Quantum ultimatum 2016 17

Quantum Ultimatum THE ANNUAL MAGAZINE OF THE MONCRIEFF-JONES SOCIETY

2016 - 17 ISSUE

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At the end of last year, I was invited to deliver a lecture to the students and parents of the Moncrieff-Jones Society at Caterham School. Having been the first British astronaut, as well as the first woman, on the Mir space station, I was delighted to share my experiences. The enthusiasm and scientific knowledge shown by the audience was most impressive and I was certainly put through my paces during the excellent Q and A. I was flattered by the long queue for photos with me afterwards where yet more questions awaited me!

Run by the Head of Science, Dan Quinton, The Moncrieff-Jones Society helps develop these young people’s love for science by giving them a platform from which to present their personal research to their peers.

May the Moncrieff-Jones Society go from strength to strength in years to come.

Helen Patricia Sharman OBE FRSC (born 30 May 1963) is a British chemist, who became the first British astronaut and the first woman to visit the Mir space station in 1991. She received a BSc in chemistry at the University of Sheffield in 1984 and a PhD from Birkbeck, University of London.

She worked as a research and development technologist for GEC in London and later

as a chemist for Mars Incorporated dealing with flavourant properties of chocolate.

On 25 November 1989, she was selected for space programme, which was known as Project Juno and was a cooperative Soviet Union–British mission co-sponsored by a group of British companies. For her Project Juno accomplishments, Sharman received a star on the Sheffield Walk of Fame.

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Hello and welcome to this year’s edition of Quantum Ultimatum, the Moncrieff-Jones magazine!

For those who do not know, Moncrieff-Jones is a prestigious society in which pupil speakers bravely present their in-depth research on scientific topics to an audience of peers and teachers; who subsequently challenge them for the next 40 minutes with probing, often obscure, questions.

The experience, though intimidating, is always hugely rewarding to the presenters, who this year have risen to the challenge admirably and shown a true passion for their chosen subjects. They have put hours of work into their talks which they later edited into the articles enclosed for you to read at your leisure. Inside you will find some of the latest scientific research on fascinating topics; from CRISPR, the gene editing tool, to neutron stars. I hope you enjoy.

A huge thank you must go out to my Vice President, Vladimir Kalinovskiy, with whose support it would made it possible to run the society this year. Another goes to Mr Quinton, for entrusting to us a society which he has put countless hours of effort into over the years and for all the guidance he has given us in our roles.

As my time at Caterham comes to a close, I now pass the baton onto next year’s President, Kamen Kyutchukov and Vice President Natalie Bishop. I wish you both the best of luck in your roles and hope that you have as much fun running Moncrieff-Jones as Vladimir and I have, especially as the society passes into its 50th year.

Happy reading!

Yours, Hannah Pook

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Junior Science Fair Awards Evening T

he Junior Science Fair Awards evening was an evening dedicated to celebrating the unique research

projects the Second Year pupils have been conducting in their science lessons over the course of the half term.

The event was modelled on a scientific conference, where groups produce their own academic science poster which were displayed to invited pupils, parents and teachers.

Six groups whose work was chosen as highly commended by Mr Quinton, Mr Keyworth and Mr Mansell presented their work to a captive audience.

Old Caterhamian Daniel Chaney, now a PhD researcher, was invited back as our guest speaker. Daniel used the

analogy of Cluedo to cleverly explain how scientists use the facts and information they have to help them deduce answers to the questions they pose. Daniel also had the unenviable task of choosing two winning posters from the highly commended category.

Many congratulations to Anoushka Gulati, Sholto Kirk, Anastasia Leyko and Abbie McDowell for their brilliant poster on solubility at different temperatures and Euan Ashmore, Samuel Choi and Rosemary Goodall for their superb project on electrifying fruit.

Thank you to all the Second Year and their class teachers for all their hard work and for making the event such a success!

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U P P E R S I X T H T A L K S 6

CRISPR GENOME EDITING

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Hi, my name is Tooki Chu and my I chose to do my Moncrieff-Jones talk on CRISPR gene editing – a new and highly promising technique.

I am going onto study Biomedical Sciences at university so this topic is also very relevant to my course. I hope you enjoy my article.

ORGAN TRANSPLANTS

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Hi, I’m Hailey Sze and I’m applying to do Biomedical Sciences at university. I am particularly interested in genetics and cell biology, and I wish to specialise in this field in the future. From a young age I’ve always imagined myself working in the lab and my dream is to grasp the complicated mechanism of the gene network within the body, which is why I am interested in discovering new treatments to incurable genetic diseases.

SPECIAL RELATIVITY . . . . . . . . . . . . . . . . . 16 Hi I'm Francesca Carver and I chose to do my talk on the topic of special relativity which is challenging to study but also an area I am really interested in. I hope that you take as much enjoyment in reading my article as I found in writing it!

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CRISPR GENO Tooki Chu CRISPR-Cas9 is the newest addition to the toolbox for genome engineering, garnering much excitement from the scientific community and media alike.

This technology has transformed the field of molecular biology by enabling researchers to manipulate the genome with unprecedented precision and ease. It is no wonder that it has quickly become a staple in many research laboratories around the world.

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ME EDITING

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CRISPR GENOME EDITING

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o what exactly is CRISPR? CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeats. These are a series of short segments of repeats that are identical and interspaced by variable sequences known as spacers. Palindromic means that reading the repeat sequence 5’ to 3' (forwards) on one strand matches the sequence reading 5' to 3' (backwards) on the complementary strand. All repeat sequences are at least partly palindromic.

CRISPR is actually a feature found in certain Prokaryotes. The role of CRISPR-Cas systems in bacterial adaptive immunity was pieced together with the help of two findings: the realisation that the spacer sequences correspond to various invasive bacteriophage sequences and the observation that several CRISPRassociated (Cas) genes coded for proteins that have nuclease domains, capable of severing phosphodiester bonds between nucleotides.

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Biology of CRISPR-Cas Systems In CRISPR immunity within prokaryotes a record of previous infections is kept in order to stimulate a rapid immune response upon re-exposure. There are five major types (I-V) of CRISPR-Cas systems, classified according to the cohort of Cas proteins used to recognise and cleave targeted sequences.

CRISPR-mediated adaptive immunity occurs in three universal stages: adaptation, expression and interference. During adaptation, a short fragment of foreign DNA is incorporated into the CRISPR array.

Two endonucleases form a complex than undergoes a conformational change upon binding to the protospacer (a fragment of invader DNA). The resulting cascade of reactions then generates a protospacer intermediate that consists of the original 23 nucleotide double stranded DNA (dsDNA) protospacer and two 5 nucleotide long single stranded DNA (ssDNA) overhangs each with a 3’-OH group.

One of the proposed mechanisms for protospacer insertion is that the two 3’-OH groups each carries out a nucleophilic attack on the 5’ end of one strand of the first repeat sequence in order to ligand protospacer strands into the CRISPR locus, keeping in mind that the 5’ end of one strand would be adjacent to the leader sequence whereas the 5’ end of the opposite strand would be adjacent to the first spacer sequence.

The subsequent ssDNA gaps formed on each strand are then repaired by enzymes to reform double stranded repeat sequences that bracket the newly acquired spacer sequence.

Expression phase involves first transcribing the entire CRISPR locus to form precursor CRISPR-RNA (precrRNA). Pre-crRNA is processed to mature crRNA which acts as an antisense guide for genomic targeting and along with other proteins (Cas9) searches for the target DNA. Interference is when the CRISPRCas9 complex goes on to degrade foreign genetic elements.

Tooki Chu

CRISPR-Cas9 Genome Modification The simplicity of CRISPR-Cas9 genome editing stems from the fact that it only requires a non-specific Cas9 endonuclease to be directed by a guide RNA to any target sequence. It is superior to other more established genome editing methods which require the engineering of a new protein for each genomic target (both time-consuming and labour intensive).

Scientists have further simplified CRISPR-Cas9 method in various ways for example, by combining different types of RNA to form a single guide RNA (sgRNA) that can be easily programmed to target any DNA sequence of interest. Spacer sequences of sgRNA are programmed differently according to which DNA strand is being targeted. When targeting the template strand, the base pairing region has the same sequence as the transcribed gene sequence; when the non-template strand is targeted, it is the reverse-complement of the transcribed gene sequence. sgRNA-Cas9 can introduce sitespecific double strand breaks which can activate one of two endogenous repair mechanisms: non-homologous end joining or homology directed repair.

Non-homologous end joining (NHEJ) is an error prone pathway that directly joins DNA strands back together, often resulting in random small insertions or deletions that disrupt the target gene. In the context of genomic modifications, the aim is to create a lossof-function mutation to knockout the gene. This is usually achieved by causing frameshift mutations or premature stop codons within the gene.

On the other hand, homology directed repair (HDR) generates much more precise mutations and knockins with the aid of a donor template. The donor template usually consists of homology arms that flank either side of the desired inserted sequence or can be presented as single-stranded

DNA oligonucleotides. In essence, 5’ broken ends are first trimmed to create 3’ overhangs that invade a homologous template to form a displacement loop of hybrid DNA. DNA polymerase then adds nucleotides to fill in the missing gaps in order to repair DNA as well as incorporate exogenous sequences.

Biological Applications One notable use of CRISPR-Cas9 technology is for the creation of genetically modified mouse models.

