Making personalised medicine for cancer a reality

Judith Potts appeared in the Telegraph today discussing the future of cancer treatments.  Her article, on defining cancer by its molecular attributes as opposed to region in the body, highlights where research should be going.

It’s becoming clearer to scientists that lumping cancers as ‘breast’, ‘ovarian’ or ‘lung’ may not be useful when it comes to treating a patient.  Within each type of cancer there are many sub-types, which are all categorised depending on their molecular, genetic and physical characteristics.  But there is overlap between sub-types of one cancer, which blurs the boundaries that define them.  Cancers can also change during progression of the disease, masking their categorised features and developing new ones.

Cancers are also individual.  Tumours derive from the patient’s own cells and so each cancer is individually characterised by the genetic and environmental factors that have influenced that person’s life.   We know that certain genetic mutations are more likely to occur in certain cancers but the individuality of cancer means we can’t expect a blanket treatment for all patients with one type of cancer.

Judith proposes that molecular profiling for individual cancer patients is the way forward, and I am inclined to agree.  This method looks at a wide range of molecular markers that each represents a particular weakness in the cancer.  A clinician could then use this information to match up each weakness with a drug to exploit it.  This would be done on data gathered from a tumour of an individual patient, providing a clear road towards fully personalised medicine.  Clinicians could also get around the evolving cancer problem by taking new molecular profiles from the patient at different points in their disease and adapting their treatment accordingly.

This type of care for cancer patients is already available in some countries, if you can afford it, but there will be several problems to overcome when the technology becomes widespread.  Biotech companies that patent molecular profiling kits could increase costs.  Confidentiality around their product could also hide whether or not the molecular profiles are accurate.  This could lead to patients receiving an ineffective treatment or a treatment that causes harm.

There is also the issue that drugs approved for use for say lung cancer, may not have been tested against breast cancer.  Molecular profiling might tell you that a patient’s cancer has a weakness for that drug, but you would struggle to be able to give it to them.  And what about new experimental drugs?  With no evidence from clinical trials it wouldn’t be possible to use one even if you knew that the patients cancer would be sensitive to the treatment.  One way around this would be to reassess how clinical trials are set up and allow for greater flexibility in trial design (a discussion for another time).

Molecular profiling is on the horizon and offers obvious benefits to the way we treat cancer.   However, for it to work, the policy and healthcare system needs to evolve with the science.

Are carbs really the key to preventing brain disease?

The Times recent promotion of a new book by neurologist, David Perlmutter, raises some interesting questions t regarding the evidence base behind the books claims.  David’s book is called ‘Grain Brain: The Surprising Truth About Wheat, Carbs and Sugar – Your Brain’s Silent Killer’ and asserts that gluten consumed through wheat and grains are responsible for triggering brain disorders such as depression, dementia, schizophrenia, epilepsy, ADHD and decreased libido.  Let’s take a look at The Times piece and see if there is any merit in the claims.

David is quoted as saying; “The origin of brain disease such as dementia is predominantly dietary, he says, and the result of us consuming too many carbohydrates (particularly wheat-based bread and pasta as well as sugar) and too few healthy fats”

Straight off I think the word dementia has been misused here as (according to Alzheimer’s Society) dementia is an umbrella term used to describe the symptoms that occur when the brain is affected by certain diseases or conditions.  So dementia is not a brain disease but a symptom of a brain disease – the most common one being Alzheimer’s.

Now while there is some evidence for diet as a contributing factor to lifetime risk of Alzheimer’s disease it has in no way ever been concluded as the predominant factor.  Alzheimer’s Research UK and the NHS both state that age, family history, genetics, smoking and other diseases including  diabetes and obesity all increase lifetime risk of Alzheimer’s.  The only mention of ‘carbohydrates’ comes from a recommendation that people with diabetes need to control their blood glucose.

