Cakealicious science: The science of baking

screen-shot-2016-09-26-at-08-16-07Food glorious food! Cakes cakes and more cakes! These sweet creations have had people drooling for centuries. There are many variations from rich chocolate to fruit and nut, covered in buttercream or marzipan, stuffed with jam or cream, the choices are almost endless. They’re perfect for big celebrations or just a chilled out half hour with a cup of coffee. But how on earth do they actually work? How can butter, sugar, flour, eggs and baking powder combine to make a delicate mouth-watering sponge?

Magic?

screen-shot-2016-09-26-at-08-15-46Well science magic anyway. Each key ingredient has its own special role, without which the cake would collapse. The major ingredients need to be roughly of equal weights. First off the sugar and fat are mixed together. During the mixing process air gets caught on the rough surface of the sugar granules and is sealed in by a film of buttery fat, this forms a light fluffy mixture akin to whipped cream. We use caster sugar in this process rather than granulated sugar because it is finer than granulated sugar and therefore has a greater surface area on which to trap air.

screen-shot-2016-09-26-at-08-16-25But sugar does more than just trap air within the cake batter. It softens the flour proteins tenderising the mixture, it also lowers the mix’s caramelisation point, allowing the crust to develop a crisp golden consistency at relatively low temperatures. Finally, sugar also helps keep the cake moist and edible for many days. Most of the moisture in a cake comes from the eggs, which provide the mix with the majority of its liquid. When everything is mixed together the eggs produce a foam which surrounds the air bubbles in the mixture protecting them from the heating process and which is also stiffened by starch in the flour. Proteins in the flour join together creating a network of coiled proteins that we know as gluten. Gluten is key to holding the cake together, it expands during baking and then, when cooling, coagulates and is able to support the cake’s weight.

For the bakers out there you may have noticed that we have missed out the baking powder, this may come across as some voodoo magic but it is basically just dried acid and an alkali. Adding water and heat to this mix allows them to react producing CO2.

Now it’s not just getting the right measurement of ingredients, but it’s also essential to get the temperature of the oven precisely right. Too low and the expanding gas cells coagulate producing a coarse heavy texture leading to the cake sinking, too hot and the outside starts setting before the inside even finishes baking, leading to a volcano-looking cake.

So when you next grab a cupcake just take a little time to appreciate the exact science that went into baking that mouth-watering little treat. So many things that could go wrong it’s a miracle we ever found out how to make these soft icing covered delights.

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Post by: Jennifer Rasal

Sources:

https://www.theguardian.com/science/blog/2010/jun/09/science-cake-baking-andy-connelly

https://en.wikipedia.org/wiki/Cake

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Woody Plants and pharmaceutics

Take a moment to think about your health over the last year. How often have you taken a painkiller to manage that headache or fever? These powerful tools have the ability to save you from a day of pain, allowing the survival of that long shift at work or half-marathon which has slowly crept up on you. How many relatives or friends have had their health improved through life saving medications such as chemotherapy or anti-depressants. There are a large variety of medications widely used today that have transformed our lives and we would struggle in a world without them. Many are aware that it is advances in medical research which have enabled the development and availability of these. However, it is often forgotten that when developing such drugs scientists will usually take their inspiration from similar compounds found in nature. But where? This article gives much deserved recognition to nature’s own pharmacologists. After all, these magicians are our true heroes.

So, what natural marvels are responsible for these compounds? – mainly plants, animals and fungi. This article will focus primarily on woody plants and their ability to produce useful chemicals. The extraction of compounds from plants goes back years. From tribes making herbal remedies to the scientific extraction of the chemicals we use today. Below are a few examples of how woody plants have completely transformed our lives:

Aspirin:

screen-shot-2016-09-19-at-20-04-45Aspirin is a silicate sold as an over the counter medication. Its main purpose is to reduce pain and inflammation. The active ingredient in this common drug originally comes from willow tree bark and has actually been used for about 6000 years. So, how does this drug work? Willow bark contains a substance called salicin which the body transforms into salicylic acid. This acid reduces the production of certain prostaglandins in our nerves. Prostaglandins are produced in response to tissue damage or infection, their role being to facilitate the healing process. However, alongside their healing properties they also cause pain, therefore reducing their production can minimise the pain associated with the healing process. It can subsequently be deduced that willow trees do much more for us than just creating a gorgeous aesthetic landscape!