Traditionally, a multistep gene targeting strategy is employed in embryonic stem cells. However, CRISPR eliminates the need for sophisticated targeting constructs or labour intensive screenings and has been demonstrated to reduce the timeline from years to as little as 4 weeks to generate founder mice. In principle, Cas9 and gRNAs can be microinjected into mouse embryos to produce a mutant allele or injected along with exogenous templates to create precise mutations, epitome tags, conditional alleles or a fluorescent reporter. Additionally, multiple genes can be altered simultaneously which further reduces the time and cost required to engineer specific mouse models.

The first clinical trials using cells modified with CRISPR is set to begin in August 2016 by a team of scientists at Sichuan University’s West China

Hospital. CRISPR-Cas9 will be used to knockout a gene that encodes for programmed cell death protein 1 (PD1) from T cells extracted from patients who suffer from metastatic non-small cell lung cancer. PD-1 is a cell surface receptor that prevents T cells from being activated, so by knocking out this gene it is hoped that more T cells will become active to target cancer cells. Most importantly, this trial will serve as an evaluation of the safety and effectiveness of CRISPR-mediated treatments.

Conclusion CRISPR mediated genetic engineering is a truly groundbreaking technology that has already seen to many innovative applications. Its specific yet inexpensive mechanism has revolutionised genetic research and its versatility enables researchers to generate virtually any genomic modification in all model organisms.

There are, of course, ethical concerns that need to be addressed and further studies need to be done in order to fill the gaps in our understanding of the molecular mechanism of CRISPR systems. Nonetheless, there is tremendous potential as to what CRISPR can help us achieve, not least in the fields of biotechnology and human therapeutics

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Hailey Sze

Organ Transplants Transplantation is a medical treatment for a particular malfunctioning organ or tissue. The traditional method of organ transplant involves the moving of an organ from one body (the donor) to another (the recipient), which could in turn replace a damaged organ with a functional one. However, transplanted organs can be rejected by the host’s immune system, which acts as the barrier against the development of this treatment.

In this article, I will cover the immunologic mechanism of transplant rejections, followed by the clinical methods used to prevent or minimise rejections.

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ORGAN TRANSPLANTS

The Immune System Transplant rejection happens when the transplanted organ is destroyed by the actions of the recipient’s immune system. The immune system is a host defence system which consists of a wide variety of cells (e.g. T-cells, antigenpresenting cells and B-lymphocytes) interacting with each other, hence producing a range of immune responses. This allows the immune system to identify and destroy any potentially harmful substances within the body. The immune system is highly sensitive to ‘foreign’ substances, it is therefore common for transplant rejection to occur after a transplantation has taken place. In other words, a transplant rejection actually means that the recipient’s immune system is acting against the transplanted organ, through a series of immune responses.

Immune responses can be classified into two main categories— the nonspecific innate immune response and the specific adaptive immune response, where the innate immune response aids the activation of adaptive immunity.

During the innate immune response, antigen-presentation takes place where the antigens of the ‘foreign object’ are displayed on the cell surface of antigen presenting cells (e.g. phagocytes). The displayed antigens then bind to the receptors on the T-helper cells and T-killer cells respectively, which in turn activates the adaptive immune

response. Once adaptive immunity has been activated, T-helper cells produce a substance called cytokines, which activates B-lymphocytes to produce antibodies specific to the target.

Meanwhile, T-killer cells produce various chemicals that are capable of inducing apoptosis (i.e. programmed cell death). It is interesting to note that apoptosis is the major form of transplant rejection, because antigens displayed on the transplanted organ can directly activate T-killer cells, hence triggering apoptosis straight away.

Histocompatibility Histocompatibility is a term describing a property in which the transplanted organ is not rejected by the recipient’s immune system. In humans, this property is determined by a set of genes called the Human Leukocyte Antigen (HLA) genes, which code for the structure of Major Histocompatibility Complex proteins (MHC proteins). MHC proteins are cell surface proteins present on almost all nucleated cells, meaning that they will also be present on the transplanted organ. As the structure of MHC proteins of the donor and the recipient may differ, the MHC proteins on the transplanted organ can act as antigen and trigger immune responses within the host, causing a transplant rejection. The structure of MHC proteins is unique for almost every single individual, because the set of HLA genes has the following three properties: • The structure of MHC proteins is polygenic, meaning that this characteristic is controlled by a set of genes interacting with each other.

• The genes are highly polymorphic, meaning each gene contains over 100 alleles.

• The genes are co-dominant, so both alleles of each gene contribute to the final structure of the MHC proteins.

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As a result, each of the three properties will have effects on the precise structure of the MHC proteins.

It is extremely rare, or technically impossible, for 2 individuals to have exactly the same combination of alleles and same structure of MHC proteins.

Therefore, apart from transplantations among identical twins, it is almost inevitable for a transplant rejection to occur if immunosuppressive therapies are not applied.

Central Tolerance So how can the immune system distinguish self-antigens from foreign ones? How is it possible for the immune system to attack the transplanted organ, without destroying other normal body cells? The answer is central tolerance, where the immune system develops in a way which means it does not respond to any self-antigens. This process happens at an early age, before the age

Hailey Sze

of two, when the immune system has not yet fully developed. The immature T- and B-lymphocytes come into contact with self-antigens and the selfantigen interacts with the lymphocytes (i.e. binds to the receptors on the lymphocytes). Those lymphocytes then either undergo clonal deletion in form of apoptosis, or encounter a process of gene rearrangement, as a result changing the shape of their receptors.

Both processes help to eliminate selfreactive lymphocytes from the immune system, and therefore the immune system does not respond to any selfantigens in the future.

When an organ is transplanted into the recipient, the MHC proteins on the transplanted organ then act as antigens which bind to receptors on T- and B-lymphocytes. This action allows the host’s immune system to recognise the transplanted organ as a foreign invader, hence triggering a series of immune responses to reject the organ. Upon activation of T- and B-lymphocytes, either the cells on the transplanted organ undergo apoptosis, or antibodies are produced which target the organ.

The antibodies are known as anti-HLA antibodies, and they attack the antigens on the surface of the transplanted organ. Both processes, apoptosis and antibody production, result in injury of the transplanted organ and could eventually lead to organ failure.

Immunologic Mechanism of Transplant Rejection The process of transplant rejection can be divided into three main stages: sensitisation, effector, and finally the cellular (in form of apoptosis) or humoral (antibodies production) immunity. The sensitisation stage occurs when the immune cells are physically exposed to the antigens on the transplanted organ. This directly activates the T- and B-lymphocytes and stimulates proliferation, allowing the immune system to be ready to

respond to the transplanted organ. Next is the effector stage, where antibodies begin to attack the tissues on the transplanted organ and lead to cellular injury. The effector stage promotes an inflammatory response which results in a massive influx of immune cells.

As more immune cells arrive at the position of the transplanted organ, the rejection process is amplified. Finally, the immune system responds to the transplanted organ in the form of either cellular or humoral immunity.

Cellular immunity results in apoptosis, because antigens on the transplanted organ directly activate T-killer cells.

This stimulates T-killer cells to produce small granules called perforin. Perforin penetrates cell membranes and creates pores in it, causing the cell on the transplanted organ to burst due to gaining excessive water by osmosis.

Meanwhile, in humoral immunity, anti-HLA antibodies are produced by B-lymphocytes. The antibodies attack the transplanted organ by targeting the antigens on its surface, resulting in cellular injury and eventually organ damage. Symptoms of organ rejection include swelling in the area of the transplanted organ, general feelings of discomfort and organ failure.

There are three types of transplant rejection: hyperacute, acute, and chronic. Hyperacute rejection is triggered when the transplanted organ is attacked by pre-existing anti-HLA antibodies. The presence of these antibodies could be caused by previous organ transplants, blood transfusions and pregnancies, where the recipient

has been exposed to other people’s MHC proteins. As the antibodies are already available, hyperacute rejection occurs within hours after a transplantation, and the affected organ has to be removed immediately. Acute rejection is also caused by the actions of anti-HLA antibodies, but it takes longer to occur as it takes time for the immune system to produce antibodies.

Finally, chronic rejection involves a wide variety of immune responses, from inflammatory response to apoptosis to humoral immunity, together leading to long term functional loss of the organ.

Prevention & Treatment Acute rejection cannot be avoided so immunosuppression is often applied to the recipient after the transplantation.

This involves the prescription of immunosuppressive drugs which lowers the immune system’s sensitivity to ‘foreign’ substances, preventing a serious rejection. Before the actual transplantation, HLA testings are carried out. This involves the screening of the recipient’s serum for any antiHLA antibodies, effectively preventing any hyperacute rejections. Moreover, acute rejection can be controlled by a HLA alleles crossmatching between the donor and the recipient, prior to the transplantation. The more similar the combination of the alleles, the less serious the rejection will be. This also helps to minimise the required dosage of immunosuppressive drugs.

Recently, scientists have been working on regenerative medicine to replace conventional organ transplants.

Modern research on stem cells makes it theoretically possible to develop in vitro grown organs in the laboratory to be directly transplanted into the patient’s body. The development of this medical technique provides potential solutions to problems from organ shortages to transplant rejections, even though this could take years for this technology to become fully mature.

