Last week we had the announcements of the Nobel Prize winners for 2019. In this post I am going to cover and hopefully explain the work that won the prize for Medicine. It is important to note with a Nobel Prize that it takes years for people’s research to be acknowledged, and the science I shall discuss began back in 1991.

The winners of the Nobel Prize showed an important and unique mechanism in how the body recognises the need for oxygen within our cells. To begin a little information about why oxygen is so important to our survival.

Respiration

The equation for energy and a requirement for us as animals to live:

Oxygen is a necessity for us to live, and our body is able to recognise when we need it and where to distribute it. To start this story oxygen enters our body through the lungs, about 20% of the air we breathe is made up of oxygen. The lungs have a massive blood supply with many blood vessels forming a maze-like lattice, and it is here within the blood that red blood cells specialised carriers for gases lie. As the red blood cells pass through the lungs they will drop off the waste carbon dioxide and collect oxygen ready for transport. The red blood cells have within them an iron containing protein called haemoglobin (this is likely reason you will have heard that iron is good for the blood). Haemoglobin is able to latch onto gases neatly storing them until they reach their destination.

From the lungs the oxygen is transported all over the body for cells to make much needed energy for their day to day functions. Within each and every cell of the body, except the red blood cell, are structures called the mitochondria (you may have heard named the powerhouse of the cell). The oxygen is used in conjunction with glucose from carbohydrates within the process of respiration to create the energy currency that powers everything within the cell.

Specifically this currency is a molecule called adenosine triphosphate (ATP). ATP is inserted into several reactions as effectively the ignition. In the process ATP loses a phosphate creating adenosine diphosphate (ADP). It is the job of respiration to put the P back on creating more ATP. Without ATP nothing would really get done and it is the universal “money” system of the body.

The recent Nobel prize winner for medicine/physiology put work together to show how cells monitor oxygen and respond to a lack of it. Nobel Prizes have been awarded previously in 1938 to Corneille Heymanns who also conducted work on how the body recognises oxygen levels within the blood. Describing the carotid body a collection of oxygen sensitive cells located within the carotid artery. In times of low oxygen signals are sent to the medulla oblongata a crucial region of the brain that controls many processes you need to live from heart rate and blood pressure to breathing and even vomiting. In this case the low oxygen levels trigger an increase in ventilation.

With the basic outline covered we shall move to the work from our Nobel Prize winners; Gregg Semenza, Sir Peter Ratcliffe and William Kaelin Jr.

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Red Blood Cell Production

When the body lacks oxygen it enters a state of hypoxia (literally meaning low oxygen). This leads to the increased breathing as mentioned before however this isn’t the only reaction the body has. There is an increase in the production of a hormone called erythropoietin (EPO). Produced by the kidneys this hormone promotes the creation of more red blood cells by the bone marrow. More blood cells mean more carriers of oxygen.

EPO has been used in the past as a performance enhancer for athletes. By stimulating red blood cell production it can be highly beneficial to long distance runners or events that require long term stamina. More of the inhaled oxygen can reach the muscles meaning a slower onset of fatigue and less build up of lactic acid. It an other synthetic versions have been banned since 1990 after their usage between 1987-89.

Semenza’s work was on EPO specificallu the genes that controlled EPO production. As well as how oxygen varied its expression. Together with Ratcliffe they found that there was an oxygen sensing mechanism in pretty much all cells. This was interesting as initial theories would have suggested that this mechanism only within the EPO producing cells of the kidney. Semenza noticed there were genes next to the gene for EPO that also responded to hypoxia.

DNA- deoxyribonucleic acid holds within it the instructions needed to make every cell in your body. Every cell that contains a nucleus has DNA that can be used to make anything the cell needs as long as the right signals are received. When this happens there are enzymes that can read the DNA strand and lead to the production of a protein, for example the EPO gene translates to the production of the EPO hormone.

Through the study of liver cells he identified a complex that bound to the region of the hypoxia related gene. It was dubbed the hypoxia-inducible factor (HIF). Work was then underway to isolate and purify a sample of HIF. In 1995 it was found that the HIF complex was made up of two proteins later named HIF-1α and ARNT (the exact reasoning for these names is not important here).

During periods where oxygen is plentiful the levels of HIF-1α are low and then during hypoxia he amount of HIF-1α increases. This inevitably leading to the reading of the hypoxic related genes. Under normal conditions i.e. not hypoxia any HIF-1α is degraded rapidly. This is conducted by a structure called the proteosome. It will effectively digest the HIF-1α preventing it from causing the activation of these hypoxic genes. However it was not known how HIF-1α degradation by the proteosome was controlled by oxygen levels.

When Research Collides

The answers to these questions were to be found in the work of Kaelin Jr. As a cancer researcher he was investing von Hippel-Lindau’s (VHL) disease. This is caused by an inherited genetic defect (similar to such conditions like cystic fibrosis) leading sufferers to be more prone to various caners including within the nervous system, the retine and the pancreas.

