Breaking into the Circadian Clock

Japan Daily Press

Sometime in the future a person could be waking up after a short 16-hour snooze. Preparing a hearty meal to start their “day”, they will probably be thinking about the hours ahead of them. Maybe they have a night shift, a morning to see friends and family, a hobby to indulge in somewhere in-between. Time is cheap when you don’t have to sleep for another 36 hours.

This of course is fantasy, but could it eventually become a possibility  – or even a necessity? After all, society in the 21^st century is “Open 24/7”. In crude terms of thinking, there is a need for us to adapt to our new social patterns.

A growing number of individuals in countries affluent and developing alike are taking on employment that requires work during hours that are deemed “unsociable”. Late-night bar workers, early-morning cleaners and night-shift security  – most people know at least one or two people who work in these sectors.

Working unsociable hours usually comes with better pay and more flexible free time in the day, but research is starting to uncover the dangerous long-term effects of an abnormal day/night cycle.

Following a rough 24-hour period and reacting to simple environmental elements, Circadian rhythms are our biological cycles that adhere to the light/dark cycle of the day. In humans they affect sleep cycles, hormone release, body temperature and many other important physiological factors. Abnormalities in these cycles can cause insomnia, depression and even obesity.

Psychology Blog

People experience the effects of going against their Circadian rhythms quite often; jet lag, lack of sleep and that groggy feeling you get after an afternoon nap are prime examples of what happens when your body is out of sync!

All human necessities are controlled subconsciously by our biological clocks, named so due to their tendency to cause the hand of our Circadian cycles to turn. These clocks drive all life, not just humans, and are genetically rigid in our make-up. Tucked in the hypothalamus part of the brain is a bundle of neurones called the Suprachiasmatic Nucleus (SCN). This construction of neurones is accepted to be the human Master Clock, the conductor of all of the other biological clocks.

Hijacking our own daily rhythms and biological routines would be a very complex ordeal, but we are starting to understand more about Circadian Rhythms.

To avoid the risks of obstructing our natural biological cycles we would need to modify our own physiology - our needs to rest and sleep (accepting that eating and drinking is, pretty much, impossible to avoid). Lots of our Circadian rhythms summate together to produce one large desired effect, which makes the “root” of each Circadian action hard to locate. Scientists at the University of Oxford have recently managed to pinpoint a very significant element involved in Drosophila (fruit fly) Circadian rhythms: a genetic “on-off switch” for sleep. Gero Miesenbock and team used light to turn on genetically modified cells that react to certain wavelengths, due to the presence of the gene. The light caused dopamine release, which inhibited sleep-promoting neurones, thus waking the flies.

Working directly with Drosophila’s neurones, Fang Guo at Brandeis University, Massachusetts, demonstrated an opposite effect: in the same type of fly, after activating neurons in a biological clock, glutamate is release which then turns off neurones in the part of the Master Clock that promotes activity.

Although we already know that dopamine in animals is generally related to active behaviour, and that glutamate inhibits areas of the SCN in humans, we can’t yet assume the same model seen in Drosophila as in more complex organisms. This type of research does, however, demonstrate that we have already started to pick-apart the inner workings of Circadian activity.

Looking at something closer to humans, Circadian rhythms in mice have been found to lengthen when caffeine is involved. We all know that coffee alters our sleep pattern, but researchers Oike, Kobori, Suzuki & Ishida found in 2011 that administering caffeine into the growth media of both human bone-cancer cells and mouse stem cells actually alters the length of the biological cycles. On an intracellular level it was seen that processes associated with high-level activity were extended, causing a lengthening shift in the whole “daily” cycle of the cell. Another experiment with caffeine was attempted which involved the stimulant being added to ex vivo (outside of organism) liver cells, which resulted in signal delays in the SCN – something that could be linked with the lengthening of the cycles.

To try something with a whole organism, the researchers ran a third test with live mice. “Limitless” supplies of caffeine were made available to the subjects for a week under normal light-dark conditions. The findings of this in vivo experiment were that the mice were indeed active later into their dark periods in comparison to the control group.

Although for these mice the administration of a caffeine fountain was a rudimentary way of modifying circadian rhythms, this study raises two interesting points: firstly, as conserved as the genetic foundations of these biorhythms are it is possible to modify them. Secondly, the modification of these cycles can be performed in complex, mammalian organisms and not just isolated tissue.

As our Circadian rhythms are firmly ingrained into our cells’ genetics, the cogitation of altering something so essential and, some could say, ancestral is a daunting task. Surely these axial genes that make up our natural rhythms are hard to get at? Yes, for now, but further specific advances in the field (which if you’re interested is called Chronobiology) have uncovered a clue to unmasking the “cogs” of the biological clock:

Scientists at the Salk Institute (CA) have discovered a tell-tale sign to identify the strength of someone’s Circadian rhythms. They were looking at the REV-ERBa structure, which is a particular receptor found on many genes associated with repressing transcription. The REV-ERBa is considered to be associated with inhibitory effects in biological clock activity, although the mechanism of its workings was previously unknown.