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Special Relativity Francesca Carver

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SPECIAL RELATIVITY

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efore looking at special relativity it is necessary to start with the principle of relativity, first proposed by Galileo Galilei in 1632 in his Dialogue Concerning the Two Chief World Systems using the example of a ship .If a ship is travelling at constant velocity, without rocking, on a smooth sea; any observer doing experiments below the deck would not be able to tell whether the ship was moving or stationary.

The principle of relativity is the requirement that the equations describing the laws of physics have the same form in all admissible frames of reference. This means if you were on such a vehicle moving at constant velocity, you would have no way of knowing you were moving; in your reference frame you are at rest. In physics, a frame of reference consists of an abstract coordinate system and the set of physical reference points that uniquely locate and orient the coordinate system and standardize measurements. If there were n dimensions, n+1 reference points would be sufficient to fully define a reference frame.

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In 1905, Albert Einstein published the theory of special relativity, which explains how to interpret motion between different inertial frames of reference — that is, places that are moving at constant speeds relative to each other. In addition to the principle of relativity proposed by Galileo, he added another postulate; The principle of the speed of light. This concludes that the speed of light is the same for all observers, regardless of their motion relative to the light source. In Einsteinian relativity, reference frames are used to specify the relationship between a moving observer and the phenomenon or phenomena under observation. In this context, the phrase often becomes "observational frame of reference" which implies that the observer is at rest in the frame, although not necessarily located at its origin. A relativistic reference frame includes (or implies) the coordinate time, which does not correspond across different frames moving relatively to each other. The situation thus differs from Galilean relativity, where all possible coordinate times are essentially equivalent.

Francesca Carver

Reference Frames

The genius of Einstein’s discoveries is that he looked at the experiments and assumed the findings were true.

This was the exact opposite of what other physicists.

Instead of assuming the theory was correct and that the experiments failed, he assumed that the experiments were correct and the theory had failed. In the latter part of the 19th century, physicists were searching for the mysterious thing called ether — the medium they believed existed for light waves to wave through. The belief in ether had caused a multitude of problems, in Einstein’s view, by introducing a medium that caused certain laws of physics to work differently depending on how the observer moved relative to the ether. Einstein just removed the ether entirely and assumed that the laws of physics, including the speed of light, worked the same regardless of how you were moving; exactly as experiments and mathematics showed them to be.

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L O W E R S I X T H T A L K S 20

MITOCHONDRIAL REPLACEMENT THERAPY . . . . . . 22 Julieta Baker Hi, my name is Julieta and I chose to do my Moncrieff-Jone talk on Mitochondrial Replacement Therapy, an innovative (and sometimes controversial) technique. I hope you enjoy reading my article.

APOPTOSIS: CONTROLLED CELL SUICIDE . . . . . . . . . 26 Kamen Kyutchukov Biology has always been a subject that interests me so for my talk I decided to explore in depth a term often mentioned in class: apoptosis, or automated cell death.

ALZHEIMER’S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Natalie Bishop Alzheimer’s is not always the easiest topic to talk about, but as an aspiring medic it is an area that I am highly interested in. My article covers both causes and treatments as well as looking to what we may see in the future.

NEUTRON STARS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Stasy Kedrina The annual dose of physics in the Moncrieff society this year fell to me with the topic of Neutron Stars.

Space is a subject that not only intrigues me, but many others as well so I hope you enjoy venturing into the void in my article.

LYNCH SYNDROME . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Jess Fatoye Hi I’m Jess, and I’m in the Lower Sixth. I study Biology, Chemistry, Maths and English and I really wanted to do a Moncreiff-Jones talk because I want to study medicine at university and genetics has always been a topic that really interests me.

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Julieta Baker

Mitochondrial Replacement Therapy For decades, many soon-to-be parents have battled with the prospect of passing on their genetic disease. How could they become the parents they'd dreamt of being without passing a deadly disease into the arms of a new born?

One such diseases is mitochondrial disease. Its lethal effects steal the lives of many young children making them lucky to reach even adolescence. This brutal disease kills around 150 children a year in the U.K. but, as with many diseases in the past, new technology and the expansion of our knowledge about the human body has made way for possible solutions to mitochondrial disease. Though coined by the press as the “three parent baby� technique, mitochondrial replacement therapy is much more than the delusive media headlines would have us believe.

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MITOCHONDRIAL REPLACEMENT THERAPY

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hen introduced to the topic of Mitochondrial Replacement therapy, one must think firstly of why our society is faced with such a disease, that to this day continues to puzzle the most qualified doctors due its remarkably wide and irregular range of symptoms. Despite how satisfying a long-winded explanation would be, the cause for this disease is simple, a single random mutation in our DNA. Contrary to what GCSE science teaches us, there are two places in a cell where DNA can be found. One of which is the nucleus (nDNA) the other is the mitochondria (mtDNA). There are 37 genes in our mitochondria, these are essential for a normally functioning mitochondrion. Our nuclear DNA contains many more genes coding for the specialized function of a particular cell, amongst many other things. A mutation in either place that codes for the function or structure of mitochondria can result in mitochondrial disease. It is essential that the mitochondrion function properly as they produce ATP. Sometimes called the “energy currency” of our cells, ATP is required in every cell of our body and without it our body cannot function.

People with mitochondrial disease have inefficient mitochondria or ones that don't work at all.

The first “pathogenic mitochondrion” was discovered in 1988, since then research has helped us develop a greater understanding of mitochondrial disease. Sadly, to this day, there is still no cure for people born with mitochondrial disease however, our developed understanding of cells and techniques such as IVF has led to new, ground-breaking methods of

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preventing children being born with mitochondrial disease.

Pro Nuclear Transfer, is one method of mitochondrial replacement therapy. The sperm and egg cells of the prospective parents are fertilised in vitro as are the father’s sperm and that of a donor female. The pronuclei of both zygotes are removed and the pronuclei of the parents is injected into the enucleated zygote of the donor. This leaves a reconstructed zygote which is expected to multiply and develop normally as an embryo which can then be implanted into the womb of the mother. This method has been trialled in mice since the 1990s but only recently with humans in 2003 in China. None of the embryos survived and research using this method has slowed somewhat.

Maternal Spindle transfer (MST) is more recognized as an effective method for Mitochondrial Replacement therapy, being the only one to work successfully in both animals and humans. Maternal Spindle transfer works similarly to Pro Nuclear Transfer (PNT), the main difference being that MST creates a healthy egg cell that can then be fertilised and PNT uses two zygotes to create a healthy embryo. MST removes the spindles

Julieta Baker

of chromosomes from both the mother and donor eggs moving on to putting the mothers spindle into the donor egg. This creates an egg cell with healthy mitochondria from the donor and the nuclear DNA from the mother. This egg can then be fertilized and continue to develop, unaffected by mitochondrial disease.

In 2016, the first human baby was born successfully using MST, a moment considered revolutionary for embryologists. Dr. Zhang and his team from New Hope Fertility Centre in New York created 5 embryos, only one of which survived however, testing on the new born showed that he had less than one percent of the mutated mitochondria in his cells. This has paved the way for

other fertility clinics and families hoping to find a solution to such a devastating disease.

Naturally this new therapy has raised concerns amongst the public and scientific community.

This technique is considered to be a form of germline therapy, this poses questions about “designer babies”, and how close we are to creating “perfect” humans. This is linked to one’s identity, what it means to be human, and how having DNA from three people impacts the individual on both personal and legal levels. Many answers to these questions are ambiguous. It is unknown how and whether this procedure will pose problems in the future, to the life of the individual

and to possible generations of people that may be born using mitochondrial replacement therapy.

The characteristics of the individual are determined by nuclear DNA only, the donor is not considered to be responsible or “related” to the said person.

The U.K. Is the first country in the world to legalise Mitochondrial Replacement therapy, which although being introduced cautiously I personally believe that it could make an unquantifiable impact on the lives of those carrying mitochondrial disease. Research should be encouraged around the world to continue making leaps in science that benefit the lives of many who suffer around us.

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Kamen Kyutchukov

Apoptosis CONTROLLED CELL SUICIDE Apoptosis is a natural process also known as.

Occurring in a controlled fashion ensures that none of the neighbouring cells are damaged or affected in any kind of way unlike in necrosis.

The name of this natural event is directly translated from Latin as “falling off�. This portrays a leaf falling of a tree in autumn, so that the tree can survive through winter. Depicting how a cell destroys itself in order for an organism to survive.

Cell not damaged

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Cell is damaged

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APOPTOSIS: CONTROLLED CELL SUICIDE

WHY WOULD APOPTOSIS TAKE PLACE?

A body cell normally receives two types of signals, positive and negative. If a cell functions normally and is not damaged it receives positive signals. Such signals make the cell carry out every day processes such as respiration or protein synthesis. If a cell does not function correctly and is damaged It starts to reject those positive signals and as a result, negative signals are automatically initiated either from inside or outside of the cell, ‘sparking’ apoptosis and activating the series of chain events which lead to the death of the cell.

Removal of cells that could harm our organism, such as virally infected cells is done by apoptosis.

Essentially killing the cell damaged and hijacked by the virus and also killing and preventing the virus from reproducing. Eradication of damaged cells is also a reason why this process would take place, due to the fact that it is more efficient for the body to create a new functioning cell, rather than support one which does not function and waste useful energy why still living.