Kaelin’s research showed that the normal VHL gene worked to prevent cancer. Interestingly he also discovered that cells with a dysfunctional VHL gene showed high levels of hypoxia-related genes. When the functional version of the VHL gene was introduced the cells reverted to a non-hypoxic state. The trail of breadcrumbs lead to further discoveries. Not only was it shown that the VHL complex was able to mark other proteins for degradation but Ratcliffe and his lab showed that this VHL complex could interact with HIF-1α. The puzzle was slowly piecing itself together.

How is Oxygen Involved?

We now had a clear picture of the players in this story, but something remained out of focus. How was this system controlled by the levels of oxygen? The answer came with the concurrent release of two papers this showed how levels of oxygen within the cell changed the actual make up of HIF-1α. Under normal conditions where the levels of oxygen are ideal for the health of the cell. The present oxygen actually binds to the HIF-1α altering its protein structure, with this groups now bound the VHL protein recognises it, marking it for degradation. When it’s hypoxic there isn’t enough oxygen for this structural change to occur so the HIF-1α is free to activate the genes needed. This completed the story of how cells are able to sense oxygen.

What Does This Mean?

We now know that HIF-1α is responsible for regulating up to 300 different genes each having a variety of roles in how our body functions. Some of these include our metabolism, response exercise, our development within the womb, and how our bodies adapt to low oxygen environments such as those at high altitudes.

Understanding the ways cells react and adapt to changes in oxygen is crucial for the investigation of several illnesses such as cancers. As most cancers are able to promote a blood supply and blood vessel formation and an increase in red blood cell production. To provide the toxic cells all they need to survive. Obviously there are problems for people with kidney diseases due to an interference in the production of EPO for red blood cells and sufferers of anaemia. Pharmaceutical companies will now be able to use this research to develop new ways of targeting the oxygen sensing mechanisms of cells.

Reading Sources

• Hypoxia-inducible nuclear factors bind to an enhancer element located 3’ to the human erythropoietin gene.
• Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O₂ tension.
• The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.
• HIFa targeted for VHL-mediated destruction by proline hydroxylation: Implications for O₂ sensing.
• Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O₂-regulated prolyl hydroxylation.
• Erythropoietin as a performance-enhancing drug: Its mechanistic basis, detection, and potential adverse effects.

The administration of opioids is commonplace in hospitals. They are the go to drug for the treatment of serious pain. Back in the 1990s pharmaceutical companies were quoted to have said that opioid pain relievers would not becoming addictive in patients. Since then the USA has entered what can only be described as an opioid epidemic. It is obvious to us now that opioids are addictive. This addictive nature of opioids has led many patients to seek out and transition to the far more dangerous heroin. In 2017 there were 47000+ deaths due to opioid overdose in the United States. Along with these deaths were an estimated 1.7 million people who suffered with substance abuse due to prescription opioids. This has cost the US over $70 billion a year.

Many pharmaceutical companies have been taken to court in the US over the promotion of opioid drugs while also downplaying their addictive nature. Many settled pre-trial, however major company Johnson & Johnson went to court in Oklahoma. They were ordered to pay $572m for their role in promoting opioid drugs to consumers. Therefore contributing to the opioid crisis within the US. An attorney for Johnson & Johnson stated that you cannot sue your way out of this crisis. In truth there are many issues at play here. The pharmaceutical companies failing to deliver the required warnings about the drugs they were promoting. Along with this is a major issue in the way drugs are so easily prescribed to patients.

Current Pain Options

To understand the problems with opioids we need to look at the pain treatment options currently available. Treatments can be divided into several categories each with their own specific function. Perhaps the most common are the non-steroidal anti-inflammatory drugs (NSAIDs) these include your aspirin, paracetamol, ibuprofen etc. These drugs act to reduce the action of the immune system in triggering pain, effective over the counter options for those day to day ailments.
There are the steroidal drugs, made up of the corticosteroids these tend to be applied to the skin in a cream. They enter through the skin and reduce inflammation by also inhibiting the activity of the immune system. Often used to treat the pain associated with arthritis or tendonitis. Steroidal treatments come with several side effects, such as the degeneration of skin layers, so can’t be used for long periods of time.
Another group I’ll mention are the local anaesthetics these work to prevent all sensation in a region, numbing the area. They do this by blocking the nerve fibres directly removing not only pain, but the sense of touch and in some cases the use of the muscle. Along with their relatively short duration local anaesthetics don’t work as the best choice for pain treatments.

Opioids

That brings us to the opioid family and the gold stand pain drug morphine. The opium poppy gave us one of the most addictive drugs in history as well as the best pain drug we have. Sadly that’s the problem, morphine can’t be beaten, its effectiveness at treating extreme pain is unparalleled. So what does morphine actually do? You first need to understand that there exist controls or fail-safes to prevent extreme pain events. The brain understands that too much pain is a bad thing and can try to override it. Morphine aids in this process basically telling the spinal cord to ignore the pain signals it is receiving. However due to its similarity to drugs like heroin there exist many associated risks with it.

