Quantum Ultimatum 2020/2021 by Caterham School

2020 - 21 ISSUE

THE ANNUAL MAGAZINE OF THE MONCRIEFF-JONES SOCIETY

Foreword It was a great pleasure to have been the guest speaker at the Moncrieff-Jones Society annual Christmas lecture in December 2020 to talk about my work in robotic surgery and disaster relief. I was so impressed with not only the huge audience but also the quality of questions afterwards from both parents and pupils of the school. This Society has been going for well over 50 years now and clearly maintains an incredibly high standard of talks each term by the pupils. The articles in Quantum Ultimatum each year are impressive and show how the pupils research their chosen topic to a depth well above A level and into undergraduate level. I was also delighted to hear from Alex Richings (President of the Moncrieff-Jones Society), Max Fogelman and Mr Quinton - as well as another pupil, Louie Steel - that a Society called The Wright Society has been created, dedicated to helping aspiring medics, dentists and vets achieve their dream. The pandemic has highlighted

like never before the importance of our amazing National Health Service and both these terrific School Societies are playing an impressive role in developing not only science skills but also communication skills. While the world needs and has brilliant scientists, we also need them to be good communicators and so I am very proud to be able to endorse both these societies this year, and wish them good luck in the future. Finally, I would like to thank Mr Quinton whose idea it was to have these Christmas Lectures so many years ago; he has been arranging them ever since. His deep passion for science is infectious and it is so wonderful so see how well he provides the pupils with the enthusiasm, knowledge and inspiration to succeed in all that they aspire to. Mr Shahnawaz Rasheed B Clin Sci, MBBS, DIC, PhD, FRCS Consultant Surgeon, The Royal Marsden Hospital

President’s Introduction In our annual Christmas Lecture, we were treated to the first ever virtual talk in which Mr Shahnawaz Rasheed, Consultant Surgeon at The Royal Marsden, shared a piece of his life’s work as he discussed the developments of robotic surgery in the treatment of colorectal cancer as well as his own interest in disaster response medicine. The popularity of his talk was backed up by the fact that it was both the longest and most attended Christmas lecture in the Society’s history. President: Alex Richings (left), Vice President: Max Fogelman (right)

Dear Reader, Welcome to the 14th edition of Quantum Ultimatum magazine. Whilst the past few months have been full of change and uncertainty, one thing we have strived to maintain is the high standards and progression of the Moncrieff-Jones Society. In a year of firsts, we witnessed the first ever talk presented virtually as we began broadcasting the lectures in September to allow the different year groups to watch. Furthermore, to accommodate various travel restrictions, the Society saw the first talk in its history delivered from another continent with lectures being presented from Hong Kong to Tenerife to Seoul. These advancements demonstrate not only how far Moncrieff has come, but also how “Covid can’t stop science” as put by Mr Quinton at the Christmas Lecture. Autumn’s Upper Sixth talks spanned a broad range of complex subjects from Deep Brain Stimulation to Inflation and the Multiverse and thoroughly demonstrated the great research and understanding of our speakers. In the following term, we began a series of fully virtual talks in which the Lower Sixth students covered topics from the Actions of p53 to Thermodynamics and not only delivered some of the best lectures to date, but also adapted well to presenting online.

With so many challenges to overcome, it is even more impressive how our speakers maintained the reputation of the Society and helped it grow in many ways. None of this would have been possible without the hard work and coordination of many people. In particular, I would like to thank the Vice President and Head of The Wright Society, Max Fogelman, for always being so reliable and willing to help. Furthermore, I am ever so grateful to Mr Evans for dedicating his time to continuing the Society even in its new virtual setting and ensuring the talks ran smoothly. Of course, I must also give huge thanks to Mr Quinton for trusting me with the responsibility of running the Society and for guiding me along the way. Finally, I would like to give thanks to everyone who attended this year’s talks as your enthusiasm has been essential to allowing the Society to continue in this difficult year. I would like to wish all the best to the succeeding President, Jason Cho, and Vice President, Rainis Cheng. I know you will both ensure the continued success of Moncrieff and hope you enjoy your roles just as much as Max and myself have. Enjoy the reading, Kind regards Alex Richings

Contents A History of the Moncrieff-Jones Society in 130 Lectures Christmas Lecture: Robotic Surgery & Disaster Response Medicine Alex Richings Upper Sixth Talks

ATP Synthase Cyrus Liu

Symmetry in Chemistry Esther Keyworth

Haemolytic Disease of the Newborn Louie Steel

Epigenetics Maddie Alcock

Inflation and the Multiverse Ben Elliot

Deep Brain Stimulation Will Kwan Lower Sixth Talks

p53 – Guardian of the Genome Jason Cho

DMARDs and Whether They Increase the Risk of Cancer Michael Wong

Thermodynamics and the Nature of Entropy Gleb Iagelskii

Situ Inversus and Ciliary Dyskinesia Rainis Cheng

Prions Brandon Kim Enrichment Olympiads Scientific Advancements The Wright Society Max Fogelman Final Reflection Dan Quinton Article References

A History of the Moncrieff-Jones Society in 130 Lectures 07-08: Luke Bashford - “Neuroscience and

08-09: Jan Niehues - “Special Relativity” |

09-10: Eleanor Croft - “Crohn’s disease” |

Matt Fenton - “Why do we Age? The Telomere Theory” | Emily McCartney - “Alzheimer’s Disease” | Leo Lobbes - “Muscle Structure and Function” | Stella Hristova - “The HIV lifecycle” | Franz Richter - “The Basic Principles Behind Heat Pumps” | Eleanor Budge - “Stem Cells: The Future of Medicine?” | Oliver Claydon - “The Cytoskeleton” | Andy Paine - “Supersymmetry” | Sally Ko “Speech: Nature or Nurture?” |

10-11: Kelvin Tang - “Savant Syndrome” |

Kyle Yeung - “Dark Energy” | Ohis Ojo - “Enzyme Inhibition” | Glen Gowers - “The Biochemistry of Taste” | Ross Hendron - “Regeneration” |

11-12: Ross Hendron - “Dealing with Disease

12-13: Emily Palmer – “Is the War on Cancer

13-14: Anne-Marie Baston – “The Amide

15-16: Pippa Baliman - “String Theory” |

16-17: Tooki Chu - “CRISPR Genome

17-18: Ben Prego - “CRISPR the Future of

18-19: Anna Gardener - “How Trees

19-20: Yuka Okada - “Neutrino Oscillations”

20-21: Cyrus Liu - “ATP Synthase” |

Louie Steel - “Haemolytic Disease of the Newborn” | Maddie Alcock - “Epigenetics” | Esther Keyworth - “Symmetry in Chemistry” | Ben Elliot - “Inflation and the Multiverse” | Will Kwan - “Deep Brain Stimulation” | Jason Cho - “p53 – Guardian of the Genome” | Michael Wong - “DMARDs and Whether They Increase the Risk of Cancer” | Gleb Iagelskii - “Thermodynamics and the Nature of Entropy” | Rainis Cheng - “Situ Inversus and Ciliary Dyskinesia” | Brandon Kim - “Prions” |

Christmas Lecture:

Robotic Surgery & Disaster Response Medicine Alex Richings

Early in December last year, we hosted the Moncrieff-Jones Society’s annual Christmas Lecture in a new virtual setting to ensure that the highlight of the academic year would continue despite the various restrictions at the time. Nonetheless, the night was a great success as over two hundred people signed up to watch the event – the most we have ever had at a lecture.

The brilliant talk was given by our guest speaker Mr Shahnawaz Rasheed, Consultant Surgeon at the Royal Marsden Hospital. Mr Rasheed is well known for his pioneering work in colorectal surgery as he is one of only a handful of surgeons in the country who has employed the da Vinci Xi surgical robot in his work. In addition, he is a Senior Lecturer at Imperial College London where he was also awarded his PhD for his research into colorectal cancer. Outside of the operating theatre, Mr Rasheed has a deep passion for global health too as he helps to coordinate the non-governmental organisation Humanity First as its global Medical Director as well as the G4 Alliance, a group dedicated to providing access to surgical, obstetric, trauma and anaesthesia care to those in need. He began the evening by introducing his role as a medical professional and explaining how rewarding life in medicine has been whilst also using his experience to provide some valuable advice to the aspiring medics in the audience. Mr Rasheed then went on to explain the common techniques in the treatment of colorectal cancers such as laparoscopic surgery as well as the importance of palliative care. One of the main focuses of his talk was the use of robotics in performing surgery and it was certainly as interesting as it sounds. Firstly, Mr Rasheed narrated a fascinating video showing an actual operation with the robot at work. He explained how by using such a specialised piece of equipment, it

allows the surgeon to work with greater precision whilst being as minimally invasive as possible. When questioned towards the end of the evening, Mr Rasheed explained how despite all the added technicalities of having to manipulate surgical equipment through the arms of a robot, performing surgeries in this way is more relaxing as it enables him to operate without being positioned awkwardly. The other main component of the lecture was disaster response medicine. In this section, Mr Rasheed began by defining the nature of a disaster before explaining the rigorous assessment procedure that is required to guide the response, where he used the 2010 Haiti earthquake as an example. Furthermore, he detailed how essential public health messaging is in order to educate the public and help minimise the impacts. This message was particularly evocative in light of the current pandemic. Following the talk, Mr Rasheed proceeded to answer the online audience’s questions in light of the very engaging presentation. Overall, our longest ever Christmas Lecture was one to remember thanks to all the fascinating insights into our guest speaker’s work. However, perhaps the most important message to take away from the talk was Mr Rasheed’s words on taking responsibility for your own learning and knowing when to ask for help from those around you.