Prevention of autoimmunity is carried out with the aid of cell suicide, essentially preventing our own immune system from targeting and killing our own body cells due to faulty T-Killer cells. It is utilised in the thymus gland through maturation of T-Killer cells, helping to eradicate those who bind to our own self-antigens (the faulty ones), preventing their release into our blood or tissue fluid. DNA damage is also a trigger of apoptosis. If a cell has DNA damage plan A is that the cell tries to repair, however if that is not successful, it goes to plan

B, which is initiation of apoptosis. Therefore, preventing future development of cancer or other damage. Removal of useless structures occurs by apoptosis, examples being the removal of the tail during the development of a tadpole into a frog or during our embryological development, when our fingers or other bodily features are sculptured. Lastly removal of stranded cells makes sure no cell divides in another tissue, therefore preventing dysfunction of an organ.

BASIC OVERVIEW OF THE PROCESS

The affected cell (i.e damaged) receives negative signals.

Those signals then trigger a series of reactions, which eventually lead to the activation of certain enzymes. Those enzymes then digest the cell from the inside, destroying vital organelles and the cytoskeleton of the cell, therefore also causing its morphology to change. The cell deforms, forming blebs and eventually condenses into separate parts (As seen in the picture on the right). While this is happening certain signals are sent to attract a phagocyte to come and destroy the cell and to finish the process off.

THE THREE APOPTOSIS PATHWAYS

Apoptosis normally occurs by three ways, all depending on where the negative signals mentioned earlier originate.

The Intrinsic pathway is initiated inside of the cell as the negative signals are produced by the cell. Usually occurs due to DNA damage. The extrinsic pathway is initiated outside of the cell by another cell, such as a T-Killer cell. Negative signals initiated outside of the cell. Normally occurs when cell is infected by viruses or our own body identifies certain anomalies. The third pathway is the AIF pathway standing for Apoptosis Inducing Factor. Normally occurring in parallel with the intrinsic pathway, initiated from inside of the cell.

THE INTRINSIC PATHWAY

Initiated inside of the cell, it greatly depends on the mitochondrion, an organelle involved in the aerobic stages of respiration. On the outer membrane of the mitochondrion you can find BCL-2 proteins which can also be described as apoptosis regulators. They are pro or anti apoptotic, and the balance of function between them is affected by the state of

Development of fingers with the aid of apoptosis.

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Kamen Kyutchukov

the cell. If the cell has DNA damage negative signals are sent which activate the genes responsible for the production of BAX proteins. BAX proteins are the initiators of apoptosis and once they are released they go and bind to the outer membrane of the MITOCHONDRION. By doing so, they puncture it and cause it to increase in permeability. As an addition, the pro apoptotic BCL-2 proteins also cause an increase in permeability of the outer membrane. Once this step has been completed, a CYTOCHROME C protein can now freely exit the mitochondrion and go into the cytoplasm. Once in the cytoplasm, the CYTOCHROME C is involved in a series of reactions which lead on to the activation of protease enzymes known as CASPASE 9, which then destroy the cell from the inside.

THE EXTRINSIC PATHWAY

Initiated outside of the cell, it greatly depends on a separate cell, such as a T-Killer cell and the binding of two types of surface proteins. Those are the “death activator” proteins found on the surface of the target cell and the “death receptor” proteins found on the surface of the T-Killer cell. Once a cell is recognized to be infected by a virus, the cytotoxic T cell’s “death receptors” bind to the complementary target cell “death activator” proteins and essentially this produces the negative signals which will initiate apoptosis. Once this happens a series of reaction are initiated to take place in the cell which cause the activation of a protease enzyme known as CASPASE 8. This protease enzyme is from the same family of enzymes as CASPASE 9 (involved in the intrinsic pathway) and essentially goes around and digests the cell from the inside, causing destruction of organelles and of the cytoskeleton of the cell, affecting the cell’s shape.

THE APOPTOTIC INDUCING FACTOR (AIF)

This is the third pathway that apoptosis could function by. This pathway is triggered inside of the cell and normally occurs in parallel with the intrinsic pathway due to the involvement of the mitochondrion.

This pathway does not involve caspase proteins(protease enzymes) used in the intrinsic and extrinsic pathways, but involves a protein known as the apoptosis inducing factor. This protein is found in the inter-membrane space of the mitochondrion.

Once negative signals are initiated inside of the cell, the mitochondrion’s outer membrane permeability decreases due to the same or similar reactions as in the intrinsic pathway. As a result, AIF is released and in the process cytochrome C is also released, therefore the two pathways, AIF and intrinsic, occur simultaneously. Once the AIF protein has been released, it immediately “migrates” to the nucleus and binds to the DNA. This then causes chromatin condensation and DNA fragmentation. Essentially this cripples the cell from the inside, preventing it from carrying out any essential functions.

THE COMPLETE ERADICATION OF THE CELL THROUGH PHAGOCYTOSIS

While the cell is being digested and destroyed from the inside, certain signals are initiated, found on the surface of the apoptotic cell as membrane proteins. Those two signals are also known as “FIND ME” and “EAT ME” signals. The first signals initiated are the “FIND ME” signals. Essentially they are released in order to attract any nearby phagocyte to come and recognize the apoptotic cell. Once a phagocyte has recognized the cell and is now next to it, a second set of signals are initiated. These are the “EAT ME”signals, essentially triggering and allowing the phagocyte to initiate phagocytosis. Consequently the phagocyte, most likely a macrophage, engulfs the apoptotic cell. Forms a phagosome around it (a vacuole) and secretes digestive enzymes which completely digest and eradicate the cell that could cause harm to the organism. Therefore completing apoptosis.

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Natalie Bishop

Alzheimer’s Dementia has overtaken heart disease as the number one killer in the United Kingdom. There are approximately 850,000 people currently suffering from Alzheimer’s Disease, and this number is set to be well over 1 million by 2025. However, there is still so much that is unknown about this disease that is responsible for so many tragic deaths every year.

Alzheimer’s Disease is a chronic neurodegenerative disease.

This means that it is a disease of the brain that progressively worsens over time. At present, there are no cures and treatments can only slow down the progression or temporarily alleviate symptoms.

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Alzheimer’s

behavioural observations along with the use of MRIs or CT scans to rule out other possible causes of memory loss (such as a tumour or a stroke). A patient can only be diagnosed with Alzheimer’s Disease with 100% certainty after death, when microscopic examination of the brain reveals two characteristic structures found in those who suffer from Alzheimer’s.

PATHOLOGY These structures are 1) Amyloid-Beta (AB) plaques and 2) Tau tangles DEMENTIA V. ALZHEIMER’S A topic that is particularly poorly understood is the difference between dementia and Alzheimer’s Disease.

According to the NIA (National Institute of Aging), dementia is “any brain disorder that affects communication and performance of daily activities.” This means that it is classed as an ‘umbrella term’ – a set of symptoms including impaired thinking and memory.

Therefore, if you are diagnosed with dementia you could have a range of different diseases such as Alzheimer’s, Huntington’s or Parkinson’s. It is similar to if you were to go to the doctor with a sore throat; this could be due to a number of causes – strep throat, allergies, the common cold etc. Alzheimer’s Disease causes two-thirds of all dementia cases, making it the most common cause of dementia.

SIGNS, SYMPTOMS AND DIAGNOSIS The early stage of the disease is called MCI, or mild cognitive impairment.

This is when movement difficulties and mild memory loss may occur. Symptoms include impaired thought or speech, confusion and disorientation.

The sufferer may also experience personality changes – in particular becoming more aggressive, demanding or suspicious. Hallucinations and depression are also associated with those suffering from Alzheimer’s Disease.

Alzheimer’s is an extremely difficult disease to diagnose. Doctors tend to base diagnosis on medical and family history of the patient and any 32

AB plaques and Tau tangles

1) Amyloid-Beta (AB) plaques Amyloid-beta is an insoluble, sticky protein that deposits and aggregates (builds up) into plaques which accumulate between nerve cells in the brain. The obstruction they cause weakens communication between neurons by blocking the synapses connecting them. This weakened communication disturbs processes that the cells require to survive.

2) Tau tangles Tau tangles are insoluble, twisted fibres found inside brain cells. Tau is a protein that forms part of a structure inside a neuron called a microtubule.

Microtubules help to transport nutrients and other substances from one part of the nerve cell to another, and are found throughout the cytoplasm as part of the cytoskeleton.

Atrophy of tissue in the brain of a person with Alzheimer’s Disease, compared to a normal brain.

Tangles form when the tau proteins become defective and the microtubules become unstable. It is thought that tangled tau leaves effected cells in little packets known as exosomes. Exosomes travel to nearby cells and deliver their contents into the new cell, making healthy tau proteins misfold – thus, spreading Alzheimer’s across the brain.

When the nerve cells do not receive the necessary nutrients, they die. This is fatal as dead neurons cannot be replaced by new ones since most do not divide once the brain matures fully.

AB plaques and tau tangles begin to form in the hippocampus, located in the centre of the temporal lobe. It is a region of the brain which is responsible for short term memory. The formations are slow at first and take several decades to form. Then they replicate rapidly, which is when is when the symptoms start to present. Long term Alzheimer’s results in atrophy, or wasting away of the brain tissue, as seen in Figure 3.

CAUSES There are two types of Alzheimer’s Disease – early and late onset.

Early onset affects those under the age of 65 and accounts for around 5% of Alzheimer cases. It is passed down families through autosomal dominant inheritance – one copy of the defective gene is enough to cause the disease.