The dangers of morphine and other opioid-like drugs like codiene and fentanyl are that they possess the addictive qualities of their more sinister cousin heroin. Once these drugs enter the body they will generate a reduction in the sensation of pain almost immediately. However they are able to reach other areas of the body most importantly the brain. Once in the brain their sadistic nature comes into fruition. They are able to activate the pleasure centres of the brain leading to the sensation of reward. Chemicals including dopamine and serotonin are released producing a sense of euphoria. It is this that leads to the drugs becoming addictive. The brain craves more of that feeling and instant satisfaction leading to addiction. This is a simplistic explanation of addiction there are many other mechanisms at play. However the take away message is that opioids trigger addiction.

There is also the problem of tolerance, the effectiveness of these drugs to treat pain get lower the longer you use them. Your body basically adapts to the presence of these compounds in your body, for example increasing the mechanisms needed to dispose of them. You will need more and more of the drug to achieve the same amount of pain relief. The more you take the more the brain begins to crave it this then leads to potential overdoses, causing breathing problems and nausea. There is also the side effect of having your pharyngeal reflex (also known as your gag reflex) with a rather unpleasant chance of death via drowning in your own vomit.

The problems facing the healthcare system is a lack of alternatives and the ease in which morphine is administered. This along with no follow up to prevent potential addiction. I would like to state that morphine is an incredibly effective drug and its use has made lives better. So please don’t come away from this with a fear of it. With better precautions in place these problems should not arise. Should there be a risk of addiction there need to be alternative treatments along with better post-treatment options.

What’s the Problem

That brings up the question as to why there hasn’t been another drug developed to compete with morphine. The reality is that there are many obstacles to get over for a pain drug to be successful. Firstly the pain system is spread throughout the body and is important for defence. Removing pain completely is not really a solution as I mentioned in my post on pain. There are many different systems that contribute to pain and selectively blocking them in the region that is injured is difficult. Then there is the fact that a majority of the pain system is located within the spinal cord and the brain (the central nervous system; CNS). From a drug standpoint this makes life very difficult. The CNS is incredibly well protected, obviously there is the skull and the spinal column. These are dense bones that prevent as much damage as possible from occurring to these crucial sensitive regions. However for drugs there is something far more important to consider, and that is referred to as the blood-brain barrier (BBB). Blood does not freely flow around the brain it is carefully filtered to prevent contaminants from getting to this vital organ easily. This means for a drug to get into the brain or spinal cord it needs to get through the BBB. Morphine is one of these drugs that can penetrate the barrier and get access to the brain and spinal cord to work its magic. If you look at the other opioids they too can easily traverse into the brain. Heroin is so good at it that it can enter the brain within seconds, and as discussed this unlimited access to the brain also leads to the major problem of addiction.

Alternative Choices

This means we need a drug that can easily gain access to the brain or spinal cord while also providing strong pain relief without the risks of addiction. A few years ago there was this potential with drugs derived from the venom of cone snails. These conotoxins were almost 100x as potent as morphine with none of the risks of addiction. The problem was that they couldn’t get through the BBB. The only way to get them to the site they needed to be was via direct injection into the spinal. This is an uncomfortable and tricky procedure that can’t really be conducted over and over again. Morphine is just more convenient. Another potential area for investigation are the chemicals found in cannabis called cannabinoids. There already exist cannabinoid-like compounds naturally within the body called endocannabinoids. The endocannabinoids have been shown to possess analgesic properties. This led pharmaceutical companies to develop drugs derived from the cannabis plant that perform the same function. Drugs that utilise the chemicals THC and cannabidiol have found success in the treatment of neuropathic (nerve pain) and cancer pain.

After the disastrous outcome of this opioid crisis the need to replacements is crucial. However as I said we cannot just dismiss morphine and other opioids. We instead need to monitor its usage and conduct careful follow up on those who were on them. Along with this it is necessary to have countermeasures in place. Methods to help those with addiction while also providing drugs that reverse overdose. All these need to be common practice while researchers are incentivized to investigate newer drug options. The opioid crisis will take time and money to eventually solve, but it is the job of the government working with pharmaceutical companies to set out better regulations. The hope for the future is to eventually replace opioid drugs as the preferred pain treatment.

Reading Sources

• US Department of Health; National Vital Statistics System.
• The Economic Burden of Prescription Opioid Overdose, Abuse, and Dependence in the United States.
• Descending control of pain. Millan M.J
• Conotoxins That Could Provide Analgesia through Voltage Gated Sodium Channel Inhibition. Munasinghe & Christie
• Cannabinoids in the management of difficult to treat pain.

Our species is suffering. We are punishing ourselves through a lack of sleep. Humanity are the only living creatures that actively deprive themselves of sleep. Here I shall discuss how sleep works, why we need it and what happens when we don’t get enough.

Falling Asleep

The statistics are clear, over a 3rd of Americans do not get the recommended 8 hours. Humanity throughout the 20-21st century have been getting less and less sleep. There are many reasons for this. Mainly we live in a brighter world now, literally. The invention of the light bulb while removing the gloom from our houses at night and bringing light to our streets. It has been detrimental to the quality of our sleep. It’s not just light either, lifestyles have changed, children are expected to get into school in the early hours of the morning, people are required to work night shifts, flipping what they know of as night and day. To understand how harmful these factors are we must look at what sleep does for us.