David continues to point out that; “Researchers have known for some time that the cornerstone of brain disorders is inflammation, he says. Gluten — consumed through wheat and other grains — and a high carbohydrate diet are among the most prominent stimulators of inflammatory pathways that reach the brain”

It would be hard to dispute that there is a link between inflammation and brain disorders such as Alzheimer’s, but to state that high carb diets are ‘the cornerstone of brain disorders’ because of potentially eliciting an inflammatory response seems a little far-fetched.  In fact, most people would argue that the greatest risk factor for Alzheimer’s is age.  Whether gluten and a high carbohydrate diet constitute a ‘prominent stimulator of inflammatory pathways that reach the brain’ is something I am not aware of, or know particularly much about, but I have yet to read anything to convince me.

Permultter argues that people should move onto a low-carb, high-fat diet, in order to protect themselves from brain disease.  To suggest nutrition is that simple is irresponsible.  Nutritional demands to sustain a healthy lifestyle are individual and increasing foods such as fats (suggested from cheese, meat, butter and eggs) could put some people at increased risk of other diseases.

It has been pointed out that very low carb diets can be a therapeutic tool for treating some neurological disorders.  However, it has been noted that ‘recommending a low-carb diet as an intervention for sick people is very different from promoting it as a preventative measure for the entire population, which is what Dr. Perlmutter does in Grain Brain’.

The truth is that we don’t know a great deal about the risk factors for brain disease, nor do we understand how they interact with each other or the level of risk each poses.  It has been stated by others more knowledgeable of this field than me that ‘which also suggest an element of blame towards the person with the condition, are unhelpful and do not do justice to the complexity of these diseases’.

Thanks to @_josephinejones for the article info

Belief in medicine with no evidence

The term ‘blind faith’ is usually attributed to someone who holds strong beliefs even when there is a significant body of evidence suggesting that they are wrong.  It is something I have struggled against when trying to engage alternative medicine supporters in the reliability of medical treatments that lack an evidence base.  Blind faith can make conversations extremely frustrating, when no matter how much evidence you present, you can’t even for a second bring that person to question their belief.  For a while I would stay engaged in conversation, mistaken that the other party would comment rationally on what I showed them, but it never happened.  However, I don’t consider these exchanges futile, because it has made me ponder on blind faith and why it’s rampant amongst the alt-med community.

I am not a psychologist and would not profess to know anything about the subject (therefore any comments on statements I make below would be appreciated for my own learning).  Luckily, the internet is vast and I found that The Tao of Reason blog provides a great introduction to the psychology of blind faith.  Essentially, any evidence that conflicts with your own beliefs, leads to discomfort (referred to as cognitive dissonance).  When these beliefs are strong, as with blind faith, the subject will dismiss this evidence by any means in order to justify their views.  This refusal to accept evidence or even rationalise in the face of it could explain the dismissive nature of the alt-med community.  The Tao of Reason goes on to suggest that when faced with compelling evidence, blind faith can cause people to not only discredit the evidence, but also strengthen their beliefs.  So perhaps these engagements are actually fuelling the belief that a certain alt-med is effective.  In a scenario where no matter how much evidence is presented will change someone’s way of thinking, is it worth debating?

This notion of defending ones belief by dismissing even the most compelling evidence is something I have seen a lot.  Someone may defend their view by making a sweeping positive statement.  You can show them that this statement is flawed and provide direct evidence to support it and in return you will usually get a second defending statement with no bearing on the first or any clear response to your rebuttal.  This is what can be frustrating and denies the conversation from ever reaching a rational debate.  In the case of homeopathy, there is compelling evidence that it is not biologically, physically or chemically plausible (Avogadro’s constant and beyond).  Yet the homeopathy industry continues to thrive on a culture of blind faith amongst supporters.  This is because elaborate dismissals of the evidence against homeopathy are constructed to defend the belief that it is plausible.  This is also not helped by the fact that misleading and bogus pseudo-evidence is allowed to accumulate in the academic press.

