Sunday, 24 May 2009

Book Review - Bad Science

Something is wrong in our society. Every day the media serves us our daily health scare, nutritionists claim their pills will cure all manner of ailments, and the pharmaceutical companies are simply evil. All three twist, ignore or hide evidence in their persistent pursuit of profits. In this book Dr Ben Goldacre sets out to equip us with the critical thinking required to protect the public from being manipulated by Bad Science in their daily lives, while also providing another opportunity for medics and scientists to snigger at the ridiculousness of homeopaths.

The book opens by tackling what seem at first glance to be relatively trivial abuses of science such as the pseudoscience used to sell cosmetics and Brain Gym, a course of government endorsed pseudoscientific exercises to improve children’s performance in the classroom. Goldacre uses these to demonstrate how science has become somewhat of a parody in the minds of the public, where ‘the science’ is something you’re not expected to try and understand, you’re just supposed to accept what the ‘experts’ say without question. What is worrying is how widespread the acceptance of this has become; even those responsible for educating our children seem to be unable to see the blatant holes in the theory behind Brain Gym exercises.

We’re then taken to the world of homeopathy, a world easily ridiculed with little thought, but this rather lengthy chapter only briefly discusses why the homeopathic theory might be considered nonsense and instead focuses on the studies that have shown it to perform no better than placebo. Where there are studies that show homeopathy to be effective, Goldacre uses these to demonstrate why not all studies are equal, and introduces the reader to the concept of good trial design and why the placebo effect has to be carefully controlled in human trials.

Nutritionists are next in the firing line, a new profession in which the people dispensing dietary advice also conveniently have a range of their own brand supplements they would like to sell to you. It doesn’t take much effort to notice they spend as much time selling the problems as they do selling the cures. They also respond to criticism of their studies with lawyers, rather than supporting evidence as real scientists would. The most well known nutritionist, ‘Dr’ Gillian McKeith has a whole chapter dedicated to her and her spurious qualifications.

While all this may seem to be doing no real harm, Goldacre has a very serious point. The ignorance of facts is becoming so ingrained into our culture it will be hard to shake off. A national campaign encouraging children to take fish oil supplements to improve exam performance inadvertently taught our children that taking pills is essential to a normal life. The suggested benefits were later disproved, but still parents fill their children with fish oil as if they’d be bad parents for not doing so. Lies often become so widespread that they become part of culture and are accepted without question. Bad health advice kills. From the old recommendation that babies should sleep on their front to the recent denial of HIV therapy in South Africa, thousands of lives have been lost due to bad science.

The later chapters explore the role of the media in presenting bad science on a daily basis, their objective being to gain audience for advertising revenue, rather than inform them. A whole chapter is dedicated to the media’s MMR hoax and how it is responsible directly for the resurgence of diseases which we really shouldn’t have to worry about now.

While Goldacre writes with good humor, there is a clear sense of his frustration with having to explain these things, as they should never have been misrepresented in the first place. His extremely well researched and explained arguments have clearly been refined by years of arguing for the sake of the truth, and for the lives that depend on it. However, at some points it did occasionally feel as if the arguments went on considerably longer than they needed to, though Goldacre admits to this in the text and reassures the reader that he does this only when he feels it is important. While he remains cheerful and makes a point of not adding to the scaremongery already out there, the underlying message is that lives depend on the good use of science and consumers being able to spot bad science. This book is an essential lesson that schools rarely teach, and as such it has something for everybody to learn about the world we live in.

Tuesday, 10 March 2009

Cryoablation: A New Tool In The Oncologists Toolbox

Prostate cancer treatment, while generally quite successful when the cancer is caught at an early stage, isn't without its problems. In the short term, radiation therapy and surgery can damage closely associated nerve bundles and cause incontinence and impotence. In the long term, resistance to therapy can develop, limiting the treatment options available. A new treatment option pioneered by doctors at the Center for Safer Prostate Cancer Therapy in Orlando, USA is an effective solution to these problems.

