minimolecule

This Data is Positively Negative!

“Positive data, positive data, positive data” – says the overbearing supervisor. What does it all mean? Well, essentially the terms positive and negative can only exist if you have a pre-existing stance on the outcome of an experiment. Scientists design experiments to test hypotheses. Indeed some of these experiments have a desirable outcome. That outcome being “a piece of the puzzle” or positive data, which falls beautifully with a little click amongst “puzzle pieces” of existing data you may already have before you.

However, the trick is to realise that there isn’t an existing puzzle to fill in the first place. I believe the best scientists are the ones that recognise that you’re not following a picture on a box. There is no box, there is no bloody template. Every time you conduct an experiment, nature is throwing a piece of a puzzle at you, some puzzle, not one that you’ve seen before. It’s your job to figure out if you can click some of these pieces of data together to complete a picture or even a partial picture which exists as a snapshot. For a moment this will be considered the prevailing thought on one of the mysteries of nature, until we discover more pieces to add, which ultimately adjusts the picture again.

This means negative data is just as important as positive data. A discovery that doesn’t fit in with what you have, is just as important as one that does fit the existing data, because it could be the missing part of another puzzle. Knowing to distinguish between the two and being nuanced about this is a delicate skill that can sometimes evaporate with the pressures of being a scientist.

Science is about truth. We as scientists cannot assume everything is true just because it fits a picture on a box. If we throw the box away we can appreciate that negative data is in fact a beautiful discovery in itself, because its no longer negative data, its just data, really useful data.

image credit: http://www.american-buddha.com/mondo.negative-positive.htm

Metabonomics: Seeking Meaningful Signatures In Your Biological Fluids

In the first of a new interview series for minimolecule.com, I caught up with Dr. Toby Athersuch to understand the rapidly growing field of metabolic profiling. This research is allowing scientists to analyse blood, urine, plasma and other biological fluids to help characterise disease states and advise on potential treatment and prognosis. It is also critical in developing new non-intrusive diagnostic techniques and may make the science-fiction-eque rapid diagnosis using a handheld bioanalytic instrument a reality!

What is metabolic profiling?

In broad terms, metabolic profiling (also known as metabonomics) is the
study of small molecules (metabolites) in biological systems. We are
interested in finding out what they do and why they change. Typically, we
use spectroscopic analysis to provide direct information of the identity
and relative concentration of many metabolites at a time, in different
complex biofluids/tissues (e.g. urine, blood, saliva) that we can sample
easily. Each spectroscopic technique we can use (and there are many)
reports on a subset of the whole, which we term the metabolome.
Investigating the metabolome can be very informative, and report on a
large number of processes in biological systems; in humans, the metabolome
is influenced by our own genetic makeup, environment, lifestyle,
occupation, and health status. Finding out which of these factors
influence the metabolome is a big part of profiling research; in many
cases, it helps to be broad-minded – if we approach our analysis with no
preconceptions (an agnostic, or untargeted approach) then we may find
signals related to our factor of interest (disease etc) that we have not
yet encountered. In this way we can start working out what these things
are, and why they might be interesting. My own research at Imperial is
involved in research aimed at characterising how metabolism is influenced
by environmental exposures, and what consequences this has on our risk of
chronic disease.

What determines a good biomarker?

Foremost, high specificity for what it represents, as this helps us be
sure that we are observing relevant changes, and that they are not
confounded by other processes. If I had a wishlist for other attributes, I
think I would opt for the following: presence in an easily accessible
biofluid/tissue (easy to get), easily detected in that biofluid/tissue
(easy to measure), a large response relating to the factor of interest
compared to normal physiological/inter-individual variation (easy to see a
response), and good translation between different biological systems (easy
to relate results at the lab bench to those in the clinic). It¹s usually
not that straightforward!

NB: These issues were recently addressed in relation to drug development
by the Predictive Safety Testing Consortium (PSTC).

Does the the metabolite profile in urine and other biofluids reflect a
disease state well?

It depends. How well one can relate changes in the metabolome to a

particular disease or treatment will depend on several factors. In
general, because metabolites mediate and regulate so many biological
processes, finding changes in one or more of them can not only tell us
about disease state, but also about the biological mechanisms that are
responsible. Other techniques can obviously be very complimentary to this,
and help get a better picture of the system we are interested with as a
whole. Additionally, I would note that different biofluids report on
different things; urine offers a good idea of the pooled excretion of
metabolites over a period of time, whereas blood is effectively an
instantaneous picture of circulating metabolites. Choosing a suitable
biofluid to sample is obviously a good start to any investigation of this
nature!

Do you feel metabonomics has a big role to play in developing more
targeted therapies and have there been any success cases so far?

The tailoring of healthcare to the individual (personalised healthcare
and precision medicine) will benefit a lot from the involvement of
metabolite profiling approaches. It has already been shown by researchers
at Imperial that the metabolism of a drug can partially be predicted by a
urine sample provided before administration pharmacometabonomics
recently reviewed in [1]. Developing this idea to relate to predicting
drug efficacy, surgical success, and therefore determine a more optimal
course of treatment is a priority for researchers in the field of medicine
at present. There has been considerable success in applying metabonomics
within the field of cancer research over recent years; cancer cells
typically have several metabolic traits that distinguish them from normal,
healthy cells, and these can be exploited from several angles including
diagnosis, patient stratification and drug efficacy monitoring.