There is a mutation in a gene on chromosome 21 that codes for a protein called the amyloid precursor protein (APP). Not much is known about the normal function of APP in our brains – it is thought to help attach cells together and may direct the formation of neurons during early development. However, in

Bobby Chan

the brains of those with Alzheimer’s, APP is cleaved by two enzymes gamma secretase and beta secretase.

Once APP is split up, it generates amyloid-beta, which can then build up to form the sticky plaques, disrupting communication between neurons.

Scientists have not yet found a specific gene that causes the late onset form of the disease directly. However, one risk gene is thought to be the APOE gene on chromosome 19. There are three different alleles of the disease – the e2, e3 and e4 alleles. The e4 allele has indicated to increase the risk of Alzheimer’s Disease by up to 15 times. It is thought it achieves this by increasing the formation of AB and tau tangles.

Other risk factors include hypertension, smoking and head injuries, while having an active mind, frequent exercise and a good diet are thought to decrease the risk of Alzheimer’s.

Psychosocial intervention includes cognition, stimulation and behavioural therapy, all of which focus on improving the quality of life for both the patient and their carers through therapy. This could be through introducing art, music or pets that may trigger a long term memory, or presenting the reality of the situation (e.g. date, time, location) to the patient.

This has shown to produce some positive results but also evoked frustration and other negative emotions in patients.

Alternative treatments are not widely supported in the medical community due to the fact that they are quite controversial. For example, cannabis has shown to improve the mood and manage some behavioural symptoms of those suffering from Alzheimer’s. However, these effects have not indicated long term results and no applications have been received by the Alzheimer’s Disease Society to fund a research programme into the use of cannabis. Other examples of alternative treatments include aromatherapy.

CURRENT RESEARCH AND NEW APPROACHES

Donepezil

TREATMENT The three main types of treatment currently being used for Alzheimer’s are: 1) Medication 2) Psychosocial intervention 3) Alternative therapy Firstly, most medications cannot cure Alzheimer’s Disease. They can only slow down or temporarily alleviate symptoms.

The main type of drug is called donepezil – it is administered throughout all stages of the disease and increases the concentrations of chemicals called neurotransmitters in the brain.

One of these neurotransmitters is called acetylcholine, and it is broken down by an enzyme called acetylcholinesterase.

Donepezil and other such drugs are acetylcholinesterase inhibitors – they stop acetylcholinesterase from breaking down the acetylcholine, thus improving communication between the cells.

One of the most exciting recent findings was through an experiment done at MIT, where scientists genetically engineered mice to have Alzheimer’s type damage.

They then directed a 40 Hz light at the hippocampus and visual cortex regions of the mice. What they found was a reduced amount of beta amyloid in these areas.

How it is thought to work is through recruiting resident immune cells called microglia, that remove toxic proteins (e.g. AB). This could potentially halt Alzheimer’s and its symptoms.

Microglia

Moreover, this could move quickly into human trials because it is noninvasive and painless – for example, patients could wear goggles in front of a strobe emitting light to get their daily dose of light therapy. However, the studies have only been done in mice and showed reduction of AB solely in the visual cortex of their brains, with no significant reduction in the hippocampus. For human trials, the hippocampus would have to be directly targeted – perhaps with electrodes wired directly to their heads.

There have been no new drugs introduced to treat Alzheimer’s in nearly 20 years. This is because most of the focus has been on removing the amyloid beta plaques. Eli Lilly is a massive American pharmaceutical company that has spent $3 billion over 3 decades, trying to find a drug that could potentially cure Alzheimer’s. Their most recent trial ended in November 2016. The drug that was being trialled is called solanezumab (sola) and it targets APP – the protein that forms amyloid beta. It was a double blind placebo trial which failed due to the results not being significant enough to warrant putting the drug on the market.

Clearly, a new approach is needed to target this tragic disease. One new proposed theory is that the AB plaque could be a symptom rather than a cause of the disease. Due to this, scientists have been trying to target the tau tangles rather than the AB plaques; a first trial of this failed but hinted at signs of improved cognition. Also, multi-drug treatments have been introduced. For example, a first drug could be used to remove existing plaque and a second to prevent new amyloid beta from forming. Finally, “switching off” the gene that codes for APP could stop the formation of AB plaque all together.

As you can see, there are so many potential leads that could result in a cure for Alzheimer’s. In the news, there is constant debate around whether dementia funding should be at the same level as cancer funding – nevertheless, I hope with sufficient support and the extensive areas of current research being explored, we will keep stepping closer to curing Alzheimer’s Disease.

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Neutron Stars Stasy Kedrina

To give a brief overview, I will explain how stars evolve, form neutron stars, and the properties that arise when main sequence stars turn into neutron stars.

Firstly, it is important to understand that despite the name “neutron star”, neutron stars are not exactly stars, but a type of stellar remnant – what is left when a star dies in an explosion called a supernova, which I will explain later on. Now, to describe what happens during the course of a star's lifetime - please bear in mind that neutron stars can only form from stars with large masses, so I will only talk about stars’ masses over 10 solar masses.

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Neutron Stars

Figure 1.1 The Hertzprung-Russell diagram, how luminosity varies with temperature at different stages of the stellar life cycle.

S

o, stars form within vast clouds of gas and dust known as nebulae, and random changes of density within nebulae lead to some gravitational attraction between the gas particles.

This leads to these gas particles being clumped together, and as the particles collide, kinetic energy is transferred to heat energy, and the temperature increases. As more and more gas particles are gravitationally attracted to this mass, temperature increases even more. This process lasts millions of years. In fact, if the temperature is high enough, there is enough energy for the nuclei of the gas particles to overcome electrostatic repulsive forces and fuse together. This process is known as nuclear fusion. Because hydrogen is the most abundant elements in the nebulae

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from which stars are formed, the main fusion reaction that occurs is hydrogen nuclei fusing into helium nuclei. This process releases some mass, and according to Einstein’s famous equation E=mc2, this results in a large release of energy. This energy comes in the form of heat, so as more and more nuclei fuse, the temperature increases, leading to a faster reaction rate. The star then enters its main life stage and becomes a main sequence star.

Main sequence stars have constant sizes, because although the gravitational forces push in the star to collapse, the gases within the star are at extremely high temperatures, so they expand, and this pressure counteracts the gravitational forces, keeping the star from collapsing in on itself. (See figure 1.3) Another factor

that keeps the star from collapsing is a phenomenon that comes from the Pauli exclusion principle – no more than 2 electrons can occupy an orbital. This prevents the star from collapsing and is known as electron degeneracy pressure.

However, the number of hydrogen nuclei is limited, so when hydrogen nuclei run out and fusion stops, the gas pressure drops and the star is no longer in equilibrium. Therefore, it starts to collapse in on itself, and the decrease in volume causes an increase in pressure within the star, and temperature increases once more, giving enough energy for helium nuclei to fuse, unlike before, when hydrogen nuclei fused. These reactions are exothermic, leading to an increase in temperature and therefore pressure, which once again balances the gravitational forces, and equilibrium is restored. Because the temperature within the star decreases as you move from the core to outer layers, layers of different elements form within the star, as more energy is needed for larger nuclei to fuse.

The star then enters a stage known as a red supergiant. The fusion within the star continues until iron nuclei form.

The fusion of iron nuclei is not energetically favorable – meaning it takes more energy to fuse them than would be released from the reaction; when Fe nuclei fuse, the reaction is endothermic. Therefore, the temperature of the supergiant decreases, leading to a decrease in pressure. Once again, the star is not in equilibrium, and there is

Figure 1.2 Internal structure of a neutron star

Stasy Kedrina

Figure 1.3 A force diagram of hydrostatic equilibrium in a star

only electron degeneracy pressure alone that keeps the star from collapsing. Once again, electron degeneracy pressure is based on the fact that there can only be two electrons per orbital.

Because the mass of the star is so high, it greatly exceeds the limit known as the Chandrasekhar limit, that would allow its existence when it is only supported by electron degeneracy pressure, the star collapses.

The iron nuclei are under so much pressure from the outer layers, that they break down into protons and neutrons, and the outer layers bounce off in an explosion called a supernova (see figure 1.4). Supernovae are able to release such high energies that the lighter nuclei are able to fuse and undergo further nuclear reactions that result in the formation of all elements heavier than iron. Without supernovae, we would not be able to have extremely useful metals such as silver, and copper which is used in wires, and other important elements such as uranium, which is used in nuclear power stations. As for the remaining core of the supergiant that has collapsed and consists of protons and neutrons – depending on its mass, it can become either a neutron star or a black hole.

I will now go over some interesting properties of neutron stars.

So, first of all, figure 1.2 shows a diagram of the internal structure of a neutron star.

The remaining iron nuclei from the fusion of the red supergiant that did not collapse during the supernova forms a solid crust, and the protons and neutrons are in the core.

Also, Neutron stars are some of the densest objects in the universe.

Because the volume the neutron star is so small compared to its mass – neutron stars have an average of 15 km radius, and a mass of 2.8x1030 kg, they have extremely high densities. The average density of a neutron star is 1017 kgm-3 – and to put this into perspective, a teaspoon of a neutron star would weigh around half a trillion kg. Another effect of such a high mass is a very strong gravitational field, which is 1011 times stronger than that on Earth. If some material collides with a neutron star, it would need to travel at nearly half the speed of light to escape, which is extremely fast.

