Tuesday, 17 February 2009

Cancer Stem Cells

We begin life as a bundle of embryonic stem cells, which divide and differentiate until you have all the various cell types required to make the many tissues and organs of the human body. In adulthood some stem cells remain to maintain the body's diverse cell types during growth, injury and aging. These adult stem cells are less adaptable than the embryonic stem cells which can form any tissue type, adult stem cells exist in multiple sets each specialised for maintaining a particular tissue types. Tissues that have been identified to contain stem cells include bone marrow, blood, brain, muscle, skin and liver. Most other tissues are also likely to contain stem cells, but their number is tiny in comparison to the normal cell population and this makes their identification difficult.

In recent years it has become evident that cancers also have tiny populations of stem cells that produce the main body of the cancer. During cancer treatment, the chemotherapy drugs and radiation therapy are often highly successful in reducing the size of the tumor, and often the cancer seems to be totally cured. However, several months or years later, the cancer often returns. This could only happen if a population of cancer cells survived the therapy, that population is likely to be very small, small enough not to be seen by a surgeon or a radiographer, it could even be a single cell. These cells are thought to be the cancer stem cells, indeed it has been shown that the cancer stem cells are highly resistant to radiation death, and are often resistant to chemotherapy too.

It would seem to make sense that cancer originates from adult stem cells that have mutated to form cancer stem cells. Adult stem cells are constantly copying their DNA and dividing to produce a specialist cell and a replacement stem cell to maintain the stem cell population. They divide like this constantly throughout your whole life to maintain your body. Each time the DNA is replicated it is vulnerable to copying errors, and over a lifetime may acquire mutations in tumor suppressor genes, inactivating the genes that control cell growth.

If current chemotherapy drugs are not effective against the cancer stem cells, it is because the majority of cancer research to date has been performed using cancer cells which are more than likely the product of the stem cells, but not the stem cells themselves. This means the drugs have been developed to be effective against the body of the tumor, but may not be targeting the cancer stem cells that drive the growth. While destroying the main body of a tumor is still useful in alleviating the pain and problems of having large masses interfering with the organs, the cancer stem cells will also need to be targeted to achieve a true cure.

Much work is currently underway at research institutions around the globe to better identify these cancer stem cells, their genetics and molecular mechanisms. For example this week the pharmaceutical giant Eli Lilly began a collaboration between its Singaporean Centre for Drug Discovery and Singapore's National Neuroscience Institute and Institute for Clinical Sciences. This collaboration has the aim of utilising newly isolated brain tumor stem cells to discover new drugs that will be effective in targeting the stem cells that cause brain tumors.

Meanwhile in Cincinnati, researchers at the Cincinnati Children's Hospital Medical Centre have recently been exploring the involvement of cancer stem cells in neuroblastoma, a cancer of the nervous system. They are also experimenting with a potential virus therapy. This virus is a specially modified herpes virus that could target neuroblastoma stem cells and kill them by infection.

Efforts in recent decades have given us hundreds of chemotherapy drugs of varying effectiveness. But until now we have been measuring their success against the general tumor mass and not on the cancer stem cells. With greater understanding of the biology of cancer stem cells we will be able to target them specifically and ensure the whole tumor is treated. This should improve the survival of cancer patients and reduce the rates of relapse following therapy.

Thursday, 12 February 2009

CCR5, HIV and West Nile Virus.

When Human Immunodeficiency Virus (HIV) finds its way into the bloodstream, it seeks out cells bearing the two receptors it requires to gain entry. These two receptors are CCR5 and CD4, both principally expressed by immune cells. particularly 'T-helper' Cells. These cells are essentially the directors of the fight against infection, activating and co-ordinating attacks by the many other types of immune cells. In the early weeks of HIV infection, the virus infects and destroys T-helper cells while the immune system fights the infection by also destroying the infected T-helper cells. This immune response successfully damps down the HIV infection but consequently causes a sudden severe drop in T-helper cell numbers. However, the virus is not totally cleared, less than 0.1% of T-helper cells remain infected. The thymus is responsible for producing replacement T-helper cells and will do so for many years, but eventually direct infection of the thymus reduces this ability and the level of T-helper cells begins its final drop. As this happens other infections take advantage of the reduced power of the immune system, and Acquired Immuno-Deficiency Syndrome (AIDS) begins.

Current treatments for HIV infection are very effective but also very expensive. Highly Active Anti Retroviral Therapy (HAART) uses a cocktail of inhibitors to target a range of points in the viral life-cycle and slow the whole replication process down. There are many variations of this line of therapy, all very effective in reducing the total number of virus in the body, but unable to remove the virus completely. This is due in part to the viruses ability to rapidly mutate and also the way the virus integrates its DNA into the host's DNA, where it can remain inactive for extended periods before re-emerging.