What is the most significant challenge in your field of research and
how do you see the field progressing over the next decade?

The sensitivity, resolution and throughput of spectroscopic
instrumentation that we use continues to rapidly increase, so we can
characterise an ever-increasing proportion of the metabolome. Making
sense of the vast quantities of data that can now be generated will
require development of advanced analysis tools and databasing solutions,
and is probably the most significant challenge at present. Advancing the
application of metabonomics in the two main areas of healthcare provision
(e.g. the Imperial NIHR Biomedical Research Centre [2]) and molecular
epidemiology studies (e.g. EU FP7 EXPOsOMICS project [3]) present
additional challenges that result from the timescales involved for
analysis, and the size of the sample sets involved.

[1]
http://acb.sagepub.com/content/early/2013/07/25/0004563213497929.abstract
[2]
http://imperialbrc.org/our-impact/case-studies/intelligent-knife-surgery
[3]
http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_19-11-2012-10-22-31

Note: TJA is a contributor to the EU FP7 EXPOsoMICS project.

Hollywood and Science: Making the unreal, real.

Don’t get me wrong, I don’t think that scientists are totally devoid of imagination. In actual fact, some of the best scientists are those that are able to bring creativity to their day to day, to think outside the ordinary and push beyond existing boundaries. There is however a great creative force on this planet. Hollywood. The scriptwriters, action choreographers and directors sit there day and night to think up new and spectacular ways to entertain us, bend reality and leave us spellbound. (The same of course applies to poets, musicians, artists and all those that work in the creative industries). To me it is one the most obvious professional sources of creativity one can find and is readily available to inspire budding scientists.

Jumping from space (Star Trek Style), Designing an antidote to a new Influenza strain in no-time (Contagion Style), Learning how to make scientists dance (Gangnam Style).

Sometimes Hollywood takes inspiration from well publicised breakthroughs in science and sometimes this occurs the other way around. Take the recent space jump by Felix Baumgartner- a crack team of engineers, scientists and meteorologists were able to safely send a man to the edge of space and then track his supersonic free-fall jump back to earth. This exercise was only possible through experimentation, measurements and sound analysis to meticulously design a remarkable space-suit, all of which are now of particular interest to NASA and of course the venture capitalists ploughing money into commercialised space travel [1]. This space-jump idea was also used in a gripping scene in the most recent Star Trek (2009) film. Seriously! Go back and watch it! Regarding Contagion (2011), maybe this is somewhat of an anomaly, as the film is actually a “medically-orientated” thriller. Nevertheless there are still some amazing scenes, where the CDC have these super-cool holograms and graphical representations of proteins interacting and allow for a cure/antidote to be mustered up in no time! Bioinformaticians take note! We want our boring script-based read-outs to have colourful pictures and illustrative projections on our screen when we work. It’ll help us discover cures!! Turns out scientists have learnt how to dance Gangnam Style [2]. Facepalm* Essentially what these movies do, is just give us an idea- no matter how insane it may be. Sometimes being able to see it on screen and visualise what a crazy idea might look like actually helps for its inception and progression to becoming a reality. For those of you that have watched Prometheus (2012), how awesome would it be if you had a robot that can perform routine operations just by pressing a few buttons- one that is programmed to work for both men and women (cough* awkward caesarean section scene)? These ideas are just conceptual now, but some scientists should watch these films for not only the entertainment but for the inspiration!

I will totally attend a “scientific” conference with Hollywood movers and shakers. Who’s with me?

It goes without saying that many people take inspiration from art, nature and exciting conversations with friends n’ family. However, what I’m suggesting here is something a little more formalised. How about we have a conference where all the creative heavy-weights of Hollywood meet all the scientific heavy-weights of…science… and we just get together! We could have a half day presentation of new scripts, CGI effects and slick graphical user-interfaces followed by half-day presentations by scientists on recent developments in their respective fields which will finally move the sci-fi genre forward from genetic mutations, being bitten by radioactive bugs and flying cars (why on earth don’t we have them yet!) Win win situation all round don’t you think?

References:

1. http://www.space.com/18061-supersonic-skydive-astronauts-reaction-felix-baumgartner.html

2. http://www.youtube.com/watch?v=CfnoI5f2IwQ

Climate Change: Why we just don’t give a….

Climate change does not tip the human moral balance according to novel research compiled by psychologists at University of Oregon. Evidence from behavioural analysts and those studying the human condition suggest that we as human beings do not feel motivated to engage in urgent action to solve the issue of climate change, although climate scientists have had a long standing consensus for action.

Why is it that only a small population of US citizens support an increased duty on electricity and gas, whilst a majority support limits on greenhouse gas emissions imposed on big business. Is it purely to do with perceived scale of responsibility? The disconnect between the public and the scientific community and ever further, climate change communicators is now impinging on our psychological processing of the climate change issue as a whole.

Psychologists have now suggested that climate change actually challenges our perceptual, cognitive and information processing systems leading to emotionally charged reactions that are either defensive or counterproductive or both. So understanding the challenge in manipulating the moral intuition within individuals is particularly important to communicators and those that wish to initiate change.