What the team at Salk found surrounding this gene was that 2 proteins work together to change REV-ERBa concentrations. They expected that this is an important mechanism used in biological clocks to lower levels of activity during night time, when an individual is asleep, and then raise levels again in the morning. The 2 proteins perform different tasks to “turn the hand” around on the biological clock; the F box protein FBXW7 selects REV-ERBa for degradation in the morning which causes activity levels to rise, and then Cyclin-dependent Kinase 1 (CDK1) phosphorylates REV-ERBa (a prominent sign of activation in biology) when activity levels become too high. What’s more interesting, is that when CDK1 phosphorylates REV-ERBa it is also signalling to FBXW7. This means that when REV-ERBa levels are very high (i.e. at night, again) FBXW7 is drawn to the component to begin the cycle all over again.

Zhao et al. (2016)

The importance of this study is that it identifies something that has not been seen before: Circadian rhythm amplitude. The strength of gene activation in these biological clocks is being controlled by 2 proteins, both dependent on each-other. If there were drugs that could potentially alter the levels of one, we would be able to not necessarily control our biological rhythms but at least steer them in the right direction. For example, If an early-morning shift worker found that they couldn’t settle-down to sleep early in the evening, they could take a drug that could induce an earlier CDK1 effect. This would lead to REV-ERBa levels increasing earlier on in the day, causing sleepiness earlier than normal and wakefulness earlier the next morning – just in time for a 5am shift.

It is very important that we understand that our biological rhythms have evolved with us over millions of years. They are crucial parts of our physiology, and although the studies explored in this article aim to show that they can be altered it must be stressed that we are a long way off from the future described in the first paragraph. For the time being we are as reliant on our natural Circadian rhythms as much as any other organism, but that doesn’t mean that our increasing knowledge of genetics can one day give us the controls to our own cycles.

Sources:

-         -  Piemental, D., Donlea, J.M., Talbot, C.B., Song, S.M., Thurston, A.J.F., & Miesenbock, G. (2016). Operation of a Homeostatic Sleep Switch. Nature, 536 , 333-337. doi: 10.1038/nature19055.

-        -   Guo, F., Yi, W., Zhou, M., & Guo, A. (2011). Go signalling in mushroom bodies regulates sleep in Drosophila. Sleep, 34 (3), 273-281. Retrieved from http://www.bio.brandeis.edu/rosbashlab/profile.php?imagename=fang.

-        -   Oike, H., Kobori, M., Suzuki, T. & Ishida, N. (2011) Caffeine lengthens circadian rhythms in mice. Biochem Biophys Res Commun, 410 (3), 654-658. doi: 10.1016/j.bbrc.2011.06.049

-        -   Zhao, X., Hirota, T., Han, X., Cho, H., Chong, L., Lamia, K. ... Evans, R.M. (2016). Circadian Amplitude Regulation via FBX27-Targeted REV-ERBa Degredation.Cell, 165 (7), 1644-1657. doi: http://dx.doi.org/10.1016/j.cell.2016.05.012.
a       - Psycology Blog image: http://a2levelpsychology.blogspot.co.uk/2015/06/a2-level-circadian-rhythm.html
         - Japan Daily Press image: http://japandailypress.com/know-your-body-clock-and-lose-weight-2810428/
- 

-         -  Salk Institute. "Powering up the circadian rhythm." ScienceDaily. ScienceDaily, 26 May 2016. <www.sciencedaily.com/releases/2016/05/160526124908.htm>
- 

Solid Genetic link to Depression Found Thanks to “Massive Crowd-sourced Depression Study”

For a long time, the study of depression has been from a psychological perspective. Studies investigating the genetic aspects of mental illness have often rendered fruitless outcomes, over-ambitious results and rifts between communities of geneticists. However, recently published in Nature, a study including several datasets of human genomes support the strongest argument yet for a genetic association to Major Depressive Disorder.

Depression is a type of mental illness that can develop in any individual regardless of age, gender or lifestyle. Its exact workings remain a mystery, as each case of depression varies from individual to individual – just like cancer. General belief is that an imbalance of chemicals in the brain, including neurotransmitters, causes depression. As a result, “wrong” genes become expressed (or inhibited) inside cells and different areas of the brain end up functioning less or abnormally.

Research released in collaboration with genome-sequencing company 23andMe earlier this year has posed genetic links to MDD in adult Europeans. The business sells gene-test kits for less than £200, and are easy to obtain through it’s online store.

Until recently most data produced by the organisation was made for customers as a personal, entertaining insight into their ethnic heritages. As well as investigating their genetic miscellanies, users of the service can accept to release their genome for research within a multitude of studies.