Cryoablation (or cryotherapy) is a minimally invasive technique where a needle is inserted through the skin and into the prostate tumor, guided to the exact location with 3D imaging. Once the head of the needle is in place, a argon gas is circulated through the needle tip, reducing its temperature and freezing the surrounding tumor tissue. Freezing is a highly effective method of tumor killing as the formation of ice crystals within the cell spear through the membranes and simply destroy the whole cell structure, whereas radiation therapy relies on DNA damage and cell suicide, a process which tumors often grow resistant to. The treatment uses two freeze cycles with an intermediate thawing step to ensure cell kill.

The study at the center followed 120 men who had cryoablation. The patients were monitored for 12 years, after which 93% showed no signs of cancer recurrence, despite more than half of them initially being assessed as at high risk of cancer recurrence. Furthermore, in the 7% of patients whose cancer did return, it was located elsewhere in the prostate gland and further cryoablation was used successfully in treating those cases, resulting in 100% effective disease management. All patients retained full bladder control and only 15% experienced impotence.

The treatment isn't exclusive to prostate cancer, great success has also been seen in kidney cancer. Doctors at Johns Hopkins Hospital in Baltimore have tested it on 90 tumors in 84 patients and observing for 3 years (two years longer than is standard for kidney treatments). They have seen 100% efficacy on tumors of 4cm or less in size, close to 100% in tumors up to 7cm in size, and two of three 10cm tumors were successfully killed. 75% of kidney tumors are less than 4cm in size at the time of diagnosis so cryoablation is a very real option for the majority of cases. Indeed, the doctors argue that the procedure should become the gold standard, replacing the current surgery which involes several days in hospital with an outpatient procedure that preserves as much kidney as possible.

Data for both studies was presented at the Society of Interventional Radiology's 34th Annual Scientific Meeting.

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.

Tuesday, 27 January 2009

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.

Sunday, 18 January 2009

Immunotherapy - Switching Anti-Cancer Immunity Back On

The immune system is a powerful tool that protects us from being infected by the many bacteria, fungi and viruses that would otherwise find a warm wet nutrient rich wound an ideal place to colonise. But it also has a role in protecting us from our own cells. Immune surveillance is the body's way of keeping a check on cells that begin to divide uncontrollably. Such cells have mutated somehow and will be recognised as defective and destroyed by the immune system. Generally this works very well for most of our lives; unfortunately it applies the 'survival of the fittest' rule to cancer cells. The 'fittest' cancer cells being those that acquire the mutations enabling them to mutate faster than the immune system can recognise them, or those that acquire a mutation that causes some kind of immunosupression. Eventually the cancer evolves to a form that completely evades the immune system, usually by secreting a cocktail of chemical messengers that stop immune cells recognising them.

Many approaches are being tried in an effort to make the immune system recognise the cancer again and begin killing it. Cocktails of lab-grown tumor cell vaccines have had mixed success in trials, ongoing are Phase II trials by Onyvax whose therapy consists of three types of lab grown cancer cells, which are injected into patients with prostate cancer. The immune system will recognise these cells as totally foreign, and in the process should notice some cancer associated proteins which it had previously missed due to the immunosuppression by the cancer. Although this approach has shown some effectiveness in previous trials by extending patients lives by around 6 months, it only slows the cancer and never causes remission. This could be because this approach doesn't do anything to overcome the immune suppression by the cancer, there may very well be a well armed immune response ready to attack the cancer, but every time it gets close it is prevented from attacking.

Dendreon is another company with a prostate immunotherapy, this one uses lab-primed immune cells called Antigen Presenting Cells (APC) and injects them into patients, once in the patient the APCs 'teach' the patients immune system to attack the cancer. This approach is similar to the Onyvax approach, but is further in development, unusually it is in its 3rd Phase III clinical trial, ideally those should only happen once. It is clearly having an interesting effect on cancer, enough to continue investigations, but its not significant enough to bring it to market yet. Again, this therapy doesn't address the issue of immune suppression.

Cell Genesys had a vaccine very similar to Onyvax's, except it included an extra immune stimulatory factor in an attempt to overcome the immunosuppression with an even more powerful immune response. This attempt failed, their PhaseIII trial was terminated and the therapy abandoned. Things are beginning to look a bit bleak, I shall bring us onto some more promising therapies.