Six psychological challenges

So why doesn’t climate change register as a moral imperative? Well Markowitz and Shariff have published their review in Nature Climate Change, attempting to untangle the mess that is our moral judgement.

1. Abstractness and cognitive complexity

To mount a response that uses our moral judgement, we have to first understand the issue. Climate change is inherently complex, abstract and cognitively challenging. First of all, there are the temporal and spatial considerations. So the issue may not affect us now but it certainly will in x number of years; and it won’t happen on my door step, rather it will affect those living on deltas. Furthermore the issue can at times seem counterintuitive which further exacerbates the complexity of the situation. So for example climate change may lead to the increased rainfall in some areas coupled with significant and sustained droughts in other areas, the idea which at first glance seems incongruent. As a result, the in depth cognitive processing required to negotiate our way through these problems leads to poor activation of moral reasoning.

2. The blamelessness of unintentional action.

The thing about climate change is that no-one actually wants it to happen, no-one is intentionally trying to make the situation worse. This further inhibits our moral intuition because there is no single identity or person to blame. It has been shown that in child behavioural psychology that our moral reasoning weighs unintentional harm as being less severe as intentional harm. Intuitively, it has also been shown that intentional harm highly motivates a corrective response. As climate change is the unintentional by-product of our modern day lives it actually reduces the motivation to correct the issue and in extreme cases some us remove the human influence in the issue altogether…(not naming any names)

3. Guilty bias.

A lot of communication trying to convince people to act upon climate change and correct behavioural programs is about invoking a sense of guilt, but this can also induce fear as an emotional response. To mitigate the feeling of guilt we assume a cognitive bias to minimise our own complicity in the issue. So by putting ourselves in the stance of “it’s not my fault, it’s someone else’s fault” we mitigate our guilt, reduce complicity and avoid engaging our moral judgement to promote an action. This is highly detrimental as in the case of climate change, those that are contributing the greatest share of the harmful effects don’t act and rather point the finger elsewhere.

4. Uncertainty breeds wishful thoughts.

Scientists studying climate change have had a very challenging task. That have had to try and communicate the implications of our actions, essentially extrapolations are the salient points in the climate change debate. Yes some of these things can be proven, but even so there are hotly contested uncertainties in the climate change debate and sadly the more space there is for uncertainty the more wishful thinking we have. The example provided by the scientists are is the 2007 Intergovernmental Panel on Climate Change report that led to interpretations that the outcomes described were much less likely than the authors had intended. Uncertainty breeds default optimism and this itself leads to a reduced motivation to act.

5. Moral tribalism.

The mixed attitudes we have towards climate change is partly due to isolated moral spheres which often fall along political divisions. Liberals focus on welfare, harm and fairness. Whilst conservatives focus on maintaining group loyalty, authority and purity. The moral framework of climate change has had a liberal bias- i.e think about the harm to future generations and the unfairness of economics that may arise out of the situation, poor people suffering more whilst the rich get away scott free. The consequence is that conservatives are not morally engaged in the debate. Furthermore, politicising the situation actually increases the probability of polarising the issue as it has been shown that our group identity has a significant impact on the way we behave on political issues. So conservatives that promote discourse that is synonymous with their in-group beliefs are less likely to accept conflicting evidence and more likely to accept evidence sympathetic with their own view without contention.

6. Long time horizons and far away places.

The idea of in-group and out-group is important here. Climate change won’t affect us now, it’ll affect us in the future, but worse it won’t ever affect us sitting in a developed country, rather it will affect those living far away, people from our out-group. This is incredibly self-destructive thinking, and yet social psychology research shows us that our treatment of out-groups are distinctly worse than our treatment of in-groups.

Strategies to overcome these psychological challenges (climate change communicators take notes!)

I particularly enjoyed reading this review, because not only have Markowitz and Shariff so elegantly broken down why our moral stasis on the issue exists, but they have also gone one step further to suggest novel approaches in communication to solve the issue.

1. Use existing moral values.

Talking about the harms and injustices caused by climate change doesn’t do enough to activate our moral intuitions so other moral foundations should be identified and used. Furthermore, over politicising the makes us fall into the trap of moral tribalism. Preliminary research has shown that if environmental degradation is discussed in terms human beings destroying the purity of the natural world, you get higher levels of moral engagement from those of liberal and conservative backgrounds.

2. Burdens vs. Benefits

Markowitz and Shariff characterise these two words very carefully. A benefit is a more stable climate system, or services such as natural resources and surpluses. Whilst a burden is referred to as a negative endowment implying heritability of the issue, such as debts and health concerns like epidemics. New research has shown that people are more concerned with growing burdens than decreasing benefits i.e the reduction in available food and clean water (a benefit) is not as concerning as a greater spread of infectious diseases (a burden), which promotes a more significant concern. So rather it is suggested that the communication be focused on discussing the burdens for the next generation to invoke change.

3. Emotional carrots, not sticks.

This is important in challenging the guilt bias issue mentioned previously. Essentially by communicating positive moral intensive emotions, such as hope, pride and gratitude you are more likely to drive prosocial behaviour and it has been shown scientifically to encourage further prosocial activities in a positive feedback loop. Communication campaigns that induce guilt, shame and anxiety are not really more successful, because it induces a defensive response followed by guilt bias, so focusing communication in a rewarding way is far more sustainable. The psychologists even suggest that communicators should increase feelings of pride, by stating that a generation can rise to the challenge of addressing climate change and reducing the associated burdens. Furthermore, scientists have shown that increasing pride improves task performance in humans, but also elevates perseverance.