Irinotecan:

screen-shot-2016-09-19-at-20-05-23Irinotecan is a chemotherapy medication primarily used to treat colon and rectal cancer. The active ingredients within this medication include camptothecin, pentacyclic quinolines and 10-hydroxycamptothecin, which are derived from Camptotheca Trees, Camptotheca acuminata. The mechanisms by which these compounds interact with the human body are complex. They inhibit DNA topoisomerase I which is important for the replication of cancer cells. It would therefore make sense that without this substance, cancer cannot thrive. This is because type 1 topoisomerases are catalysts for the transient breakage of DNA and for the re-joining of the strands following this during cell replication. Without this catalyst, replication would occur at a very slow rate. Cancer is a devastating disease and advances such as this are hugely important.

Digoxin:

Top: Normal heart activity. Bottom: Heart fibrillation

Top: Normal heart activity. Bottom: Heart fibrillation

Digoxin is well established in the treatment of heart arrhythmias including atrial fibrillation. It is extracted from the leaves of the common foxglove plant, Digitalis purpura. It works by slowing down the heart alongside improving ventricle filling which increases the blood supply available for each pump. The heart is one of the most important organs in the body, subsequently reflecting the importance of this medication and its lifesaving qualities.

These are just three examples of how woody plants have transformed our lives. However, there are still many unidentified species that have not yet been discovered in our ecosystems which have the potential to contain life-saving chemicals. In addition, there is the potential for the availability of medication that has fewer side effects to those currently in use. Unfortunately, many biomes are currently being destroyed at such a rate new species, and perhaps medically active chemicals, are being removed before any possible benefits can be uncovered. Therefore, the increased rates of deforestation may be destroying more than just habitats, they may be taking with them a wealth of potentially undiscovered medicines. This is just one more example of why conservation work is so important and I urge that it is taken seriously. Effective conservation is clearly vital to improve the lives of our future generations. It can be concluded that plants have played a huge role in our lives over many generations and continue to help us on a daily basis thus reflecting the importance of conserving them.

Take home message: Next time you take that aspirin in a moment of despair, take a moment to really appreciate the unsung heroes of pharmacy – woody plants. It is a shame that whilst many plants save us, we thank them by cutting them down, destroying biomes and causing extinction.

Post by: Alice Brown


References:

http://medicinalplants101.blogspot.co.uk/2014/01/camptotheca-aka-cancer-tree.html

http://sitn.hms.harvard.edu/flash/2011/where-does-medicine-come-from/

http://www.arthritisresearchuk.org/arthritis-information/complementary-and-alternative-medicines/cam-report/complementary-medicines-for-rheumatoid-arthritis/willow-bark.aspx

http://www.biologicaldiversity.org/publications/papers/Medicinal_Plants_042008_lores.pdf

http://www.ebi.ac.uk/interpro/entry/IPR018521)

http://www.kew.org/science-conservation/plants-fungi/digitalis-purpurea-common-foxglove

http://www.sciencedirect.com/science/article/pii/S1319610310000578

https://www.bhf.org.uk/heart-matters-magazine/medical/drug-cabinet/digoxin

https://www.drugs.com/aspirin.html

https://www.google.co.uk/search?q=Irinotecan&biw=1366&bih=667&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiygLePlu7NAhXJB8AKHRwJBloQ_AUIBigB#imgrc=kiktTvOYld7YIM%3A

https://www.google.co.uk/search?q=type+1+topoisomerase&biw=1366&bih=667&source=lnms&tbm=isch&sa=X&ved=0ahUKEwishr_Uke7NAhULAsAKHZxHAeIQ_AUICCgB#tbs=sur:fc&tbm=isch&q=arrhythmias+&imgrc=rri9FbPzjvwvoM%3A

https://www.google.co.uk/search?q=willow+tree&biw=1366&bih=667&source=lnms&tbm=isch&sa=X&ved=0ahUKEwjxs7bnje7NAhXoC8AKHQhNC2YQ_AUIBigB#q=willow+tree&tbm=isch&tbs=sur:fc&imgrc=nDpmo_llPSg_1M%3A

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Are we finished editing CRISPR?