Upper Sixth Talks ATP Synthase Cyrus Liu Coming across a video by Harvard online, I found out how much more there is to respiration than taught at school, and especially the intricacy of the electron transport chain. ATP synthase stood out the most from all the protein complexes and since then I have been absolutely fascinated with this protein. From its origin as a bacterial motor protein to how it actually forms ATP, every part of it is enthralling to learn about. I wish to see what the future holds for this amazing complex in the field of science.

Symmetry in Chemistry Esther Keyworth I chose to talk about this topic because it brings together maths, physics, chemistry and biology. Although I focused more on the mathematical and chemical side of it, there was something for everyone. It fascinated me how this relatively simple mathematical idea underlies the whole of our current understanding of ourselves, our world and the universe. The fact that there are these concepts so universal and so key to everything we study and do is fascinating.

Haemolytic Disease of the Newborn Louie Steel

I chose to do my talk on haemolytic disease of the newborn because I found the science that underpins the disease really fascinating. My inspiration came from reading about the disease as part of extension work in biology. From here, I researched the disease further and was especially interested in the complexity of the mother’s immune response against the antigens. I really enjoyed the opportunity to research a topic in such depth, and then subsequently share this knowledge with my peers.

Epigenetics Maddie Alcock I focused my Moncrieff-Jones talk on how epigenetics plays a key role in the regulation of gene expression. This rapidly developing field of research examines how chemical changes to the DNA structure affect whether or not a gene is transcribed without changing the underlying base sequence. I was particularly interested in Conrad Waddington’s ‘Epigenetic Landscape’ as a principle for determining cell fate, which can be used to understand how completely different cell types can function in completely different ways despite containing a copy of the same genome, simply because of which genes have been switched off.

Inflation and the Multiverse Ben Elliot Did the universe really start with a “big bang” or is there a better theory to describe how our universe really started, explaining how the very matter both you, I and everything around us is made up of? This question has always fascinated me, and it is for this reason that I chose to research deeper into the beginnings of our universe, coming across very fascinating modern cosmology and quirky science fiction ideas like a multiverse which really captivated my imagination.

Deep Brain Stimulation Will Kwan While it is intriguing to learn about the intricate relationships between brain chemistry and behaviours, its complexity also gives rise to many idiopathic diseases. Thus, I took this opportunity to delve more deeply into the pathophysiology underpinning Parkinson’s and realised how the misfolding of a single protein, along with other cellular dysfunctions are conducive to the onset of this disease to a varying degree. While looking into advancements of deep brain stimulation as a potential treatment, I also uncovered limitations such as hardware malfunctioning, unwanted stimulations, and ethical problems.

ATP Synthase Cyrus Liu

The reason we call this enzyme F0F1 ATP synthase is because there are two main regions that make up this molecule - the F0 and the F1 region. The F0 region is embedded within the inner mitochondrial membrane where there are three main parts that form the region the a-subunit, c-subunit and the γε stalk. The a-subunit is connected to one section of the of the c-subunit which is then tightly connected to the γε stalk. The F0 region is where protons diffuse back into the matrix.

In terms of the F1 region, this is the part of the enzyme that sticks into the matrix, which is where ATP is synthesised from ADP and Pi. The F1 region consists of an α3β3 hexamer structure which is attached to the top part of the γε stalk. Although it is a hexamer structure, it is only the β-subunits that are involved in the synthesis of ATP, where the α-subunits do not really take part in the reaction. Attached to the side of the α3β3 -subunit would also be a δ-subunit and two b-subunits, where the bottom b-subunit is also attached to the a-subunit.

The NADH and FADH2 molecules deposit two high energy electrons to their respective protein within the ETC where through a chain of proteins and redox centres, the electrons are finally accepted by oxygen to form water, which we all know is a product of respiration. In this process, the energy lost from electrons passing through these proteins is used to pump protons across the membrane, allowing the proton gradient to be formed. Depending on which protein along the ETC the molecules deposit their electrons at, typically 1 NADH molecule is able to pump 10 H+ ions across the inner mitochondrial membrane and FADH2 can pump about 6 H+ ions. PROTO N T RANS LO CAT IO N

P ROTON G RADI E N T

In essence, ATP synthase is driven by what is known as the proton-motive force or the electrochemical force. This is due to chemiosmosis brought by the difference in proton concentration between both sides of the inner mitochondrial membrane. So how do we create this proton gradient? The short answer would be the electron transport chain (ETC). What happens is during respiration, where we go through glycolysis, pyruvate oxidation, and the Krebs cycle, we form three main products - ATP, NADH, and FADH2. NADH and FADH2 are what we call hydrogen carriers which are responsible for bringing the hydrogen atoms to the electron transport chain which is located at the cristae.

After explaining where the proton gradient came from, we can now talk about how ATP synthase uses this gradient and the proton-motive force to drive the molecule to execute its function. Protons tend to be too hydrophobic to be able to just diffuse pass through the phospholipid bilayer, hence we know that it has to pass through the membrane via some sort of protein. It turns out, there are two half channels in the a-subunit, one which has an opening on the inter membrane side (access channel) and ongoing out towards the matrix side (egress channel). Protons enter ATP synthase via the access channel, where they bind to a molecule in the c-subunit called aspartate-61 residue. The c-subunit then rotates in an anti-clockwise motion until that residue is in line with the egress channel to allow the proton to diffuse into the matrix. This rotation then happens continuously, which is where the water wheel analogy comes in. An interesting fact about this mechanism is that although one might refer the motion of this enzyme to be somewhat similar to a water wheel, the c-subunits can only rotate in one direction. This is because as the protons enter the c-subunit, the amino acid side chains alongside the c-subunit repel the bound proton, causing the clockwise motion of the c-subunit ring to be energetically unfavourable.

As the c-subunit ring rotates every 120 degrees, the β-subunits change states. The original open state subunit will change to a loose state, the loose state subunit will change to a tense state and the tense state one will change into an open state. Every time an ATP molecule is released into the matrix, a new set of ADP and Pi will bond with the β-subunit that is vacant. This process happens three times per one full rotation of the c-subunit, and thus we can deduce that 3 ATP molecules are synthesised per rotation of the c-subunit ring/γε stalk. AT P SYN T HE S I S

As the c-subunit rotates, the γε stalk rotates as well. This brings a certain set of conformational changes in the 3β-subunits that lead to the synthesis of ATP. Β-subunits normally exist in three states - tight, loose, and open. The tight state is where ADP and Pi are brought together very closely to form ATP, the loose state is where ADP and Pi are trapped within the molecule and the open state is when the ATP formed is released into the matrix. The three states all exist at the same time, yet each β-subunit will always have a different state to each other. The bonding of ADP to the β-subunit is by the formation of hydrogen bonds between the two, where a magnesium ion also bonds to ADP in order to neutralise the charge of the phosphate.

E VO LU T IO N

How ATP synthase got to where it is now could have been from two functionally independent subunits combining, giving itself a new function. This change as we know would need have happened fair early in the history of evolution, as ATP synthase is practically everywhere and is such an essential part of life. V-ATP synthase is something similar to our ATP synthase, yet it does the complete oppositebreaking down ATP to generate a proton gradient. There are also similarities between ATP synthase and motor proteins that are used to drive flagella, where both use proton gradients to drive the protein and have alpha helixes that rotate in relation to nearby stationary proteins.

Symmetry in Chemistry Esther Keyworth

In maths, symmetry is defined such that an object is symmetrical if you can apply a symmetry operation and the object remains unchanged. Technically everything is symmetrical because you can apply the identity operation (which is where you do nothing to the object) and it therefore remains unchanged but obviously some things are ‘more’ symmetrical than others. You’ll have come across different types of symmetry before like rotations, reflections and translations but although there is quite a lot more to it than that, all of those concepts are still the same. Group theory is the area of maths that can be used to explain and

explore symmetry from a more mathematical angle rather than just looking at it geometrically. The mathematical definition of a group (G,*) is that G is a non-empty set with an associative closed binary operation and an identity element.

Associative means if you wrote it as an equation you could put brackets anywhere and the outcome would be the same. The fact it is closed means every element has an inverse and its inverse is also a member of G. A simple example of this is the set of integers under the operation of addition. All the symmetry operations for a given object form a group. There are two types of groups used to describe symmetries: point groups and space groups. Space groups are used for patterns that extend throughout space whilst point groups are used for objects where at least one point of the object remains unmoved when a symmetry operation is applied to it. Crystalline lattices like metals, diamond, NaCl and any other giant lattice structure would have space groups whilst all simple molecules have point groups. For regular packing in giant structures in three dimensions, unit cells are the base object that is repeated. A unit cell is defined as the smallest possible repeatable unit. Crystalline lattices are made up of hundreds and thousands of unit cells and the symmetries of the unit cells effect the properties of the whole structure. There are 14 different types of lattices called the Bravais lattices after August Bravais from 1850. These are made by changing the ratios of a, b, c and alpha, beta, gamma (the three side lengths and angles surrounding one vertex respectively). There are 230 possible arrangements for a three dimensional periodic, space filling design. Within these lattices there are layers of atoms which can slide over each other; these are called slip planes which are defined by the shape of the unit cell. The face centred cubic or cubic close packed structure has eight slip planes hence metals like silver, copper and iron are more malleable whilst hexagonal packed metals like cobalt, magnesium and zinc are more brittle because they only have 1 slip plane. This perfectly illustrates how the fundamental symmetries of a structure determine its physical properties. Some other examples of Bravais lattices which you will have heard of are anhydrous copper sulfate, which

is orthorhombic, whilst hydrated copper sulfate is triclinic and sodium chloride is a face centred cubic. The shapes of these substances’ unit cells translates into the shape of the larger crystals. I could go on at great lengths about symmetry, lattices and packing but there are too many other examples to mention here.

Image showing hydrated copper (II) sulfate crystals

defects to a generation of children. Despite these dangerous qualities it is still used today as treatment for leprosy and some types of cancer but is kept far away from anyone who may even potentially have a baby. It is incredible how such a small change in structure has such huge implications.