Moreover, because during a supernova, angular momentum is retained, neutron stars spin many times per second.

Angular momentum is a conserved quantity, and is proportional to the object’s radius and its mass. As the radius of the neutron star is much smaller compared to the red supergiant, the neutron star’s rotational velocity is much higher than that of the supergiant. It is perhaps easier to use a simpler example – if you have seen ice skaters – when they spin with their arms out and then pull their arms in, they rotate faster. It's the same in neutron stars.

And finally, another important property of neutron stars is their extremely strong magnetic fields of unknown origins, that are up to 1015 times greater than those on Earth, that lead to emission of electromagnetic waves, mainly in the radio spectrum. This is important because this is how neutron stars were first observed – in 1930s with radio telescopes.

On a slightly lighter note to conclude - I mentioned above that a teaspoon of a neutron star weighs half a trillion kilograms. But what happens if you actually want to eat a teaspoon of neutron star material?

First of all, getting to a neutron star would be problematic – the nearest one is called Calvera, and it's location is estimated to be between 250-1000 light years away, so suppose its actual distance is 250 light years, at the minimum estimate. The oldest neutron stars can live up to 10 billion years, so even if we got lucky and the neutron star Calvera would live for 10 billion years, you would need to travel at the speed of 270 km/h for the next 10 billion years to get to the neutron star.

The temperatures and radiation from the stars would kill you immediately, the luminosity would blind you, and the gravitational force of the neutron star would be so strong that you would be immediately engulfed by the neutron star and the atoms you are made of will be broken down into protons and neutrons, so you would become part of neutron star material. But suppose you found a way to get a teaspoon of neutron star material, and suppose the teaspoon was able to withstand the temperature and the weight of the material, and you eat it.

In this case, the gravitational attraction would be so high that you will be ripped inside out!

Figure 1.4 The remnant of the SN 1054 supernova

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Jess Fatoye

Lynch Syndrome 38

Lynch Syndrome is a cancer syndrome. A cancer syndrome is essentially a set of gene mutations wanted to do a Moncreiff Jones talk because I want to study medicine at university and genetics has always been a topic that really interests me.

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Lynch Syndrome

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ith Lynch syndrome, certain gene mutations inherited predispose an individual to the development of colorectal cancer particularly but not exclusively, as well as other cancers, such as endometrial and ovarian cancer. As Lynch Syndrome is caused by gene mutations, then it must have an inheritance pattern.

Lynch Syndrome is inherited in an autosomal dominant fashion, meaning that it is caused by mutations in genes present in autosomes (any chromosome from 1-22, not a sex chromosome).

Lynch syndrome is commonly caused by four genes in particular – MLH1, MSH2, MSH6 and PMS2, and they are part of a system called the mismatch repair system, which is a correctional system responsible for identifying and fixing random insertions, deletions and mismatches of bases. Human DNA is composed of four bases, adenine, cytosine, guanine and thymine. Adenine and thymine, and cytosine and guanine bond together is something called complementary base pairing, which occurs due to the number of hydrogen bonds each base is capable of forming. Cytosine and guanine are both capable of forming three hydrogen bonds due to their structures, so therefore are complementary, however adenine and thymine are capable of forming two hydrogen bonds, so are therefore complementary to each other. However, hydrogen bonds can form between bases that do not have a matching amount of possible hydrogen bonds, and this is when an error occurs. As DNA is constantly being replicated in the body in order for new cells to be produced for growth and repair, a mistake is bound to occur due to the sheer mass of DNA being replicated. This is when the mismatch-repair system becomes relevant in DNA replication and will act to target these areas or mistake.

During DNA replication, the first step is for an enzyme called DNA helicase to split the two stranded, double helix structure of DNA into two single strands ready for replication in something called a replication fork.

DNA helicase does this by breaking the hydrogen bonds between the base pairs. Whilst DNA helicase breaks the bonds along the DNA, an enzyme called DNA polymerase will go along the replication fork and incorporate new bases, however, about 1 in 1 billion incorporations is a mistake and if these mistakes were allowed to accumulate, a mutation might occur that could cause cells to divide rapidly and uncontrollably in a way that is cancerous or malignant. The mismatch repair system at the point when a mutation accursed becomes active. This is particularly useful in the cases of mismatched base pairs.

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Two of the four proteins commonly responsible for Lynch Syndrome – MSH2 and MSH6 form one of the initial responses to a mistake in DNA replication. Both of these genes code for proteins and these proteins, called Mutator S or MutS proteins, the MSH2 and MSH6 protein will form a dimer, or complex that will identify when a mismatch or mistake occurs in DNA replication, and bind to this site. The binding of this dimer to the mistake will in turn trigger the protein dimer formed by the two other commonly responsible genes – MLH1 and PMS2, which form proteins called MutL proteins, to bind to the MutS proteins. This interaction between the MutL and MutS dimers will then trigger the next step of mismatch-repair which is to remove the incorrect base and insert a correct one. So therefore, a mutation in any one of these genes could result in an increased risk of cancer as it could result in an inability for the dimers to form or to carry out their role properly. There are several tests that are used to test for Lynch Syndrome, however, there are two that are mainly used in the diagnostic process: Microsatellite instability testing and Immunohistochemistry testing.

Microsatellite instability is a phenomenon that occurs in the microsatellites present in a genome as the result of an improperly functioning mismatch-repair system.

A microsatellite is a repeating sequence of nucleotide bases. The most fascinating thing about the nature of microsatellites is that despite their highly polymorphic nature across the human population, across the lifetime of an individual they maintain high levels of stability and should remain constant throughout a lifetime. However, microsatellites can become unstable if a person has an ill-functioning mismatch-repair system, as mutations in microsatellite will no longer be able to be repaired by the mismatch-repair system’s ability to identify and fix random insertions, deletions and mismatches. Microsatellite instability is a condition of hypermutability of a microsatellite of as the result of an impaired mismatchrepair system.

To test for this, microsatellites in a tumour specimen from the patient are compared to those in the patient's normal tissue, five microsatellite markers – BAT25, BAT26, D5S346, D2S123 and D17S250 are used to assess MSI. If the microsatellites differ between the tumour tissue and the normal tissue, then the person will be put forward for further genetics testing for Lynch Syndrome.

Immunohistochemistry uses antibodies that are complementary in shape to the proteins produced by the MLH1, MSH2, MSH6 and PMS2 genes. It takes place

Jess Fatoye

Normal

Abnormal

MLH1

MSH2

MSH6

PMS2 in three steps using primary antibodies, secondary antibodies and a microscope. The primary antibodies bind to the proteins produced by the genes, the secondary antibodies bind to the primary antibodies and deposit a dye at the site of the proteins, and the microscope is used to view the pattern produced by these proteins to identify what, if any, proteins are missing to see which genes are affected to cause Lynch Syndrome. Using all of this information to diagnose Lynch and also to discover which

genes cause and individuals increased risk of cancer, modern science can now find tailored ways to treat Lynch Syndrome, such as regular screening, and preventative surgery and upon development of cancer, personal treatment plans for chemotherapy. Lynch Syndrome and its research, though only just beginning to dig beneath the surface, is pioneering a way in modern genetic research and cancer prevention techniques.

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CLUBS & TR I P S

Medicine Mock Interviews

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Applying for Medicine at Caterham School

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fter catching the wrong train (nobody told me that two different trains can leave from the same platform), I arrived enthusiastic to see what doing research was really like.

Within the first hour we had already learned about things we had never heard of before. Some of the research 42 being conducted was looking into the causes of graft versus host syndrome, an unprecedented side effect of stem cell transplants in which the donor cells, used to rebuild the immune system, started to attack the cells of the person they were meant to be defending.

While in another department, we learned that the researchers were looking into chemicals released by our own body cells that actually aided the growth of tumours and possible ways to block them. This all sounded very exciting, but next we came to face the realities 42

of performing experiments. There was much more time spent planning before even starting than we had anticipated and when the experiments did begin there was an unprecedented amount of pipetting, centrifuging and flow cytometry (although this revelation did teach us a lot more about research that watching enthralling experiments ever could). The truly exciting part actually came (surprisingly) in the data analysis; seeing whether the results were significant and whether the molecule being tested had worked in the way it was expected to.

Ultimately, the week did give both of us attending a true insight into the realities of research, but we did also get to hear about some of the most current and interesting science out there, only serving to further emphasise its importance to the future of the world.

or those unfamiliar with the term, MMI stands for ‘multiple mini interviews’, referring to a series of short (usually 5-8 minute) interviews faced by most aspiring medics, and otherwise synonymous with utter terror.

One cold (and most likely rainy) lunchtime in late November, everyone in the Upper Sixth year applying to medicine stood in the biology department clutching their scoring sheets anxiously waiting for the mock interview circuit to begin. Inside we would meet eight teachers sat at separate desks, each possessing a challenging question gleaned from old medicine interviews.

The stations ranged from questions about our opinion on recent news stories to a role play involving an argumentative lecturer (the one that I personally found most difficult). After the allocated time, we handed over our score sheets to our interrogator who gave us a mark out of five and a few lines of written feedback on how to improve.

Although disappointing not to come away with straight fives, the experience did teach me a lot and was extremely helpful in preparing for my real interviews. Thank you to all the teachers for their advice and for sacrificing one of their lunchtimes to listen to students discussing medicine.