The academic world has been abuzz in the last few years with talk of a new gene editing technology known as CRISPR.  We hear about it on the news and are told that it could one day be a game-changer for modern medicine in terms of genome editing. But, like this article, all new techniques require proofreading and adaptation. So what I’m really wondering is: are we finished editing CRISPR?

CRISPR stands for ‘clustered regularly interspace palindromic repeats’, a mouthful even in the scientific community! CRISPR is a constituent of prokaryotic DNA and is used by these cells as a simple immune system, protecting them against viral attacks. We can imagine prokaryotic DNA as a piece of string (below: labeled as bacterial DNA), with repeated segments (circles) broken up by spacers (rectangles). Bacteria are able to detect invading viral DNA and add short sequences from the viral DNA in between the repeated sequences of their own DNA, creating a catalogue of past infections (a bit like our own immune system). If a virus attacks the same cell again these spacer regions are recognised by a special group of proteins called Cas proteins.  Cas proteins are nucleases which use the CRISPR-incorporated viral DNA segments to chop up the infecting viral DNA and inactivate it.

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Scientists have harnessed the power of the CRISPR/Cas9 system by replacing viral DNA spacers with synthetic guide RNA’s that match a specific DNA sequence – this can be anything the scientist wants to modify. Researchers can then direct the Cas9 protein to their selected gene, causing a break in the DNA and the deletion of that region of the gene, ultimately allowing them to control expression of selected genes.

In theory CRISPR has the power to edit and even remove harmful genes associated with both acquired and hereditary diseases. In fact, just this year Anderson and colleagues at MIT demonstrated its potential in mice, correcting a harmful metabolic mutation. So why are we not using CRISPR in the clinics already?

While most people have no issue with treating acquired conditions, such as cancer, in previously healthy people, concerns arise when we talk about germline editing: i.e. editing human embryos prior to birth. From a medical perspective embryo editing could enable children with life threatening and debilitating conditions to lead a ‘normal life’. However, some parents believe that editing their child’s genome will change the child’s identity. Researchers also argue that, not only will germline editing reduce genetic diversity but we also don’t know enough about the genome and its regulation to confidently make such drastic and heritable changes. On a personal note, my main concern is where would germline editing stop? Where do we draw the line at disease state? For example obesity, my own area of research, and its predisposition is now considered as a disease.  The more conditions we begin label as ‘diseases’ the easier it could be to edit for desired traits.

All these issues exist before we even begin to think about the safety aspects of this new technique.  How do we deliver this system effectively into the human body? And, once there, how efficient and specific will it be. For example off target effects have ranged between 0.1-60%, levels still too risky for the clinics.

While acknowledging that CRISPR does have great potential in the future, much editing and rewriting may still be required before we can click submit.

Post by: Stephanie Macdonald

Sources:

http://www.nature.com/news/crispr-1.17547

http://www.nature.com/articles/nbt.2884.epdf?referrer_access_token=vn4y2fRlT6MSfnjiTkEah9RgN0jAjWel9jnR3ZoTv0NYT9zJj6mpbqWqBhkZTqLWByT9ZihiHupT0fSw150iFynOlHiUTmOgoLqeCBiezScmQzKXSWZlhANyZY8taAUjw7mxZP3DyqCYVeWMBSDBoB_ExZ0FQkLTfyBfhnOubzmO0jxfwklUENzc3pAW-hXzt-7A-uc2YpLGwekIaMKzouz-lsbrPIE9Dozc5RIYLf8%3D&tracking_referrer=www.nature.com

Figure adapted from:

https://en.wikipedia.org/wiki/CRISPR

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How to perfect your astro-photos.

In my last post I discussed why astronomers take multiple identical photographs of the same astronomical object in order to reduce the effects of random noise. I discussed how this noise arises and gave examples of the improvements gained by stacking multiple photos together. Of course, reducing random noise within your image is an important first step but, if you really want to obtain the perfect astro image, there is still more to consider. Both your camera and telescope can introduce a number of inconsistencies in your images, these occur to the same extent in every photograph you take, meaning they cannot be cancelled out like random noise can. Here I will discuss what these inconsistencies are and the ways astrophotographers remove them.

