A Brief History of Life

In order to reach the level of life that we have reached, we have had to progress from more primitive forms. We are vertebrates and so have a spinal cord. The earliest known occurence of something with a spinal cord is in a type of animal which has remained unchanged for millions of years: The sea-squirt. Adult sea-squirts are pretty basic tubular filter feeding creatures which remain stuck to the same place for their whole life, but the larval form of a sea squirt looks like a tadpole and possesses the crucial spinal cord. It is believed that around 550 million years ago, some of these sea-squirt tadpoles never found a rock to attach to, and instead remained in their fishy form, went on to evolve into fish and eventually into us.

Lets take it back even further. Before we evolved to the multicellular tadpole stage, we would have had to have been a single celled organism. Cells like ours with a nucleus that contains the genome, are known to exist as far back as 2.7 billion years ago. Lets go back further, before our cell can wrap its genome in a nucleus, you need a cell with loose genetic material, like modern bacteria. The oldest fossil record of bacteria is from 3.5 billion years ago. This is only a billion years after the earths crust cooled from boiling magma to solid rock.

What we have in common with bacteria is that we are vehicles for our DNA to replicate itself. We are a lot bigger and more complicated, but we do the same thing, we duplicate our DNA and we pass it on to a new generation. So where did this DNA come from? We make DNA with proteins and enzymes that are made with instructions from the DNA, so which came first? At this point its easier for me to just jump right to the start, its not that far away now.

Once the earths crust formed the oceans began to form, natural reactions began in the salty mineral rich water and organic chemicals began to form. These organic chemicals provide the well known 'primordial soup'. This soup would collect and become concentrated in the rock pools on the coasts, in here the first amino acids would have formed, as well as the first nucleotides. Amino acids are the basic building blocks of proteins. Nucleotides are the basic building blocks of RNA and DNA. These can assemble themselves and interact with eachother, eventually some proteins will randomly have developed a structure that enabled the nucleotide chains to be copied. Other proteins could use nucleotide chains to produce a new protein. Suddenly we have the first instance of replication.

As this chemical replication proceeded, in its very early form it would have been imprecise and many errors would occur. But errors are good in biology, errors produce variation, variation produces differences in performance. The best performing combinations of proteins and nucleotides would become the most common. The complexity of the combinations would have increased with time. The single strands of RNA formed complimentary double strands, and acquired functions that outperformed the primitive proteins. Some of these RNA functions still exist within our cells. For a while the world was dominated by the RNA chains, with help from proteins.

Eventually the RNA would have found a performance boost by being isolated within a bubble of oil, the products of its work being kept close instead of washing away into the ocean. This is essentially the cell membrane that us and bacteria possess. The complexity of the replication reaction has taken another step and inside the bubble complexity grew ever greater. Sometimes however, other more primitive RNA systems might get into the bubble, and take advantage of the resources there, we call them viruses today. Later proteins became more complex and outperformed RNA which was replaced with DNA and life started to look like something we would recognise.

Thats a heavily summarised account of the most accepted theory of how life developed. But at what point can we say life actually commenced? Do simple chemical reactions count as life? Is it the basic replication where life starts? The fact is that we are the product of a basic chemical reaction that began more than 4 billion years ago, and inside us the reaction continues, growing ever more complicated as long as it enables us to reproduce ourselves better. We are only aware of our environment because awareness helps us to find food, survive and reproduce. Every aspect of human nature can be related back to how it helps us ensure successful propagation of our DNA. With the global human population nearing 7 billion, we're certainly doing quite well, but not nearly as well as those bacteria, there are a hundred trillion of them in your gut alone, and bacteria will be around long after humans are forgotten.

Viruses in Gene Therapy

Since the publication of the human genome in 2003 great developments have been made in genetic technology. But one of the big challenges is developing reliable methods for the delivery of the desired gene to cells in a human body. This is where our old enemy the virus can help us, as I mentioned briefly in my post about targetting therapies.

Viruses are the smallest form of life, essentially just parasitic packets of genetic material. They have adapted to infect a a variety of tissues, using a variety of different methods to get their various forms of genetic material into the cell. All this variation makes viruses more diverse than all the other forms of life put together, as viruses have adapted to use them all and for each species there are a whole collection of associated viruses. This variation also provides us with a potential toolbox which we can use to achieve our own objectives.

Having small and well understood genomes, viruses are easily modified to carry genes of human interest, and there you immediately have a highly efficient gene delivery mechanism. This method has produced an interesting range of viral therapies for a range of diseases. One company that is pursuing this technology in a broad range of diseases is Oxford Biomedica, which has a range of viral based gene therapies for diseases including Parkinson's disease, age-related and diabetic sight-loss, and in early development; motorneurone disease, AIDS, spinal cord injury; haemophilia. These developing therapies all utilise a modified horse Lentivirus to deliver therapeutic genes to a specific tissue.

