Month: August 2012

When medicine gets personal: the ups and downs of personalised medicine

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We are without doubt one of the worlds most complicated machines. Our bodies are made up of trillions of cells, most of which contain a full copy of our own individual genome. Despite containing identical genetic information individual cells vary hugely in structure and function, for example, just think of the differences between skin and brain cells. This variation is achieved through the specialised way each cell reads it’s own copy of the genome, allowing cells to create only the components they require to function. One of the biggest challenges faced by biologists and medics today is bringing together our understanding of genes, gene processing, cellular and systems biology to gain a better understanding of how our bodies work, and what happens when things go wrong. Such research has lead us to appreciate just how individual we really are! It has highlighted how a combination of genes, environment and even our own compliment of bacteria can profoundly affect the way our cells function and ultimately our health. This ability to delve deeper into our inner workings has also spawned a new field of medicine known as personalised medicine.

Personalised medicine refers to the idea of tailoring treatment to an individual – the right drug or medical intervention for the right patient. In practice this doesn’t mean making a new set of drugs for each individual, instead, it focuses on defining specific groups of people who are more or less likely to respond to treatment. Our current system relies on a ‘blanket’ method of treatment, i.e. everyone suffering from the same ailment will be treated with the same drugs/procedures. However, we now know that differences in genes and gene expression mean that individuals are unlikely to respond in the same way to medical treatments. This may go some way to explaining why between 30% and 70% of patients fail altogether to respond to drug treatment (1). It is ultimately hoped that a better understanding of how genes influence drug metabolism and function will improve both patient prognosis and reduce unnecessary spending on unsuccessful treatments. Indeed, progress is already being made towards a more personal approach to medicine:

One of the first major successes for personalised medicine came from the breast cancer drug Herceptin (Trastuzumab). In approximately 20% of invasive breast cancers a cell surface protein known as the HER is over produced causing cells to replicate uncontrollably. Screening tests have been produced to detect this defect and HER positive patients have been successfully treated with herceptin (an antibody which binds to the HER protein reducing cell replication). This breakthrough was soon followed by the discovery of a genetic abnormality, known as the Philadelphia translocation, associated with chronic myelogenous leukemia (CML). Since a high percentage of individuals with CML (~95%) also express this genetic abnormality, drugs targeted at blocking the protein produced by this abnormal gene were developed as a treatment. One of the most successful of these drugs (Gleevec) has now been FDA approved for the treatment of ten different cancers. These findings show how patient-specific genetic information can lead to improved health outcomes and novel therapeutics.

The scope of personalised medicine is not limited to drug development, it is also being used to assess the long term prognosis and treatment requirements of some cancer patients. A number of genetic screens have been developed to assess the likelihood of tumour recurrence following initial treatment in certain types of breast cancer. One of the more widely used tests, Oncotype DX, assesses 21 different genes found in tumour cells and, from these, predicts the likelihood of regrowth. This means that patients with low recurrence scores, therefore good prognosis, can be saved the stress of further unnecessary therapy and the healthcare system saves on the cost of providing unnecessary treatment. The success of this predictive screen has lead to further research into similar screening for other types of cancer and it is hoped that these tests will soon be widely available as predictive tools.

Beyond cancer, personalised medicine is also being investigated as a way of understanding the adverse side effects linked with certain drug treatments. Current research has highlighted a number of genes associated with drug hypersensitivity and variations in metabolism. It is hoped that this knowledge will, in the future, allow doctors to predict which individuals are more likely to experience adverse side effects to during treatment and tailor their prescriptions and doses accordingly.

However, despite these successes, personalised medicine still has a long way to go before its full potential can be realised. One of the first and arguably most important challenges facing this field will be defining which genetic and cellular abnormalities lead to disease. In a small number of cases this has already been achieved, for example we know exactly what gene leads to to cystic fibrosis. However most disorders are more complex, stemming from abnormalities an any of a number of different genes. Therefore uncovering the precise risk factors for these disorders will require a staggering amount of data from a huge number of individuals. Also, just to make things a bit more complicated, the emerging field of ‘epigenetics’ is now challenging the belief that we are simply the sum of our genes.

