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.  

The human machine: non-standard components

The previous post in this series can be found here.

In a previous post I alluded to the origins of mitochondria, the tiny chemical power plants found within all our cells. These hard-working machines are responsible for aerobic respiration, which is the way in which the vast, vast majority of the energy you use is released from the chemical energy in the food you eat. The way in which they do this is very cool, involving currents of electrons and protons in a manner very similar to standard battery. If you're interested in this then I direct you to my earlier post on this topic here, but in this post I will be discussing a rather odd thing about mitochondria: they're not in fact human...

What do I mean by this? Well, obviously they are, kind of, human since they're inside all of us, they're born with us and die with us, they don't wander off on their own to live an independent life elsewhere. Nonetheless, mitochondria are different to the rest of the machinery in our cells - they have their own genomes, they regulate their own replication, they make proteins their own unique way - in fact they closely resemble lifeforms that we might consider to be evolutionary polar opposites of ourselves: bacteria. That sounds pretty odd, right, that there might be bacteria living inside our cells that somehow want to help us by churning out energy for us to use? Seems pretty implausible, but there is a mountain of evidence supporting it.

If it barks like a bacterium...

Firstly, mitochondria do, kind of, look like bacteria. They are about the right size to be bacteria (0.5-1 micron in length) and have internal structures similar to many bacteria. The main difference is that mitochondria possess two membranes and no cell wall, whereas most bacteria for one membrane and a robust cell wall. The inner membrane of mitochondria is also far more ruffled than most bacteria, creating a much larger surface area - this is highly important for reasons that I'll come to!

Spot the difference: mitochondria on top, bacteria on the bottom. 

The business of ignorance

Those of you who read this blog regularly may well be waiting on a post on the latest developments in stem cell therapy that I promised recently. I want to reassure you that this is coming, don't fret! However, a story has come to my attention of late that made me reconsider the topic of this post. The story has shocked, saddened, and angered me in equal measure and I felt that it needed sharing with you, dear reader, as it is a prime example of why the public engagement of science is a vitally important task. Given Shaun's heroic efforts last month to bring us the news from the latest  Cosmological Perturbations post-Planck conference, I thought it was fitting to exemplify just why this kind of science reporting is important.

I was first made aware of the story that shocked me so much by an excellent Panorama documentary that aired last month (UK readers can still watch the show online here). For those non-Brits amongst you, Panorama is a highly respected investigative documentary show produced by the BBC, not the kind of programme that bothers with unimportant issues. You can imagine, therefore, that my interest was piqued by the title "Cancer: hope for sale?". I had expected perhaps an exposé on some counterfeit medication ring, or maybe a look at a big pharmaceutical company pushing drugs through ahead of time in countries with lax regulation laws. I could not in my wildest dreams have imagined just how scandalous the actual story turned out to be, nor could I believe that this was the first I was hearing about it.

The main protagonist of this story is a Polish doctor called Stanislaw Burzynski - I had never heard of him before last week but he may be more familiar to those of you from the States. Dr Burzynski has been running a clinic out of Houston, Texas for over 30 years that offers treatment to cancer sufferers and has had thousands of patients through its doors. Burzynski's treatment is based on the notion that there exists a group of peptides (very short proteins) that exist within our bodies and have an immunoprotective effect against the development of cancer and other diseases, which he has given the reassuringly scientific-sounding name 'antineoplastons'. Cancer sufferers, it is claimed, can be treated by oral and intravenous administration of cocktails of various antineoplastons alongside a number of other components of the medication, such as steroids and anti-inflammatories. The antineoplastons used at the Burzynski clinic used to be purified from human urine but are now artificially synthesised from basic chemicals, and, it is claimed, are little short of a miracle weapon in the fight against cancer. The Burzynski clinic proudly asserts that not only do antineoplastons boost the immune response against cancer, but that the correct combination of antineoplastons can be used to generate therapies targeted against specific genes involved in different cancers and so allow for effective, personalised treatment.