Parkinson's disease involves a depletion in the brain of the critical neurotransmitter dopamine which adversely affects the brains normal functioning. Oxford Biomedica's viral therapy carries three genes into the brain tissue, which encode enzymes that produce dopamine. This new dopamine production increases the level to a point where normal brain function can resume, as shown in animal models and currently looking very promising in early human trials. The sight-loss therapy works in a similar way; The virus is modified to target only the desired retinal cells and delivers genes that halt the uncontrolled growth of blood vessels on the retina that occurs in certain eye diseases.

Hereditary conditions have been successfully treated, as shown by experiments by University of Pennsylvania Medical School and University College London with a rare form of hereditary blindness called Leber congenital amaurosis. In this therapy they inject into the eye a tamed strain of Adenovirus carrying a working copy of the mutated gene that causes the blindness. Vision improved enough for the patients to sucessfully navigate an obstacle course in dim light, a task that would previously have proved very difficult for them. There are six genes involved in the disease so further improvements may be made to the treatment by including more of these genes. The teams also believe the treatment may cause more improvement in children, as their retinas will have degenerated less than adults.

As the understanding of genetic causes of diseases, both acquired and hereditary, are being developed faster than ever by geneticists, the opportunities for gene therapies such as those described become ever more numerous. Viruses are going to be instrumental in delivering these therapies to the cells that need them.

Targeting Therapies

Getting your drug therapy to the tissue that you want to treat is easy, the body's circulatory system is perfect for that. The problem occurs when the drug gets into other tissues and causes side effects, a long list of which can be found on the information sheet supplied with any drug.

There are a multitude of different ways of specifically targeting certain tissues or cells, and many new ways being developed with the use of new nanotechnology. One such method is being developed at the City University of New York. Here the drug is attached to a mesh of fatty acids, making it inactive. This mesh will disperse around the whole body like any other drug, but could be designed so that the drug can be detached from the mesh by an enzyme that is only present in the tissue being targeted. In this way the drug is only released in its active form at the desired location, thus limiting the chances of the drug getting into other tissues and causing side effects. This is in very early development and has yet to be proven outside of bench-top experiments, there is undoubtedly still a lot of work to be done to make this method work, but it shows us the kind of thinking going on in this area at the moment.

Here's some background to a different problem. DNA encodes the 'blueprints' for all the proteins your cells need to do their business, it is like the master copy. When the cell needs to make a protein it uses a slightly different chemical called RNA to make a copy of the gene, the cell then uses that copy to construct the protein. Many copies are made and transmit the message of how to construct the protein to the cellular machinery. When a cell is making a protein that it isn't supposed to, it can often cause disease. In the lab it is possible to block the RNA message by designing small segments of interfering RNA that stick to the RNA message. As the cellular machinery works its way along the message, making the protein as it goes, it reaches this interfering RNA segment and can't read the message anymore because it is blocked out and so the protein is never completed. Inject this interfering RNA into the body however, and you'll find it is destroyed pretty quickly in the blood before it ever reaches where it supposed to.

Calando Pharmaceuticals in California are testing in humans a kind of Trojan-horse system where the interfering RNA is packaged inside a nanoparticle studded with a molecule called transferrin. They chose this molecule because cancer cells are abnormally rich in receptors for that molecule, and when they detect it on the particle they will take the whole particle inside the cell. The acidity inside the cell is different to the blood, and this causes the particle to burst, releasing the interfering RNA into the cell where it can do its job. This technique is very promising as it can relatively easily be modified to target any receptors and deliver interfering RNA to all sorts of cells, not just cancer cells, and could potentially be adapted to deliver regular drugs.

A third approach is to make the cells produce the drug themselves. Viruses exist by infecting cells and making them produce all the proteins it needs, the virus just brings along the appropriate genes and the cell does all the work. Viruses are also very specific about the cells they infect, which is half the work already done for us. They are already being used selectively infect cancer cells, thereby killing them. Companies such as Oncolytics, Genelux and others are carrying out trials of this method. Viruses or artificial virus-like particles can be designed to deliver a gene for a specific enzyme that makes an active drug out of an inactive 'pro-drug' that is injected normally. This means the infected cell becomes a kind of drug factory at the precise location the drug is required, minimising the exposure of the rest of the body to that drug.

In ways such as these the treatments of the future will have a much reduced range of side effects, while at the same time being more effective and improving the quality of life of people suffering from chronic diseases.