NovaRX have a therapy similar to that of Onyvax and Cell Genesys but for advanced lung cancer, it uses four sorts of cancer cell in its vaccine; crucially it also blocks a signal protein called TGF-β, which is an immunosuppressor secreted by the tumor cell. This approach seems to be highly effective, extending patients lives by years in a phase II study and is now in a PhaseIII study.

These types of therapies are important, because once a working therapy is produced for one cancer type, the same approach can be used for nearly all other types of cancer. In all of these trials however, the vaccines usually only work for a certain subpopulation of those tested. I wrote previously about the great variation in cancer between people and the need to personalise treatments using biomarkers. These companies will be monitoring patients and discovering biomarkers that will help optimise future treatments with their products.

One way to overcome the problem of treating unique cancers with general vaccines, is to make the vaccine unique to the patient. Antigenics have a vaccine which is tailored to each patient by taking a biopsy of the tumor, taking it to the lab and creating a personalised vaccine from it. This vaccine has been effective in prolonging survival in kidney cancer and melanoma has been approved for treating kidney cancer in Russia and has been submitted for approval in Europe.

I have presented a small selection of therapies here, a search of 'cancer vaccine' on provides a list of 303 clinical studies that are seeking patients, hundreds more have completed recruitment and are ongoing. So there is much more information to be gained in the not too distant future. Using this information the next generation of cancer vaccines are likely to incorporate several modes of action including blocking the immunosuppressive activity of the tumor, priming the immune system to attack, and boosting that attack with immunostimulators. Perhaps by doing this, we will be able to extend lives by decades rather than months and years.

Saturday, 17 January 2009

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.

Sunday, 11 January 2009

Book Review - The Time Traveller: One Man's Mission to Make Time Travel a Reality

The story of Ronald L. Mallett's life has essentially been defined by one tragic moment in his childhood. In 1955 Ronald's 33 year old father died suddenly and unexpectedly of a heart attack and 10 year old Ronald lost the man who was the centre of his universe. After this event he receded from his friends and his life, instead developing a passion for reading. A year after his fathers death he discovered a comic book version of H.G. Wells' The Time Machine, and this lead him to dream of the possibility of travelling back in time to warn his father of the heart attack and thereby prevent his untimely death.

While most of our childhood dreams fade with time, Ronald never forgot his, indeed it became a secret obsession that he would see his father again and he became determined to build a time machine. Using knowledge of electronics he had learnt by helping his father repair television sets, he secretly built a replica of the machine depicted in The Time Machine. Of course it failed, and he realised he needed to learn more if he was to make it work. His autobiography details how he overcame the hurdles of poverty and racism in order to gain himself an education in theoretical physics, eventually receiving a PhD from Penn State University in 1973.

Ronald knew he was unable to openly admit his goal was to build a time machine as he would not be taken seriously and would be ridiculed, thus far the only person he had told of his plan was his wife. So in 1975 he joined the University of Connecticut as an assistant professor, and studied the only thing that was known to manipulate time: Black holes. He pursued an academic career there becoming more and more despondent as the years passed and he seemingly got no closer to his goal. His marriage failed, as did his health, himself suffering from heart trouble and having to take time out from his career. Realising he was running out of time he reignited his research, and eventually produced a 4 page paper with an equation that predicted that light, as well as gravity is able to manipulate time and built a small experimental model of a time machine to demonstrate it.

He published the paper, and after 40 years of secret work, found that there was a great interest in his work, and the physics community took him completely seriously. He revealed the driver behind his life's work after a question and answer session at a presentation of his theory in Washington DC. In response to this story, Bryce DeWitt, who proved Einstein's theory of relativity, said in front of the conference audience that he didn't know if Ronald would ever see his father again, but did know he would be proud of him. That statement provided the validation of his life that Ronald had always needed, but one part stuck with him, DeWitt had said he wasn't sure Ronald would see his father again. Ronald went back to the equations and soon realised that even if he did build a time machine, the farthest back in time he would ever be able to travel to would be the moment the machine was first switched on. But that didn't matter anymore because he already knew his father would be proud of him, and didn't need to see him to know that.

The book is an inspiring life story as well as an introduction to the various theories of time manipulation. The physics of Ronald's work is presented in easily readable metaphors and although you might not understand them completely (I certainly didn't), you get the general idea and that's all you need to know to follow the story in this book, it really is more about a man missing his father than it is about physics. I certainly enjoyed reading it and believe it is worth a few hours of antibody's time to read this story.