The paper, lead by geneticist Dr. Ashley R. Winslow, is the largest study of it’s kind. The research uses a technique called Genome-wide Association Study. This is a commonly-used bioinformatical approach that takes the DNA of people suffering from a disease and compares it, base-by base, to healthy DNA genomes. In this case, the healthy genomes and the genomes of individuals with MDD both came from consenting-users of 23andMe.

Individuals gave important “self-report data” to the organisation, alongside their DNA submissions. Dr. Winslow’s team performed a meta-analysis, combining the 23andMe data with previous MDD association-study datasets. Using the self-reports the researchers confirmed a total of 75,607 individuals declaring some history of clinical depression. This group was transferred to a new dataset and compared to the 231,747 individuals that reported no personal history of depression.

After the comparative assessment, 5 stand-alone “variants” from 4 regions were identified as being unique between the two groups. Upon analysis of loci (their locations in the genome) the team uncovered 17 independent Single Nucleotide Polymorphisms/ mutations from 15 regions that seemed to have a large effect on the genome.

Note: the 17 SNPs were identified after loci with P values more than 1 x 10^-5 were excluded.

In previous studies using whole genome sequences some of these loci had shown associations with psychiatric traits. This means that the regions aforementioned can be scrutinised in individuals to observe whether certain SNPs in these areas can increase the risk of MDD.

The paper aims to set a “diving-board” for more investigations into the biology of depression. As a large undertaking by Winslow et al., this novel study in the field has demonstrated the potential of larger collaborative datasets that are made publicly available. The results could also encourage second-glances at previous studies, such as Cai, Bigdeli, Kretzschmar & Li (2015), which pointed links between MDD and 2 loci in female Chinese populations.

Considering the future implications of public, crowdsourced genetic datasets it would not be unfair to suggest that we could begin to investigate the mechanics of these identified loci. New drugs could be synthesised that target the variants within these regions, and advanced methods of MDD detection could be a possibility. However, the latter may be a long way off. From what is known about its genetic association the risk of depression is down to mutations at hundreds of loci, each having a miniscule effect on the overall outcome.

What can definitely be said is that these findings are a positive re-enforcement, if not an affirmation, that mental illness does has a genetic factor. We now know even-more-so that lifestyle may not be a preventive or causative issue for the development of psychological disorders in some individuals.

References:

·       Winslow, A. R., Hyde, C. L., Nagle, M. W., Tian, C., Chen X., Paciga S. A., Wendland J. R., Tung J. Y., Hinds D. A., Perlis R. H. (2016) Identification of 15 genetic loci associated with risk of major depression in individuals of European descent, Nature. DOI: 10.1038/NG.3613

·                    日本語要約 (2015) Sparse whole-genome sequencing identifies two loci for major depressive disorder, Nature, 588-591. DOI: 10.1038/nature14659

·       “Study points way to finding genes affecting depression risk” – Malcom Ritter (09/2016)http://hosted.ap.org/dynamic/stories/U/US_MED_DEPRESSION_GENETICS?SITE=PASUN&SECTION=HOME&TEMPLATE=DEFAULT

·       “23andMe Pulls Off Massive Crowdsourced Depression Study” – Antonio Regalado (09/2016) https://www.technologyreview.com/s/602052/23andme-pulls-off-massive-crowdsourced-depression-study/

·          Harvard Health Publications http://www.health.harvard.edu/mind-and-mood/what-causes-depression

• Image 1: http://www.wwu.edu/healthyliving/education/Depression/images/causesDNA.png
• Image 2: https://upload.wikimedia.org/wikipedia/commons/thumb/e/ec/23andMe_logo.svg/2000px-23andMe_logo.svg.png

The Rising Tide of Antibiotic Resistance

For the past 70 years state-of-the-art healthcare has been saving countless lives around the world. Since the discovery of antibiotics in the late 1920s, the era of Modern Medicine in which we live in has allowed us to live longer, happier and more fulfilling lives - but all of that could now be in jeopardy.

Theorised and pioneered since the 1880s "antibiotic chemotherapy" is the process in which a drug is used to specifically target a bacterial organism to combat or prevent an infection. Each antibiotic drug works by targeting specific receptor sites on the organism's cell membrane, and bringing about a series of changes that kills the organism. The most well-known antibiotic is Penicillin, discovered accidentally by Alexander Fleming in 1928 and still used today, although in less occurrence.

Before antibiotics many people had a much shorter life expectancy, dying from minor injuries and complications. The problems weren't the ailments themselves but the infections that injured and ill people were more prone to. To give an example, the first patient to be administered Penicillin was Albert Alexander - a British Policeman who was so ridden with bacterial infection that he could not be recognised by his family. His head was covered in abscesses, doctors even had to remove an eye, all because days before he had scratched his face on a rose thorn in his garden.