This is close enough to real science to sound fairly convincing to the non-specialist. Some peptides are well known to have roles within the immune system (defensins, for example), and gene-targetted therapies represent a huge and promising area of oncology research. It all sounds pretty technical and reassuringly complex. That is enough for desperate individuals looking to cure themselves or loved ones when all else has failed; they're on the first plane to Texas.

The human machine: setting the dials

The previous post in this series can be found here.

It may seem sometimes that nature is a cruel mistress. We are all dealt our hand from the moment of  liaison between our lucky gold-medalist sperm and its egg companion. We are short or tall, broad or skinny, strong or weak because of the haphazard combination of genes that we wind up with, and that should be the end of the matter. Yet, as any seasoned card player will tell you, it is not the hand that matters, but how you play it! This, it turns out, also holds true when it comes to our genetic makeup - we can only play the cards we're dealt, but we don't have to play them all and can rely on some more heavily than others. In this post I'm going to discuss the ways in which DNA is organised and its activity regulated, and how this regulation is a dynamic, ever-changing process with cards moving in and out of play all the time. What's more, we'll explore the ways in which we can all consciously take control of our own DNA to help promote good health and long life!

Esoteric instructions laid bare

Most people are familiar with the concept of DNA - the instruction manual for every component that makes you you - but most are perhaps unaware of how DNA is actually organised within your cells. The importance of DNA has led to it achieving a somewhat mystical image in the public perception: a magical substance that sits inside you with omnipotent influence over every aspect of your construction. This perhaps might lead a layperson to think that we don't really understand how genes work, a perception that is encouraged by the abstract way in which the link between genetics and diseases is reported in the mainstream media. However, this impression is entirely false; we understand very well how genes work: DNA acts as a template for the generation of information-encoding molecules called RNA, which are in turn used as templates to make proteins, which then make everything else. This is called the 'central dogma' of molecular biology, which I'm not going to go into in detail now but have touched upon more thoroughly in a previous post: here.

The mystification of genetics in the mainstream perception can encourage people to forget that DNA is just a molecule, with as much physical presence and chemical potential as any other molecule in your body. As such, its supreme influence over you is dependent on pure chemistry and physics. The most obvious consequence of its being a physical entity is that it needs, in some way, to be arranged and organised. DNA exists within the nuclei of your cells, but it doesn't just float around randomly and aimlessly - its organisation is tightly regulated. First of all, DNA exists as a number of different strands, each its own molecule. These are chromosomes, humans have 46 in each cell nucleus, 23 of which you inherit from your mother, and 23 from your father. The classic image of a chromosome is the tightly packed 'X' shape like those in the image below, but actually this is a comparatively rare structure in the life of DNA as this only forms as the cell is dividing.

Chromosomes seen under an electron microscope. Image is from http://trynerdy.com/?p=145.

In non-dividing cells, DNA does not exist in the cosily familiar 'X' shapes, but instead spreads out to fill the whole nucleus. This is out of physical necessity - the DNA in compact chromosomes like those above is simply too tightly packed to do anything! Proteins and other molecules that need to interact with the DNA in order for its influence to be felt just can't get to it because there's no space. If the DNA spreads out to fill the nucleus, however, there's plenty of room for manoeuvre. Nonetheless, this organisation is not random and is still highly organised. DNA never exists on its own in a live cell - it is always bound to proteins called histones, which act as a scaffold around which DNA is able to wind, like a string around a ball. There is about 1.8m of DNA in each cell of your body, but once wound around histones it has a length of only around 0.09mm - a pretty significant space saving measure! Each little ball of DNA and histone is called a nucleosome; it is held together by attraction between the negatively charged backbone of the DNA and the positively charged side chains of the amino acids making up the histone proteins. 