So…what are these inconsistencies? Well they come in three types and each must be dealt with separately:

The first of these is a thermal signal which is introduced by the camera. This tends to look like an orange or purple glow around the edge of an image. It develops when heat from the camera excites electrons within the sensor. As we take a photo, these heat-excited electrons behave as though they have been excited by light and produce false sensor readings. This effect gets stronger with increasing exposure time and temperature. The best way to remove this is to take an equal length exposure at the same temperature as your original astro image but with no light entering the telescope/camera (perhaps with the lens cap on). The resulting picture will contain only the erroneous thermal glow. This ‘dark’ frame can then be subtracted from the original image.

fig_1

Figure 1. The original exposure (showing the constellation Orion at the bottom) shows a strong thermal signal in the top left. By taking a dark frame of equal exposure, we can subtract out the thermal signal, giving a better result.

The next inconsistency is known as bias. This constitutes the camera sensor’s propensity to report positive values even when it has not been exposed to light. This means that the lowest pixel value in your picture will not be zero. To correct this, it’s necessary to shoot a frame using the shortest exposure and the lowest ISO (sensitivity) possible with your kit then subtract it from the original frame. For most modern DSLR cameras, this subtraction has a very small effect but it does increase the contrast for the faint details in the picture – which is particularly important when shooting in low light.

Finally, and arguably the most important image inconsistency of all – uneven field illumination. This problem occurs when the optics within a telescope do not evenly project an image across the camera’s sensor. Most telescopes (and camera lenses) suffer from this problem. A common cause of uneven illumination is dirt and dust on the lens or sensor, which can reduce the light transmitted to parts of the sensor.

This is the objective lens from my telescope before and after cleaning. Although small specs of dust do not seriously affect the overall quality of the image, they can contribute to uneven brightness in the image.

This is the objective lens from my telescope before and after cleaning. Although small specs of dust do not seriously affect the overall quality of the image, they can contribute to uneven brightness in the image.

The final cause of uneven illumination is vignetting, this is a dimming of the image around its edges. Vignetting is normally caused by the telescope’s internal components such as the focus tube and baffles (baffles stop non-focused light entering the camera). These parts of the telescope can restrict the fringes of the converging light from entering the camera. So how do we combat this…keep cleaning the lens? Rebuild the internal parts of the telescope?…no. The answer is simple; take a ‘flat’ calibration frame. All you need to do is take an image of a evenly illuminated object (such as a cloudy sky, white paper, or blank monitor screen). Since you know the original scene is uniformly bright, any unevenness in the brightness of this image must be due to issues with the telescope. You then divide the brightness of the pixels in the original image by the pixels in the flat frame and magically, the unevenness is gone.

For your enjoyment, here’s some examples of flat frames taken from across the Internet, the middle image is from my scope. There are some diabolical flats here; I wonder if it’s even possible to conduct useful astronomy with such severe obstructions in a telescope!

Some examples of flat field frames taken by different telescopes. All these frames show were light is being blocked from reaching the camera sensor. My telescope’s flat frame is the middle picture; it looks good in comparison.

Some examples of flat field frames taken by different telescopes. All these frames show were light is being blocked from reaching the camera sensor. My telescope’s flat frame is the middle picture; it looks good in comparison.

By applying the flat frame correction, the background of the image becomes more even, and dark patches due to dust disappear! No need to clean your scope! (Image taken from http://interstellarstargazer.com).

By applying the flat frame correction, the background of the image becomes more even, and dark patches due to dust disappear! No need to clean your scope! (Image taken from http://interstellarstargazer.com).

For many people starting to turn their cameras and scopes to the heavens, all of this does sound rather arduous but there is software out there that will automatically combine your star images with the three calibration images and spit out what you want (see Deep Sky Stacker). I was amazed that for reasonably little effort and no extra money, I could improve the quality of my images significantly.

Post by: Daniel Elijah

 

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Can I please buy one of your kidneys?

Should we legalise the sale of human organs?

In the UK alone the average waiting time for a kidney transplant is 3 years, this costs the NHS around £24,000 per patient per year and in 2013 – 2014 1000 people died whilst on the transplant waiting list. Dialysis patients also often say they feel that they are just existing rather than living. But, if these patients could get a transplant from a living donor, their life expectancy would increase up to 23 years and their lives could really begin. With increasing cuts to the NHS budget is it possible that the cost-effectiveness of kidney transplant might persuade the government to legalise a market in human organs?  The implementation of a legal organ market would also increase the human organ supply and eliminate the consequences of the black market.