Image showing sodium chloride crystals

Just as symmetry gives rise to interesting phenomenon, so does the lack of symmetry. Asymmetrical molecules are described as chiral. A chiral centre is a carbon atom bonded to four different groups meaning there is no plane of symmetry. The mirror image is non superimposable (unlike symmetrical objects) like your hands which is where the name comes from. “Chiro” means “hand” in Greek and chirality is a handedness of a molecule. The mirror images are called enantiomers and although they have many similar properties, they also exhibit different properties; one of these being how they rotate the plane of plane polarised light: one enantiomer to the right, the other to the left. For this reason, they are known as optical isomers. This is where the principle of the naming came from but being chemists there are at least 3 different naming systems; some of these are + and -, L and D, S and R. The naming is based upon the handedness of the molecule, the left being S or L, the right being D or R. S stands for the word “sinister”, the Latin word for left and R for rectus from the Latin word straight or right. There are many examples of this phenomenon but probably the most famous is thalidomide (pictured below). It was first produced in Germany in 1957 and then distributed to pregnant women in the late 50s/ early 60s to quell the effects of morning sickness. Although the R enantiomer was successful, the S enantiomer was teratogenic and caused severe birth

A few other examples of this include alpha and beta glucose (which you may have learnt about at A level biology) but glucose in its ring form has 5 chiral centres so there are actually 10 different enantiomers. Ibuprofen (pictured below) is another example with 1 chiral centre (on the second carbon from the right). The S enantiomer is the pain killer and the R enantiomer has no known negative side effects, so it is produced as a racemate where the S and R enantiomers are in equal quantity because it is cheaper and easier not to separate them or create them individually.

Although very important in both physics and chemistry this is probably more important in biology. All the most common amino acids (except for glycine) have at least one chiral centre but the body only deals with the L enantiomers thus showing just how important symmetry and a lack of symmetry are to us in so many ways. These ideas are key not only to science but to life in general.

Haemolytic Disease of the Newborn Louie Steel

This disease refers to when the mother launches an immune attack against her unborn foetus’s red blood cells due to blood type disparity. Haemolytic disease of the newborn is caused by a variety of different foreign antigens which may be found on a foetus’s erythrocytes; including antigens categorised within the Rhesus blood group (my focus) and ABO blood group. RHE SUS STAT U S AND P R OT E I NS

The Rhesus blood group is characterised by surface rhesus proteins found on erythrocytes. There are 45 different types of rhesus proteins, and their main roles are to maintain the integrity of erythrocyte membranes and also to act as ammonia transporters. When considering the blood types of mother and baby, the protein denoted as Rh D is the most

important to take into account. Rh D proteins differ to other proteins found within the Rhesus classification by 32-35 amino acids. This is in comparison to other proteins, which differ by only a few amino acids. Therefore, the D antigen is capable of triggering a much deadlier immune response from the mother, and so is the defining factor in whether haemolytic disease of the newborn will occur.

If the mother is Rh D negative, and the foetus is Rh D positive, the mother can launch a large immune response against these foreign erythrocyte proteins, causing haemolytic disease. SE N SI T I SAT I O N E V E NTS

This refers to any event in which the blood of the mother and foetus mix. Most are caused by foeto-maternal haemorrhages, where the placenta is ruptured. Other causes include an ectopic pregnancy, where the embryo attaches outside the uterus, or placental abruption, where the placenta separates early from the uterus. Once the blood of the foetus and mother mix, and the mother’s immune system encounters the foetus’s foreign Rh D antigens, an immune response is launched by the mother. Mother launches an immune response and produces anti-d IgG antibodies. The mother’s immune response to the foreign D-antigen is to form anti-D antibodies against them. There are multiple steps to this process:

1. B -CE LLS B IND TO ANT IG E N

B-cells (immune cells) have membrane-bound antibodies on the surface, as well as B-cell receptor proteins. The foreign D-antigen from the foetus circulates throughout the lymphatic system and forms an antibody-antigen complex with the B-cell. The B-cells antibodies have a complimentary shape to the Rh D antigen. 2. ANT IG E N PRE S E NT E D O N MH C II MO LE CU LE

The B-cell absorbs the antigen through a process called B-cell receptor endocytosis (the process of bringing substances into a cell). Once the antigen is in the B-cell, it is broken down to form antigen fragments, which are shorter polypeptide chains of the Rh D antigen. One of these fragments is presented on the MHC class 2 molecule, a protein that presents antigens to other immune cells. 3. NAÏVE T H CE LLS B IND TO MH C II AND ARE ACT IVAT E D

Naïve t-helper cells (another type of immune cell found in the lymph node) dock to the MHC class 2 with the antigen fragment with a CD4 t-cell receptor protein by forming a protein complex. The chemical and physical changes caused by this T-cell MHC complex initiate a cascade that results in surface proteins called interleukin 4 receptors being presented on the T-cell surface. Other immune cells (other T-cells, mast cells and basophils) secrete interleukin 4, which binds to the receptors found on the naïve T-cell surface. This is an example of autocrine signalling. These changes accumulate and result in T-cell activation and differentiation.

4 . T- HE L P E R C E L L S NOW H E L P AC T IVAT E B- C E L L S TO B E CO ME P L AS MA C E L L S

After T-cell activation, the protein CD40 ligand is presented on the T-cell, which forms a complex with another protein on the B-cell surface, CD-40. Furthermore, the activated T-cells secrete other interleukin proteins which can bind to interleukin receptors on the B-cell. These two factors help stimulate chemical and physical changes within the B-cell to cause it to differentiate into a plasma cell. These changes may be caused by conformational changes in shape caused by the formation of protein complexes, stimulating a chemical cascade. The cytosol (liquid medium found within cells) content increases, and the nucleus gets smaller. There is now more area for protein synthesis to make antibodies, and increased protein factors production boosts the process of cellular transcription. B-cells can also differentiate into memory B-cells, which secrete antibodies in the case of exposure to the antigen in the future. 5. A N T I BO D IE S S E C R E T E D A R E S P E CIFIC TO T HE F OET U S D ANT I GE N

The plasma cell now secretes antibodies against the Rh D antigen. The B-cell was specific to the Rh D antigen encountered in the lymph, since the antibodies on the B-cell surface had a specific complimentary shape to form a complex with the antigen. Therefore, only certain specific T-helper cells were able to form a complex with the specific B-cell. The T-cell helps stimulate the correct plasma cell required to secrete the antibodies that work against the Rh D antigen.

6. H AE MO LYT IC DIS E AS E O F T H E NE WB O RN O CCU RS DU RING T H E S E CO ND PRE G NANCY

Anti-D antibodies formed are now able to move across the placenta by endocytosis and subsequent exocytosis. The foetus is generally not harmed in the first pregnancy when the antibodies are formed. One reason for this is because the antibodies cannot be secreted at a fast-enough rate to cause much damage to the first foetus and its red blood cells. However, by the time the mother is carrying a second foetus, possibly many years later, the memory cells formed secrete antibodies at a faster rate, with greater quantity. These cross the placenta and attack the red blood cells of the foetus. This causes severe haemolytic anaemia in the unborn, resulting in a variety of deadly diseases. This includes hydrops fetalis and pathological jaundice.

Epigenetics Maddie Alcock

Every eukaryotic cell in the human body contains a complete copy of the human genome. This contains about 3 billion base pairs, and within this around 30,000 genes as well as regions which do not code for a protein at all. Of these genes only about 1/10th are expressed (turned on and read to synthesise a protein) which allows the variety of cell functions within the human body. Epigenetic modifications help to regulate which genes are expressed and which are repressed and so switched on/off.

T HE E P I G EN O ME

While genome describes the complete set of genetic material present in an organism, epigenome literally means “on top of the genome” and so describes all of the chemical changes to DNA or histones which alter gene function but leave the base sequence itself unchanged. The two main types of epigenetic modification are: (i) DNA methylation (ii) Histone acetylation D N A M E T HYLAT I O N

Hypermethylation (lots of -CH3 groups) can prevent the binding of transcription factors, so this process of synthesising the protein cannot occur – the gene is switched off. The gene MeCP2 codes for methyl CpG binding protein 2 (MeCP2) which helps to regulate gene expression by modifying chromatin. This protein only binds to methylated DNA and attracts other proteins to help switch off the gene (deacetylates histones – see below). This gives rise to a more condensed chromatin structure (“heterochromatin”) to prevent the transcription machinery from binding to the promoter so transcription cannot occur. H ISTO NE ACE T YLAT IO N

DNA methyltransferases (DNMTs) add a -CH3 group to cytosine and adenine bases. A large proportion of the time methyl groups are added to carbon-5 on the cytosine bases in CpG islands, which are abundant in the promoter region of DNA. The effect this has is that the more methylation there is in the promoter, the less transcription, as transcription proteins cannot bind therefore the gene is repressed. In transcription, transcription factors bind to the promoter sequence to allow RNA polymerase to join and use the template strand to synthesise complementary mRNA. This mRNA then leaves the nucleus and enters the cytoplasm where it goes to a ribosome for translation. tRNA carries specific amino acids and these join by peptide bonds to form a polypeptide which forms a protein.

Histone acetyltransferases (HATs) add -CH3CO groups to the positively charged histones. Phosphate groups give DNA a negative charge, allowing them to associate with the positively charged histone proteins. Lysine in the histone tails becomes acetyllysine which makes the histones less positive. The negatively charged DNA is now less attracted to the histones due to the less positive histones. This results in a less condensed chromatin structure (“euchromatin”) which makes the DNA physically easier for RNA polymerase to read. Transcription factors can bind easily so there is more transcription – the gene is expressed. The more acetylation, the more transcription.

