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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

Introducing the epigene-environment framework

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)

I must have the "Call of Duty" gene.

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

Both scientists and members of the public alike can relate to the determination of this billboard.

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.

Breast Cancer Survival Rates, Cancer Research UK.