The fact that the belief system is so rigorously sustained in that person’s mind means that removing it would leave an incomprehensible void.  Perhaps it is this dissonant void that religious converts or people that lose faith in their religion experience.  If so, then at least we know that there is a possibility to alter a person’s belief about alt-med, no matter how steadfast they are.  What is important is that in the process of challenging medicine with no evidence we don’t lose sight of the rational and critical thinking that leads us to do so.  New evidence is presented all the time, and we must be willing to change our own views, if there is any hope of changing someone else’s.

A disease shaped by history

Breast cancer, like all cancers, is a highly complex disease.  The combination of genetic mutations, environmental pressures and lifestyle choices make it difficult to pin down causation.  Plus the fact that each cancer is a product of self adds a level of individuality that only impairs classification.  New research out this week exposes the complexity of breast cancer and also highlights a strange correlation between race and risk.

The use of hormone replacement therapy (HRT) to reduce the symptoms associated with menopause has long been associated with an increased risk of breast cancer.  The study published this week shows for the first time how other factors combine with HRT use to affect breast cancer risk.  Amongst other things they discovered that factors like body mass index and breast tissue density determined the level of risk a women was at from using HRT.  The researchers also looked at any correlation with race and found that there was at least a 20% increased risk from HRT use amongst white and Hispanic but not black women.

The statistics on ethnicity and breast cancer are complex.  In the US, white women have the highest overall risk of breast cancer, while black women are much more likely to die of the disease.  There is a higher incidence of BRCA mutations amongst Eastern European Jewish (Ashkenazi) women, thus they have an increased risk of hereditary breast cancer.  Women of African ancestry seem to be at an increased risk of developing more aggressive forms of the disease such as triple negative breast cancer (TNBC).  Male breast cancer is also more prevalent amongst men of African ancestry than any other ethnicity.

But why is this?

Ashkenazi Jews can trace their roots back to a small Jewish community with origins to the ancient Israelites of the Middle East.  Generations of reproductive isolation following their movement into central and Eastern Europe may have contributed to specific genes becoming prevalent.  The general idea is that random changes to genes that confer a survival advantage will inevitably replicate within a population and come to dominate the genetic landscape by a process called adaptive evolution.  The problem with this theory is that BRCA mutations would have to confer a survival advantage, which as of yet, no one has managed to ascertain.

In depth studies into the statistics, genetics and variation in BRCA mutations amongst modern Ashkenazi Jews suggest that processes such as random genetic drift and the founder effect are more likely to be responsible.  These phenomena may have occurred due to a population bottleneck when a small portion of Ashkenazi Jews migrated to Europe.  If the majority of these migrants carried BRCA mutations then natural selection would not remove them from the population, rather they would remain dominant, creating a drift in Ashkenazi genetics that has remained in modern descendants.

So what about the fact that TNBC is much more common amongst women of African ancestry?

This is still a bit of a mystery but one recent study of breast cancer genes found several mutations that were more prevalent in the African American population.  Moreover, these mutations were strongly associated with triple negative breast cancer, suggesting that genetic predisposition may play a big part.  It turns out that BRCA mutations are also linked with triple negative breast cancer so it has been postulated that African ancestry might be associated with a hereditary disposition to TNBC.

Genetic and population history sets out a nice story explaining the relationship between racial history and diseases.  Of course it’s interesting to put the timeline of events together but the real benefit will come from knowing how to use it to improve prevention so that incidence and risk is not confounded by ethnicity.

Stratton stirs up a ‘thunderstorm’

A couple of weeks ago, the charity I work for hosted the 2nd International Triple-Negative Breast Cancer Conference at Church House, London.  On a long list of distinguished speakers was newly knighted, Professor Sir Mike Stratton, from the Sanger Institute in Cambridge.  Mike Stratton has strong links with the charity I work for (Breakthrough Breast Cancer), having been involved in some of their earliest funded research, which resulted in the discovery of the BRCA2 gene.