C A N C E R A N D E P I GE NE T I C S

Cancer results when uncontrolled cell division forms a tumour that can invade surrounding tissue (malignant). The two genes which control cell division are: (i) Tumour-suppressor genes (ii) Proto-oncogenes If there is unfixable DNA damage in a cell, it should induce apoptosis to prevent potential development of cancer. If there is a mutation or incorrect expression of a gene which regulates cell division, this could lead to cancer. This can happen when a tumour suppressor gene is inactivated, or when a proto-oncogene is expressed unnecessarily. Tumour-suppressor genes produce proteins which stop cell division or induce apoptosis. These are what slow down cell division, therefore if they become inactivated by hypermethylation in the promoter sequence, transcription factors cannot bind so transcription does not take place and the proteins will not be produced. This will mean that cell division is no longer slowed down and can become out of control, potentially causing cancer. Conversely, proto-oncogenes produce proteins which facilitate cell division when it is needed. These allow cell division to happen and speed up. However, if they become hypomethylated and so develop into an oncogene they will be constantly turned on even when cell division is unnecessary. This is because there will be an increased level of transcription of this gene due to the low levels of methylation upstream of the coding sequence. This can lead to uncontrollable cell division and tumour formation.

WADDINGTO N’S E PIG E NE T IC LANDS CA P E

This can be used to help visualise the development of a cell as it differentiates and specialises for its function, as different epigenetic marks establish different cell fates by regulating the expression of different genes. Differentiation is represented by the ball rolling down and going into different troughs at the bottom of the hill. Each trough illustrates how a completely specialised cell will keep its specific function because it cannot differentiate further. The ball’s position at the top of the hill shows that the zygote can differentiate into any type of cell (totipotent). This then gives rise to pluripotent stem cells which can differentiate into many cell types (excluding the placenta). John Gurdon’s experiment discovered that mature frog nuclei can be removed and injected into an egg cell, which is able to develop into a tadpole. This reprogrammed cell is called an induced pluripotent stem cell, and this enables genes which had formerly been switched off to be transcribed so the cell can differentiate again. As it differentiates again, the cell’s epigenome will adapt, repressing genes which do not need to be turned on for that cell’s specific function (and similarly increasing the expression of the genes which code for something which the cell requires).

Inflation & the multiverse Ben Elliot

Do we live in a multiverse? Is there a parallel universe out there with another you living a life without a pandemic? These seem to be the questions of science fiction, however it was not until I did some research into the theory of Inflation – the leading scientific theory used in conjunction with the big bang to describe how our universe started – that I realised a multiverse might be more fact than fiction.

W HAT I S T HE T H E O RY O F I NF L AT I O N ?

E VIDE NCE FO R INFLAT IO N

The theory of inflation has five stages:

With any scientific theory we always need to consider what evidence there is to support it. While there exists no evidence with which could “prove” inflation, we can see what inflation would predict in the world around us today. There are four main aspects of this:

• False vacuum • Negative pressure • Expansion of the universe • Quantum fluctuations • Matter released These five stages, in brief, describe how a false vacuum drives a negative pressure which in turn drives the rapid expansion of the universe through something known as the Freidmann equations with quantum fluctuations bringing this rapid expansion to an end and causer fundamental particles and matter to be released. The Freidmann equations describe how a universe evolves and can be derived from special relativity:

These are the equations which Einstein didn’t believe could exist and were a part of what is described as his “biggest blunder”. W HAT HA P P E NS TO T H E U N I V E R S E D URI N G I N F L AT I O N ?

What actually happens to the universe during inflation in terms of numbers? The universe grows from a patch the size of a trillionth the width of an electron, to the size of a marble in seconds. To put that into perspective that’s like something the width of a human hair growing to be the size of the observable universe in a time many trillion, trillion times shorter than the blink of an eye.

• large scale uniformities in cosmic background radiation • small scale non-uniformities in cosmic background radiation • the monopole problem • the flatness problem LARG E S CALE U NIFO RMIT IE S

We know cosmic background radiation (light released when the uniform was very young) is very uniform and comes from no one direction. In fact, it is uniform to 1 part in 100,000. A mechanism needed to establish this in the standard model of the big bang would mean that energy and information would have to travel at 100 times the speed of light. This is physically not possible by special relativity. Inflation fixes this problem as the universe can start much smaller meaning light has to travel much less quickly and much less far – thus giving making the theory of inflation superior to the standard big bang. S MALL S CALE NO N-U NIFO RMIT IE S

As much as cosmic background radiation is uniform, it does still have inconsistencies. Scientists used satellites to measure these smallscale inconsistencies, and when overlaid onto the theoretical values calculated from the theory of inflation [graph below] you can see it maps out these points incredibly precisely. As you can see from this graph, inflation predicts the observations from satellites much better than any other theory, which leads us to believe that inflation might be true.

WH AT WAS T H E U NIVE RS E B E FO RE INFLAT IO N?

T HE M ULT I V E R S E

One of the consequences in inflation is the existence of a multiverse, or a very large number of other universes. This is the case through inflation because of something called “eternal inflation”. To describe this: We know inflation must stop at some point, so it must have a rate at which it stops with. However, the patch of space inflating also expands rapidly, meaning there is more of it. We know from calculations and real-world data that the growth rate is much greater than the decay rate. This means that for every second that passes there is more area rapidly expanding than there was last second, even though some of the inflation in one area has stopped. We see these local areas which have decayed as a “local big bang” with its own “pocket universe” which our big bang and the universe we are living in now are both one of. It has been calculated that there are other universes out there. Now this is a number so large that if you tried to remember every digit of it at once, a black hole would form in your head and engulf you.

In truth – we have no idea! However, there are some suggestions that have been made by cosmologists. One of these is the idea that speaking of a ‘before’ the universe is impossible as time only came about as part of space-time when the universe came into existence. How inflation started in a place when time and space don’t exist is attributed to some weird quantum mechanical effect where the universe tunnelled out of nothing. This theory has been suggested by Stephen Hawking amongst others. A different theory is that given enough time somewhere will eventually have to have the right conditions for inflation to happen even with nothing before. FINAL WO RDS

So, do we live in a multiverse? The leading scientific theories suggest we do. Is there a parallel universe out there with another you living a life without a pandemic? Unfortunately, we believe not, even with that many other universes out there. The theory of inflation is the cornerstone to modern cosmology, describing how our universe started and also how it is evolving to this day.

Deep Brain Stimulation Will Kwan

PA RK I N SO N ’ S DI S E AS E ( P D)

Parkinson’s is a complex neurodegenerative disorder, the aetiology of which is not clearly discovered. This occurs when dopaminergic neurons in the substantia nigra are lost, from which the lack of dopamine leads to primary characteristics such as bradykinesia, rigidity, postural abnormality and

resting tremor. By the time a person experiences these, they have already lost approximately 50 - 80% of their dopaminergic neurons. Patients also experience non-motor symptoms, including diminished facial expressions, fatigue, dystonia, depression, anxiety and dementia. NE U RO NAL DE AT H PAT H WAYS

Although the cause of this dopaminergic cell death is largely unknown, there are multiple studied pathways. In those locations, an intracellular protein, alpha-synuclein (α-syn) is found in high concentration, where they misfold and clump together, forming oligomers, fibrils and ultimately Lewy bodies. More specifically, α-syn misfolding can be either spontaneous or induced, where one misfolding could induce another, also known as permissive templating. The accumulation of these misfolded proteins in forms of oligomers and fibrils give rise to endoplasmic reticulum stress, consequently activating unfolded protein

response where cell death mechanisms are induced. The aggregation of α-syn also leads to slowing down and even blocking the release of dopamine in presynaptic neurones. Dopamine can then build up and oxidise into dopamine o-quinone, that undergoes further auto-oxidation by reducing oxygen to superoxide radicals (O.2). The build-up of reaction oxygen species (ROS) leads to MD, causing lipid peroxidation to occur. This chain reaction causes serious damage to the mitochondria and leads to osmotic lysis. MD in neurones then creates even more ROS that leads to damage to proteasomal and lysosomal functions and further aggregation of α-syn. ROS also modify proteins’ tertiary structures, inducing more dysfunctional proteins. D EE P BRA I N ST I MU L AT I O N ( DB S )

DBS is a functional neurosurgical technique that has revolutionised treatment for movement disorders, specifically PD. This surgical technique involved the implantation of a pair of electrodes into various regions depending on symptoms of patients, and a neurostimulator in the clavicle subcutaneously. This neurostimulator has a titanium casing with a region of biocompatible polymer that allows the wires to be plugged in, while electrodes are made out of platinum-iridium alloy. The programmable handheld device controls the stimulation parameters, where clinicians have full control of.

DBS is described as a stereotactic surgery, which is minimally invasive and usually performed under local anaesthesia and so the patient would be awake. A stereotactic frame is placed and locked onto the patient’s head, which is used to mark the drill location and hold the patient in place. MRI or CT scans are done after the frame placement to generate a 3D coordinate of the target, allowing surgeons to plan the trajectory of electrodes. Hair is then shaven and burr holes are drilled to place the microelectrodes inside the brain, which stimulate and pick up real-time signals of brain cells firing, allowing surgeons to identify the targets by electrophysiological signature and mapping. Patients are asked to perform specific tasks to see if symptoms are reduced. Those microelectrodes are replaced with a different set of permanent electrodes after confirming successful insertion and wires are left under the scalp for later connection.