This week the New England Journal of Medicine published a report detailing a treatment method which appears to have totally eradicated the virus from a patients body. It is an extreme method that is not suitable for use with everybody and has only a 60% chance of survival, but it highlights the possibilities. A treatment option for leukaemia (cancer of the blood cells) is to use chemotherapy to completely destroy the source of blood cells: The bone marrow. This leaves the patient with no immune system at all, and so a bone marrow transplant from a donor is required to re-establish one.

This is the procedure that Dr. Gero Hutter performed at Charite Universitatsmedizin Berlin in Germany on an American living there. Dr. Hutter's patient had a 10 year HIV infection as well as leukaemia, and so it was decided that the bone marrow donor should be one that has a mutant gene for the CCR5 receptor. Around 2% of the European population have this mutant gene with a sequence that is deleted. This gives them immunity from most strains of HIV as the virus cannot recognise this mutant. The bone marrow transplant was a success, and the patients new immune system lacked the normal CCR5 receptor. More than 2 years after the operation no HIV has been detected in the patients body even without HAART which was essential before.

This is not likely to become a common procedure for people infected with HIV due to the high risk of death, but it does indicate a potential route for gene therapy. If the CCR5 gene can be specifically mutated or replaced with the mutant version, it could have the same effect. There might be a catch though, like all proteins in the human body, it must be there performing a function of some sort, just because the mutant version doesn't cause death or illness doesn't necessarily mean we can do what we like with it and not worry about consequences. Giving people mutant CCR5 may well give them protection from HIV, but it has also been shown that mutant CCR5 may make people more vulnerable to infection by West Nile virus.

West Nile virus is transmitted via mosquitoes, recent outbreaks have been seen in Europe, Asia, The Middle East, Africa and Oceania. In 1999 it became established in the USA, beginning with an outbreak in New York City and subsequently spreading throughout North and Central America and the Caribbean. In the USA thousands of cases are recorded each year and annual deaths have previously numbered in the 100s. Altering the CCR5 genetics of a population may provide relief from the HIV pandemic, but it might make the West Nile virus problem even worse. We cannot know the precise reasons why natural selection has left us with the genes we have, nor do we fully understand the immune system; So it may be wise to tread carefully when using genetics to impart resistance to infectious diseases, in case we inadvertently leave our population vulnerable to a new pandemic with potentially fatal consequences.

Sunday, 8 February 2009

MMR and Autism: How The Media Endangered Children

Looking back 100 years into the US Centres for Disease Control and Prevention mortality statistics, 27% of all deaths in the USA during 1908 were children under 5 years of age, in total 190,000 children died before their 5th birthday. In that year measles killed 4611 people which equated to 1 death per 10,000 people. Around the world that year in some cities such as Glasgow, Rome and St. Petersburg the rate was as high as 1 in 1000. Measles was one of the main causes of childhood death, but there was a whole host of other diseases including scarlet fever, whooping cough, diphtheria, croup and meningitis which all contributed to the poor survival of children at the time. The potential for saving a great many lives by minimising the incidence of these diseases was recognised at the time and medicine had reached a point where something could be done about them. Over the following decades vaccines were introduced for each of them and childhood survival in the countries that could employ them was greatly improved. Measles was declared eliminated from the USA in 2000, however the World Health Organisation reported that globally, 750,000 children still died that year from measles. A global vaccination effort to reduce that number achieved a 75% reduction by 2007, showing us the great life saving power of the vaccine, with continued efforts measles may soon be globally eradicated.

The combined Measles Mumps and Rubella (MMR) vaccine was first used in the USA in 1971, and introduced into the UK in 1988. It was not the first combination vaccine, Diphtheria Tetanus and Pertussis vaccines combined to create the DTP vaccine in the 1940's and many other combinations have since been made in an effort to reduce the total number of jabs a child has to endure. In order to keep measles at bay 95% of the population must be immune to it, if the number drops below that then incidences quickly begin to rise and child deaths are the inevitable result.

In 1996, a doctor named Andrew Wakefield was paid vast sums of money by a solicitor to find a link between the MMR vaccine and Autism after some parents raised concerns about the vaccine. The following year Dr. Wakefield filed a patent for a 'safer' single measles vaccine, not combined with the mumps and rubella vaccines. A year later in 1998 The Lancet published a scientific paper by Dr. Wakefield about a study of 12 children with developmental disorders in which the parents of 8 children believed that MMR vaccination was the trigger for their child's autism. No conclusive proof was given other than this speculation by the parents. Dr. Wakefield then held a press conference in which he recommended all parents give their children the single measles vaccine rather than MMR, of course he failed to mention that he happened to own a patent for the single vaccine. The Daily Mail led media campaigns supporting Dr. Wakefield in attacking the MMR vaccine despite the lack of conclusive evidence behind his claims consequently bringing 100 years of vaccine development into question.