Due to a shortage in organs, the black market and transplant tourism is thriving. Annually, 15,000 – 20,000 illegal kidney transplants take place around the world, often in developing countries such as India and the Philippines. There are even slums in the Philippines dubbed “kidney-vile”, as the majority of the slum’s residents have been driven to sell a kidney. But the black market is built on systematic deception. Brokers coerce desperate workers to sell a kidney then give them much less money than they were promised. Nor do they care about the surgical quality and often leave donors with little or no aftercare. Consequently, donors often become ill and are unable to continue their usual hard labour, which perpetuates their poverty, rather than alleviating it. Recipients are also affected by black market fraud: often these kidneys are not screened properly and donors are coerced to cheat their medical records. As a result of these schemes and poor hygiene standards, recipients often contract diseases such as hepatitis B/C and HIV.

Group of men from Baseco “Kidney-ville” in Philippines, displaying their scars from selling a kidney.

Group of men from Baseco “Kidney-ville” in Philippines, displaying their scars from selling a kidney.

Iran is currently the only country with a compensated and regulated kidney donation program. In this system, there are no brokers and it is charity organizations that coordinates donors with recipients. The government pay a fixed price for organs and cover the costs of all necessary aftercare for donors. Due to this system, Iran is currently the only country with no kidney transplant waiting list. It has also successfully eliminated its black market, and has still maintained a respectable percentage of altruistic donations. Nevertheless there are flaws to the Iranian system as discussed here.

Erin & Harris proposed an ethical, highly regulated, system in which only individuals within a nation are eligible to sell or receive organs. The market would have one purchaser (e.g. the NHS in the UK) and organs would be allocated fairly, giving recipients an equal chance of receiving a transplant regardless of their economic background. This system would also remove the draw for brokers, and subsequently reduce the exploitation of vulnerable people. Medical screening would ensure only healthy individuals could sell an organ, which would to minimise risk (Gill & Sade, 2002). Such a system would also provide proper medical care for donors who would also benefit from a full psychological evaluation, to make sure they are aware of the consequences of their actions.

A study of 478 donors from the Iranian regulated system has shown their health did not deteriorate after the sale, and that 90% of them were content with selling their kidney. These results contrast markedly with the study of 305 Indian donors in an unregulated market. The health of 90% of these donors declined, people living below the poverty line rose up to 20% and 79% of donors would not recommend selling a kidney. This shows that within a regulated program, both vendors and patients are better cared for and are more satisfied with the transplant process.

The strongest argument against the sale of organ is the possible exploitation of the poor. Critics argue that legalisation could lead to a market that would exploit poorer people, as they might view organ sale as a last resort. But, is it exploitation if a person makes a reasoned decision to take an action they consider to be the best option to improve their life? One can’t assume that money would simply overrule a person’s judgment. A black market would also lead to greater exploitation than any legalised market ever would. Prohibiting an organ market is paradoxical, to restrict an individual’s autonomy and cause moral harms to liberty.

Another prominent argument against the sale of human organs is that it would lead to commodification of the human and therefore corrupt human dignity. Commodification is an unsuitable term to use for the sale of a kidney, since there are numerous other circumstances when paying money does not insinuate loss of dignity, such as surrogacy.The scarcity of organs and, death and exploitation of people will not be resolved through rhetoric of moral repugnancy and human dignity.

Under prohibition, patients are suffering and dying whilst waiting for a transplant. Both vendors and recipients are exploited by the black market, and the human rights of poor people are violated. These problems will continue to exist as long as there is a dearth of organs. So, should a market in human organs from living persons be legalised? Or is it merely a naive and impractical idea, only appropriate for a dystopian future. Either way, the possibility of legalising a regulated and ethical market should be explored.

Post by: Alyssa Vongapai


References

Erin, C. A., & Harris, J. (2003). An ethical market in human organs. Journal of Medical Ethics , 29 (3), 137–138.

Ghods, A. J. (2009). Ethical issues and living unrelated donor kidney transplantation. Iranian Journal of Kidney Diseases , 3 (4), 183–191.