ME CH ANIS MS U NDE RLYING DB S – IO N RE DIST RIB U T IO N

The mechanisms that underlie DBS are not fully understood, but it is believed to modulate the brain at an ionic, cellular and network level. The redistribution of ions in the extracellular space in the brain is observed as electrodes are polarised to become cathodes when stimulated, causing them to attract positive ions. This induces a potential (voltage) difference across the cell membrane, which is picked up by NaV channels that open

and create an action potential in the neurone. This action potential then propagates down the axon just like a normal action potential would, exciting or inhibiting the following neurones depending on the frequency and types of neurone stimulated. NaV channels are transmembrane protein complexes that consist of voltage sensing domains and pore forming domains. The voltage sensors are composed of positively charged amino acid such as arginine. The -70mV resting potential creates an electric field that attracts the positively charged voltage sensor downwards, restricting the pore forming domain to be shut. During depolarisation, the outside of the membrane becomes less positive and the inside becomes less negative. This causes the voltage sensors to relax upwards, opening the voltage gate. A partial depolarisation ranging from -30 to -40mV is enough to relax the voltage sensors. Sodium then travels down its electrochemical gradient into the cell, causing further depolarisation down the axon for more opening of voltage-gated channels. This opening will only occur for roughly 1ms, then the inactivation gate will swing across and block the voltage gate, restricting the flow of sodium ions. This safety mechanism prevents prolonged membrane depolarisation. To reset this mechanism, KV channels are responsible for repolarisation as they release potassium ions out of the cell, allowing channels to prepare for the next action potential. M EC HA N I SM S U NDE R LY I N G DB S – M I C ROEN V I R O N ME N T C H ANGE S

Stimulation in the extracellular area causes a calcium wave, which is a sudden movement of large amounts of calcium ions, which is believed to activate astrocytes. Astrocytes are a type of non-neuronal glial cell that exists in the central nervous system. Their functions include extending connections between neurones and blood supply, as well as providing structural support and maintaining ion and nutrient concentration outside neurones. Activation leads to arteriole dilation and increases regional blood flow in the brain, bringing nutrients

and oxygen supply in a higher concentration to connected neuronal pathways. Astrocytic activation results in release of various gliotransmitters, mainly glutamate and ATP. ATP is released under the same conditions and converted to adenosine by ecto-ATPase in the extracellular space. Adenosine is found to have effects on decreasing tremor levels by promoting inhibition, which has also shown to regulate homeostatic functions of sleep and calmness. Astrocytes also form tripartite synapses with neurones, where the released glutamate binds to receptors on the presynaptic neuron, inducing an influx of calcium ions which broadens the action potential. This increases neuronal excitability and the probability of neurotransmitters being released from presynaptic terminals. Continuous stimulation of receptors results in modulating synaptic plasticity, where synapses strengthen or weaken based on stimulating patterns. Glutamate release led to an increase of efficiency and number of receptors on postsynaptic neurones. Moreover, scaffolding proteins are generated to regulate and enhance signalling pathways, as well as increasing the number of vesicles carrying neurotransmitters and number of dendritic spines. This is also known as long-term potentiation. Evidence also shows that neurones are increasingly protected. In fact, the actual insertion of DBS electrodes has shown astrocytic activation, where a mild reactive gliosis is observed. This is the proliferation and hypertrophy of cells; glial cells both increase in number and size, and regional neuroinflammation can be seen. Glutamate, specifically, plays an important role in allowing more calcium ions to flow into presynaptic terminals as they bind to receptors. Calcium ions are essential for vesicle docking and hence releasing neurotransmitters via exocytosis. There are SNARE (Soluble NSF Attachment REceptor) proteins present in the membrane of vesicles, as well as the presynaptic membrane. When calcium ions are present to bind on synaptotagmin, these SNARE proteins bind together and form a SNARE

complex and fuse the vesicle with the phospholipid bilayer in the presynaptic membrane, releasing neurotransmitter across the synaptic cleft. Hence, enhancing the number of calcium ions increases the probability of passing down neuronal signals. D BS P ROBL E MS A N D L I MI TAT I O N S

DBS problems can be largely classified into operation, hardware and stimulation. Operating complications include intracranial haemorrhage and misplacement of electrodes. However, risks are relatively low due to increasing accuracy and precision in the planning stage of radio imaging. Hardware related problems such as electrode malfunction, migration, infection and erosion are rarely observed, but more often in patients suffer

from subsequent head injuries. Conventional battery replacement occurs every 2-5 years and can be problematic for young adults. Luckily, modern designs incorporated a rechargeable feature that can be done via transdermal recharge, quite similar to wireless charging for our mobile devices. Stimulation of non-target areas could lead to psychiatric experiences such as shortterm depression, transient confusion and mood and personality changes. Ethical considerations are therefore essential; although DBS is highly effective in relieving PD symptoms, its associated surgical risks sometimes outweigh the benefits for many elderly PD patients. As DBS might also have significant impacts on a patient’s personality and autonomy, its effects lie beyond an individual’s control and free will and therefore unavailable in some regions. POT E NT IAL U S E S

DBS is highly resource intensive and open to research and studies for many different disorders. Mental health issues have been increasing in the past decades, which many of those are treatment resistant. This table shows disorders that are under investigation, including where and why they are stimulated.

Disorders

Considered targets

Why this location

Stages of study

Depression (MDD)

Subgenual cingulate cortex

Emotional regulation

Phase 3

Obsessive-compulsive disorder

Subthalamic nucleus, ventral striatum

Decision-making, reward stimuli

Phase2/3

Tourette syndrome

Globus pallidus internus

Output of basal ganglia (motor control)

Phase 1/2

Schizophrenia

Temporal and prefrontal cortex

Episodic memory, decision-making

Preclinical

Addiction

Nucleus accumbens

Centre of reward circuit

Phase 1/2

Lower Sixth Talks p53 – Guardian of the Genome Jason Cho Discovered by David Lane in 1992, the p53 protein is crucial in the battle against tumour formation and has been the main subject for cancer research, as over 50% of human cancer cells contains mutations in the p53 gene. I was fascinated by the sheer number of molecular pathways that it can control, and I believe the biochemistry that underlies its function is key to developing a new and better cancer drug in the future.

DMARDs and Whether They Increase the Risk of Cancer Michael Wong Rheumatoid arthritis is one of most common types of arthritis and around 1% of people are diagnosed with it globally. While DMARDs are the major treatments for rheumatoid arthritis, several studies suggest that they may increase the risk of cancer. I chose to speak on this topic because I had first read about rheumatoid arthritis and DMARDs from an article and was really fascinated by it.

Thermodynamics and the Nature of Entropy Gleb Iagelskii

I decided to research entropy and the laws of thermodynamics for my Moncrieff-Jones talk because of how important yet often misunderstood these concepts are. Ever since I was introduced to the second law of thermodynamics, I have been genuinely interested in the field and the reasons behind the laws and the way they function. I find this topic truly thrilling and hope that the experience of presenting in the Moncrieff-Jones Society will help me as I aspire to study chemistry at university.

Situ Inversus and Ciliary Dyskinesia Rainis Cheng

The cilium is one of the earliest observed organelles, but only in recent decades did we discover their abilities in chemoreception and mechanoreception. Due to their sensitivity and motile functions, cilia play a large role in immunological defence, fertility, and even organ positioning. Of these tasks, how cilia affect organ positioning interested me the most. How can the defects of such small cellular structures be able to shift the entire structures in the thoracoabdominal cavity?

Prions Brandon Kim Having encountered the phrase “protein that causes incurable disease”, I was left with many questions. What makes it incurable? How does a protein cause a disease? What mechanism is behind it? My questions began to surmount, and I started researching vigorously. As I read further, I found out that there was a high level of uncertainty in this area, due to its infrequent occurrence, and its unique properties. However, it could only make me feel even more fascinated, as it felt like exploring a new world. I then wanted to present this idea of “uncertainty” with my peers as we are so used to areas of science that are supported strongly.

p53

Guardian of the Genome

Jason Cho

p53 is a tumour suppressor protein that regulates the cell cycle. First identified by Lane, Crawford, Linzer and Levine in 1979, it is a sequence-specific transcriptional regulator that suppresses tumour growth by initiating cell cycle arrest, senescence or apoptosis at various cell cycle checkpoints under cellular stress. p53 responses are brought about by a vast network of genes. The action of p53 allows a non-cancerous mitotic cell division and protects the integrity of the genome and was thus dubbed as “the guardian of the genome” and “the cellular gatekeeper”. Although extensively researched, much of the cellular mechanisms and pathways of p53 remain to be discovered and understood.

T HE C E L L CYC L E

Most cells in the human body remain in the G1 stage. Some of them can respond to extrinsic stimuli such as mitogens, also known as growth factors, which stimulate mitosis. Growth factors activate a variety of transcription factors or enzymes, which upregulate the transcription and production of proteins called cyclins. Cyclins bind with their respective cyclin-dependent kinases (cdk) and activate them. This allows them to phosphorylate other substrates which activates transcription factors that will drive the progression of the cell cycle. Different types of cyclins and cdks are needed in different stages of the cell cycle. The mechanism that governs the transition between the G1 phase and the S phase, through the G1/S checkpoint, is mediated by cyclin E/cdk2 complex. The cyclin E/cdk2 complex hyperphosphorylates the retinoblastoma protein (pRb), inactivating its function of inhibiting the transcription factor E2F. E2F is activated and able to promote the transcription of genes that are required for proliferation, such as other cyclins. Under the influence of DNA damage stress signals, p53 will activate a specific pathway that results in cell cycle arrest, until the DNA damage is fixed. REG UL AT I O N BY MDM2

The level of p53 is mainly regulated by the oncoprotein MDM2 which forms an autoregulatory feedback loop with p53.

p53 itself is a transcription factor for the MDM2 gene, it upregulates the MDM2 transcription by binding to its promoter. MDM2 binds to the N-terminal transactivation site of p53, thus physically blocking it from interacting with other transcription factors, inactivating its ability to transactivate other genes. MDM2 is a E3 ubiquitin ligase, which ubiquitinates p53 at several lysine residues. It induces monoubiquitination and nuclear export of p53 at low levels of MDM2, while high levels promote polyubiquitination and degradation by proteasomes. G 1 ARRE ST PAT H WAY STAB ILISAT IO N O F P53

When exposed to ionising radiation, the DNA may suffer damage such as double-stranded breaks, where both strand of the double helix strand are broken. In the presence of a double-stranded break, ataxia telangiectasia mutated kinase (ATM) is activated. Upon activation, ATM phosphorylates the Ser-15 residue of p53. Furthermore, ATM phosphorylates checkpoint kinase 2 (CHK-2) and activates it, further amplifying the signal, which in turn phosphorylates p53 at the Ser-20 residue, which lies within the

segment which p53 interacts with MDM2. These post-translational modifications of the transactivation domain prevent MDM2 from binding to p53 and promotes the dissociation of the two, inhibiting p53 translocation from the nucleus to the cytoplasm and its ubiquitin-mediated proteasome degradation. This results in the activation and accumulation of p53.

