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:

Cosmetic Modifications

These include, but are certainly not limited to:

Adding Desirable Traits

There are some alleles that appear to promote health or other useful traits. For example, the D allelle of the ACE gene increases endurance slightly and certain alleles of Apo-lipoprotein E protect against Alzheimer's disease.

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.

Further Links

References

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Anders Sandberg / asa@nada.kth.se