Goyal, M. (2002). Economic and Health Consequences of Selling a Kidney in India. Journal of the American Medical Association , 288 (13), 1589.

Higgins, R., West, N., Fletcher, S., Stein, A., Lam, F., & Kashi, H. (2003). Kidney transplantation in patients travelling from the UK to India or Pakistan. Nephrology Dialysis Transplantation , 18 (4), 851–852.

Hippen, B. E. (2005). In defense of a regulated market in kidneys from living vendors. The Journal of Medicine and Philosophy , 30 (6), 593–626.

Kidney Org. (2010). Transplantation Cost Effectiveness. [Online] Available from:http://www.kidney.org.uk/archives/news-archive-2/campaigns-transplantation-trans-cost-effect/. [Accessed on 5 Aug 2016]

MacKellar, C. (2014). Human Organ Markets and Inherent Human Dignity. The New Bioethics: A Multidisciplinary Journal of Biotechnology and the Body , 20 (1), 53–71.

Moazam, F. (2009). Conversations with Kidney Vendors in Pakistan. Hastings Center Report, (June), 29–44.

New Internationalist. (2014). Human traffic: exposing the brutal organ trade. [Online] Available
from:http://newint.org/features/2014/05/01/organ-trafficking-keynote/. [Accessed on 5 Aug 2016]

Organ Donation. (2015). Transplant save lives. [Online] Available from:http://www.organdonation.nhs.uk/newsroom/fact_sheets/transplants_save_lives.asp.
[Accessed on 5 Aug 2016]

Pat Roque. (1999). Group of men from Baseco “Kidney-ville” in Philippines, displaying their scars from selling a kidney [Photograph]. At: https://digital.newint.com.au/issues/88/articles/1890. [Accessed on 5 Aug 2016]

The Wall Street Journal. (2015). Cash for kidneys: The case for a Market for organs. [Online] Available from:http://www.wsj.com/articles/SB10001424052702304149404579322560004817176.
[Accessed on 5 Aug 2016]

World Socialist Web Site. (2015). Dramatic increase in worldwide illegal organ trade. [Online]
Available from:http://www.wsws.org/en/articles/2012/07/orga-j14.html. [Accessed on 5 Aug 2016]

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Insight from behind the lab bench: Could a period pain treatment be re-purposed to treat Alzheimer’s disease?

Today we are lucky enough to have the opportunity to publish a post written by Mike Daniels – one of the researchers behind the recent discovery that a drug used for the treatment of period pain may have a role to play in the treatment of Alzheimer’s disease. We hope you enjoy the opportunity to slip behind the lab bench and see what happens behind the scenes of a big scientific discovery.

My name is Mike Daniels, I am a PhD student working at the University of Manchester. We’ve just published a paper in the journal Nature Communications on how currently available drugs may be used to treat Alzheimer’s disease. The Brain Bank North West got in touch with us and gave us a fantastic opportunity to add our voice to the current media storm surrounding this research. I hope I can give you a detailed look at the ins and outs of this important research and offer some insight into the workings of a big research project.

Screen Shot 2016-08-19 at 20.48.07Our lab group are particularly interested in AD, not just because it affects over 26 million people worldwide without any truly effective treatment but also because our speciality is immunology and research suggests that an overactive immune system may play an important role in AD. One particular part of that immune system recently implicated in AD is something called an inflammasome. The inflammasome is a large bundle of proteins which forms a kind of machine within cells whose job it is to produce proinflammatory cytokines. These cytokines go on to promote inflammation in the brain which can worsen AD.

What’s particularly exciting for us is that this inflammasome appears to be largely redundant in everyday immune functions like fighting bacteria or viruses. This means we should be able to inhibit it in patients without rendering them susceptible to infection.

OK so we have a plan – inhibit the inflammasome complex in the hope of improving outcomes for people living with AD. But how do we do this? We could design new drugs (something our lab is involved in right now) but the process of getting a new drug from bench to clinic can take around 20 years and cost around 1.6 billion dollars. Another quicker, cheaper option is to do something called ‘repurposing’, this basically means taking a drug already approved and on the market and using it to treat a different disease. With this in mind our lab head Dr. David Brough decided to test a number of drugs from a large class called non-steroidal anti-inflammatory drugs (NSAIDs) to see if they could inhibit the inflammasome and thus potentially be used in AD. So, this was the project I was tasked with in my first week of PhD life nearly two years ago.