Our sleep cycle is controlled internally by our body clock, referred to as our circadian rhythm. There is a tiny area of the brain called the suprachiasmatic nucleus (SCN) which functions as a literal clock turning on and off every 12 hours. Even when dissected from the brain and placed in a dish it will still without fail turn on and off every day and night. The SCN is crucial for the coordination of when you are awake and when you are asleep. It also helps to balance an array of chemicals that are released in the body to control your awake and sleeping states. The SCN is located within a very important region of the brain called the hypothalamus. Its role is to maintain a normal bodily environment, this means control of body temperature, appetite, hormone release and of course sleep. We call this maintaining of body normality homeostasis.

Throughout the day your body is producing hormones such as cortisol ( also known as the stress hormone) along with the protein hypocretin these work to maintain a level of alertness in the brain by promoting excitation within your cortex. As night slowly falls and darkness becomes more dominant, there is a change in this chemical balance. The onset of sleep is controlled by many factors, there two I shall mention. Firstly a build up of adenosine within the brain during the day is linked to triggering drowsiness. Secondly there is the light dependent hormone melatonin produced in brain by the pineal gland its levels controlled by how much light your eyes can see.

Evolutionarily the colour of light is also important, our brains react most strongly to light blue, which by no coincidence happens to be the colour of the sky (and importantly today the main colour produced by computer screens). Typically this was our brain’s way of determining day from night. This brings into question those people who suffer with blindness. It has been shown that those people with complete or highly reduced sensitivity to light suffer greatly with an inability to have solid controlled sleep.

Melatonin itself does not cause sleep, but works to promote it. As it gets darker more and more melatonin is produced leading to the release of the inhibitory chemical GABA within the brain. This acts to reduce the excitation of the awake brain basically turning areas off in preparation to fall asleep. 

Phases of Sleep

Your brain goes through several phases during a normal sleep cycle specifically there are 4 stages each with their own unique functions and recognisable features. The first 3 can be grouped together as what is called non-REM sleep (REM: standing for rapid eye movement). Stage 4 obviously being called REM sleep. You can record the differences in these stages using an electroencephalogram (EEG) which measures brain activity. There are also some features that you will recognise without the need of scientific equipment.

NREM-1 – the first stage of sleep and the bridge between the waking and sleeping states. On an EEG this is signified by the brain’s production of theta waves. There is also the occurrence of hypnic jerks, which is the fancy name for that falling sensation you can sometimes feel while in bed.

NREM-2 – the brain produces more theta waves there are additional waves called sleep spindles and K-complexes. These are thought to help memory consolidation, organising the information from the day.

NREM-3 – signified by the beginning of slow delta waves this is the stage of deep sleep. At this point you are dead to the world, it is very difficult to wake up. If you are prone to sleeping talking or walking this is the phase where that will occur. Along with the potential for night terrors in children.

REM – As its name suggests during REM sleep your eyes will rapidly move beneath the eye lids. There is also a mass inhibition of the muscles in the body leaving you effectively paralysed. REM sleep is also the time where you will dream. It is assumed that the paralysis is to prevent you from acting out the dreams that you have. REM sleep is often called paradoxical sleep as the brain activity looks almost identical to that of a waking brain. If REM sleep is interrupted, as shown in research on mice, there is a huge loss in the ability of the subject to remember things they had previously learned that day.

Dreams remain a mystery among researchers, they are almost impossible to study due to the inability of people to remember their dreams (an estimated 95% of dreams are forgotten). You can’t quantify a dream with numbers and everyone experiences something different. The general consensus is that dreams are our brain’s way of processing information. You can measure the activity within the brain as someone is learning a new task and then record the activity as they sleep and the patterns will be similar. As if they are replaying what they have learnt. Another aspect of dreaming is lucid dreaming, the ability to know when you are dreaming. This allows a person to make decisions and change the outcome of the dreams they are having. There are many tutorials out there to help achieve lucid dreaming, as it is a very desirable and often times fun.

You do not simply traverse from one phase to the next during a night’s sleep, but cycle between all four. Each cycle lasts about 90-110mins passing from NREM-1 through 2, to 3, to REM with the end of each REM cycle leading to a phase of wakefulness before entering NREM-1 again. This will produce around 4-6 cycles each night.

Why Do We Sleep?

Ancient Greek physician and philosopher Galen believed the brain was full of a liquid that was dispensed to different areas of the body during the day. This would eventually dry the brain out so at night sleep was required for the brain to reabsorb the “brain juice” to be reused the next day. We know this not to be the case, but the brain requires sleep to effectively recharge its stores in a few different ways as well as conduct some much needed maintenance. 

There are several prevailing thoughts on the reason we sleep and much of the evidence is in favour of memory consolidation, and repair/replenishment of lost and consumed resources. During the day we fill up an area of the brain involved in short-term memory, the hippocampus. This region is shown to be active during sleep with the purpose of transferring new memories held in this short-term holding area to long-term memory storage. As mentioned, during dreams we go over tasks we learned during the day in the hopes of remembering them the next time we are confronted with them.