THIS Y EA R’S N O B E L P RI Z ES

Medics Club

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he Medics Society at Caterham School provides students with the opportunity to broaden their knowledge on current medical affairs.

The society gathers together every Thursday lunchtime at 1pm and discusses assigned topics of personal interest, giving the opportunity for presentation, questioning and debates.

Developing communication skills is at the heart of the society as it is vital to be able to clearly converse with patients. During the debate, students may discuss current medical affairs, ethics and areas of concern within the medical world providing them with sufficient depth of knowledge required at medical interviews. Apart from presentations, we have also done role play between doctors and patients and organized trips up to London to study medicine specific examinations so students are able to be fully prepared for university applications.

This Year’s President: Desmond Chui

T

he 2016 Nobel Prize in Physiology or Medicine is awarded to Yoshinori Ohsumi for his discoveries of mechanisms for autophagy.

Macroautophagy (“self-eating”, hereafter referred to as autophagy) is an evolutionarily conserved process whereby the eukaryotic cell can recycle part of its own contents. Unlike other cellular degradation machineries, autophagy removes long-lived proteins, large macromolecular complexes and organelles that have become obsolete or damaged. Autophagy mediates the digestion and recycling of non-essential parts of the cell during starvation and participates in a variety of physiological processes where cellular components must be removed to leave space for new ones. In addition, autophagy is a key cellular process capable of clearing invading microorganisms and toxic

protein aggregates, and therefore plays an important role during infection, in ageing and in the pathogenesis of many human diseases. Although autophagy was recognized already in the 1960’s, the mechanism and physiological relevance remained poorly understood for decades.

The work of Yoshinori Ohsumi dramatically transformed the understanding of this vital cellular process.

In 1993, Ohsumi published his seminal discovery of 15 genes of key importance for autophagy in budding yeast. In a series of elegant subsequent studies, he cloned several of these genes in yeast and mammalian cells and elucidated the function of the encoded proteins. Based on Yoshinori Ohsumi’s seminal discoveries, the importance of autophagy in human physiology and disease is now appreciated.

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TH IS YEA R ’S N O B E L P R I Z ES

molecular machine, or nanomachine, refers to any discrete number of molecular components that produce quasi-mechanical movements (output) in response to specific stimuli (input). The expression is often more generally applied to molecules that simply mimic functions that occur at the macroscopic level. The term is also common in nanotechnology where a number of highly complex molecular machines have been proposed that are aimed at the goal of constructing a molecular assembler. Molecular machines can be divided into two broad categories; synthetic and biological.

A groundbreaking step in development of molecular-sized machines was taken in the early 1980s,

when Jean-Pierre Sauvage and his group discovered an efficient way to make molecules that are attached to each other using mechanical bonds. The group thus managed to link two molecular rings together in a so-called catenane, where the rings could move freely relative each without being separated. This marked a breakthrough towards molecular machinery, and Sauvage was able to show how such structures can undergo controlled motion.

By the turn of the 1990s, Fraser Stoddart and his group made other important advances towards molecular machinery.

For example, the group used another type of mechanical bond and developed socalled rotaxanes in which a ring-shaped molecule was tied to move between set positions along an axle. Both Stoddart and Sauvage were also able to show

how the movement in these structures could be controlled from external input, and subsequently developed a wide range of machine-like structures, such as molecular muscles, actuators, elevators, memories, motors and pumps.

The motor components are of central importance in machines, able to drive other parts of the constructions.

By the late 1990s, Ben Feringa and his group made a significant breakthrough when they demonstrated a molecular rotary motor. The construction was driven by light and heat and was based on isomerisable bonds and molecular asymmetry, where the motor parts could rotate unidirectionally relative each other. The group was later able to improve the design to create motors that can rotate in either direction at very high speeds, and showed how the components can affect the rotation of much larger objects. In a more playful example, Feringa’s group also constructed a four-wheel drive “nanocar” that can move over a surface.

Through the design and synthesis of very challenging structures, combined with the understanding and development of controlled motion and function, Sauvage, Stoddart and Feringa have created functional molecular machines.

Their work has formed the basis for an entirely new field of research, for which the three Laureates have been groundbreaking pioneers and sources of inspiration.

Jean-Pierre Sauvage

Sir J. Fraser Stoddart

Bernard L. Feringa

Nobel Prize in Chemistry

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T

he three Laureates' use of topological concepts in physics was decisive for their discoveries. Topology is a branch of mathematics that describes properties that only change step-wise. Using topology as a tool, they were able

to astound the experts. In the early 1970s, Michael Kosterlitz and David Thouless overturned the then current theory that superconductivity or suprafluidity could not occur in thin layers. They demonstrated that superconductivity could occur at low temperatures and also explained the mechanism, phase transition, that makes superconductivity disappear at higher temperatures.

In the 1980s, Thouless was able to explain a previous experiment with very thin electrically conducting layers in which conductance was precisely measured as integer steps. He showed that these integers were topological in their nature. At around the same time, Duncan Haldane discovered how topological concepts can be used to understand the properties of chains of small magnets found in some materials.

We now know of many topological phases, not only in thin layers and threads, but also in ordinary three-dimensional materials. Over the last decade, this area has boosted frontline research in condensed matter physics, not least because of the hope that topological materials could be used in new generations of electronics and superconductors, or in future quantum computers. Current research is revealing the secrets of matter in the exotic worlds discovered by this year's Nobel Laureates.

ACH IEVEME N TS I N S CIE N C E

T

he Royal Society of Biology has now confirmed that we have achieved our biggest ever haul of medals in this year’s UK National Biology Olympiad.

We won 14 medals in this year’s contest!

Many congratulations to these pupils: GOLD: Rui Huang, Tooki Chu, Vladimir Kalinovsky, Aishi Symmons, Hailey Sze SILVER: Alice Fish, Leo Chan, Michael Lai, Tony Cheng, Raymond Ho BRONZE: Sam Burns, Tom Green, Tom Gilshenan

Great news from Old Caterhamian Nikita Komarov who has just been offered a funded fellowship at the world famous Francis Crick Institute in London. This is superb news as freshers are very rarely considered.

Nikita is one of just 24 successful applicants, from a total pool of 800, and is also the only first year to be successful in the past five years! His project involves modifying model

organisms to mimic mammalian mitotic processes, which could, way down the line, have massive implications in regenerative treatment, and allow safe, ethical testing of certain factors on pathological disease, such as oncology or degeneration.

While Nikita’s project is only at the start of the journey, it is still invaluable knowledge and experience,that will hopefully lead to the betterment of understanding of cellular processes in model organisms.

Congratulations Nikita!

Nikita at a recent Old Caterhamians Reunion – March 2017

Science Evening: Dexter

O

n Friday 17 March, 72 parents attended the ‘Dexter’ event run by the Senior Science department and the PA. Parents were invited back to school to be taught physics, chemistry and biology as our senior pupils are. It was a fabulous evening full of experiments, laughs, frights and enthusiasm. Thanks to everyone who attended and to the science staff who gave up their evening to teach and entertain the parents.

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R ESEARCH CAR R IE D O U T BY T EAC H ER S

Designing a PhotoWarhead to Elucidate a Binding Site The central dogma of Biology

C

ancer is one of the most voracious killers of modern day society with the strike rate now reported to be 1 in 2 people who may be diagnosed with what it is a horribly debilitating disease. The mechanism of a tumour is part of its efficacy, as it has the ability to spread throughout the body infecting the host further as it goes. The action is simple, reproduction of cells at an uncontrolled rate compared to their surroundings, burrowing into the tissue and affecting organs leading to their ceased function.

Most of the current medical methods involve ceasing growth of cells, thus halting the disease in its tracks in order to then try and destroy, or excise the growth. In our research we had discovered a drug that could halt a process common to all cells, known as splicing.

Splicing is the process of removing non-coding strands of mRNA, known as introns, leaving the coding material (exons) to be translated into proteins. One of the ways some cancers (and other diseases, such as retinitis pigmentiosa or spinal muscular atrophy) arise is due to mistakes in this process, leading to mutated cells. Some cancers spread these mistakes into new cells, thus proliferating the process of forming mutated proteins from mutated proteins.

Splicing is carried out by a large, highly dynamic protein complex called the spliceosome, primarily composed of 5 uridine-rich small nuclear ribonuclearproteins

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(or snRNPs). These 5 large proteins manoeuvre themselves and the pre-mRNA being spliced into various positions in order to allow two key transesterification reactions in the RNA polymer to occur. This process essentially snips out the seemingly useless white noise of pre-mRNA, and patches together the real meat of the biological code.

The structure of the spliceosome is similar in size to the ribosome, but is not conserved between steps and the five U-snRNPs are assembled and dismantled around the RNA in a stepwise manner during splicing. As such the structure and mechanism of the spliceosome has not been precisely defined.

Our research group decided that an effective of stopping the spread of cancer would be to halt the splicing process in effected cells. We had previously discovered a relatively cheap, reasonably effective drug that had been shown to reduce the splicing process. The mechanism was simple – stop splicing, thus increasing the amount of unspliced premRNA in cells, inducing cell death, and preventing growth of the tumour.

To improve this it would be necessary to elucidate the mechanism of the drug’s action. We had reason to believe the drug, a widely used steroid antibiotic, bound to one of the proteins in the U5 snRNP responsible for positioning of the mRNA during both transesterification reactions.