DNA wrapped around histone proteins to form nucleosomes. Adapted from Muthurajan et al. (2004) EMBO J. 2004; 23(2):260-71

Shaken not stirred - how to extract your own DNA

Last week I eagerly sat down to watch the first episode of a new series: Dara O Briain's Science Club. For those of you from outside the British Isles, Dara O Briain is an Irish comedian who, in recent years, has become one of the most popular comedians and broadcasters in the UK. Not only is he a very funny guy, he's also got a pretty sharp mind inside his (frankly massive) shiny head: he studied mathematics and theoretical physics at University College Dublin and has managed to hang on to his love of science despite moving into the world of entertainment. He, along with other big names like Brian Cox and James May, has been instrumental in advancing British popular science broadcasting in the last decade and has presented a number of science programmes, such as School of Hard Sums and Stargazing Live, giving science that much-needed welcoming and friendly face. 

His new series is most definitely worth watching and I await the next episodes with bated breath. The first was on the subject of genetics and epigenetics and my curiosity was more about how these complex topics would be presented rather than actually learning something (I'm already fairly familiar with the fields)! I was delighted by the casual and approachable way in which it was structured, and how debates about scientific funding and application were mixed in with the hard facts. 

Possibly my favourite moment, however, was when we were shown how to perform a simple task that I am very used to doing in the lab, but in your own home: extracting DNA. Perhaps appropriately given the latest addition to the James Bond franchise, this entailed the use of cocktail-making equipment and the kind of very strong vodka needed to make that perfect Martini. Some might think of this as a big gimmicky and irrelevant, but I quite like the idea of making somewhat abstract scientific principles more tangible in the mind of the general public. Bringing such a standard research procedure into people's homes helps to demystify the scientific method and hopefully give people a greater sense of ownership over this work than they might otherwise have.

So, today's post is a shameless plug for Dara O Briain's Science Club with the aforementioned DNA recipe thrown in for those of you unfortunate enough not to be able to watch it online! Enjoy.



1. Collect some of your cheek cells by swishing some (around 100ml) salt water around your mouth for 30 seconds or so. The solution will be a bit cloudy afterwards.

2. Add a few drops of washing-up liquid (to dissolve the cells' membranes) and a shot of pineapple juice (the proteases in this will degrade the myriad proteins found in your cells). Pop it all into a cocktail shaker and give it your best shake!

3. Pour through a cocktail strainer to remove bubbles, ideally into a martini glass or something in which it's easy to layer different liquids.

4. Chill some very strong (>80% abv) vodka on ice and they carefully layer over the top of your mushed up cell solution. At such a high concentration of alcohol DNA comes out of solution and so precipitates at the boundary between the two solutions. This looks like a white cloud forming at the bottom of the vodka layer, which can be scooped out by wrapping it around a toothpick or something similar. Et voilà! It may not look like much, but you have successfully extracted the chemical instructions that make you you. Not bad for 5 minutes work.

The human machine: coding and decoding

The previous post in this series can be found here.

It's been an exciting week for molecular biologists, and should have been for everyone else too! This week, the Encyclopaedia of DNA Elements programme has revealed its first results about the role of the 99% of the human genome that has, until now, represented a fairly sizeable gap in our understanding of how DNA works. This has made big waves in biological circles and has to some extent penetrated the mainstream media, on the BBC for example, but I thought I'd herald this great work by giving you a brief explanation of what DNA is, how it works, and why so much of it was a bit of mystery until now.


From humble beginnings

DNA is unbelievably complex yet unbelievably simple at the same time. The principles upon which it is based are extremely simple: a string of code made up of four chemical units (called nucleotides: G, C, A and T) on two intertwined strands where units on opposite strands are paired either G:C or A:T. The complexity that arises from such a basic principle emerges much in the same way that vastly complicated computer programs can emerge from the binary 1 and 0 system of computer code; principally, that it is a code there to store information that, when read correctly, is vast. And when you have around 3 billion units of this code in every cell in your body, that vastness can quickly become unfathomable! 

Nonetheless, we've come a hell of a long way in the last 60 years. It was only in 1952 that the Hershey-Chase experiment conclusively demonstrated that DNA and not protein, as had also been suggested, was the information-carrier of the cell. Just a year later Watson, Crick, and Franklin discovered the now famous 'double-helix' structure of DNA, and the race was well and truly under way to decipher this mysterious molecule.