Sleep is also crucial for the upkeep of the body particularly for the immune system. During sleep there is a production of several inflammatory chemicals as well as the unique receptors of these mediators. Therefore good sleep is important for the protection of our body from external invaders. All this is well and good, but the truth of the matter is that we don’t get enough sleep and there is some sad news with this fact. We cannot store sleep, it is not a resource we have a banking system for. If we miss a meal or enter starvation the body has stores of fat, evolution has designed these back up systems to provide energy when we are unable to acquire it ourselves. There is no such fail-safe for lost sleep. If you don’t get your recommended 8 hours you can never truly regain that which was lost. 

Sleep Deprivation

As I said you can’t store sleep so what happens when you don’t get enough. There are many detrimental effects to your body without sleep. Firstly learning, you brain during sleep processes all the information learned throughout the day, without sleep your hippocampus activity is dramatically impaired. It has been shown that after a loss in sleep there is almost zero activity within the hippocampus. This translates to an inability to form new memories. This can equate to a 40% reduction in learning which can be the difference between a pass and a fail. Studies were done on children in the state of Minnesota where the school start times were changed to be later allowing for children to get more sleep. They saw increases in the scores on their SATs. Although many have found fault in this study. Repeated research has shown that getting the full amount of sleep, both before and after learning provides the brain the ability to absorb and retain new information better, than someone who is sleep deprived.

I’m sure many of you have had a bad night of sleep, or known someone who has, to find that they may be more irritable or grumpy than normal. The reason for this is very simple, lost sleep equates to a reduction in emotional control and stability. One might say you had woken up on the wrong side of the bed. (The origin of which is back during the Roman period where is was believed to be unlucky to get out of the left side of your bed). It is the amygdala that has its activity increased after sleep deprivation leading to increased emotional outbursts and a loss of logical/controlled responses. As its job is linked closely with that of fear and anger evidence shows that its size is a good determinant of aggression across different species. The amygdala has also been linked to conditions such as anxiety, depression and post-traumatic stress disorder (PTSD). Unsurprisingly people with these conditions also report poor sleep quality.

The deterioration of your immune system can lead to many issues including increased susceptibility to bacterial or viral infection. Lack of sleep causes huge losses in the presence of important inflammatory mediators, including a group called the interleukins. They work as messengers, getting your immune system to respond correctly and rapidly to problems. However there is a far bigger risk to your health with sleep deprivation. Specialised immune cells, natural killer cells (NK cells), another member of the immune defence force are reliant on getting those 8 hours. Their job is to deal with your own cells that have become infected with viruses or mutated into cancer. Throughout the day your cells undergo replication either due to age or the need to repair lost or damaged tissues. This replication can go wrong leading to mutated cells and potentially cancer cells. These mutations are also caused by radiation such as UV light and a huge variety of other factors. NK cells recognise this dysfunctional cells and eliminate them. Studies have shown that after only a single night of bad sleep the activity of NK cells is reduced by up to 70%. This means that sleep deprivation has been closely linked to increases in the chance of cancer. Night shift work is even listed by the world health organisation as a “probable carcinogen” due to how disruptive it is to the biological clock, and hence the immune system increasing the chances of cancer.

Looking to Medicines

There exist many ways to induce sleep in a person or attempt to aid in the process, but there currently exists nothing that can truly mimic natural sleep. This may be disappointing to learn. Many of these following methods will “knock you out” with the consequence that many of the crucial events discussed in this post won’t occur properly, if at all.

Firstly we shall discuss one of the biggest groups of sleep-inducing drugs known as sedatives, these effectively shut the brain down. These include antihistamines, benzodiazepines and probably most well known alcohol. Histamine as well as being one of the triggers of allergies is also an excitatory chemical within the brain. Therefore by inhibiting its activity it will cause drowsiness, this is why many allergy medicines are designed to not enter the brain to prevent this effect occurring. The benzodiazepines are often used as general anaesthetics as well as in sleep medication. They work by activating the receptors for GABA, reducing brain activity within the cortex inducing a sleep-like state. As I said these methods suppress the brain to such a degree as to prevent the crucial sleep processes from happening particularly during REM sleep. Alcohol is a well known recreational substance that at high enough consumption will cause sleep, but is also a member of the sedative family. Alcohol will actually cause a large disruption in the sleep phases causing many more waking moments during the night, many of which will not be remembered due to the inability to make new memories.

Another treatment people often turn to is melatonin. Melatonin is naturally produced to induce sleep, but it takes many more triggers and downstream activators to create the complex harmony that is true sleep. Sadly the effect of melatonin is usually negligible in producing sleep and many of the observed benefits are placebo (so if it works for you keep going). It is however effective with treating jet lag.

Methods to get Better Sleep

I have gone on about why sleep is important to our health and wellness. So here are some tips for getting those 8 hours. Sadly there is no easy way of going about it, but there are several simple things you can do to aid in it.