After chromatin modification, p53 transactivation domains (TAD) recruit general transcription factors. The TFIID complex is one of the transcription factors, containing the TATA-box binding protein (TBP) and other TBP-associated factors (TAFs). p53 also recruits TFIIH to the promoter to stimulate transcriptional initiation. ACT IO N O F P2 1

T RA N SAC T I VAT I O N BY P 53

Once stabilised and activated, p53 oligomerises into a tetramer and binds to the promoter region which contains the p53 response element of the CDKN1A gene, promoting the transcription of cyclindependent kinase inhibitor 1, also known as p21.

The p21 protein produced is an inhibitor of all cell cycle cyclin-dependent kinases. It will act as the inhibitor of cdk2 in this context. p21 binds to cdk2, which disrupts the binding of cyclin E to cdk2, preventing cyclin E/cdk2 complex form hyperphosphorylating pRb. pRb thus remains active and does not release E2F, inhibiting the its ability to promote the transcription of cyclins needed in the S phase of the cell cycle. Thus, stopping the cell from entering the S phase, resulting in G1 arrest.

DNA binding by p53 tetramer

p53 will interact with chromatin modifiers to open the chromatin, most of which are histone acetyltransferase (HAT) such as p300. These HATs are recruited to acetylate histones in close proximity of p53REs. The acetyl group (-C2H3O) has a negative charge while histones have a positive charge. Acetylation makes a histone less positive, causing attraction towards the DNA to decrease, thus having a less condensed chromatin structure making DNA more accessible to other transcription factors. p300 is also found to acetylate p53 itself, further stabilising p53 and enhancing its transcription activity.

FU NCT IO N O F G 1 ARRE ST

By not allowing the cell to enter into S phase, the p53-mediated cell cycle arrest buys time for DNA repair mechanisms to repair the damage done before DNA is replicated, many of which are also regulated by p53 transactivation functions, cementing the role of p53 tumour suppressor as a master regulator of many cellular processes.

DMARDs and Whether They Increase the Risk of Cancer Michael Wong

Disease-modifying anti-rheumatic drugs (DMARDS) are a class of drugs indicated for the treatment of mainly rheumatoid arthritis and many other autoimmune disorders.

W HAT I S RHE U MATO I D A R T H R I T I S?

Rheumatoid arthritis is a musculoskeletal illness (inflammation of the joint) and is an autoimmune process, which attacks the synovial tissue and other connective tissues. It is also a systemic inflammatory disorder with progressive and symmetric joint destruction. However, the aetiology of rheumatoid arthritis still remains unclear, but it depends on a high-risk genetic background and an environmental trigger. For example, a person with a certain version of a gene for an immune protein (HLA-DR1 and HLA-DR4) might develop rheumatoid arthritis after getting exposed to something in the environment like cigarette smoke which causes modifications to

our antigens and citrullination in proteins (e.g. collagen or vimentin). Rheumatoid arthritis occurs when immune cells recognise them as non-self. Antigens then get picked up by antigen-presenting cells and are

carried to lymph nodes, which activates CD4+ T-helper cells. They stimulate B-cells which differentiate into plasma cells and produce antibodies. T-helper cells and antibodies enter the blood circulation and reach the joints. T-helper cells secrete cytokines (e.g. interferon-γ and interleukin-17) and recruit more inflammatory cells like macrophages, which also produce inflammatory cytokines (e.g. TNF-α, interleukin-1, and interleukin-6). This results in a thick swollen synovial membrane (pannus) which causes damage to cartilage and other soft tissues and erodes bones. Activated synovial cells then secrete protease which break down the proteins in the articulation cartilage. Without the cartilage, the underlying bones are exposed and directly rub against each other. Moreover, inflammatory cytokines increase RANKL (a protein on the surface of T-cells). RANKL allows T-cells to bind to RANK (protein on the surface of osteoclasts) to get them start breaking down bones. On the other hand, antibodies such as rheumatoid factor (an IgM antibody that targets altered IgG antibodies) and anti-cyclic citrullination peptide antibody (CCP) , an antibody that targets citrullination proteins, enter the joint space. When antibodies bind to their targets, immune complexes

are formed and accumulated in the synovial fluid, which promotes joint inflammation and injury. For chronic inflammation, it may develop angiogenesis (formation of new blood vessels). More inflammatory cells will arrive as a result, and more joints on both sides of the body will become more inflamed and gradually destroyed. Inflammatory cytokines may reach and attack other organs through the bloodstream. Commonly affected joints are on the hands or feet, then shoulders, elbows, knees, and ankles. To diagnose rheumatoid arthritis, we can use blood tests or imaging. For the blood test, we can test the presence of rheumatoid factor and anti-citrullinated antibody. For imaging (X-ray), low bone density, bone erosions, swelling of soft tissue, and narrowing of joint space can be easily spotted. WH AT ARE DMARDS AND H OW DO T H E Y WO RK ?

DMARDs are long-term medications for rheumatoid arthritis. The purposes of DMARDs are to decrease inflammatory disease activity to a minimum, minimise joint damage and enhance physical function and quality of life. There are two categories of DMARDs: biological and synthetic small molecules. Some common biological DMARDs are TNF-α inhibitor and T-cell costimulatory agents. TNF-α (Tumour Necrosis Factor) is one of the inflammatory cytokines produced by macrophages or monocytes. TNF-α inhibitors bind to TNF-α in circulation and synovium, preventing it from interacting with the surface TNF-α receptor. This decreases TNF-α activity and minimizing downstream proinflammatory effects. For T-cell costimulatory agents, they interfere with the interaction between antigen-presenting cells and T-cells. For synthetic DMARDs, the most common ones are methotrexate, hydroxychloroquine and sulfasalazine. Methotrexate and hydroxychloroquine are immune system suppressants and suppress inflammation, while sulfasalazine reduces inflammation, pain, and swelling in joints.

For methotrexate, a double-blind, placebo-controlled, randomised clinical trial with 6158 people was led by David H. Solomon to investigate whether methotrexate increases the risk of skin cancer. It was then found out that around 30% of patients receiving low-dose methotrexate compared to the placebo group had elevations in risks for skin cancer or gastrointestinal, infectious, pulmonary, and haematological adverse events. Most patients diagnosed with rheumatoid arthritis start on synthetic DMARDs, but if the drugs fail to sufficiently control disease activity, then biological DMARDs would be used. D O D M A RDS I N C R E AS E T H E RI SK OF C A N C E R ?

In recent years, many have questioned whether there is an increased risk of cancer after long-term therapy of autoimmune disorders with DMARDs. Several studies have illustrated rheumatoid arthritis increases the risk of getting some type of cancer like lymphoma and skin cancer, by around 5-10%. There have also been studies showing an increase in the number of patients getting cancer after taking in DMARDs. However, up until now, there is no clear evidence that proves the link between long term DMARDs and an increased risk of cancer. Below are some of the DMARDs that have undergone studies or trials to investigate whether they increase cancer risk:

For TNF-α inhibitor, a study with 25,738 people from Denmark aimed to test the safety of anti-TNF-α therapy in people with a history of cancer and with an immune-mediated disease. It was then found out that the use of anti-TNF-α therapy was not associated with recurrent or new primary cancer development in patients with previous cancer. Timing of anti-TNF-α therapy after an initial cancer diagnosis did not influence recurrent or new primary cancer development. Although several types of research and studies are carried out and some of them show increased cancer risks, uncertainty still remains because of the fact that there may be other factors increasing cancer risk, and even recent studies and trials failed to prove and confirm a strict correlation with increased risk of cancers. In conclusion, more future clinical studies are needed to provide more evidence on the topic and the risk of cancer should not stop patients from taking DMARDs when doctors prescribed them, especially given the benefits these treatments offer.

Thermodynamics and the Nature of Entropy Gleb Iagelskii

Thermodynamics is the science which studies relations between heat and other forms of energy and their effects on matter. According to thermodynamics, entropy increase is what drives processes such as diffusion, chemical reactions and phase transitions but what precisely is entropy and why does it need to increase?

To better understand entropy one first needs to consider the fundamental laws of thermodynamics. F I RST L AW – CO N S E RVAT I O N O F E NE RGY

where pi is the probability of occurence of the quantum state i and Ei is the energy of the quantum state i. Ei can be found by solving the Schrodinger’s equation of the system and pi is given by:

The first law of thermodynamics follows from the general law of conservation of energy and can be mathematically written as: where is the change in internal energy of the system, q is the heat added to the system and w is the work done on the system. Thermodynamic systems are generally considered to be at rest and with no external fields applied which means that they have no kinetic or potential energy as a whole. The only energy of the system which changes is said to be internal energy(U). W HAT I S I N T E R NAL E N E R GY

Internal energy accounts for all the energy of the system which can change in a physical process or a chemical reaction without a change in kinetic or potential energy of the whole system. U incorportes random molecular rotational, translational and vibrational energies which vary with temperature, as well as electronic energy and energy of intermolecular forces which depend more on the nature of the substance itself.