Image: Sanger Institute

Professor Stratton has been a key player in the emergence of whole cancer genome sequencing and its use for advancing cancer research.  He started the Cancer Genome Project at the Sanger Institute; work which led to the identification of cancer-causing mutations to a gene called BRAF and rapidly led to the development of successful treatments.  Most recently he embarked on an ambitious project to understand the mutational processes that continually bombard DNA and lead to the development of cancer.  It was the impact of this work on breast cancer research that Mike presented at the conference.

Mike’s work grew out of a hypothesis that cancers could be defined by the genetic mutations they have accumulated through-out their life.  It was known that different mutagens (such as tobacco or UV-radiation) cause very specific types of mutation to DNA but what we didn’t yet know was how large numbers of these mutations combine over time to produce what is called a ‘mutational landscape’.  So the question Mike wanted to address was can we define cancers by their mutational signature (or landscape) and use this information to understand the mutational processes that mould cancer genomes?

Taking whole genome sequences of tumours from over 7000 cancer patients, ranging across 30 different types of cancer, the team found that all human cancers shared 21 mutational signatures.  Some of these signatures were common to all cancers, suggesting they are early stage mutations that may drive cancer initiation.  Others were restricted to single types revealing specific genomic patterns attributed to certain cancers.  With regards to breast cancer, Mike and his team showed that 5 of the 21 signatures were operative, but the combination of these 5 signatures was highly diverse across individual breast cancer cases.

They used this information to mine the literature and find a protein that may be responsible for producing the kind of mutations they were seeing in breast tumours.  What they discovered was a protein called APOBEC could explain the signatures observed in breast cancer patients.  What was of particular interest was that APOBEC is usually involved in the immune response to viral infection such as HIV or Hepatitis B.  The suggestion made was that response to a virus early on in life may cause an increase in the activity of APOBEC, which if remains sustained, could produce cancer causing mutations and the signatures observed in Stratton’s analysis.

Even more remarkable then this finding was the presence of a genetic phenomenon termed by the team as ‘kataegis’ – Greek for thunderstorm.  Kataegis refers to clusters of mutations that appear in cancer genomes at defined regions along DNA.  They are beautifully represented in ‘rainfall plots’ which show clusters of mutations and their position along the genome.  When the team took a closer look at the mutational signatures of breast cancer they noticed that many of them were similar types and wondered if APOBEC could be responsible for kataegis.  It turns out that yes it can.  When you genetically engineer yeast to make lots of APOBEC their genomes show a similar pattern of kataegis.

Rainfall plots showing 'kataegis'

Rainfall plots showing ‘kataegis’

So there appears to be a role for APOBEC driving historical mutations that could, in turn, drive more mutations in the region and result in kataegis.  This is highly significant because it gives a sort-of ‘back in time’ perspective of cancers genetics.  This in-depth information could have massive impact on our understanding of cancer causation and what we can do to prevent and treat it in the future.  I think that this work really highlights the power of whole genome sequencing and if anything, demonstrates why we need to continue funding genomics research.  Mike Stratton has done exceptional work to lead the way in cancer genomics and his contributions to science are in doubt deserving of a knighthood.

Genomic privacy – is it possible?

In the wake of Edward Snowden’s whistle-blowing on the NSA, the public debate over personal security has never been so heated.  The global concerns over privacy filter into all domains and no less in the spotlight is the ever-evolving field of human genome sequencing.

In 2004, the first ever human genome sequence was published; reporting in A’s, T’s, G’s and C’s the twenty or so thousand genes defining what makes a human being.  This was the culmination of the 14 year long Human Genome Project (HGP), costing billions.  Less than 10 years later and we are on the cusp of the ‘£1000’ genome – accomplishing what the HGP did in a matter of days and for a (ridiculous) fraction of the cost.  Although technologies and methods have been refined, the debate over ethics and privacy of genome sequencing has always remained an issue.