1. Regularity: your brain works on a cycle and sticking to it helps maintain the chemical flow within your brain and body. Waking up and going to bed at consistent times helps sync up with your biological clock mean you’ll get tired at night and be alert during the day.
2. Light: we need darkness to trigger the internal mechanisms for sleep. With house lights and computer screens we deprive ourselves of the darkness we need, it is therefore recommended to avoid bright lights up to an hour before going to bed.
3. Temperature: the body needs to cool down by up to 1^oC during sleep so it is far better for you to have a colder room than a hot one. This is also why hot baths can help. The reason it works is after leaving the bath your body will naturally vent the excess heat, technically cooling your core down.
4. Lying in Bed: your brain is fantastic at making connections to specific events, by spending extended periods in bed while awake has your brain disassociate being in bed with going to sleep.
5. Avoid Stimulants: That coffee you had after lunch probably isn’t for the best. Caffeine spends a very long time in your system it can naturally stay in your body for up to 12 hours after consuming it. This will obviously interrupt your good night’s sleep.

Sleep is a crucial life process, important in both our general and mental health. You will spend a third of your entire life asleep and it’s for good reason. I hope that this article will answer some of the questions you may have had about sleep and why we do it. There is so much more to this subject and the study of sleep, and how to aid it is still researched greatly. Some future advances in sleep aid is the application of electrical stimulation to the brain during each phase enhancing the waves produced and improving the quality of the sleep. This technology is however several years away from becoming commercial. I hope that with a little help all of you can achieve good sleep. If you are interested in learning more about sleep, I will recommend the book “Why We Sleep” by Matthew Walker a fantastic read and in depth explanations of sleep and its importance. In summary good night and sleep tight.

Reading Sources

• Effects of caffeine on sleep quality and daytime functioning, Callaghan et al.
• Visual impairment and circadian rhythm disorders, S.W. Lockley
• The impact of light from computer monitors on melatonin levels in college students, Figueiro M.G et al.
• The role of adenosine in regulation of sleep, Huang Z.L et al.
• Basic Sleep Mechanisms: An Integrative Review, Murillo-Rodriguez et al.
• Sleep and inflammation: partners in sickness and in health, Irwin M.R
• Edina Sleep Institute Minnesota Study
• A deficit in the ability to form new human memories without sleep, Yoo S.S et al.
• The sleep deprived human brain, Krause A.J et al.

It’s that time of the year again that many of us dread. The flowers bloom and the horrifying sounds of lawn mowers fill the air. Tissue companies rejoice as flu season ends for the torment of summer hay fever to begin. Hay fever is one of the most common allergies we as humans suffer from, and although very rare can affect our poor pets too. As a sufferer myself I thought this was a good opportunity to talk a little about it and allergies as a whole. How do allergies occur and how to treat them?

Allergies are a response from our immune system to something that normally isn’t threatening, but our bodies effectively panic. We can think of allergies as the immune system having an overreaction to something that it doesn’t recognise. In many cases allergic reactions will cause a mild response; the cold-like symptoms of hay fever (runny nose and sneezing), however can reach lethal levels causing asphyxiation (choking through constriction of the throat) such as in individuals with nut allergies.

The Immune System

Let’s first look at how the body responds to foreign entities. When our bodies are invaded by pathogens like bacteria and viruses it is the job of our immune system to recognise it and destroy it. However when it comes into contact with something not harmful but just as foreign it can go through the same processes to dispose of it with the potential of becoming sensitised. Leading to allergies forming.

Our immune system can be divided into two main components called the innate and adaptive. The innate immune system is the first line defence and always responds the same way to invaders. Its job is to recognise something that shouldn’t be there warn the body and then do its best to eat up and destroy it. The adaptive immune system will adjust to the attack and will learn to better deal with it in case of future meetings. This is the theory as to how vaccines work, an introduction to a damaged or dysfunctional version of the bacteria or virus to prepare the body should it encounter the full blown thing.

The key to the adaptive immune system are the antibodies however they are also the doorway to the development of allergies. Every cell has structures on their surface called antigens. There are the ones found on your own cells termed “self-antigens” for example your blood cells are covered in them and they are what determine your blood type. Then there are the antigens found on bacteria, these make the bacteria unique therefore allowing the body to recognise them as foreign. Antibodies are protein structures produced by specific immune cells called B-cells. They are made to bind to specific antigens for example one antibody is made to fight e-coli, but won’t work on salmonella another one needs to be made. The information after making an antibody is stored in the aptly named memory cells ready to be made should the infection ever come back.

The immune system can become sensitive to other foreign entities such as pollen. Pollen alone poses no threat to the body however in some cases the immune system will react generative antibodies against the antigens present on pollen or other such allergens. Antibodies are split into five classes and the one associated with allergies are the IgE (immunoglobulin E) made by plasma cells. When a B-cell encounters an allergen it will differentiate (changing its form) into a plasma cell. The plasma cells produce IgE which binds to another immune cells called the mast cells leaving them in a primed state to the antigens of the allergen. These cells are the producers of histamine, when activated they go about a process called degranulation releasing histamine from capsules called vesicles and triggering an immune response. With things like pollen or dust as they tend to get into the nose or eyes histamine will cause cold like symptoms along with potentially sore eyes. Food allergies are far more dangerous causing inflammation within the mouth and throat. Swelling of these areas can close the airways leading to a serious chance of asphyxiation if untreated.