For the last half-century antibiotics have dissipated the number of deaths from infection. Antibiotic treatment is commonplace in healthcare and even considered the backbone of our medicinal practices. They prevent diseases, work alongside compromise immune systems, allow those who have undergone surgery or other treatments to recover faster and safer.
In the next 50 years, this could all be about to change due to antibiotic resistance.

All life on this planet has evolved to be where it is today, including bacteria. Unlike many multi-cellular organisms they evolve at a much faster, uncomparative rate. With every new generation mutations can occur - some of these bad, some neutral and some even advantageous - and with a generation time of around 20 minutes bacteria can develop (through a build-up of "accidental mutations") advantageous abilities within an extremely short period of time. When a bacterial organism develops an advantageous mutation to survive in the presence of an antibiotic drug it is said to be resistant.

Projections of Antibiotic Resistance

The main factor to address is that, if antibiotic resistance increases enough, many more people will die from infection. A study conducted by RAND Europe in 2014 showed that in the US and Europe 50,000 people die yearly from infections that no drug can help. This is mostly because the vast majority of antibiotics that we use belong to a generation of drugs that were made in the 1980s. The World Health Organisation predicts that by 2050 10 million people will die every year from antibiotic-resistance infection.

Bacterial disease may not just be caused by infections of infamous "hard-hitting" species, in fact a rise of resistance within many species of common bacteria that we live with would become deadly; potentially resistant infections like strep. throat and salmonella could mean death, as it did at the beginning of the 20th century.
Just a few months ago a senior medical official of the NHS reported to GPs that a super resistant strain of Neisseria gonorrhoeae had surfaced in England, meaning many of it's carriers could have a completely non-treatable Gonorrhoea infection.

A Provoked Resistance?

Nature will always find a way to adapt, so the evolution of bacteria to resist harmful drugs that they are being exposed to is inevitable. But that isn't to say that our practises have caused this rate of resistance appearance to sky-rocket.
As briefly mentioned, almost no new antibiotics have been discovered and approved since the 1980s. Back in that time, pharmaceutical companies believed that the various classes of antibiotic drugs were enough to tackle any infection for the foreseeable future. Since then only 1 effective antibiotic has been discovered, and it will not be available for the next 5 years (See Teixobactin). With no other new antibiotics in circulation, 30 years or so has been more than enough time for bacteria to develop a resistance to most of our antibiotic arsenal.

A linked cause (and potential reason) to the non-existing new generations of antibiotics is an economical one - many pharmaceutical companies do not see making new antibiotics a financially beneficial venture. This mainly because bacteria have began to evolve so quickly that it's not in their best interests to fund potentially new antibiotic drugs that could become inadequate in the next 10 years. The figure above backs up their opinions on the matter.

Fourthly, antibiotics are being abused. This is the broadest and most harmful cause of microbial resistance, and the misuse of antibiotics doesn't solely lie with human use.
In a society that relies on industrial farming, many animals are fed a variety of antibiotics on a daily basis. Rather than treating a present infection, most are said to be needed to increase the meat yield and health of the animal. Some antibiotics are even used on plant crops.

In the case of human medicine, is the general practice of some doctors is to prescribe a "shotgun" cocktail of antibiotics for a patient that may have not even been screened for any bacterial infection at all. The UK's National Institute for Care Excellence reported that last year 10 million antibiotics were unnecessarily prescribed - that equates to 1 in every 4 capsules.
The way in which we individually use antibiotic medication is often wrong too. Many people who are given a prescription stop taken it immediately after they start to feel better. In the case of antibiotics this is very dangerous as it gives the trace amounts of the infection left to adapt and grow, bringing back the infection and increasing the chance of this resistant colony to pass on it's genes to other bacteria in the environment.
Taking antibiotics incorrectly or even unjustifiably also harms your body flora - the "friendly" bacteria that live predominantly in your intestines and help you absorb nutrients from food.

What Could We Do to Slow Down the Rate of Resistance?

The easiest ways to tackle this problem are socio-economical. In the here and now, with no scientific development, governments could put pressure on Health services to scrutinise the ways in which antibiotics are prescribed. Institutional audits could question every decision as to whether a patient should be given antibiotic treatment - backed up by regular and commonplace patient screening tests to ensure an specific infection is present and has need for treatment. Changing the public attitude towards typical antibiotic use (targeted equally at non-western countries with less awareness of proper use) could prevent worried parents from demanding that their child has antibiotics for a non-credible, minor illness. These implementations could swiftly slow down the rate of resistance, and reserve many antibiotics for more effective uses in surgery, artificial replacement operations and for those with compromised immune systems.