4. Be wary of extrinsic motivators.

Extrinsic motivators are defined in the paper as something like “green jobs”, you highlight the economic benefit you automatically motivate corporations and individuals alike to act responsibility towards the environment. However, such extrinsic incentives have been shown to work antagonistically with the desired outcome. Repeated reinforcement of the extrinsic motivator leads to a reduced self-mediated approach to continue the positive behaviour, i.e. once you remove the motivator the whole process comes to a halt. Although the researchers have stated that these motivators are good in the short-term, we should consider the long-term sustainability of such an approach.

5. Highlight positive norms.

This one is quite interesting. An experiment where home owners were sent an invoice saying that their electricity use was lower than the average household led to an increase in electricity usage in the subsequent month. But homeowners that simply received a smily face on the invoice- a sign of approval, kept their usage in the subsequent month at the same level encouraging maintenance of the existing behaviour. So taking this example communicators should look for pro-environmental social norms which have a consensus across all societies, one such example provided by the researchers was to “avoid wastage” something that is a golden rule for most societies in the world.

Looking forward

The review by Markowitz and Shariff brings in my opinion a novel spin on the climate change debate. Now it’s not just about providing the evidence for climate change, but it is about learning how to communicate the issue in such a way that we will act upon it. I really hope we do, even if it takes a full analysis of the human psyche!

As always full reference below, I really recommend reading the original paper, it’s not too tough to digest!

Reference:

Markowitz, E.M. & Shariff, A.F., 2012. Climate change and moral judgement. Nature Climate Change, 2(4), pp.243–247.

Mother’s Love

A few weeks ago, actually maybe a few months ago now I was day-dreaming at my desk. I was supposed to be busy conducting experiments and reading research papers but I had a sudden burning question. Admittedly my question was rather odd and led me on a 2hr procrastination path. Don’t worry though, I managed to get something out it. I learnt something pretty awesome and it made me appreciate my precious mother, that oh-so-bit more.

I was transporting myself to 1987, while I was still in my mother’s tummy, I was wondering why my mum’s immune system didn’t go out on a mission to destroy me. I like to think it’s because she loved me to bits and yes, she still loves me no doubt! It seems a little odd though doesn’t it? We all know if we catch a cold, we will eventually get better because our immune system will find the bad bugs and eventually kill them off one by one. The reason is somewhat simple, those bugs are foreign and as a result your immune system does not recognise it as “self” and anything that is not “self” is eliminated. So with that rationale in mind it does seem a little confusing that when you have some growing inside you, that isn’t exactly “self” but rather 50% of “self.”

Lucky for me, I wasn’t the first person to think of this conundrum (gah, the problem of being a scientist after all the great discoveries have been made). Back in 1953, an immunologist by the name of Medawar, formulated three explanations for maternal-foetal tolerance. His first suggestion was that the physical separation between the mother and foetus allows for immunological tolerance, the second was that the foetal tissues were not mature enough to be recognised by the maternal immune system, and the last suggestion was that the maternal immune response was somehow inert. Although none of these suggestions were entirely accurate, it paved the way for considerable research into understanding the relationship between the mother and foetus in the context of immunity.

The maternal immune system turning a blind eye.

So first off, lets consider “the other 50%” – the paternal side. Given that the foetus is a product of both mother and father, you would assume the paternal molecular characteristics of the foetus would be the expected target for a maternal immune response. Some mothers report pregnancies riddled with complications which dissipate with a change in partners. In these cases it is believed the adaptive immune system recognises paternal alloantigens. An alloantigen is like a molecular fingerprint, and if it is not of “self” origin it is destroyed by the immune system. The real question however, is why doesn’t this happen all the time in every pregnancy.

The answer lies in foetal tolerance. You could consider this as the maternal immune system turning a blind eye to the developing foetus. One of the first experimental examples of foetal tolerance by the immune system was demonstrated in mice. By taking pregnant mice and grafting paternal tissue matching that of the male that impregnated the mouse, allowed the graft tissue to sustain. However, once the female had delivered her pup, the tissue graft would then be rejected. Furthermore, pregnant mice grafted with tissue from a third party male (i.e not the one that made the female pregnant) was rejected immediately. This demonstrated two important points, the first is that the immunosuppressive effect is specific to the paternal alloantigens and also this suppression is temporary in nature.

Immunological ignorance.

The implantation site of the foetus is richly populated by a number of different white blood cells with entertaining names like natural killer cells and T-cells to the more terribly named myelomonocytic cells. These are all components of the immune system. To ensure these components do not mount an attack on the foetus particularly the placenta the maternal immune system turns a blind eye in what is scientifically described as immunological ignorance. Turning off the immune system is no trivial feat and actually you wouldn’t want to turn it off entirely. It has to be a localised numbing of the immune system at the point of interaction between the maternal tissues and the foetus. One such example is the localised availability of the amino acid tryptophan. When tryptophan levels drop, it leads to a decrease in T-cell proliferation. This is achieved by the production of…wait for it… indoleamine 2,3 dioxygenase (IDO) in the maternal tissues and the invading foetus.