[youtube http://www.youtube.com/watch?v=kp1bZEUgqVI]

Epigenetics is revealing how interactions with the environment can change the way our cells read our genetic code. This means that two people with identical genes could still suffer from very different ailments depending on what environmental factors they are exposed to. Finally it is important to consider the ethical implications of these procedures, i.e. data protection, patient confidentiality and access to (perhaps costly) personalised treatments (this is discussed in more depth here).

Although certainly challenging, I don’t think these problems are insurmountable and the gains of personalised treatments will certainly be worth the scientific investment. Therefore, with continued funding and research effort I hope it is only a matter of time before we see more personalised diagnosis and treatment available to the wider public.

Post by: Sarah Fox

(1): Progress towards personalized medicine, Stewart Bates, Drug Discovery Today 2010. Subscription required for full access.

The neuroscience of race – is racism inbuilt?

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The topic of race is one of fierce debate; never far from our minds and commonly discussed both in the media and down the pub. Britain is one of the most diverse and multicultural countries on the planet but the development of this multiculturalism has grown from a torrid past and race relations continue to dominate the national psyche. The ever-growing diversity of our country means that race relations are becoming more and more crucial to many socio-political advances. Indeed a number of intergroup interactions come to the forefront every year, with prominent events from this year including the allegations of racial abuse against former England football captain John Terry. Understanding what defines our prejudices and creates these racial tensions is an aspect of race relations which does not receive widespread media coverage, despite its potentially major implications for society – so what is currently known about the neuroscience of race?

Most of the early work on race relations came from the field of social psychology. Henri Tajfel and John Turner were early pioneers of ‘social identity theory’ – a theory which explores people beliefs and prejudices based on their membership and status within different social groups. Their work at the University of Bristol (UK) in the 1970s described the phenomena of ingroups and outgroups. They assigned volunteers to one of two groups based on relatively superficial preferences, i.e. individuals may have been assigned to a certain group due to their appreciation of a certain style of art. Individuals within these groups were then asked to rate their preference for other volunteers either within their own group (ingroup) or in another group (outgroup). Tajfel and Turner consistently found a prejudice towards the outgroup individuals and a preference for ones ingroup. This research suggests that we have an innate mechanism of preference towards those who we perceive to be similar to ourselves over those who are ‘different’ – no matter how insignificant or trivial that difference may be.

Interestingly this inbuilt prejudice can be masked, as is often the case in similar studies using different racial groups. However, recent neuroscience research suggests that prejudices may still exist despite the conscious effort to hide them.

Research by Elizabeth Phelps and colleagues at New York University (US) believe they have uncovered one of the brain pathway involved in determining reactions to faces of different race. This research provides some intriguing insights into our views of different racial groups. Using fMRI (functional magnetic resonance imaging), Phelps and her team have discovered a network of interconnected brain regions that are more active in the brain of white participants in response to a picture of a black face than to a white face.

This circuit includes the fusiform gyrus, amygdala, ACC (anterior cingulated cortex) and the DLPFC (dorsolateral prefrontal cortex). Activity in the fusiform gyrus is not surprising, since this region has been linked to processing of colour information and facial recognition. Intuitively, this region should play a simple role in the initial recognition of a black face. The next region in this circuit is the amygdala. The amygdala is responsible for processing/regulation of emotion and it is here where the circuit becomes more intriguing. A simple explanation of amygdala involvement could be that black faces evoke more emotion in white participants than white faces. Further along the circuit the roles become more complex as we move into the higher areas of the brain. The ACC and the DLPFC are regions that have both been linked to higher order processes. The ACC is commonly reported to be active in tasks that involve conflict. This region is commonly activated in tests such as the ‘stroop test’: this involves naming the font colour of written words which either agree (BLUE) or disagree (BLUE). In this case, the ACC is active during the second conflicting task. The DLPFC is one of the most sophisticated areas of the human brain, responsible for social judgement and other such complex mental processes.