Even at conception it was realised that the HGP would bring with it serious social and ethical implications.  In 1988, Thomas Murray – then Director of the Centre for Biomedical Ethics – pushed to have 3% of the budget allocated to dealing with ethical, legal and social issues.  His concerns were with issues of ownership, who would be allowed to use the data, the accuracy of the information and how to control access to the data.

In 2010, these sentiments were echoed again when the ‘UK10K’ project was launched by the Sanger Institute.  This project aimed to sequence 10,000 genomes of patients with specific diseases to build a database for global genetic research.  The ethics report behind UK10K leaned heavily on data access, ownership and how to communicate the findings.  This year, to celebrate the 65th anniversary of the NHS, the Government announced an ambitious project to sequence 100,000 genomes as part of Genomics England.  Again, the same ethical and social considerations have been thrown into light.

But is there any basis for these concerns?  Advocates would argue that genome sequencing will lead the way for discovery of the genetic basis of complex diseases, allowing new treatments or even cures to be developed.  The main ethical consideration can be summed up in a quote by Professor of Philosophy and Ethics Carol Tauer – “the notion that our genes are the program that determines who we are, and that when we know all the genes we will know the human being, both generically and individually”.

We can see evidence of this as recently as March 2013 when German scientists published the genome of the common laboratory cell line, HeLa.  More personally, they published the genome of Henrietta Lacks, the women whom the HeLa cell line was originally obtained.  Henrietta died in 1951 but the release of her genome into the public domain still sparked international controversy.  The descendants of Henrietta were never consulted before release of the genome which raised concerns over whether there was any consent given.  Henrietta’s genome was quickly retracted and remains private while the ethical debate continues.

Henrietta’s family have right to be concerned – after all, information derived from her genetic code could provide sensitive data on her descendants.  As such, many people have concerns that the misuse of genome data could potentially lead to an individual being identified and provide an avenue towards ‘biological spying’.

But how easy is it to identify someone from their genome?  One man put it to the test.  Yaniv Erlich, a computational biologist from the Whitehead Institute for Biomedical Research, published a report in 2013 exposing the vulnerabilities in databases holding sensitive genomic information on individuals.  Yaniv had the idea that by using short tandem repeats (STRs), or the portions of DNA used to identify individuals, he could hunt through public genealogy databases and find a name.  He tried it out on a full genome that was published in 2007.  Using the STR profile of the Y chromosome Yaniv scoured a genealogy database and found a few likely candidates.  Digging a little deeper he discovered one name which matched the location and age of the donor listed in the genome publication.  It belonged to J. Craig Venter – the genomics pioneer who was publicly known to be the owner of that particular genome.

This was merely a proof of concept for Yaniv and he used Venters genome as it wouldn’t raise any ethical concerns seeing as the information was already public knowledge.  Yaniv moved on and tested his method against anonymous donors with disturbing results.  His team managed to identify nearly 50 people from apparently ‘anonymous’ DNA donors.

So as the genomics era soldiers on we are continually met with the same concerns that were there at the birth of whole genome sequencing.  It will always be a struggle to maintain a balance between ethics and scientific advancement, particularly when it involves information as personal as your genetic code.  With increasing technical capabilities and the exponential growth of personal data available freely on the web – security, privacy and anonymity may never be guaranteed for those promised it.

It seems obvious that better safeguards need to be offered so people can feel more comfortable with supplying genetic information.  But how we go about it is a complex issue spanning science, ethics, policy and law.  What we should aim to emphasis is that the privacy issues should never retract the importance of whole genome sequencing to medical research.  Genetic studies such as the Cancer Genome Project at the Sanger Institute have revolutionised our understanding of cancer and led to the development of successful treatments.

In an attempt to expose the exploitation of personal information by the US Government, Edward Snowden has ignited a revolution in digital privacy, a move that may cost him his freedom.  Let’s hope that something so drastic doesn’t have to happen in the future in order to protect the one thing that makes us truly individual – our genome.