is inactivated by the presence of
certain disease-indicative chemicals (several repressors could be linked, so
that only certain highly selective combinations would cause the colour-
shift). It would not be that hard to add a quite large number of such
indicators to the genome, especially by using the techno-gene. Each could
even code for a slightly dissimilar pigment, making diagnosis easier.

The most important use is of course in detecting cancer, which of course is
a quite complex problem. One method would be to let the colour-gene activate
each time the cell divides; cancer cells would thus tend to have a different
colour (very useful for applying treatment) and tend to colour the urine.
The problem is of course designing the system so that normal cell division
does not cause a false alarm. Another method would be to react to expression
of known oncogenes, or perhaps known combinations of them (like loss of the
expression of the epithelial cell-binding molecule E-cadherin and heightened
expression of proteases, which signifies risk for metastasis).

Molecular Support for Cryonic Suspension

One of the main problems with current methods of cryonic suspension is the
fact that ice crystals tend to disrupt the cells. However, certain animals
contain anti-freeze proteins or fill the cytoplasm with carbohydrates which
prevent the growth of large crystals. The genes for these systems could
presumably be added to the human genome, decreasing the damage due to
suspension.

Artificial Hormones

Many genes remain dormant until they are activated by the removal of a
repressor protein or the binding of a promoter protein close to them. These
genetic switches are sometimes controlled using signal substances or
chemicals (such as lactose and glucose in the case of the lac gene),
sometimes by more complex cascades of messenger proteins. It would not
appear inconceivable that we could add similar systems to our own genes,
giving us the ability to control which genes to express and which to
inhibit.
------------------------------------------------------------------------

Very Advanced and Speculative Procedures

These may or may not be possibly, and are mainly intended as inspiration for
further speculation. They will probably require a very detailed
understanding of the genome and chemistry, and in some cases advanced
nanotechnology.

Metabolism Optimisation

Evolution has created a complex web of chemical reactions which form our
metabolism, but it has not been particularly targeted at any goal except
continued survival. It might be possible to design enzymes which speed up
certain reactions much more, or allow alternative reaction-paths. This would
open up the possibility of using special high-energy foods in demanding
situations.

Gene Therapy Hooks

The main problem with today's genetic engineering is that it works best on
individual cells (by direct physical insertion) or on cell populations (by
retroviral infection or drastic mechanical methods), which makes it hard to
apply to adult organisms. One solution might be to add "hooks" for gene
therapy, where additional genome could be inserted. For example, one could
imagine injecting a gene protected by a viral protein coat, with linked
proteins which seek out the hooks and cause the insertion of the gene.
However, this would only change a few cells. A much more complex solution
would be to design "messenger viruses", essentially viral chain letters
carrying a desired gene around the body. Each cell would absorb one or more
messenger viruses, insert the message gene into the genome, create a certain
number of copies and release them and then become immune against the virus.
In this way, the virus would infect almost every cell in the body and change
the genome. The big problem is of course designing it and making it safe
(one solution to the risk of mutation would be to try to design it to be as
evolutionary brittle as possible; any change in any part would destroy it).

Genome Encryption

Using advanced technologies (like nanotechnology), it might be possible to
change which codon codes which amino acid. If this can be done, the genetic
material would be unusable to other lifeforms (like viruses), and vice
versa. If all retroviral material and other latent viruses were removed from
a person's DNA which was then "encrypted", that person would now be immune
to all viruses; an attacking virus would insert genetic material that would
not produce any usable proteins. People with identical encryption would be
able to have children unaided, but incompatible codes would require
translation before they could be combined.

To achieve this, we need to learn how different kinds of transfer RNA bind
different amino acids, and how to change it (beside being able to re-code
the entire genome).
------------------------------------------------------------------------

Footnotes and Explanations

Transposable Elements

Genomes usually contains many varieties of transposable elements, which are
able to move around or replicate themselves within the genome. Some move by
encoding the enzyme transponase, which moves the transposomes from site to
site. Others move through RNA intermediaries. This is a prime example of a
selfish replicator. The movements often modify surrounding DNA or move
entire genes around the genome. This movements is a major factor in causing
spontaneous mutations, and under environmental stress the organism can
undergo transposition bursts, where many transposomes shift their positions.
This has an evolutionary advantage, as new varieties of organisms can
quickly develop under stress, but also destabilizes the genome of the
individual. Transposome movements are able to create oncogenes by
accidentally moving close to a proto-oncogene.

Telomeres and Telomerase

The telomeres form protective ends of the chromosomes, since normal
replication tends to cut of the outermost parts of the DNA strands. At each
cell division some more of the telomeres is lost, but the enzyme telomerase
rebuilds these sequences.

However, apparently the telomerases gradually loose their efficiency (or are
less promoted by the cell) as it ages, and the telomeres gradually shortens.
When they vanish, coding genome will begin to be lost and the cell dies.
This is assumed to be one major cause of cell senescence and death, the so
called Hayflick-limit on cell division.


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