A study conducted by Mahzarin Banaji and a team from Yale and Harvard Universities in the USA may explain why activity is seen in areas involved in conflict resolution and social judgement when viewing ‘outgroup’ faces. This research showed that activation of these pathways was time dependent. When images of ‘outgroup’ faces were flashed for a very short time (30 milliseconds) significant activation was seen in the fusiform gyrus and amygdala but none was observed in the ACC or DLPFC. However, when these images were shown for a longer period of time (525 milliseconds) activity in the amygdala was virtually abolished, replaced by strong activity in the ACC and DLPFC. This research yields vital insight into the role of the ACC and DLPFC and the possible presence of inbuilt prejudice. One interpretation of these findings is that after a short presentation, the ‘raw’ inbuilt activity is strong, showing unintentional emotive activity to ‘outgroup’ faces, while after the longer exposure time this activity is abolished by the influence of the ACC and the DLPFC, which provide a more rational regulation of this response.

This suggests that a member of today’s society knows consciously that racial prejudice is wrong and so activity in the DLPFC could represent a conscious decision to be unbiased. The ACC activity may represent conflict between this conscious DLPFC process and the subconscious emotion seen in the amygdala activity. Obviously, a mere increase in amygdala activity does not necessarily signify negative emotion. Therefore this automatic activity may not represent inbuilt racism, instead it may simply reflect heightened awareness and deeper thought when assessing faces from another racial group. However, one thing it does highlight is the obvious differences in the processing of ‘outgroup’ faces.

This research could have serious implications for our understanding of inter-race relations. Therefore, although this activity is subconscious and unlikely to be linked with conscious racial discrimination, it may still play a key role in influencing how we go about our daily lives – choosing jobs, places to live, friends and so on. However, since our brains are malleable, racial prejudice such as this can be lessened, a prime example being through inter-racial friendships and marriages. It is possible that this ingroup vs. outgroup association of race will diminish more and more as our education and upbringing continues to become more multicultural. But for now, easing these racial divides may take a lot of thought.

Guest Blog by: Oliver Freeman @ojfreeman

References (only accessible with subscription):

  • Kubota et al. The Neuroscience of Race. Nature Neuroscience
  • Cunningham et al. Separable Neural Components in the Processing of Black and White Faces. Psychological Science

Learn a little more about Oliver:

My research looks into the effects of diabetes on the nervous system. Diabetes is nearly 4 times as common as all types of cancer combined and around half of those with diabetes have nerve damage. Most people are not aware of this very common condition and I am trying to increase awareness of the disorder and understand what causes diabetic patients to feel increased pain and numbness/tingling in their hands/feet.

Parasitic worms: Friend or foe?

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Intestinal parasites infect more than a billion people world-wide, of which approximately 10% become ill. Although the thought of parasitic worms may be enough to turn people’s stomachs and put them off their food, for some sufferers of severe auto-immune diseases these worms may actually be able to provide relief or even remission of symptoms. We understand the negative effects worms can have such as nausea, vomiting and weight loss. However, research is now highlighting circumstances where their presence may indeed be beneficial in relieving symptoms of a number of diseases.

Helminthic therapy is a type of treatment where patients suffering from immune diseases are deliberately infected with parasitic intestinal worms in the hope that this will relieve their symptoms. Although this therapy is relatively new, there are a handful of promising studies indicating that worms may indeed represent a viable treatment for these diseases.

One of these studies was carried out by P’ng Loke, a parasitic immunologist. Loke’s work centred on the study of a man he met in 2007 who he later found had deliberately infected himself with parasitic worms. At first glance the man appeared to be perfectly healthy with nothing more than a genuine interest in parasites. However, it was soon revealed that, in an attempt to cure his inflammatory bowel disease (ulcerative colitis), he had infected himself with human roundworm which burrowed into the lining of his colon. Ulcerative colitis is an auto-immune disease characterized by open sores in the colon lining leading to intense abdominal pain and vomiting. Although the precise cause of this disorder is not well understood, severe cases have been linked to disruptions in mucus production within the colon. After coming across the controversial work of the parasitologist Joel Weinbeck, the man ingested a large quantity of the worm and was soon symptom free.