Another way to look at the problem would be to devise alternatives to antibiotic treatment. Preliminary research into predatory bacteria is currently being conducted by the US Defence Advanced Research Projects Agency, which investigates whether species of bacteria could successfully kill other bacteria which cause infection in the human body.
Similar to antibiotics, genetically produced components in a cell - or peptides - with antibacterial activity have been isolated from several different organisms to see if they can be used pharmaceutically. One drawback to this approach is that just like antibacterial drugs, bacteria would eventually become resistant to many of these peptide drugs.

The most promising alternative to antibiotics is already used in many laboratories on tissue, and some have been trialled for therapeutic use in the past (In the Soviet Union, for example). Phage therapy involves a small virus that attack bacteria (a phage) being introduced into the body of an infected individual. The phage is genetically designed in a way that it should infect and kill the harmful bacteria and that bacteria alone. Progress to clinical trials has been reached in European health institutions although only for one particular treatment (an infection associated with burns).



In all, something has to be done to prevent the impending damages that antimicrobial resistance could cause to our modern civilisation. Since their discovery, these drugs have come with warning predictions from the very pioneers of the field - spelling out a disastrous post-antibiotic era.

"The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin resistant organism"

- Sir Alexander Fleming, 1946.

- Information researched from many sources, including Mary Mckenna's TED talk "What do we do when antibiotics don't work anymore?"
- Photo of resistance figures taken from M McKenna's TED talk "What do we do when antibiotics don't work anymore?"
- Photo of doctor prescription taken by Anthony Delvin/ PA
- Photo of phage and bacteria taken from http://www.foodsafetynews.com/2016/01/bacteriophages-an-old-antibiotic-alternative-becomes-   new-again/#.Vppc-9SLTIU
- other references http://www.theguardian.com/society/2015/aug/18/soft-touch-doctors-write-10m-needless-prescriptions-a-year-says-nice
- www.nature.com/news/antibiotic-alternatives-rev-up-bacterial-arm-race-117621

Gene Editing Introduced to the Farming Industry

The last 20 years has seen a great advancement in the field of genetics, as we begin to unravel the mysteries of the genome.

This month US company Recombinetics managed to edit the genomes of individual dairy cows, causing the loss of their ability to grow horns. The company was approached by farmers to improve the quality of life for the cattle (and probably the odd irritating farmer that gets too close). 
Usually the horns of dairy cows would be removed after birth, leaving large scars and often painful bruising. In the past farmers have bred hornless cows with horned cattle to mask the horned gene, but this form of selective breeding has hindered herds with the absence of many desired traits. This process of gene editing has been hailed as a major milestone in the introduction of genetic modification in the farming industry.

Gene editing is significantly different from standard genetic modification. Whilst the latter adds foreign genes or bundles of nucleotides into a genome to "transform" the organism, gene editing makes tiny tweaks - minuscule even on a genetic level - to knock out or express genes of interest. Because this technique doesn't introduce any foreign DNA, the organism isn't deemed to be a conventional GMO (Genetically Modified Organism). Taking into consideration the general mood of GMOs right now however, farmers may have to shy away from these untraditional methods for the time being. Only at the beginning of this month Scotland had made claims to formally ban all GM crops once new EU powers come into place next year.

As most farmers acknowledge themselves, the use of GMOs is becoming a necessity due to the rising level of quality produce demanded by the consumer.
GM animals is understandably significantly different scientifically and ethically, but the abundant benefits of gene editing are starting to become widely apparent. Recombinetics are now looking to tweak the DNA of other cattle breeds to tolerate harsher environments, particularly warmer and more humid climates. If they succeed, many countries with typically inapt environments would be able to access a suitable, high quality breed of cattle to boost their economies.

What do you think about GMOs and gene editing? Do you think that we should advance into the field of commerical GM animals, withdraw from genetically manipulated produce altogether, or maybe focus on another method of providing sufficient benefit in the industry, for both farmer and consumer?

Leave a comment below!



Images retrieved from http://cdn.images.express.co.uk/img/dynamic/1/590x/cow-395509.jpg
 and http://www.farmersweekly.co.za/img/fwa201366134312.jpg

Why We Can't Live Forever

The average life expectancy of the typical human living 100 years ago was 31 years. Since the last century most of us now have a projected life expectancy of just over double that of a person living in the 1900s. The 2010 world average life expectancy at birth is 67.2 years (Provided by the CIA, see reference below), but still we cling to the prospect of extending our lives to live out further into older age. As well as different healthy lifestyle plans, guides to happiness and the abundance of medical care, the turn of the millennium has seen a rise in claims of "Miracle pills" that promise to extend life up to several decades, or even slow the ageing process itself. Pseudoscience or a breakthrough in modern medicine, it is an important field of science that illustrates the often conflicting nature of research. This article aims to outline the reasons why it is so hard for any living thing to biologically lengthen the duration of their lifespan.
3 "causes", or signals, of ageing stand out above the rest. They are as follows:

Telomere Shortening

The chromosomes in our genome carry all of the genes needed for an individual. Humans have 46 arranged into 23 pairs, which are replicated when a cell divides. An enzyme called DNA polymerase (DNA Pol) is needed to replicate the DNA in chromosomes during this process. DNA Pol enzyme has evolved over time to be very efficient at it's job, although one major drawback is that the enzyme falls off, just short of the end of every strand it uses to copy. In effect, the daughter strand produced is shorter than the original piece of DNA which arises concern, as the strand could now be missing important pieces of genetic material not copied across. Luckily organisms have adapted to combat this by protecting their chromosomes with telomeres - long repeats of Thymine and Adenine bases which "coat" the tips of the chromatids. The addition of telomeres at the end of DNA sequences protect coding DNA near the ends, so now where DNA Pol now falls off (in the telomere region) it erases a few codons of essentially otherwise useless fragments of TA repeats.
The human foetus synthesises/lengthens telomeres using Telomerase, an enzyme not normally found in the body after birth. As telomeres aren't replaced or lengthened over time once born, countless cell replication cycles shorten telomere regions over time until they disappear altogether. At that point, any genetic material located at the ends of chromosomes that was before protected would now be directly in the "firing line" of deletion. The absence of telomeres in old age has been linked with dementia as important cognitive genes have been erased during cell replication. Some cells are clever enough to notice when telomeres become a dangerously short length, but destroy their selves in order to prevent gene damage.
The shortening of telomeres cannot be stopped as an individual ages, except with the help of telomerase. Mice genetically modified to possess telomerase have been shown to reverse the signs of their own ageing in several studies. However, the addition of telomerase in somatic/adult human cells causes cancer.

Oxidative Stress

The mitochondria in our cells act like power stations, producing energy for our metabolism, growth and repair. Contrastingly, the process in which these organelles produce energy can actually damage cells in the long term.

Mitochondria are very similar to watermills - they produce a gradient (of protons taken from hydrogen, instead of water current) that is released and channelled through certain structures from one side of a membrane to another. These structures act like rotors, just like the wheel of a watermill, turning to create energy in the form of ATP. At the end of the line mitochondria are left with a handful of electrons that caused the gradient in the first place, so oxygen absorbs these to prevent any reactive species in the environment (reduction). However, often some oxygen atoms are reduced insufficiently causing Reactive Oxygen Species known as Free Radicals. Their reactivity can cause a lot of damage to cell membranes, proteins and even genetic material.
Over time a build up of free radicals has the potential to exert a large quantity of damage to tissue in the body. The build up of free radicals is called Oxidative Stress, and gets larger and more concentrated as an individual ages. Mitochondria can never stop producing energy or the cell will die, which means that free radicals will always be produced. 

There are specific enzymes that regulate these reactive species in the human body, and Vitamins E and C play a role in inhibiting free radicals from reacting with fat and genetic material. However the build-up of oxidative stress over time overtakes the regulatory catalysis of free radicals.

Human Evolution

Organisms live for different amounts of time before they begin to age; oak trees can endure centuries before they start to wither, whereas mice only live for a few years. It was previously thought that the size of an organism positively correlated to it's age but many examples in life have quashed this theory (e.g. smaller breeds of dog nearly always live longer than larger breeds, the same goes with humans too).

Evolution has caused species to live out longer or shorter lives for the reasons of reproduction. The whole point of living, from a biological perspective, is to pass on genes to the next generation by means of producing offspring. After peak maturity/adulthood, reproduction is usually no longer on the cards so ageing begins.
The place of a species in the food chain, it's environment, even it's local population plays a part in determining it's age of sexual maturity, it's age of senescence (ageing) and it's ultimate longevity. To explain how evolution has shaped many species' lifespans, here are a few examples:

- Mice have a lot of selective pressure on their shoulders - they are the perfect food for many predators - so for an individual mouse to have any chance of passing on it's genes it must sexually mature very fast before it's eaten. It takes a mouse no longer than 10 weeks to mature, and once a mate is found the gestation period for a female mouse is only around 19-21 days. After 9 months mice age and die very fast to make way for the new generation of sexually mature young.

- African Elephants are just about at the top of the food chain, by contrast. They live in herds on vast grasslands, often close to water sources. Every year each herd migrates to avoid the dry season, and the female elephant usually gives birth to just one offspring at a time, after a 20 month gestation period.
The life expectancy of an African elephant is 70 years. With no selective pressure from predators, the availability of food, and stable life in a herd, elephants have never needed to adapt to mature quickly. In fact the opposite has probably occurred. The long distance migrations over desolate savannah have caused elephants to adapt to extend their lifespan, increasing that probability of finding another herd for a suitable mate.

In terms of us, humans reside at the very top of the food chain. We are clever enough to shape our own environment which gives us a very comfortable lifestyle. Evolution is easy on us and gives us a long childhood as well as an adulthood of suitable length. Moreover, many males stay fertile even in old age to increase the chances of transferring their genes. Human life expectancy can range from 50-80 years worldwide, but could we be doing anything more to allow evolution to grant us more happy years?