S E CO ND LAW – E NT RO PY STAT E ME NT

Similar to the first law which introduces internal energy, the second law presents a concept of its own – entropy denoted with letter S. Entropy has multiple definitions, but for now it can be thought of as measure of the disorder of the system. The more disordered a system is the more entropy it has. For instance, liquid water is more disordered than ice because H2O molecules in water are not bound to any specific position and are allowed to move randomly. Therefore, water is said to be more disordered then ice. The second law regards entropy’s most important property: “the total entropy of any isolated thermodynamic system tends to increase over time, approaching a maximum value”. Here, “isolated” refers to a system which does not exchange matter or energy with its surroundings – universe, for example, can be treated as an isolated system. By calculating the entropy change of any physical process or chemical reaction one can determine whether it can theoretically occur because for any feasible process:

We shall soon see why the second law works and a multitude of ways of thinking about entropy. Statistical mechanics allows us to write a generalised expression for internal energy:

C L AUSI US E N T R O PY

The original calculations of entropy (sometimes referred to as thermodynamic or Clausius entropy) were derived by Rudolf Clausius in 1856. In fact, Clausius coined the term “entropy” from the Greek “en” and “trope” – “a turning”. It is believed that the origins of the word relate to the fact that any mechanical energy eventually turns into useless heat. Clausius is famous for his entropy change equation:

In this formula is the heat transferred and “reversibly” means that the absolute temperature of the system is only allowed to change infinitesimally over a very long period of time. In practice almost all processes are irreversible but entropy being a state function means that any path which connects two thermodynamic states is going to have the same entropy change as any other path. Certain processes like phase transitions happen at constant T meaning that the equation can be applied as However, if a process starts and ends at different temperatures (e.g. 210 and 220 K) calculus can be used to show that for constant isobaric heat capacity denoted :

Though Clausius knew how to calculate an entropy change he was largely oblivious to what entropy really was, partially due to the controversies around the concept of molecules in his time. EN T ROPY – P R O B AB I L I ST I C AP P R OACH

As one can imagine disorder is generally a subjective concept which is hard to quantify. Classical thermodynamics provides us with ways to calculate a change in S but not with understanding of entropy or ways to calculate it for any system in an equlibrium. To understand what is entropy and the reason why the 2nd law holds one needs to reserve to statistical thermodynamics.

If we consider two inert gases A and B mixing it becomes apparent that the reason state 3 is the equlibrium state is because of the probabilities of different thermodynamic states. Any particle of gas A or gas B has the same chance of being on the left or right side of the box (50%). The probability that all gas A particles will be in the left half and all gas B particles in the right half (state 2) is extremely small. An analogy to the one mole of two gases spontaneously separating into two halves is tossing a coin 6.022 x 1023 times and getting 6.022 x 1023 heads or 6.022 x 1023 tails. The probability of this outcome is non-zero but vanishingly small. A much more likely outcome is getting a similar number of heads and tails which is evident from the binomial distribution. As the number of tosses increases, the probability of significant deviations from ~50% heads diminishes, that is, as the number of molecules increases the chance of violation of the 2nd law decreases.

We can now establish that the system going from the state of low entropy to the state of high entropy is simply the system moving towards a more probable state. This allows us to write entropy as a function of propability of a thermodynamic state: BO LTZ M A N N’S E N T R O PY

Astonishingly, use of the single fact that entropy is an extensive state function allowed Ludwig Boltzmann to find the function in the formula above. To do this, he considered a system composed of two independent, noninteracting parts 1 and 2 (like gases A and B before the partition is removed). Entropy is an extensive property, so the entropy of the composite system is given by:

mean of the distribution. This means that immense number of microstates will be observed as the same macrostate, not only the mean of the distribution but also any other spacing of the molecules close enough to the mean (the pink bit on the binomial distribution can be though of as microstates of the same macrostate). This means that for most equlibrium systems observing a spontaneous density change is extremely improbable. Thinking about entropy as probability makes the second law more understandable: if a vase has been broken it will not “unbreak” because the chances of random molecular motion leading to peaces combining back into a whole vase are rather miniscule. VIO LAT IO NS O F T H E S E CO ND LAW

Probability equation gives: where functions h, f and l are not necessarily identical because the systems are different. However, probability of two independent events occuring is simply the product of the probabilities of this events: Boltzmann recognised that the only way to satisfy this equality is with a logarithmic function. We therefore have: where and are unknown constants. Through later careful consideration of of mixing of two inert gases given by classical thermodynamics, Ludwig Boltzmann established his final formula for entropy: where

The statistical nature of the second law has very important implications for nanotechnology and any machinery on a microscopic scale. Statistical mechanics predicts that highly minituarised heat engines will be able to run “in reverse” for short periods of time converting heat from the surroundings into useful work. As the size of the engine decreases the probability of the violation of the second law occurring increases and is given by the fluctuation theorem which was proposed by Wang and colleagues in 2002. Since then it was empirically demonstrated that the second law can be violated on a very small scale with thermal fluctuations of water observed to exert significant force on latex particles. This theorem can also be applied to cellular organelles such as mitochondria. The fluctuation theorem can be formulated as:

is the Boltzmann constant given by:

and is the number of microstates of the system corresponding to a macrostate and is related to probability. It is important to mention that even our highly accurate devices can only measure a change of density of one part in a million. For relatively large systems this kind of density change is several thousands of standard deviations away from the

The theorem relates to the probability distribution of the time-averaged irreversible entropy production, denoted . The theorem states that, in systems away from equilibrium over a finite time t, the ratio between the probability that takes the value A and that takes the value of the opposite, -A, will be exponential in At.

T HI RD L AW

The third law of thermodynamics tells us that: “a system’s entropy approaches a constant value as its temperature approaches absolute zero” so zero nuclei can have different spins even at absolute zero. We can see that this allows more than one microstate to be the ground state of the system (i.e. ) because nuclei with different spins are distinguishable from one another. We shall now see why this is the case from the Boltzmann’s principle. At absolute zero the system has no molecular translational or rotational kinetic energy (the system at absolute zero still has some kinetic vibrational energy known as zero-point energy). This means that only one energy state is available to the system and for most perfect crystalline solids we can clearly see that i.e. only one unique microstate exists. This results in an entropy of: However, certain systems possess interesting properties which allow them to have at . The entropy of the system when it is in its ground state is called residual entropy.

Here are a few examples of the properties which cause the non-zero residual entropy: 1) Nuclei of atoms have a spin quantum number - I. The number of possible spin states which a nucleus can adopt is given by 2I+1. Therefore, for any I greater than zero the nuclei can have different spins even at absolute zero. We can see that this allows more than one microstate to be the ground state of the system because nuclei with different spins are distinguishable from one another. 2) What do chemists mean when referring to pure substances at absolute zero? For most substances this actually means several isotopes of some elements being present. Pure HCl is mostly HCl35 and HCl37. These isotopes have small differences in their intermolecular interactions which is why they should separate into two different crystals to achieve . However, at temperatures close to absolute zero the molecules of chlorine fluoride simply do not have enough kinetic energy to separate. Thus, hydrogen fluoride freezes in a metastable state with some entropy of mixing left. The effect which causes residual entropy to stay above 0 in this case is known as isotopic mixing.

Primary Ciliary Dyskinesia and Situs Inversus Rainis Cheng

Cilia are hair-like projections on the surface of eukaryotic cells, made up of microtubules coated by the plasma membrane. There are three different types of cilia: motile cilia, non-motile cilia and nodal cilia. Motile cilia are present in the respiratory tract and reproductive system, non-motile cilia are present on various vertebrae cells, whilst nodal cilia are present in early embryonic development. Cilia have locomotive, cellular signalling and sensory functions. They are also involved in mechanoreception and chemoreception.

stroke needed to bend the cilium. The inner dynein arm controls the rhythmic motion of cilia as part of the nexin-dynein regulatory complex.

ST RUC T URE O F C I L I A

CILIA IN E MB RYO NIC LE FT-RIG H T AXIS DE T E RMINAT IO N

From the development of a zygote to a foetus, the fertilised egg has to separate and specialise into the organs we need to function and survive. Cilia play an immensely important part in the determination of left-right patterning and asymmetric positioning of internal organs for situs solitus, the normal configuration of thoracic and abdominal organs.

Figure 1: 9+2 axoneme and adjacent structures of motile cilia

OV E RA L L ST R U C T U R E ( AXO N E ME )

Nine microtubule doublets form an outer ring, linked together by nexin proteins. It is anchored to the cell by a basal body, which is a ring of triple microtubules. Two central singlet microtubules are held together by a central bridge and surrounded by a central sheath. There may be additional motilityrelated structures attached. The presence and absence of these features differ in the three types of cilia, as detailed in the table below:

In early embryogenesis, posterior tilt and clockwise motion of nodal cilia creates a leftward fluid flow in the extracellular space. This leftward movement is possible as these cilia lack a central pair. The non-motile cilia sense the flow and send signals to the lateral plate mesoderm which gives rise to visceral organs and cavities enveloping them. This model in which one type of cilium generates flow and another senses it is referred to as the “two-cilia hypothesis”. Chemical morphogens that are secreted into the cavity of the central node accumulate on the left periphery as a result of the flow. For example, a study shows that nodal vesicular parcels (NVP), containing electron-lucent particles, emerge from all

Type of cilia

Present in

Nine doublet microtubules

Two singlet microtubules

Motility-related structures

Motile cilia

e.g. respiratory tract

Present

Non-motile cilia

Nearly every type of vertebrae cell

Present

Absent

Nodal cilia

Early development of embryo

Present

Absent

Present

M OT I L I T Y- RE L AT E D ST R U C T U R E S

These are attached to the A ring of doublets in motile cilia and nodal cilia. The radial spoke assists in the attraction of the doublets to the central singlets. The outer dynein arm provides the power

regions of the ventral node but flow towards the left periphery where they then burst and are absorbed. Different concentrations of morphogens affect the expression of genes in a particular cell, paving the way for specialisation into tissue and organs.