Friday, 9 January 2009

A Little Help from Man's Best Friend

My last post suggested that some new drugs don't make it to market because the existing trials process doesn't provide critical information that can be used to optimise the trial design and reveal the true potential of the drugs being tested.

A change in the existing trial process would have serious legal and ethical issues to contend with, and so is unlikely to occur. It can however be supplemented in such a way that streamlines the process, more accurately determines the effect of a cancer drug and can reduce the time to market. That solution is dogs. These are not your typical animal experiments, such as the rat or mouse models of cancer, in which the animal often lacks a fully functional immune system and the cancer itself is a cross-species 'xenograft' implant. Its fairly easy to see how these models do not accurately represent the type of cancer that occurs naturally in the body, and that's where the dogs come in.

In the USA up to 6 million pet dogs are diagnosed with cancer every year. Canine cancer is surprisingly similar to human cancer. Dogs get the same types of cancers as humans, they are genetically similar to humans and crucially, large scale genomic analyses of canine tumors have shown that there are no differences in the genetic mechanisms of the cancer. The other similarities in canines include their size and the fact that they possess fully functioning immune systems. The similarity between dogs and humans is so close that most existing drugs can be used to treat equivalent diseases in both species.

Naturally dog owners are keen to pursue any therapies that may prevent the death of their pet. Fortunately they can, in the USA the National Cancer Institute operates a network of animal hospitals, fully equipped with state of the art imaging technologies to accurately diagnose and monitor canine cancer. Similar work is carried out at the Roslin Institute in Scotland. These centres are used to test new therapies on the plentiful supply of canine patients following Good Clinical Practice guidelines and central reporting of dangerous side effects not too dissimilar to those in place to protect human patients.

The canine trials can start providing detailed information on the mechanisms of the drugs action before even the Phase I trial in humans starts. Information such as genetic profiles for which the drug is ineffective or blood markers that can be used to determine successful responses in advance of significant tumor reduction. These can all be translated to human systems and used to better design the human trials. These types of biomarkers are not often discovered until around Phase II of human trials, and are usually validated during phase III. Having them in place for Phase I is very useful as they can be validated in the early phases and used to optimise the later more expensive and time consuming phases. For example selective enrolment of patients who have the genetic or biochemical profile compatible with the drug would make the trial more decisive, while freeing other patients to pursue other therapies with more likelihood of success for them. Another benefit is instead of waiting years to determine the survival of the patient and therefore whether the drug was effective, biomarkers that provide advanced indicators of survival could provide that information in months, drastically reducing the length of the trial and therefore the costs.

Comparative Oncology such as this has the potential to give us a much more detailed understanding of the drugs we are testing and should help bring more new drugs to market and quicker. Cancer is a complex and diverse disease that will not be overcome by a single therapy alone, we will need to use combinations of therapies specifically targetted to a patients personal disease to attack it from several fronts. Therefore understanding each cancer type and each drug as much as is technically possible will be critical in determining potential drug synergies and creating successful recipes for treatment.

Wednesday, 7 January 2009

The Problem with Clinical Trials

All new medicines undergo a rigorous series of controlled studies to establish safety and efficacy before they are licensed. The need to test drug safety on a small scale before allowing it to be prescribed was underlined in the early 1960's by the well known Thalidomide Tragedy, a situation where the drug thalidomide was prescribed to pregnant women in Europe and Canada as a treatment for morning sickness. Unfortunately the drug had only been tested in animals, and nobody foresaw the severe birth defects that would be inflicted on the children of these women. In 1962 the US Food and Drug Administration (FDA) put a system in place to ensure all new drugs would be rigorously tested before coming to market.

This has resulted in the clinical trial system we have today which typically consists of three phases. Phase I begins if laboratory and animal experiments have shown convincing evidence that a new drug is effective and safe. At this stage the primary concern is drug safety and only the minimum number of patients will be treated, initially with a very low dose of the drug, increasing gradually as the trial proceeds. If the trial goes well and no patients were harmed by the drug, then it may enter phase II. In Phase II the objective is often to establish an effective treatment regime, different dose levels and frequencies are likely to be tried in order to establish how to make the drug most effective. At completion of this phase the data will be studied to determine if there is a benefit associated with use of the drug. If there is, then phaseIII will begin, often with hundreds of patients in a large scale placebo controlled study across many sites to establish beyond doubt whether the drug is truly beneficial.

