The science of three-parent children

2015 has already been a significant year in the field of human medicine as February saw the UK become the first country in the world to legalise the generation of so-called 'three-parent' children. This marks a milestone for preventative genetics and embryology and offers hope to many people around the UK and beyond who would be unable to have healthy children otherwise. The votes to bring this into law were fairly comfortably won by those in favour - 382 vs 128 in the House of Commons (the lower house) and 280 vs 48 in the House of Lords (the upper house) - however there have been a number of vocal opponents to the measure. In this post I hope to explain just what the process involves, and why it is considered necessary by the majority of British MPs.

A cellular energy crisis

Mitochondria, as you may recall from a previous post, are the powerhouses of our cells. They metabolise a range of molecules derived from food at use them to generate energy in the form of another molecule, ATP. You would not last long without them - just try holding your breath for a few minutes, since anaerobic respiration is all a cell without mitochondria would be able to manage. It is not surprising, therefore, that problems with mitochondrial function can be fairly nasty. Mitochondrial diseases are a range of genetic disorders in which the proper role of the mitochondria is disrupted due to mutations in one of the genes responsible for making mitochondrial proteins. These diseases never completely knock out mitochondrial function (since an embryo with such a disease could never survive to full development) but still cause severe symptoms in sufferers. Depending on the exact mutation, these can include blindness, deafness, diabetes, muscle weakness, cardiac problems, and problems with the central nervous system. Prognoses vary from one disorder to the next, but they invariably shorten lifespan, often severely. Sufferers of Leigh's disease, for example, rarely live past 7 years of age, and spend their short lives experiencing muscle weakness, lack of control over movement (particularly of the eyes), vomiting, diarrhea, an inability to swallow, and heart problems, among others. 

The human machine: obsolete components

The previous post in this series can be found here.

In my last post in this series I described some of the ways in which gene therapy is beginning to help in the treatment of genetic disorders. A caveat of this (which was discussed further in the comments section of that post) is that currently available gene therapies do not remove the genetic disorder from the germline cells (i.e. sperm or eggs) of the patient and so do not protect that person's children against inheriting the disease. This could be a problem in the long run as it may allow genetic disorders to become more common within the population. The reason for this is that natural selection would normally remove these faulty genes from the gene pool as their carriers would be less likely to survive and reproduce. If we remove this selection pressure by treating carriers so that they no longer die young, then the faulty gene can spread more widely through the population. If something then happened to disrupt the supply to gene therapeutics - conflict, disaster, etc. - then a larger number of people would be adversely affected and could even die.

Although this is a significant problem to be considered, it is one that is fairly simply avoidable by screening or treating the germline cells of people undergoing gene therapy in order to remove the faulty genes from the gene pool. This is currently beyond our resources on a large scale, but will almost certainly become standard practice in the future.

All of this got me thinking: are there any other genes that might be becoming more or less prevalent in the population as a result of medical science and/or civilisation in general? If so, can we prevent/encourage/direct this process and at what point do we draw the line between this and full-blown genetic engineering of human populations? This is the subject of this post, but before we get into this, I want to first give a little extra detail about how evolution works on a genetic scale.

Imperfect copies

Evolution by natural selection, as I'm sure you're aware, is simply the selection of traits within organisms based on the way in which those traits affect that organism's fitness. An organism with an advantageous trait is more likely to survive and reproduce and so that trait becomes more and more common within the population. Conversely, traits that disadvantage the organism are quickly lost through negative selection as the organism is less likely to reproduce. The strength  of selection in each case is linked to how strongly positive or negative that trait is - i.e. a mutation that reduces an animal's strength by 5% might be lost only slowly from a population, whereas one that reduces it by 90% will probably not make it past one generation. In turn, the strength of that trait is determined by the precise genetic change that has occurred to generate it.

The human machine: replacing damaged components

The previous post in this series can be found here.

The major theme of my 'human machine' series of posts has been that we are, as the name suggests, machines; explicable in basic mechanical terms. Sure, we are incredibly sophisticated biological machines, but machines nonetheless. So, like any machine, there is theoretically nothing stopping us from being able to play about with our fundamental components to suit our own ends. This is the oft feared spectre of 'genetic modification' that has been trotted out in countless works of science fiction, inexorably linked to concepts of eugenics and Frankenstein-style abominations. Clearly genetic modification of both humans and other organisms is closely tied to issues of ethics, and biosafety, and must obviously continue to be thoroughly debated and assessed at all stages, but in principle there is no mechanistic difference between human-driven genetic modification and the mutations that arise spontaneously in nature. The benefit of human-driven modification, however, is that it has foresight and purpose, unlike the randomness of nature. As long as that purpose is for a common good and is morally defensible, then in my eyes such intervention is a good thing.

One fairly obvious beneficial outcome of genetic modification is in the curing of various genetic disorders. Many human diseases are the result of defective genes that can manifest symptoms at varying times of life. Some genetic disorders are the result of mutations that cause a defect in a product protein, others are the complete loss of a gene, and some are caused by abnormal levels of gene activity - either too much or too little.  A potential means to cure such disorders is to correct the problematic gene within all of the affected tissue. The most efficient means to do that would be to correct it very early in development, since if you corrected it in the initial embryo then it would be retained in all of the cells that subsequently develop from that embryo. This is currently way beyond our technical limitations for several reasons. Firstly, we don't routinely screen embryos for genetic abnormalities and so don't know which ones might need treatment. Secondly, the margin for error in this kind of gene therapy is incredibly narrow as you have to ensure that every single cell that the person has for the rest of their life will not be adversely affected by what you do to the embryonic cells in this early stage - we're not there yet. Thirdly, our genetic technology is not yet sophisticated enough to allow us to remove a damaged gene and replace it with a healthy one in an already growing embryo - the best we can do it stick in the healthy gene alongside the defective one and hope it does the job. There is certainly no fundamental reason why our technology could not one day reach the stage where this kind of procedure is feasible, but we are a long way off yet.

So, for the time being what can we do? Well instead of treating the body at the embryonic stage, the next best approach is to treat specifically the affected cells later on in life.  This involves identifying the problematic gene and then using a delivery method to insert the correct gene into whatever tissues manifest the disease, preferably permanently. This is broadly known as gene therapy, and is one of the most promising current fields of 'personalised' medicine.