Endoscopic image of a bowel section known as the sigmoid colon afflicted with ulcerative colitis. The internal surface of the colon is blotchy and broken in places.

Colonoscopies of his intestines following infection revealed that wherever the worms formed colonies, there was a concurrent decrease in the number of ulcers. This decrease in ulceration is believed to be a beneficial side effect of the body’s immune response against these worms. Upon infection the body’s immune system increases production of both inter-leukin IL-22 (a protein important for healing the colon lining) and a number of mucus-producing cells found throughout the colon. This increase in intestinal mucus forms a protective barrier across the surface of the gut, protecting it from bacteria and thereby reducing inflammation.

Along with a possible role in the treatment of colitis in humans, studies in animals have found that infection with worms can either alleviate symptoms or entirely protect against diseases such as asthma, rheumatoid arthritis and some food allergies. A role in Crohn’s disease (a long term condition causing inflammation of the lining of the digestive system) has also been suggested. Results from a clinical trial show that ingestion of swine whipworm causes remission of symptoms in 72% of cases, and improvement but not remission of symptoms in a further 7%.

What is interesting is that the prevalence of auto-immune diseases in the developed world is high, but the incidence of parasitic worms is relatively low. In contrast, in the lesser-developed world where the incidence of worms is high, the occurrence of auto-immune diseases is sparse. Could it be that in our quest for sanitation and clean water, we may have damaged one of our friends, one of our bodies natural source of defence against itself; the intestinal parasite?

Although some cases show evidence that parasite infection may play a role in protecting against certain disorders, it is still impossible to predict how any one individual will respond to such an infection. Indeed, it may be the case that in some patients the worms may cause more harm than good. Therefore continued research into safe and effective forms of helminthic therapy is required before we can truly distinguish these parasites as friend or foe!

Post by: Sam Lawrence

Science fiction vs. science fact: The use of viruses to cure disease

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Several popular blockbusters, including I Am Legend and Rise of the Planet of the Apes, have envisioned the use of viruses, rigged to deliver therapeutic DNA to patients as a way of curing disease. In these films the scientists using these techniques are ecstatic when they discover that they’ve been successful, but their joy quickly turns to horror as the virus mutates out of control and begins to destroy the human population. This is undoubtedly a nightmare scenario, but how close do these films come to the truth? Can viruses, commonly known to cause disease, actually be used as a cure? How likely is it that they will mutate out of control and destroy the world? If this is the case, then why are they being used at all?

Viruses are responsible for a range of diseases, including the common cold, influenza, HIV (Human Immunodeficiency Virus) and Ebola. The sole selfish function of a virus is to infect a host (e.g. a human) then use this host to make more copies of its own DNA. It does this by entering a host cell and hijacking its DNA-making machinery, forcing it to make more viral DNA. However, it doesn’t stop there. Once the host cell has made sufficient viral DNA the virus then commandeers the host cell’s other machinery to create more intact viruses which “bud off” from the infected cell ready to infect its neighbours.

So, if viruses are so deadly and infectious can they seriously be used to cure disease? Surprisingly, the answer is yes. The use of viruses to deliver new DNA to human cells is being investigated as part of a technique known as Gene Therapy.

Certain diseases, such as cystic fibrosis, are caused by known defects in a single gene. The idea behind gene therapy is to fix damaged DNA. This can be achieved by either swapping the defective gene for a working one, repairing the damaged gene by mutating it back to a healthy form or by “switching off” the defective gene. Viruses are being investigated as carriers or ‘vectors’ for delivery of new, undamaged, DNA. However, gene therapy cannot offer a miracle cure for all known disorders. In fact it is only a feasible treatment for disorders stemming from a small number of recognised genetic mutations. Therefore, the idea of a single gene therapy functioning as a cure for Alzheimer’s or all known cancers, as seen in the movies, is purely fictitious!