We began by testing a number of these NSAIDs on immune cells cultured in a petri dish. This gave us the important opportunity to screen a large number of drugs without unnecessary use of animals. When we ran these screens we had a bit of a surprise. The more famous NSAIDs such as ibuprofen (Nurofen) had no effect. However, one drug, mefenamic acid, was able to inhibit the inflammasome and prevent release of inflammatory cytokines in the cells. Mefenamic acid is only available by prescription and is prescribed largely to treat period pain.

So, how does mefenamic acid inhibit the inflammasome?

Research suggests that ion channels on the cell surface play an important role in inflammasome activation and that mefenamic acid may inhibit some types of ion channels. To better understand this we formed a collaboration with a London-based research group led by Dr. Claudia Eder – an expert in electrophysiology (researching ion channels). It was with the help of Dr. Eder’s lab that we identified the target of the drugs as a chloride channel called the volume-regulated anion channel (VRAC).

Screen Shot 2016-08-19 at 20.56.56Now we had the drug and the mechanism but we still don’t know whether this drug would be effective in treating AD. This is where we needed to look at the drugs action in a living system. The first model system we chose was a rat model of amyloid-beta induced memory deficits. Build-up of amyloid-beta is a thought to be a major factor in memory impairment and AD. Indeed, if injected into the brain of rats, amyloid-beta causes permanent memory deficits. As part of a collaboration with Dr. Mike Harte’s lab here at Manchester, we injected a group of rats with either mefenamic acid or a placebo and found that those which received the drug were completely protected from amyloid induced memory deficits.

We then moved to look at the effect of the drug in a genetic mouse model of AD. These mice had been altered to express some of the same genes found in humans with the genetic form of AD and, like human sufferers, these mice develop memory deficits with advancing age. When treated with mefenamic acid at the age of onset, these mice did not develop memory deficits, unlike animals treated with a placebo. We also found that the brains of placebo mice displayed signs of intense inflammation while those of drug treated mice remained completely normal.

So to conclude, AD is a terrible and currently incurable disease which we believe to be partially caused by an overactive immune system – specifically over-activity of a protein complex called an inflammasome. We found that the commercially available drug mefenamic acid was able to inhibit the inflammasome and reduce memory loss in both mouse and rat models of Alzheimer’s-like memory deficits.

But what’s the next step? We are hoping to begin to move mefenamic acid into clinical trials to see if it could really work in humans. Luckily, because the drug is already known and approved we can skip the safety testing stage of the clinical trial process. Unfortunately however, clinical trials remain extremely expensive and, as mefenamic is off patent and can no longer be sold for profit, gaining funding through pharmaceutical companies is nigh-on impossible. This means we are relying on grants from fantastic charities such as Alzheimer’s Society and Alzheimer’s Research UK in order to move this study forward.

A lot of work is needed and it will still be a while before we have results in people currently living with AD, but this remains an exciting step and we can only hope that it will go some way to treating this horrible disease.

Guest post by: Mike Daniels

Screen Shot 2016-08-19 at 20.25.13Mike is currently studying for a PhD in neuroinflammation at the the University of Manchester, UK. His work is based mainly on the role of a huge protein complex called the inflammasome in diseases such as Alzheimer’s, stroke and haemorrhagic fever. When he’s not in the lab he’s usually found up a mountain or out in the countryside somewhere and is always on the lookout for any new science outreach ideas!

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Fat vs fat in the fight against obesity and diabetes

Using fat to treat obesity and obesity-related conditions, such as type II diabetes, may sound like a strange idea. Nevertheless, this is exactly what scientists are working to achieve. So the question is, why?

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There are in fact two types of fat in the body. The more familiar of the two – white adipose tissue (WAT) – is the tissue we refer to colloquially as “fat” and associate with gaining weight. The second, and lesser known variety of fat, is brown adipose tissue (BAT). This unique tissue is densely innervated by the body’s sympathetic nervous system (SNS – initiator of the “fight or flight” response) and is well supplied by blood vessels. Originally believed only to exist in small mammals and human infants. BAT is used to produce heat without the need for shivering. This is particularly important for these organisms as a way of maintaining their core temperature in mild cold conditions.