In short, no. Evolution works both ways - we have a set maturation period, set peak reproductive period and a set senescence period. All set by our genes: the ultimate decider of our fate. Genes can endure in two ways: they can live in a single immortal individual or they can be passed on to another. Examples of "immortal" organisms are actually quite abundant in prokaryotic world. Some bacteria can produce spores when in environmentally unfavourable conditions, containing their own DNA. The spores are extremely resilient and can last millions of years. When environmental conditions because favourable the spore develops back into the bacterium. This method of endurance essentially cancels out any need for reproduction.

Unfortunate as some people may think, evolution has virtually decided that we're too delicate for immortality and has chosen to give us the ability to transfer our genes by reproduction. If an individual can reproduce, there comes a time where they have move aside for the next generation. Pretty philosophical.



Figures retrieved from https://www.cia.gov/library/publications/the-world-factbook/rankorder/2102rank.html

Could diabetes become curable within the next 10 years?

Image retrieved from Scientific American

In Britain today, more than 29,000 people are diagnosed with either type 1 or type 2 diabetes. 1 in 3 adults suffer from diabetic-like symptoms, including fatigue, high blood sugar and problems with vision.

Diabetes is diagnosed in every 17 out of 100,000 children yearly in England and Wales. Although the least common type as a whole, 90-95% of diabetics under 16 have Type 1 diabetes, which is normally caused by genetic factors in an individual.

Because of this, hundreds of research projects around the world are dedicated to treating, preventing and possibly curing the condition that affects the daily lives of so many people.

But how close are we to actually “curing” diabetes in humans? What research is out there, and what changes can we expect to see in the next decade?

This article aims to illustrate some of the pioneering studies in several institutions that are tackling type 1 diabetes. Before this, here is an explanation of the disease and how it affects the body:

Type 1 Diabetes Mellitus is an autoimmune disease, which means that it causes the body to attack itself. Autoantibodies – immune system components that mistakenly break down tissue in the body – attack beta cells in the pancreas. These specialised cells secrete a hormone called insulin, which acts to lower glucose levels in the bloodstream after eating or during periods of rest. The damage to the beta cells means that they cannot secrete insulin, causing dangerously high concentrations of glucose in the blood to bring about symptoms such as hyperactivity, frequent urination and increased thirst.

When all of the glucose in the blood has been used up, the body goes into panic mode because there isn’t any stored glucose around for energy. This is called hypoglycaemia, and leads to symptoms such as blurred vision, extreme tiredness and in severe cases, epileptic seizures.

Diabetes can be treated by frequent administrations of insulin to keep blood-glucose levels at bay, although this can be inconvenient and enforces a diet that has to comply with the insulin doses. The insulin has to be administrated intravenously, either through a small pump-device attached to the body or by injections. No cure is available for diabetes at this moment.

The first study in this article looks at a 3 year analysis of 33 infants in Finland, who were selected for their genetically-higher risk of developing type 1 diabetes. The researchers wanted to look at the progress of each infant as they grew up. By the age of 3 most of the children were healthy, but 4 had already developed diabetes. When analysing these children, researchers discovered a significant absence of body flora in their gastrointestinal tracts (GIT). Body flora is the “good” bacteria found in an individual’s body, and can be found on the skin, in mucous, but mostly in the GIT.

When the body floras of the diabetic children were studied, larger than normal populations of species were found that trigger inflammation of the GIT - which has been known to be a secondary symptom of diabetes as the species are thought to also attack the beta cells in the pancreas.

When looking at the healthy children, 11 of them had already started to produce autoantibodies. The researchers wanted to know why the autoantibodies hadn’t caused the disease in these children, so they came up with the idea that normal, or enhanced, levels of body flora in the body were tackling the onset of the condition in the children.

To extend on this hypothesis, a study in New York shows the bacterium Lactobacillus gasseri (found in probiotic yoghurt) can transform intestinal cells in rats to act like beta cells and secrete insulin. The bacteria possess the enzyme Glucagon-peptide 1, which is thought to bring about the intestinal cell changes. The study observed diabetic rats being fed probiotic yoghurt for 30 days, and found that at the end of the observation the rat’s had a 30% drop in glucose levels compared to healthy rats. Moreover, the diabetic rats could use their insulin-secreting intestinal cells to reduce their blood sugar levels as fast as their healthy counterparts.

This study takes the hypothesis of positive body flora modification and applies it practically. The next step in application would be to produce a bacteria-containing pill that diabetics could take daily, instead of injections.