[youtube http://www.youtube.com/watch?v=0qPYMkZqEjc]

A typical virus consists of a viral-coat (like the skin of a balloon) enclosing DNA and a small number of proteins. In gene therapy, the virus is modified so that its DNA is replaced with DNA required for the therapy. The virus is then injected into the patient where it targets and infects cells, replacing damaged DNA with the new healthy DNA. The part of the virus which allows it to replicate has been removed, meaning that whilst the virus retains the ability to infect cells and alter DNA, it has lost the ability to replicate itself and infect neighbouring cells (this infectious ability is called virulence).

Viruses which are currently being investigated for use in gene therapy include: adenovirus (responsible for the common cold), retrovirus (HIV is a retrovirus) and Herpes Simplex virus (as the name suggests, is responsible for herpes infections and also cold sores). Part of the appeal of using viruses in gene therapy is that they may be used to target healthy DNA to specific cell types. This can be achieved by manufacturing viruses which can recognise and infect only certain types of cell. This means that “innocent”  cells which are not expressing the disease-causing gene should not be infected.

In the films, the therapeutic virus mutates back to its virulent form, or an even more virulent one. It then spreads a fatal disease throughout the population, causing a global catastrophe. One of the concerns about using viruses for gene therapy is that this nightmare scenario might come true. This possibility is currently under intensive study within controlled research environments. Although current research has found that recombination and a return to virulence may be possible for certain viruses, this may not be the case for all viral vectors used in gene therapy. However, if this technology is proven to pose a real risk then such research will likely be discontinued.

There are also other problems with using viruses as DNA carriers. The introduction of any foreign material into the body is likely to produce an immune response. The surface of the viral-coat is not smooth, it actually expresses a number of extruding proteins which may be recognised by a patient’s immune system. This means that the host’s immune system may recognise the foreign body and attempt to dispose of it. Strong immune responses can be fatal, especially in someone already weakened by a genetic disease. This problem could, in theory, be circumvented by removing proteins and other foreign bodies from the outside of the virus to lessen the chances of it being recognised as a foreign object.

Currently, gene therapy using viral vectors is not approved by the U.S. Food and Drug Administration (FDA) since concerns have arisen surrounding the deaths of two patients participating in gene therapy trials. One died of a severe immune response to the viral carrier. The other appeared to develop leukaemia, leading to fears that viral vectors may cause cancer.

A liposome

There are alternatives to using viruses for gene therapy. One option is to use liposomes, small balls of lipid (fat droplets found in the cell membrane) which contain the DNA needed to fix the gene. These shouldn’t produce an immune response since liposomes are made from materials found naturally in cells. However, the disadvantage of liposomes is that they can’t target specific cell types. Another alternative is to simply inject the DNA directly into target cells. The advantage of this is that it won’t cause an unwanted immune response. However, injecting DNA is an immensely tricky process and may only be possible with certain types of cell. Also, since this ‘naked’ DNA does not integrate well into cells, it may not be expressed as reliably as DNA delivered by other methods.

So how likely is it that in the future viral vectors will be used to help cure disease? Although the process is still in its infancy and concerns over its feasibility need to be addressed the principle is promising. Indeed, there have already been some positive steps towards implementing these techniques! In 2008, a group at University College London (UCL) used gene therapy to successfully improve the sight of a patient with the eye disease Leber’s congenital amaurosis. The patient suffered no adverse effects since the study used an adeno-associated virus, a strain which cannot replicate itself without the addition of a partner virus. The adeno-associated viral DNA also usually inserts itself into a specific region in chromosome 19 (whilst insertion from other viruses may be random), meaning it is less likely to interfere with other functional DNA.

Therefore there is still hope that viruses can be used as vehicles for gene therapy. If current problems can be overcome, it may prove to be a revolutionary method for treating ‘single-gene’ diseases. Indeed, it is unlikely that viruses will cause the apocalyptic effects seen in these films, since any reversion to virulence is likely to be caught long before it infects the general population. But that wouldn’t make for such entertaining viewing would it?

References:

http://learn.genetics.utah.edu/content/tech/genetherapy/

http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml

Post by: Louise Walker