The key to BAT’s ability to produce heat is a special protein called uncoupling protein 1 (UCP1), which is housed within the large number of mitochondria found in this tissue. In general, mitochondria act as the “powerhouses” of all cells, producing energy in the form of ATP which allows the cell to perform all its required functions.

However, in cold conditions, sensors on the skin send a signal to the part of the brain responsible for regulating body temperature. The brain, in turn, sends a message to BAT via the SNS, releasing noradrenaline and stimulating UCP1. Upon activation, UCP1 is able to “override” the usual ATP-synthesising function of BAT mitochondria, instead releasing energy as heat.

Importantly, this process of heat production requires a significant amount of energy to achieve. As the main fuel used by BAT are fat molecules, such as lipids and fatty acids, the idea that BAT could potentially be used to help reduce body weight in obesity is not as ludicrous as it may first appear. This is supported by the finding that both UCP1- and BAT-deficient mice models display increased weight gain.

Screen Shot 2016-08-14 at 20.48.58Despite evidence of the role BAT plays in controlling body weight in experimental rodent models, BAT was originally believed to be absent in adult humans. More recently, however, the use of radioactive tracer PET and CT scans have demonstrated the presence of functional BAT in adults in mild cold conditions using large cohorts of patients. Further analysis of PET and CT data has also uncovered an inverse association between BAT activity and BMI, with lower levels of activity in patients with severe obesity. Though the average human adult is estimated to possess just 50–80g of BAT, this mass is believed to use up to 20% of our daily energy intake, making BAT a desirable candidate to aid weight loss in obesity.

BAT has also been shown to express high levels of the glucose-transporter protein and displays comparable glucose uptake to muscle in response to insulin. Given that a key risk factor for type II diabetes is being overweight, and that this disorder is characterised by high blood glucose and insulin resistance, targeting BAT as a method of treatment is also under investigation. Notably, insulin-activated glucose uptake into BAT is significantly lower in those with obesity compared to subjects of a normal weight.

Given the mechanism of BAT activation discussed above, as well as the observation during PET and CT scans that BAT activity is inhibited when human subjects are warmed, the simplest way to stimulate this tissue for therapeutic reasons may be with the use of cold temperatures. In support of this theory, a small study involving healthy Japanese volunteers, who were repeatedly exposure to mild cold stimuli over 6 weeks, reported increased BAT and resulted in a loss of body fat in subjects. In another study, exposing healthy volunteers with active BAT to short-term mild cold led to increased insulin sensitivity.

Screen Shot 2016-08-14 at 20.49.22A second potential method of stimulating BAT with the aim to treat obesity or type II diabetes is via the SNS, specifically through beta-adrenergic receptors (βARs). It should be noted that anti-obesity medications which target these receptors have been tested in the past. However, these attempts failed due to unspecific activation of βARs throughout the body – particularly the heart – resulting in serious side effects, including increased blood pressure and heart rate. Nevertheless, the use of more specific βAR agonists have been used successfully to increase BAT activity and lessen obesity and insulin resistance in rodent models, without such side effects.

Alternatively, it may be possible to target the thermoreceptors on the skin responsible for sensing cold, known as TRPs. As cold exposure cannot be controlled easily, activating these receptors artificially may provide a more efficient way of using BAT to treat obesity or type II diabetes. Interestingly, there are already a number of foods which activate TRPs, including menthol in mint and capsaicin in chili peppers. Animal and human studies of capsinoids – non-pungent analogues of capsaicin – have demonstrated that these compounds increase active BAT and reduce body fat.

Despite sounding rather contradictory, adipose tissue may prove useful in the treatment of obesity and the obesity-related disorder, type II diabetes. Unlike its white counterpart, BAT actually uses up lipids and glucose from the body as fuel in order to produce heat. However, in doing so, evidence suggests this can also result in weight loss, reduced insulin resistance and lowered blood glucose, making it a potential treatment for obesity and type II diabetes. Possible methods of activating BAT for this purpose may include cold stimuli or agonists which target βAR or TRP receptors. It is still early days for this treatment possibility but the idea certainly isn’t as strange as it may first appear.

Post by: Megan Barrett

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