Understandably parents who had no real understanding of the scale of death that would be incurred without these vaccines began to consider whether they should protect their child by giving them no vaccinations at all. Many parents insisted their child only have the single vaccine, but many also neglected to give their children any protection at all. In 2003 the UK vaccination rate in 2 year olds had dropped to 78.9%, far below the 95% required to keep measles at bay in the population.

In 2004 Dr. Wakefield's source of funding was exposed, revealing that he had made the conclusion he was paid to make. The editor of The Lancet, Richard Horton also admitted that the study had been fatally flawed and apologised for publishing it. 10 of the 13 authors listed in the study publicly retracted the association between MMR and autism. But the damage had already been done. Parents were already suspicious of the MMR and vaccines in general, and no campaign was launched by the Daily Mail or the other papers to correct the damage they had done.

In 2006 the vaccination rate still stood below the critical level at 82% and the first victim of measles in the UK in 14 years died as a result. In 2008 the total number of clinically confirmed cases of measles recorded by the Health Protection Agency was 1348, compared to just 56 ten years earlier. Of those 1348 cases, two children died. Ironically the Daily Mail reported at the end of 2008 on the fear of an upcoming measles epidemic, an epidemic it will have had a large part in creating, though they don't mention that part in the article. The Daily Mail itself has been criticised by the government's Chief Scientific Adviser and others for its continued misleading of the public on this issue. Further criticism of Dr. Wakefield's study have now been made with a Sunday Times investigation finding that his conclusion was based on faked data.

A catchup campaign was launched by the Department of Health in August 2008 to attempt to restore the vaccination rate to 95% and hopefully prevent an inevitably fatal measles epidemic. The World Health Organisation's Measles Initiative aims to reduce global deaths and eventually eradicate the disease, you can help them by donating to the American Red Cross.

Tuesday, 3 February 2009

The Genome: Still an Enigma

The publication of the human genome was a groundbreaking scientific moment. Previously scientists found and isolated genes of interest and sequenced them afterwards. This left many genes hidden for a long time as they had not been noticed, the more obvious genetic disorders being easier to spot and associate a particular gene with. Sequencing the entire genome turned the process on its head. DNA contains strict codes indicating the start and end of protein coding sequences, and so by looking for these codes in the whole sequence the total number of genes and their precise location could be identified. For the first time scientists had a list of every single gene, and one by one were able to figure out their roles.

When the project was originally undertaken it took 12 years of work and $3 billion of US taxpayers money (Or $300 million for the privately funded alternative project). It was anticipated that once this project was complete, we would know everything there is to know about genetics and with it would come cures for many and possibly all diseases. That is still some way off, but progress is being made in gene therapy and the diagnosis of genetic diseases is now much easier. The cost of sequencing a human genome is now less than $500,000 and falling rapidly each year, it is now cheap enough to consider sequencing not just one, but a thousand human genomes to see the variations between them and the distribution of particular gene variants, as is the plan for the Personal Genome Project which aims to complete this by 2011.

Before the genome was sequenced, it was estimated that there must be around 100,000 genes, based on the size of our genetic material and the genes we already knew at the time. The results surprised everyone; 20,000 genes is closer to the real number. Also curious was the finding that less than 5% of the genome actually codes for proteins, vast stretches seeming to be nothing more than 'junk DNA'.

Many scientists maintained that it can't all be junk, because that much junk would actually hinder organisms, taking so much energy to replicate that they would be out competed by other organisms and fail to survive. Some blamed viruses, retroviruses specifically, as they infect by integrating their genes into your genome. When the infection is fought off, often those viral genes remain in a damaged non-functional form and if the right cells were infected, the genes will be passed on to your offspring. As much as 10% of your genome has been found to be made of such material, accumulated over many millions of years, much of it mutated into non-functional junk. But this still leaves 85% of the genome unexplained.

RNA is the intermediate molecule used to make protein from DNA. As I discussed previously, life evolved in an RNA world, where strands of RNA themselves carried out functions as well as encoding proteins. So it is perhaps unsurprising that a project at Harvard and MIT recently discovered a whole new class of genes, genes that do not encode proteins, they are simply the template for functional RNA. Small RNA molecules such as Micro RNA, around 22 nucleotides in length, have been known to have gene regulation functions for many years, but this new class of large RNA molecules are thousands of nucleotides long and there are thousands of them. Crucially, their sequences have been conserved through evolution, indicating they have important functions as yet unidentified. 1600 of these genes were found in the study but it is thought many more thousands are still hiding in plain sight.

We already had quite a job on our hands to understand the 20,000 genes we originally identified, now there is a whole new class to understand, which operates in a whole other way. This new class may go some way to explaining what some of that junk DNA is there for, but there is still lots the genome has left to teach us. Just because we don't know what it does doesn't mean it is useless, just a few hundred years ago the brain was considered largely useless because it didn't do anything as obvious as the heart, lungs or stomach does. However, that is the process of science; learning new things and adjusting current opinion accordingly.