White blood cells are murdered.

A more spectacular example of localised immunosuppression is mediated by the foetus alone. Apoptosis is the word used to describe cellular suicide. Although, considering it solely as suicide is somewhat misleading as the process can at times be initiated by other cells nearby. This “death signal” is started by a molecular key called the Fas ligand which fits into a cell surface receptor called Fas. It’s a bit like having a self destruct button on the outside of the cell that can only be pressed by other cells that have the finger (or Fas ligand) to press it. In our context, white blood cells that would usually attack the foetus express this receptor and cleverly the foetus also expresses the Fas ligand leading the apoptosis of white blood cells or in this case the murder of white blood cells! This mechanism was discovered by using pregnant mice with mutations in the Fas receptor, which lead to an increase maternal white blood cells in the placenta followed by the destruction of foetal tissues, pretty neat.

Sometimes, just sometimes, foetal tolerance can be rejected.

I think the most interesting part of this molecular ballet is that intricate balance required to maintain a growing foetus. Whilst you need the immune system to be suitably suppressed for foetal survival there is always the off chance that a massive uterine infection occurs. In such cases, you need the immune system to ignite back to its former strength. Sadly, in these cases you get a spontaneous abortion – although this process is not well understood. The disruption of maternal-foetal tolerance is thought to arise from the presentation of paternal alloantigens in the frenzy of fighting an infection leading to an immune response not only directed at the infection but also the foetus. You might think the system is imperfect, but I like to take solace in knowing every baby has entered this world by dancing and playing molecular hide and seek with the notorious and powerful maternal immune system.

References:

Trowsdale, J. & Betz, A.G., 2006. Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nature Immunology, 7(3), pp.241–246.

Image credit to: http://pregnancy.baby-gaga.com/cartoons/cartoon22

Your Environment: Friend or Foe?

A significant challenge in medical research is understanding why we fall ill. Why is it that some of us get certain diseases whilst others do not. Although we are genetically very different from each other (unless you count your identical twin), understanding the reasons behind variability in health does not just fall onto the obvious candidate – genetics; rather we have to consider another very important variable, the environment.

A report published in 2006 by the World Health Organisation states that 13 million deaths occur from environmental causes and up to 24% of these deaths are actually preventable [1]. A large number of these environmental factors are pollutants such as metals and hydrocarbons, whilst some exposures arise as a by-product of our agricultural efforts like the use of pesticides. To really understand how we fall ill from these environmental factors, we have to understand how we as biological entities respond to our environment.

We are equipped with a static toolkit – the genome

The environment is highly dynamic, from weather patterns, to the air that we breath and the availability of water. Whilst we are equipped with a static toolkit – the genome, we have to turn on and off certain genes depending on stresses imposed on us by the environment. A classical example is the heat shock response, which is involved in turning on genes and making proteins that help to protect your cells, from a variety of stresses from exposure to heavy metals, cytotoxic drugs and viral infections [2]. It’s pretty clever actually, it allows your cells to “brace themselves” through a tough time. However a really interesting point here, is how is this communicated?

This is where a nascent field of research is taking the limelight. Environmental epigenetics is being used to interrogate our relationship with the environment. What is epigenetics? It is the study of heritable changes in gene expression without changes in the DNA sequence. Through epigenetics, we are able to adjust the the expression of certain genes in response to an exogenous influence, i.e. the environment. This is achieved through a variety of mechanisms, broadly referred to as epigenetic modifications. Examples include adjusting the levels of methylation on DNA to silence genes and adding chemical groups to proteins called histones which act as a scaffold for your DNA. This allows the DNA to have varied accessibility to the molecular machines involved in expressing your genes and more importantly it allows for variation in the relative expression of certain genes at specific times in response environmental stimulus.

The traditional gene-environment model, is not enough.

Traditionally, health outcomes were considered to occur from gene-environment interactions. In this model, diseases resulted from interactions between an individual’s genetic make up and the environmental factors. Those studying genetics have stood by the concept that the expression of a particular physical characteristic (phenotype) is variable and dependent on the environment to which the individual is exposed to. In this example, some people may have a relatively low risk in developing a disease in response to environmental factors, whilst others are more likely, purely due to their genetic differences or polymorphisms [*]. It has now become apparent this this approach is too simplified.

Recent research published in Nature’s Heredity, has stated that we should add an epigene-environment approach. In the epigene-environment framework, the relative differences in an individual imposed by epigenetic mechanisms are also important and of similar weight to our genetic differences. In this example, epigenetic differences, so the way in which I express my genes in response to the environment compared to you, may also adjust our susceptibility to diseases [3]. It also means that in addition to our genetic make-up, our epigenetic make-up will have an impact on our health in response to environmental exposures.