Treatment of Allergies

Now that we have covered how the body reacts to allergens we need to discuss the ways in which we treat these allergic reactions. There are two main approaches; for seasonal allergies such as hay fever we are fully aware that during the summer months the likelihood of us encountering pollen is pretty high. It’s literally in the air we are breathing should we go outside or open a window. There isn’t currently a way to reverse an allergy once you are sensitised it is usually for life. However there are cases of people becoming desensitised with age. So the best way to treat this is to either seal ourselves away for 3-4 months each year in an air filtered bubble until the plants have finished their mating season, or to face the problem head on and use medication to prevent it.

Honey! Some of you may have heard of consuming local honey as a way of treating or preventing hay fever. I am sorry to inform you but this is a myth. A study done back in 2002 found that there was no difference between giving honey or a placebo to pollen allergy sufferers. The pollen that tends to affect people with allergies is small and light often coming from trees and grasses, plants that bees don’t usually visit.

For seasonal allergies the treatments usually consist of antihistamines or nasal sprays. Antihistamines are probably the most common, they work by preventing the histamine released by mast cells from triggering a response. Histamine once released will be detected by specific receptors causing an immune response. The antihistamines will stick to these receptors instead blocking the histamine from working. If you think of receptors as locks and the histamine as the key, an antihistamine effectively fits in the lock but can’t open it. Common over the counter drugs like cetirizine and loratadine work in this way.

In pharmacology we define chemicals or drugs that bind to and activate receptors as agonists. The drugs that block receptors are antagonists. For example histamine is an agonist for the histamine receptor whereas cetirizine is an antagonist for the same receptor.

Most antihistamines are taken orally, but as mentioned can also be administered with a nasal spray. This will work directly on the inflamed site aiming to reduce irritation and open the sinuses. Other drugs that can be found in nasal sprays are the corticosteroids these also work to reduce the inflammation within the nose and sinuses. Steroidal drugs have a multitude of effects their main one being the reduction in the production of inflammatory mediators. This is done through the inhibition of various genes within the immune system that lead to the creation and release of these mediators. As with other conditions it is often finding what works best for you.

For the more serious allergies such as those to nuts, bee stings or specific medications (e.g. penicillin) the treatment needs to be given in response to reaction. The Epipen which is an automatic syringe to administer adrenaline directly into the bloodstream is the main course of action with these extreme reactions. Adrenaline is naturally produced by the body and activates the fight or flight response. During a period when you need energy fast, adrenaline is released, this will increase blood flow to vital regions such as the lungs. Relaxing the muscle of the throat and opening the airways in preparation for exercise be it fighting or running away. By administering adrenaline immediately to someone experiencing an extreme allergic reaction will counteract the potential asphyxiation. Attendance to the hospital will very likely still be required, but a life will be saved.

Allergies take on many forms and can disappear with age or some might develop later in life. Any concerns regarding allergies can be dealt with by your doctor and having an allergy test is simple and very informative as well as giving a lovely patchwork arm design for a week. So if you are like me and can have your day ruined by nature reproducing, good luck and stock up on those tissues.

Reading Sources

Effect of ingestion of honey on symptoms of rhinoconjunctivitis. Rajan T.V et al.
Blood Groups and Red Cell Antigens. Chapter 2
Immunobiology: The Immune System in Health and Disease. 5th edition.
How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Peter J Barnes
Rang and Dale’s Pharmacology

Welcome to my first post on this blog. I decided that my opening should be something within my field of knowledge. This is to act as an introduction to both myself and what I plan to use this blog for. My aim is to make science simple and to express things in a way that anyone would understand. I see regularly that the general media can sometimes misinterpret or blow out of proportion scientific research. The term “scientists have said” is more cliche than Sean Bean dying in every movie he appears in. I wish to translate what they’re saying and why along with some information about how this could change our understanding of the world around us.

What makes me feel qualified to talk about this, to put it simply I am a scientist or at least I have experience studying it, working in a lab, attending conferences and giving talks about it. However I was always spent my time talking to other scientists. I want to reach out and communicate with people who aren’t experts in the field and hopefully have them develop an interest. I have always had a love for science. During my final year of school, I ended up attending a talk about how science has affected our day to day lives. I would highly recommend Better Looking, Better Living, Better Loving the fantastic book by the speaker John Emsley. From skin care products to the development of contact lens, the area that I found most engaging was the creation and development of drugs. This led me to undertake a degree in Pharmacology, which is not as one friend thought farm ecology and that I would be studying the breeding grounds of sheep (they ended up at Oxford so you all have a chance). After my degree I intended to pursue science further, spending four years working on a PhD focusing on understanding pain. I thought the best place to start was with a little introduction to pain and how it works.