Probably the most notable breakthrough in diabetes this decade came from a Harvard diabetes institute in October 2014. After 23 years of research initiated by the diagnosis of his son with type 1 diabetes, Dr Doug Melton and his research group managed to produce artificial, insulin-secreting beta cells from stem cells. The “beta units” were observed to secrete the hormone upon glucose-induced stimulation, resemble typical beta cells found in the pancreas genetically and structurally, and in transplantation manage to bring about a positive effect on hyperglycaemic mice.

The stem cell-derived beta cells are currently undergoing trials in other animals, but not yet primates. Because of the complexity of artificial cells we may not see beta cell transplantation in humans for at least another decade.

 A final study that deserves attention is an ongoing project at the Massachusetts Institute of Technology (MIT).  Researchers are experimenting with insulin release mechanisms by modifying the hormone itself. So far, the team at MIT have been able to change the chemical structure of insulin molecules so that it stays in the blood stream for longer, which would mean for patients that frequent injections of the hormone would not be needed. The researchers have achieved this prolonged presence of insulin by adding a hydrophobic (water-repelling) domain to the molecule. The theory behind this is that the molecule would be more likely to bind to proteins in the blood, preventing it from being broken down by sugars.

Image retrieved from Medcity News

As well as adding the domain to the molecule, a chemical group was added that binds to glucose and brings it into contact with insulin. Therefore, in high concentrations of sugar, protein-bound insulin is likely to be broken down by surrounding glucose. The combination of these two mechanisms means that insulin can not only stay in the blood for longer periods of time, but also still reduce blood-glucose levels when the blood is hyperglycaemic.

This modified insulin has already been tested on mice that are deficient in the hormone. The results showed the mice reacting more efficiently to spikes in blood-glucose concentration, compared to traditional insulin.

At this moment, further test-stages are required before this treatment can be made available on any health service, but the project is ongoing and the researchers at MIT are dedicated to produce the modified hormone in purer and safer quantities.

The field of diabetic research is a constantly progressing, and has been at an immense speed since the 1990s. Molecular biology, pharmacology and the fairly recent advanced understanding of cell biology has made all of this possible. Just by looking at the 3 studies mentioned, it’s fair to say that diabetes will become a curable disease within the next 10 years. 







Images retreived from : http://medcitynews.com/2014/04/jdrf-partners-insulin-startup-thermalin-ultra-rapid-acting-insulin-t1d/

http://www.scientificamerican.com/article/a-diabetes-cliffhanger/

Gene Therapy Experiment Creates Biological Pacemakers

Researchers at a heart institute in California have synthesised biological pacemakers that could potentially replace mechanical pacemaker implants for patients suffering from irregular heartbeats.

                                                                                                        

After nearly 12 years of research, a team of cardiologists at the Cedars-Sinai Heart Institute, LA, have managed to create "pacemaker" tissue from heart muscle cells in living pigs with heart arrhythmias. The success of the research contributes to a reinforcement in the larger field of somatic therapy - non-inherent genetic manipulation of vegetative cells (non-sex cells) in an organism. The Director of the Cardiogenetics-Familial Arrhythmia Clinic, Dr Eugenio Cingolani, believes the implications of this breakthrough are wide and could be very beneficial: 

      "It is possible that one day, we might be able to save lives by replacing hardware with an injection of genes."

The minimally-invasive experiment involved the insertion of a specific gene into the cardiac tissue of certain pigs with conditions that caused them to have very slow or irregular heart rates. The gene in question is the T Box 18 (TBX18), which is involved in the embryonic development of the heart. A catheter was used to access the heart tissue inside the test-subject pigs, and the gene was transfered through an artificial adenovirus - a basic, medium-sized, non-enveloped virus. The adenovirus would have been injected into the tissue and would have incorporated the TBX18 gene into the cardiac cells' DNA. A transformation would have taken place, changing the virus-infected cardiac tissue into a "pacemaker" for the heart, the Sino-atrial (SA) node. This new SA tissue would have begun to send out regular electrical signals, causing the hearts of the pigs to contract at a normal, healthy rate.

The 14 day study looked at the adenovirus-infected pigs alongside non-infected pigs with the same heart conditions. After the first day the transformed pigs were already observed to have stronger, faster heartbeats compared to the other pigs. The research is already being branded a huge success amongst scientific communities, and because the procedure is so minimally invasive scientists are looking at more complex applications. For example babies with congenital heartblock could be treated before they are even born, reducing the complications after birth.

The full scientific paper was published by Science Translational Medicine, and can be found on their website (Link below).

Sources:

• LINK TO SCIENTIFIC PAPER http://stm.sciencemag.org/content/6/245/245ra94.abstract?sid=7b6dce60-bb1e-4dd3-99a0-c8716aa8854b
• http://www.medicalnewstoday.com/articles/279760.php
• http://www.bbc.co.uk/news/health-28325370
• http://www.ncbi.nlm.nih.gov/gene/9096
• Image of heart retrieved from  http://www.citruscardiology.org/arrhythmias.html