This approach is growing momentum due to the increasing evidence of epigenetic changes that occur as a result of environmental factors. Particulate matter and air pollution is believed to adjust the levels of DNA methylation of the iNOS gene, leading to negative health outcomes. Furthermore, environmental stresses during pregnancy can lead to permanent changes in epigenetic modifications, leading to stresses in the newborn child, which has recently been shown by studying women that were pregnant during the 9/11 attacks [4]. This idea of inheriting an experience with an associated health outcome is particularly alarming. In mice exposed to air from a steel manufacturing plant, it has been shown that the DNA in their sperm is hypermethylated and this persists even after removal of the exposure, suggesting that such epigenetic abnormalities can be transmitted transgenerationally [5]. In addition to DNA methylation, aberrant histone modification has also been identified as a result of exposure to metals such as, nickel, chromium, lead and arsenic – the latter is found in abundance in the water table of developing countries, allowing for a chronic exposure. As histone modifications can regulate the levels of gene expression, environmental factors that impinge on this process can be destructive often leading to cancer and neurodegenerative disorders [6].

Although the epigene-environment framework described above has yet to to be formalised, there is growing evidence that epigentics may assist us in predicting the risks and susceptibility of an individual to develop disease. The challenges now are to determine what the epigenetic alterations are and also to understand the physiological meaning of these events in the context of disease.

References:

1. Pruss-Ustun A, Corvalan C., (2006). Preventing disease through healthy environments. Towards an estimate of the environmental burden of disease. Geneva, World Health Organization (WHO).

2. Santoro, M., (2000). Heat shock factors and the control of the stress response. Biochemical Pharmacology, 59(1), pp.55–63.

3. Bollati, V. & Baccarelli, A., (2010). Environmental epigenetics. Heredity, 105(1), pp.105–112.

4. http://news.bbc.co.uk/1/hi/health/4508879.stm

5. Yauk C, Polyzos A, Rowan-Carroll A, Somers CM, Godschalk RW, Van Schooten FJ et al. (2008). Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location. Proc Natl Acad Sci USA 105: 605–610.

6. Fragou, D. et al., 2011. Epigenetic mechanisms in metal toxicity. Toxicology Mechanisms and Methods, 21(4), pp.343–352.

*(to know more about polymorphisms please refer to the Call of Duty article)

Is there a gene for loving Call of Duty?

Genes are brilliant; and yet the way they are depicted may seem to oversimplify some really complex issues.

If you watched BBC’s Horizon last week, entitled “Are you good or evil” you would have been entertained with the idea that scientists have uncovered the genetic basis of being evil. The “warrior gene” as it has been dubbed is thought to induce aggressive behaviour after provocation. In the documentary they showed a case where a man murdered his wife, but avoided a conviction for first degree murder, because scientists measured the expression of the “warrior gene” which convinced the jury that an underlying genetic trait was to blame for his actions………….I know.

If you also picked up the Metro on the 6th September (every Londoner does), you would have caught the following headline: “Lazy people are missing athletic gene according to new study”. This gene called the “exercise” gene is believed to be deficient in couch-potatoes. The research was actually carried out in mice and the scientists demonstrated by deleting the “exercise” gene, that these mice were less active compared to their wild-type (normal – undeleted) counterparts. The gene actually encodes for an enzyme called AMP-activated protein kinase and it is a fundamental enzyme involved in metabolism, homeostasis and with glucose uptake in muscle tissues as a result of muscular contraction. Whilst it is an interesting find to demonstrate the physiological impact in mice, it might be stretching it slightly to say that it is “the” exercise gene.

Of course, our love for genes doesn’t end there, one post in a lifestyle feature describes – the “happy” gene. You guessed it, it is the gene that determines whether or not you have a bounce in your walk and see the glass as half full rather than half empty. I relish the fact that its called the “happy” gene because scientists actually called the gene 5-HTTLPR. This gene encodes for a serotonin transporter, which is a neurotransmitter (a brain chemical) that has been shown to influence mood and happiness. So albeit slightly indirectly 5-HTTLPR is believed to play a role, by affecting the transport of serotonin. One of the comments on this article is slightly amusing but also raises an important question.

tspears0901 says ” I dont care which ” gene ” anyone has, if life is tough, it makes you depressed, end of.”

“The relationship is rarely one to one.”

You see after reading these articles, I feel slightly sorry for genes. It is almost as if every single gene must have a really important purpose. The fact of the matter is, one gene does not control complex outcomes like being evil, lazy or happy. The relationship is rarely one gene to one outcome and thats without weighing in the other important factors such as nurture. So how do you even begin to unravel the importance of multiple genes at the same time and see if it can lead to complex issue? One method is by conducting gene expression profiling experiments. So taking our case of understanding the genetic basis of being “evil” you would take a group of psychotic people and then sample lots and lots of genes with the hope that you’ll identify a group of genes that you think might be important in psychosis, because it is either up or down regulated (expressed highly or less). You’ll then compare those same genes against a group of people that are not psychotic to truly identify if these genes are important, this is called your control sample. The output of such an experiment will form a genetic “profile” which, is more reliable as a measurement because you’re not just measuring one gene; it also provides a sort of genetic signature or fingerprint for that particular physical state, in this case, psychosis.

Another important aspect to consider is the functional relationships between genes. In an article published in Nature, Dr. Heather J Cordell discusses how gene-gene interactions are important in understanding human disease (link provided at the end). She states, “If a genetic factor functions primarily through a complex mechanism that involves, multiple other genes and, possibly, environmental factors, the effect might be missed if [one] gene is examined in isolation…” The crucial point here is that analysis of a gene in isolation is probably giving you an incomplete picture. Dr. Cordell then continues to describe some of the mathematical models that are used to determine working relationships between genes and this is because more often than not, it is many genes working together that leads to outcome – not just one.