The problem with this system is that it is very expensive and is a very long process, taking up to a decade or more to complete. The race to get the drug to market means companies often try to complete the first two phases as soon as possible, they see promising data from these trials and dive headfirst into PhaseIII to save as much time and money as possible. This means that detailed studies into the method of action of the drug are often overlooked, as it isn't considered worth spending the money on that until you know the drug is safe and effective, its as if nobody cares how the drug works, they just want to find out if it is effective at treating the disease. This is thought to be one large factor in why so few drugs make it through PhaseIII to market. If you don't know how the drug works, then you don't know why its failing. Within a trial the drug may work well for some patients, and have no effect on others, frequently the benefit is seen in so few patients that the drug is considered ineffective and dropped from the process. Any benefits that were seen are easily forgotten once the trial is branded a failure. There was however a potential to learn a lot from these studies, information which when used correctly could have meant the drug could have been brought to market.

The trial system is certainly protecting the public from potential dangers of new drugs, but it may also be indirectly harming them by being such an expensive and time consuming process that drugs that only seem to have a small benefit, or benefit only a small selection of patients, are never brought to market. In my next post I will explain how a surprising addition to the current system is already giving us the information we need to optimise the trial process and bring more drugs to market.

Monday, 5 January 2009

The Increasing Use of Biomarkers in Cancer Research

Hello and welcome to my first 'SciBite'. Whilst looking for a subject to write my first post about I came across an article about prostate cancer and a particular type of androgen (male hormone) receptor. This article details the discovery of several variants of androgen receptor, and how the expression of one particular variant seems to be responsible for enabling prostate cells to grow even without the androgens they usually require.

This is important because current standard treatment for prostate cancer often involves disrupting this androgen signal, either by castration, or more commonly in the richer countries of the world, hormone therapy. Both of these methods are initially highly successful, often large decreases in the size of the tumor are observed, but frequently the cancer develops independence from the androgens that used to dictate its growth, and a new phase of the disease is entered.

The discovery of this variant androgen receptor sheds some light on the mechanism of the cancers evolution to this phase, but usefully it also provides a 'biomarker' to help consultants decide the best course of therapy to place their patient on. It is possible to test a biopsy of the tumor to establish if this variant receptor is present, if it is already present at a high level then hormone therapy may not be a very successful option and the patient may benefit from an alternative treatment. For patients who are undergoing hormone therapy, it may provide a useful guide as to how far along the tumor has got to becoming androgen independent, and enable a switch to another treatment before tumor growth becomes completely uncontrolled.

This is one good example of a current trend in cancer research and treatment: Identification and utilisation of biomarkers to better diagnose, monitor and treat cancer. Previously cancers have been categorised according to the organ or tissue of origin, and all cancers of that origin tended to be treated the same way. However, more recently new technologies such as gene expression profiling have shown that the genetics of tumors can differ greatly between patients, even if the tumors are in the same tissue. Furthermore it has exposed the fact that there can be large genetic differences even within a patients own cancer, primary tumors being significantly different to secondary tumors. The differences extend beyond the genomic level, as all changes at that level are translated into cellular changes, the up or downregulation of tumor specific proteins may be detectable in the blood as is the case with PSA in prostate cancer.

These differences go some way to explaining why cancer treatment has until now been so hit-and-miss. If cancers of the same tissue can be caused by completely different mechanisms, then it is unreasonable to expect one treatment to be successful with them all.

The advantage we gain from the genetic analyses available to us now is that we can see easily which genes are undergoing changes in the development of a cancer, and investigate them specifically. This will inevitably provide many new cancer biomarkers to help us understand the processes occurring within cancers, give us a clue about the prognosis for the patient and enable us to more precisely target specific processes in the tumor with proven drug combinations.

I recently heard a speaker at a lecture say something along these lines: "We don't need to develop any new cancer drugs, we already have a lot of those, we just don't fully understand how they work or who they will work for, and that is where we need to focus our efforts".