This protein had been given the catchy name “snu114” … but that’s biologists for you. If we could work out exactly how and where the drug ligated this protein, then we could adapt its structure and improve its potency.

Design of Molecular Structures for Photo-labelling The idea of photo-labelling is not a new one – a photoactive moiety is attached to a ligand. The compound is then allowed to bind to the active site, and the complex irradiated. Once irradiated a new bond is formed between the ligand and the amino acids surrounding the binding site. This bond - unlike the ones binding the ligand to the active site - is a strong covalent bond, and irreversible.

The ideal photo-crosslinking group should have a number of qualities, firstly it should be easily synthesised and attached to the ligand compound. Secondly it should be reactive once activated to insert, but chemically stable enough to undergo the synthetic conditions needed to attach, and avoid it being rendered inert, or undergo premature cross-linking before binding. The ideal crosslinking compound would not affect the solubility of the ligand once attached but at the same time would not have an affinity for the solvent either. Finally should be able to undergo smooth, reliable photolysis at non-harmful wavelengths to the surrounding proteins, usually over 300 nm. This tightrope of conditions means that synthesis is not always an easy process. New compounds are proposed and eliminated often as they do not fulfil exactly the criteria needed for these studies. The molecules presented below are the most popular; amino acids are coloured blue, and the bottom half of the diagram shows the insertion into the chain by the cross-linkers.

Some common photoactive labelling compounds

The first of these examples we chose is benzophenone, an interesting ketone species with the carbonyl sandwiched between two aromatic rings – first reported in the ‘70s, it is easily synthesised using Friedel Krafts chemistry followed by chromium oxidation chemistry to convert to a carboxylic acid for attachment. The oxidation was a highly exothermic reaction using two types of concentrated acid and resulting in extraction of beautiful white crystals from a swamp green toxic sludge – not the cleanest reaction, or the safest if in the wrong hands, but rewarding in its simplicity.

Insertion of benzophenone

Once made it is highly stable until irradiated, at which point one of the non-bonding electrons on the oxygen atom will be raised in energy to an unpaired electron, generating a highly reactive di-radical capable of insertion.

The drawbacks are that it can regenerate the carbonyl species before insertion, and it has a slight bias for the amino acid methionine.

Excitation of benzophenone

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Synthesis of the diazirine as a benzoic acid derivative

The next example is the trifluoromethyl aryl diazirine.

Synthesis of this group is a much longer and - due to the high reactivity of synthetic intermediates - low yielding process. Involving some incredibly interesting and precise Grignard chemistry, some mind-numbingly boring column chromatography, some exceedingly cool liquid ammonia chemistry in a high pressure reaction ‘bomb’ and finally some beautiful and colourful iodine oxidation chemistry – the synthesis was a roller-coaster of emotions.

Due to their highly reactive nature and the fact they generate nitrogen, diazirine compounds can be explosive if handled the wrong way. A diazirine is formed of two nitrogen atoms and a carbon atom in a highly strained three-membered ring. This triangular shape is eager to break up – resulting in release of a nitrogen molecule and formation of a reactive lone pair species on the carbon atom known as a carbene. The addition of an electronegative –CF3 group stabilises the ring by pulling electron density towards itself.

Excitation of a diazirine to generate a carbene

The lone pair generated is incredibly reactive and will react with almost anything in close proximity extremely quickly, via two possible forms of diazirine – a singlet and triplet – as 48

the two unbonded electrons of the carbene can be expressed as either two unpaired electrons in separate orbitals or a single lone pair in one orbital. These two species will follow different pathways, both ending in the same product.

Insertion of carbenes

These two “photo-warheads”, once attached can be activated and, if successful the whole complex can be broken down using proteases into fragments which can then be analysed using mass spectrometry – thus elucidating the structure of the binding site by the signature masses of the amino acids.

Once this whole process is complete the next step, the one that is currently underway takes place – further refinement of the ligands is performed, hopefully guided by results from studies such as these. New molecules are built, and new tests are run on these potential medicines, and slowly, step-by-step new drugs can be born. The global fight against cancer continues.

QUANTUM

ULTIMATUM THE ANNUAL MAGAZINE OF THE MONCRIEFF-JONES SOCIETY

Quantum Ultimatum THE ANNUAL MAGAZINE OF THE MONCRIEFF-JONES SOCIETY

MJ

MJ 2014 - 15 ISSUE

Do c

en d o F iat S a pie ntia

2015 - 16 ISSUE

Do c

en d o F iat S a pie ntia

50 years of the Moncrieff-Jones Society

by Dan Quinton

I

t is a testimony to the input of so many generations of Caterhamians that the Society survives and thrives after all these years. I am incredibly proud to be overseeing this amazing institution in its 50th year. We look forward to celebrating its birthday on Friday 22 September which features a lecture on the current state of Neuroscience by Dr Luke Bashford OC 2001-2008.

Luke was a pupils I taught many years ago and who is now at the cutting edge of research at Caltech.

The thrill of teaching pupils like Luke and helping them become better than you is exhilarating.

The MJS reached another level during Luke's 6th Form years. It was his love of Science and in particular Biology, that inspired me to make him the first ever President of the Society. I cannot thank him enough for all he did a decade ago, and wish our latest President and Vice President (Kamen Kyuchtkov and Natalie Bishop) every success in their leadership of the Society during this important year.

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Society Summary

by Dan Quinton

T

he Moncrieff -Jones Society is very dear to my heart. Thanks to science we live in an extraordinary technological age. A world of Twitter and sound bites.

A world where ill-informed people will give their opinion without really understanding the facts. Science often requires a knowledge of a vast array of facts before you can begin to understand and certainly before you can give a worthwhile opinion. It requires incredible discipline yet is also, at the cutting edge, incredibly creative. The brave students giving lectures at the Society’s fortnightly meetings receive no help from staff , and are cross questioned by the audience for around 40 minutes – they must teach themselves a vast array of facts and then understand them if they are to survive a Moncrieff -Jones Lecture! MJS must be the ultimate in terms of independent learning – a skill the top universities are looking for in their undergraduates.

The MJS talks have reached an extraordinarily high standard and there are always more students wanting to do MJS talks than there are weeks available in the term.

I cannot thank Hannah and Vladimir enough for all they have done this year. They have worked tirelessly to organise and promote the society and to maintain its position as the most popular and prestigious society in

the school. John Jones founded the Moncrieff Society in 1967, as a ‘liberal science society’ – its mission to address a gap in the range of Sixth Form societies.

Sir Alan Moncrieff was an eminent Old Caterhamian in the medical field and John Jones was a Head of Chemistry at Caterham School for many years. When I took over the Society I decided it should be renamed the Moncrieff -Jones Society in the year that John Jones retired, as a way of recognising the massive contribution John made to Science at Caterham School. True to the liberal spirit in which MJS was formed, meetings over the years have included the reading of scenes from Brecht’s ‘Life of Galileo’, pictures depicting the beginning of life at hydrothermal vents, and even an entertainment based on scientifi c themes. Individuals have spoken on interests as diverse as cell biology and thermodynamics, and intellectual tours de force have ranged from the quantum world of the very small to the vast sphere of astrophysics. We live in an age of science. There has never been a greater time to study science. With the massive problems the world faces, it is through science that we look for solutions. It is a testimony to the input of so many generations of Caterhamians that the society survives and thrives some 50 years on.

Dan Quinton is Head of Science at Caterham School 50

PAST MONCRIEFF PRESIDENTS, VICE-PRESIDENTS & ENDORSERS

2007-2008 President Luke Bashford (University College London) Vice President Edd Simpson (University of Leeds) 2008-2009 President Tonya Semyachkova (Balliol College, Oxford) Vice President Raphael Zimmermann (University East Anglia) 2009-2010 President Alex Hinkson (St Catherine’s College, Oxford) Vice President Alexander Clark (Robinson College, Cambridge) 2010-2011 President Oliver Claydon (Gonville and Caius College, Cambridge) Vice President Sally Ko (Imperial College London) 2011-2012 President Glen-Oliver Gowers (University College, Oxford) Vice President Ross-William Hendron (St Peter’s College, Oxford) 2012-2013 President Rachel Wright (St Peter’s College, Oxford) Vice President David Gardner (University of Nottingham) 2013-2014 President Holly Hendron (St Peter’s College, Oxford) Vice President Anne-Marie Baston (Magdalen College, Oxford) 2014-2015 President Ollie Hull (Merton College, Oxford) Vice President Cesci Adams (University of Durham) 2015-2016 President Thomas Land Vice President Cesci Adams (University of Durham) PAST AND PRESENT MONCREIFF-JONES SOCIETY ENDORSERS Dr Jan Schnupp, Lecturer in Department of Physiology, Anatomy and Genetics at the University of Oxford Dr Bruce Griffin, professor at Surrey University, specialising in lipid metabolism, nutritional biochemistry and cardiovascular disease Dr Simon Singh, popular author and science writer, including the book 'Trick or Treatment?'

Dr Mark Wormald, Tutor of Biochemistry at the University of Oxford Dr Nick Lane, Reader in Evolutionary Biochemistry, University College London

Caterham School, Harestone Valley Road, Caterham Surrey CR3 6YA Telephone: 01883 343028 Email: enquiries@caterhamschool.co.uk

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