“Take the word “competitive” and imagine that it is a gene.”

Some genes at this moment in time simply have no purpose, we haven’t figured out what every single gene does and it is one of the reasons why we have lots of genome projects currently engaged. One example is the “The 1000 Genomes Project” which is sequencing the DNA from a large group of people from different ethnic backgrounds. This experiment aims to identify our genetic differences and determine if such differences give rise to specific disease states. This is because for a specific gene, there can be variations in the underlying DNA sequence in specific groups (such as ethnicity) of people and as a result the functional consequences might be differ too. One way to think of it, is to consider a thesaurus. Take the word “competitive” and imagine that it is a gene. If you look up the word in a thesaurus you’ll get the following words, “ambitious”, “aggressive” and “keen”. You could in a sentence replace the word “competitive” with any of the three that I have mentioned, but it wouldn’t really give you the same meaning.

My friend Sunniyat, he is so competitive. vs. My friend Sunniyat he is so aggressive.

Genes are similar. There are slight variations of the same gene that can have different functional consequences. Its called a genetic polymorphism. So take the “happy” gene for example, it actually may not be the secret to happiness for all of us because of our individual genetic interpretations of a single gene.

“DNA doesn’t all code for genes”

Genes are not the only functional aspect of our DNA. It may seem a little strange, but DNA doesn’t all code for genes. This is a little difficult to explain, so forgive me if this example fails to work. Imagine opening up a story book (yes another literary based analogy) and you start reading it, but it looks like this :

“dfasdOncesdfauponadaadfastimeasdas”

Imagine each word that you see in that quote is a gene, something that has a meaning and function. Our DNA is also like the above, full of lots of code that we don’t quite understand yet. The ENCODE genome project is attempting to characterise what all the code in between the genes actually do. This is called “non-coding DNA” because these sequences don’t code for genes, but just because they don’t encode for genes and they harbour an apparent lack of function, doesn’t make these sequences less important. In actual fact over 90% of our DNA is non-coding and to assume that 90% of our DNA has no functional consequence would be wrong.

“The thing about scientific research is that it is a field that builds upon current knowledge”

I don’t think scientists or science journalists are to blame here. The thing about scientific research is that it is a field that builds upon current knowledge. Hence incremental progress is reported in the papers usually with an exciting sweeping headline (ahem…) So the next time you come across an article where it describes a single gene, and how novel research has correlated it to single outcome, whether that be a disease state, behavioural outcome or physical characteristic just remember that its probably a little more complicated than that. And no, sadly there isn’t one gene for loving Call of Duty, but there might be a few!

References:

Evil gene: http://www.bbc.co.uk/programmes/b006mgxf

Exercise or Lazy Gene (depending on which way you want to look at it): http://www.metro.co.uk/news/874579-lazy-people-are-missing-athletic-gene-according-to-new-study

Happy Gene: http://lifestyle.aol.co.uk/2011/09/10/have-you-got-the-happy-gene/

Gene-gene interactions: http://www.nature.com/nrg/journal/v10/n6/abs/nrg2579.html

Cancer: Why we don’t have a cure just yet.

To say that cancer is a complex disease to understand and a difficult disease to treat would be a great understatement. Those that have lost loved ones to cancer describe the experience as a long and torturous path, full of deception. At times those diagnosed with cancer seem as though they have their energy back, eating food and sharing moments with close family members in a growing air of optimism, which is then subdued by unpredictable crashes of ill-health. What is certain however is that the experience is not the same for everyone. My own mother-in-law passed away from cancer sadly before my wife and I got married. Seeing my wife grieve was difficult because I felt very helpless. I was studying at the time and in fact, I contribute the direction that my life is heading now to that moment in time.

I work in the exciting field of cancer research. I’m fairly low in the academic hierarchy (as a first-year PhD student), but what I lack in experience, I make up in enthusiasm and of course, one of the most frequent questions that is asked of me by my friends and family is whether or not we are closer to finding a “cure”. I usually try to provide some sort of answer, but if I am honest with myself it is rarely clear enough for everyone to understand. So this time lets start from the very beginning.

“To understand cancer, you have to come to terms with a shocking fact.”

With cancer the relationship status is “complicated”. Our body is made up of trillions of cells. Each cell has a particular identity and purpose both of which are programmed by genes coded by DNA. These genes are turned “on” and “off” at different rates and for changeable durations during the lifetime of that cell. You may without realising tried to imagine this like a light switch; instead a better way to consider it is like a dimmer switch. The output in this case is the great macromolecules called proteins. So DNA is the language that describes the genes, whilst the genes encode for proteins, this is often referred to as the central dogma of molecular biology. The proteins are the hard-working molecules in the cells that have a specific function. Some of them provide structural support, others are involved in elegant processes such as DNA replication whilst some proteins have crucial enzymatic activity to allow them to control cellular metabolism and to pass information from outside of the cell to the inside of the cell. As you can imagine, the inside of a cell is a busy place and in amongst this chaos there is a delicate balance keeping that cell alive.