A Painful Start

What is pain? Why is my body doing this? These are some thoughts that may go through your mind after stubbing your toe on a table leg, along with a chain of expletives. In most cases from our body’s point of view the answer is simply defence, pain is an evolutionary benefit to our survival. Warning us when we put ourselves in danger, as well as enforcing the mindset to not repeat it. Learning that it isn’t a good idea to put your hand in a beehive or directly onto a hot pan. The body reacts at an incredible speed to prevent damage from occurring hopefully managing to escape with a mere “ouch!” Providing us information as to where something is wrong is valuable, some signs of serious problems are often accompanied by pain such as appendicitis or cancer.

There does exist a small group of people, truly a minute percentage who do not experience pain at all. Some may call this a gift or a super power, but it comes at a price. Gory stories of horrific burns and broken bones without the person even noticing anything had happened. Pain as horrible as it can be is in most cases (sadly pain can go wrong) is a necessary evil to protect us.

The pain system itself is made up of three distinct regions, the site of injury, this could be damage to the skin or muscle as well as internal organs. The spinal cord which functions as the body’s information highway travelling on to the final area; the brain. All of these regions are connected by nerves the electrical circuitry of the body linking together your paper cut to the rest of the pain system.

The main pain detecting nerves are the nociceptors (noci translates to pain or injury). They have the specific purpose of recognising unpleasant inputs. They are covered in different receptors that can detect the type of pain being experienced. We have categorised pain into three main categories; mechanical (cuts and bumps), chemical (acids, bleach) and thermal (burns through heat or cold). There are specially evolved receptors that are able to distinguish between all these different sensations. There are a huge number of different types, each with a distinct purpose and accompanied by a lovely long name.There are far too many to go into, but as an example the transient receptor potential vanilloid 1 or TRPV1, the first in the family of vanilloid receptors can detect changes in heat. The chefs among you may notice the similarity in name to vanilla, the vanilloids are a large family of chemicals that are able to interact with this receptor. However there is a far more infamous vanilloid that is able to turn these receptors on tricking your body or more typically your mouth into thinking it’s hot. Found in chilli peppers the chemical capsaicin sticks to these receptors turning them on producing the sensation of feeling hot. Always a good idea to wash your hands as you don’t want that capsaicin getting anywhere more uncomfortable.

If you were to cut your finger the cells that make up the layers of protective skin would break releasing their contents into the surrounding environment. The waiting nociceptors are able to detect these chemicals generating within them an electrical signal that shoots from your hand to the spinal cord. The spine functions as a junction box passing information to the brain while also relaying another set of signals back to the arm triggering muscles within the arm to pull your hand away from whatever cut you, known as the pain reflex.

Nociceptors aren’t the only factors at play they are heavily influenced by the actions of the immune system. In response to cell damage immune cells are recruited to the area. Your skin no matter how many times you wash will have bacteria on its surface. The skin is the best barrier we have to keep things that would mean us harm out. With a wound now open these bacteria will seize the opportunity to rush past the breached walls, and it is the immune system that will send forward the ground forces to deal with them. The main immune cells of the body are a family called the white blood cells making up the majority are the neutrophils. They release cytokines and other inflammatory chemicals. These function to call other cells and increase the blood flow to the area. This is what causes the swelling and redness you see around injuries. These chemicals referred to as inflammatory mediators are able to affect the function at the nociceptors. They do this by reducing the required threshold to turn them on meaning things that wouldn’t normally be painful become so. The reason for this is again defensive, by making an injured area more sensitive to pain you are more likely to protect it. This is called allodynia the sensation of non-painful inputs becoming painful.

Neutrophils and macrophages are specialised white blood cells that work to protect the body from foreign threats. Cytokines released by these cells act to signal other immune cells to come to the area like a homing beacon or alert signal. Other chemicals released also act to sensitise the injured or invaded area to potentially help in defending it from further harm. Along with this they work to basically eat up bacteria in a process called phagocytosis. The cell will basically wrap itself around the bacterial cells and consume it.

The immune cells then go to work clearing up the debris of broken cells and any bacteria that may have made their way from your skin inside. The macrophages go round eating up any foreign invaders. The site of the injury will then return to normal as new skin is made to eventually seal away the outside world and any other damaged tissues are replaced. The immune cells return to a resting state and the nociceptors lose their increased sensitivity; bringing the tissue back to a relative normal.

Most of what I’ve discussed only covers the events at the site of the injury and doesn’t even scrape the surface of the pain system. The roles of the spinal cord and the brain as well as different types of pain. We can also experience neuropathic (nerve damage), visceral (internal) and cancer related pain. I will get to discuss the role of the spinal cord and brain in a follow up post. For now it’s important to see that pain is there for our benefit providing us the knowledge of where the pain is and how intense it feels. Without it we would be walking disasters not really know what has happened to us.

Reading Sources

• Textbook of Pain, Wall & Melzack.
• Central sensitization: implications for the diagnosis and treatment of pain, Clifford Woolf.
• Cellular and molecular mechanism of pain, Basbaum AI et al.
• A capsain-receptor homologue with a high threshold for noxxious heat. Caterina MJ et al.