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 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

The human machine: decommissioned components

The previous post in this series can be found here. 

Happy 2013 from all of us here in the Trenches! We successfully made it one more time around the sun, and if that's not a good excuse for a party I don't know what is! Sadly, however, not all of your cells have been having such a swimmingly good time since the calendar ticked over to January the first - in fact nearly one trillion of them have died in the past fortnight alone, at a rate of roughly 70 billion a day, or 800,000 per second. Don't be alarmed, however, as this has been going on for your whole life and is a vitally important part of being a multicellular organism such as yourself. A human without cell death would be like society without human death - overcrowded, unpleasant, and rife with infirmity. Your body needs a system by which damaged, old, or infected cells can be removed in a controlled manner; this process is known as apoptosis.

In this post I will be discussing what we know about how apoptosis works and how it is a key player in the development of cancer and the fighting of infectious disease. I'll also show how our understanding of how this process works has allowed us to devise targeted therapeutics against a number of debilitating conditions.

Cellular suicide - picking the moment

Your cells are team players - they're willing to do anything to serve you, including laying down their lives. Apoptosis depends on this loyalty because it is actually a form of suicide that your cells perform on themselves. Arguably the most important aspect of this is timing - if your cells are in the habit of committing suicide before it is necessary then you'll waste a lot of energy and resources building replacements that shouldn't be needed. On the other hand, if the cell leaves it too late to kill itself then it may find itself incapable of doing so.

So, how does a cell know when to die? Well the most obvious markers for cell death are simply the various forms of damage that can occur to the components of the cell itself. If a cell's membrane becomes damaged, for example, this can cause excess calcium to leak into the cell and so be sensed by a number of calcium-binding proteins, such as calpain, which in turn signal that apoptosis should begin. Similarly, damage to DNA is sensed by the complex machinery of the DNA repair pathway. For example, PARP is a protein that binds to single-strand breaks in DNA caused by DNA damaging agents such as radiation (think sunburn!) or chemical mutagens like free radicals. PARP and other DNA damage sensors relay their information to a number of signalling proteins, most importantly p53. If p53 is activated in response to DNA damage it signals to stop the usual processes of cell division and begin DNA repair, but if the damage is just too bad it makes the call to start apoptosis and destroy the cell.

Worshipping the funding mountain

It was announced last week that an anonymous benefactor is to donate £20 million to be split between the University of Southampton and Cancer Research UK (CRUK), which will conduct its work in the new Francis Crick Institute, currently under construction in London. This money is going to be used primarily in the advancement of cancer immunotherapies, a branch of cancer treatments in which the patient's immune system is harnessed to fight cancerous cells. I wrote briefly about the use of the immune system in the fight against cancer in a post a few months ago, but since this field is now in the spotlight (in the UK, at least!) I thought I'd give you a short update on the kind of work that's being done and why £20 million is significant.

Targeting the traitors

Cancer, as you're probably aware, is the condition that arises when an individual cell or subpopulation of cells accumulates sufficient mutations in the genes that control cell division as to become rogue entities within the body - replicating indiscriminately and dangerously. As a species we are highly susceptible to cancer because we just live so damn long and generally don't die from the things that kill most other species (hunger, illness, predators etc.), and finding effective treatments remains one of the major goals of medical research. If  a cancer forms a tumour and stays like that then treatment is simple surgery to remove it and is highly effective. The killer scenarios are either when tumourous cells metastasise and circulate in the body as individual cells, establishing too many new tumours to be removed; or when the original cell is one that does not form a tumour, as is the case for leukaemia or lymphoma. In these cases, chemotherapy or radiotherapy is commonly used to attack the cancerous cells but often ineffectually and almost always with nasty side-effects. The idea behind cancer immunotherapy is to nudge the immune system into attacking these cancerous cells, thereby clearing the disease with minimal damage to other tissues.