To really understand what cancer is, you have to come to terms with a shocking fact. Your cells are constantly thinking of suicide. It’s called programmed cell death or if you prefer the buzzword, its called apoptosis. For cells to continue to grow and divide they need to respond to growth signals which allow them to progress through the cell cycle. The cell cycle is composed of periods of growth, replication (mitosis) and resting. Crucially, cells are not supposed to go through this cell cycle without regulation. So there are molecules that create checkpoints, that ensure that cells are progressing through this cycle correctly. Occasionally this cycle becomes entirely unregulated, allowing the cells to grow uncontrollably. If this happens, apoptosis kicks in and the cell decides to kill itself rather than going on an endless cycle of proliferation. It is a noble act, cells killing themselves to ensure the survival of the whole organism, and yet cancerous cells are far from noble. Some cancer cells are able to turn off the process of apoptosis entirely, but it doesn’t stop there. They are also able to evade cell cycle checkpoints giving them a clear path to continue replicating, growing and dividing. What started off as a humble, single cell soon turns into a tumour (a group of cancerous cells). This is what cancer is. It is a disease that starts from one cell before becoming many damaging cells.

“The vast majority of cancers are sporadic.”

Scientists have been working hard to understand the origins of cancer. At the most basic level, cancers arise as a result of one cell gaining a genetic mutation. This is where the DNA in the nucleus of the cell becomes damaged, particularly the parts of the DNA that encode for a gene. If it affects the genes then you might be thinking that cancers are always inherited, this is actually not true and in fact only 5-10% of cancers show strong dominant mode of inheritance, whilst 10-15% show a relatively weak correlation and may require additional environmental factors leading to the onset of cancer. Sadly, the vast majority of cancers are sporadic. This makes it incredibly difficult to determine who will and who won’t get cancer.

Having said that, scientists have attempted to characterise both the genetic and the non-genetic risk factors for some of the cancers. A genetic risk factor, is where a mutation (DNA damage) in a specific gene results in an elevated incidence of cancer. For breast cancers, a genetic risk factor includes mutations in the BRCA1 and BRCA2 genes. These genes are called tumour suppressors, because when these genes are turned “on”, the resulting protein stop uncontrolled cell growth – hence the term suppressor. When the gene is mutated the protein that the gene codes for doesn’t work properly and the important function it could once do is lost. A non-genetic risk factor is relatively easier to understand, such as smoking. Smoking is so clearly correlated to lung cancers, there has been significant effort made to ensure smokers are aware of the said risks. Characterisation of these genetic and non-genetic risk factors take considerable time, but that hasn’t stopped some scientists. The Sanger Institute in Cambridge is currently embarking on the Cancer Genome Project which is trying to identify the genes that are mutated in cancers, particularly the ones that arise as a result of sporadic mutations. It is believed that this study will be able to identify a list of genes that play a significant role in cancer progression and allow for the development of focused therapies. Identification of the non-genetic risk factors is in contrast less focused, with numourous research groups working on the issue by attempting to understand the environmental background of people that get cancer. Some of these examples include levels of exercise, diet, viral and bacterial infections, alcohol abuse and so on. These are believed to be factors that you can control and unlike your genetic make-up, which cannot change after birth, health professionals can instead help you make behavioural decisions to prevent the onset of cancer. One more reason to eat your 5-a-day!

“The most profound issue is specificity.”

What about therapies, what is the biggest challenge? Trying to remove cancerous cells from your body is like trying to do something very precise with an extremely blunt and large object. The most profound issue is specificity. When people think of cancer treatments, more often than not, they think of chemotherapy; a mixture of drugs taken to kill the cancer cells. However, ensuring that the drugs only target the cancerous cells is substantial challenege. One of the physical characteristics of cancer cells is their ability to divide rapidly and continue growing at a faster rate than healthy cells. As a result many drugs attempt to inhibit the DNA replication machinery in these cells, as cells need to replicate their DNA to continue dividing. These therapies are non-specific and healthy cells that also grow fairly rapidly are affected by the treatment. One such example are the white blood cells that are fundamental in mounting an immune response against bacteria and viruses. So whilst the chemotherapy may have an opportunity to kill the cancerous cells, the cancer patient is likely to become immunocompromised after sustained chemotherapy, it can lead to the increased risk of patient suffering from opportunistic infections. All is not lost though. Novel treatments include targeted therapies by using antibodies to deliver a payload of cytotoxic (cell killing) drugs. Antibodies are molecules that are able to specifically bind to bacteria and viruses allowing your white blood cells to find them and destroy them. Rituximab is an example of a chimeric antibody which is able to bind to cancerous white blood cells and initiating apoptosis. Such targeted therapies are an important focal point for cancer research and continues to be a promising avenue of research.

“We are steadily winning the battle against cancer.”

Cancer researchers are one of the most determined bunch of scientists I have ever met. They often work deep into their week nights and over their weekends. Although scientists have yet to find a “cure” for cancer, there is hope knowing that we are steadily winning the battle against cancer. The below chart shows how over the last 30-years the survival rates for breast cancer have increased, which is a great achievement against one of toughest medical challenges faced by modern day humans. What is certain though, as per the billboard by the Leukaemia Research Fund, is that scientists won’t hang up their coats until the job is done.