P RI M A RY C I LI ARY DYS K I N E S I A C I L I A I N P RI MA RY C I L I A RY DYS K I NE S IA

The most prominent and noticeable defect in cilia of PCD is the abnormal functioning of dynein arms. Different kinds of defects in PCD are shown in fig.2. In relation to situs inversus, the types of defects that would cause abnormal positioning of visceral organs would be the defects in dynein arms and disorganisation defect. Absent dynein arms cause a weaker or random movement of the cilia. In contrary to the misbelief that cilia in PCD are immotile, the defects cause weaker randomised movement instead of strong directional beating. It is notable that primary ciliary dyskinesia usually affects the motility-related structures, thus defects relating non-motile cilia such as in the central complex and radical spokes do not have effect in causing laterality defects as situs inversus or situs ambiguous.

health consequences, but diagnosed patients have to carry around identification in the form of a bracelet or a card in order to inform medical professionals of special attention. For example, appendicitis is presented as pain in the lower right abdomen of individuals with situs solitus but on the left in individuals with situs inversus. However, situs ambiguous is commonly seen with other complications such as congenital heart disease, complications with systemic and pulmonary blood vessels, and cardiac development defects. As established previously, in embryogenesis, nodal cilia create a leftward flow as to migrate morphogens to the lateral plate mesoderm for cell specialisation. Without the function of nodal cilia, the nodal flow is slow or absent, thus thoracoabdominal laterality becomes random. In some genetically identical twins with PCD, reports have shown one with situs inversus totalis and one with situs solitus. The cardial apex (C) points towards the left in situs solitus, with the liver (L) on the right and stomach bubble(S) on the left. In situs inversus, the visceral organs are completely mirrored, but in situs ambiguous, both the stomach bubble and the liver are on the same side, showing that normal placement of organs are not all or none.

Figure 3: A: situs soliltus; B: situs inversus totalis; C: situs ambiguous

Figure 2: Defects of PCD

P C D A N D SI T U S I NV E R S U S

Situs inversus is a congenital condition in which the major visceral organs are reversed or mirrored from their normal positions. Situs inversus does not require treatment and does not cause major

The cilium was one of the first organelles to be identified but only recently have we understood that they do not only generate movement but also responds to chemical stimulation. From there, the importance of cilia in embryogenesis and organ formation became evident, such that we could locate one of the explanations of situs inversus. However, not all cases of situs inversus are caused by PCD as much about the condition still remains a mystery; the science is for us to uncover in years to come.

Prions Brandon Kim

The first transmissible spongiform encephalopathy (TSE) to be described was scrapie in 1732, which was thought to be caused by a “slow virus” after the discovery of microorganisms and viruses. However, investigation of scrapie agents displayed unexpected properties. The agent resisted doses of radiation that easily inactivated viruses and bacteria. Their chemical sensitivities were different to those of viruses and were resistant to UV lights and relatively high temperature (up to 500 degrees Celsius) suggesting that the agent did not depend on nucleic acids.

Further studies showed that a protein, with high resistance to proteases, was required for these properties. This deduced a widely accepted hypothesis that TSEs rely on a protease-resistant protein. The protein was named as a prion, a shorthand for proteinaceous infectious particle. C EL LUL A R P R I O N P R OT E I N

Sequencing of protein fraction produced by limited proteolysis of infectious prion particle allowed the identification of PRNP, a cognate gene for cellular prion protein. Despite the function of cellular prion protein remaining largely vague, it is suggested to be associated with metal ion regulation, cognition and behaviour, neuritogenesis, neuronal differentiation, neuroprotection, and cell signalling. Cellular prion protein, often referred to as PrPc, is a non-infectious prion particle that our body produces readily. The infectious prion protein is referred to as PrPSc, with the “Sc” coming from scrapie. PrPc and PrPSc share the same amino acid sequence, which PRNP encodes. However, the entire ORF (open reading frame) is on one exon, suggesting that the properties of PrPSc or PrPc are from post-translational modifications.

PrPc with prominent α helices

PrPSc with prominent β pleated sheets.

mutation in the PRNP gene (fCJD), or by medical procedures using contaminated tissue or hormones (iCJD). PrPSc may also arise spontaneously with no identified reason (sCJD). PRPS C RE PLICAT IO N CYCLE

The Ovine PRNP gene, with exons and introns labelled from left to right

The structure of PrPSc is comprised of 43% β pleated sheets and 30% α helices, whilst PrPc is 3% β pleated sheets and 42% α helices. The heavy β pleated structure of PrPSc allows the monomers to stack on top of one another, allowing polymerisation of PrPSc. P RP SC P RO DU C T I O N

PrPSc can be produced in the body in several ways: contact of PrPc with pre-existing PrPSc will induce conformational changes to PrPc, producing PrPSc. PrPSc can also be obtained genetically with individuals carrying an autosomal dominant

The most commonly proposed models in PrPSc replication cycle is the heterodimer model (A) and the autocatalytic nucleation (seed)-dependent polymerisation model(B). The heterodimer model shows a monomer of PrPSc binding to a PrPc monomer, forming a heterodimer, and catalysing a structural change of PrPc to form a homodimer of PrPSc. The homodimer then splits into two, resulting in two PrPSc monomers, which repeats the process. Later on, the monomers gather together to form plaques.

The autocatalytic nucleation polymerisation model requires a “seed” or nuclei of PrPSc. The chance of “seed” formation is very low but once the seed is made it can convert PrPc to PrPSc by the multivalent interaction. Then, after further polymerisation by recruiting more PrPc, the grown seed undergoes breakdown into smaller seeds. The seeds can form fibrils and plaques, potentially causing disease.

T RANS MISS IB LE S PO NG IFO RM E NCE PH ALO PAT H IE S

TSE (transmissible spongiform encephalopathy) is another name for prion disease. “Spongiform” means a structure resembling that of a sponge, “encephal-” refers to the brain and “-opathy” means disease; a transmissible, degenerative brain disease characterised by sponge-like lesions in brain tissue causing deterioration in neurological functioning.

List of TSEs with primary/secondary occurrence and transmission route: Transmissible Spongiform encephalopathies

Primary occurrence

Transmission route

Identified secondary occurrence

Sporadic Creutzfeldt–Jakob Disease(sCJD)

Humans

Unknown. Theories suggest mutation of body cells, or spontaneous conversion of PrPc to PrPSc

Other primates, lab rodent

Variant Creutzfeldt–Jakob Disease (vCJD)

Humans

Ingestion of BSEcontaminated food

Other primates, lab rodent

Familial Creutzfeldt–Jakob Disease(fCJD)

Humans

Germ-line mutations of the PRNP gene

Other primates, lab rodent

Iatrogenic Creutzfeldt–Jakob Disease (iCJD)

Humans

Accidental medical exposure to CJD-contaminated tissue or tissue products

Other primates, lab rodent

Kuru

Humans

(Ritualistic) cannibalism of the dead who had the disease

Other primates, lab rodent

Fatal familial insomnia (FFI)

Humans

Germ-line mutations of the PRNP gene

Lab rodent

Gerstmann-Straussler-Scheinker syndrome (GSS)

Humans

Germ-line mutations of the PRNP gene

Other primates, lab rodent

Bovine spongiform encephalopathy(BSE)

Cattle

Ingestion of contaminated food

All Bovidae; cats, goats, lab rodent, mink (repassage), pig, human, other primates.

Scrapie

Sheep, goat

Ingestion, horizontal transmission

Other primates, cattle, lab rodent

Chronic wasting disease(CWD)

Elk, deer, moose

Ingestion, horizontal transmission

Cattle, ferret, lab rodent (repassage), mink, squirrel monkey, goat

Feline spongiform encephalopathy(FSE)

Domestic and zoological cats

Ingestion of BSE contaminated food

Lab rodent

Transmissible mink encephalopathy(TME)

Mink

Ingestion of BSE contaminated food

Cattle, ferret, raccoons, lab rodent

* “Repassage” means secondary transmission after adaptation in an intermediate species

IS PRPS C T H E MAIN CAU S E ?

Scrapie infected sheep (left) and CWD infected deer (right)

HOW D OES P R P S C DE ST R OY N E URON A L CE L L S?

PrPSc is thought to aggregate by its β pleated sheets and form amyloid plaques that induces neurotoxicity. The specific mechanism of how these plaques (or PrPSc by itself) can induce neurotoxicity remains unclear. However, it is suggested to be associated with unfolded protein response (UPR) and/or oxidative stress. During prion diseases, UPR activation or increase in eIF2-alpha (eukaryotic translation initiation factor) phosphorylation is detected to shutdown protein translation. However, overexpression of GADD34, a specific eIF-alpha–P phosphatase, or PrP level reduction by lentivirally mediated RNAi was effective in reducing eIF-alpha-P levels. This led to restoration of vital translation rates in ER which resulted in survival rate increase. This suggested that UPR plays an important role in PrPSc associated cell death. Furthermore, despite the relationship between reactive oxygen (ROS) species and PrPSc production being obscure, ROS levels in cells were shown to correlate with PrPSc levels in cells, inducing oxidative stress, which is another potential cause of cell death by prions.

Despite the widely accepted hypothesis of PrPSc and its aggregates being directly toxic, there are other arguments too. In an experiment, inoculation of PrPSc to PrPc knockout mice after transplantation of tissue over-expressing PrPc was carried out. However, despite the transplanted tissue allowing PrPSc to multiply and move to other areas of the host brain, even after 16 months, no trace of pathological effects was detected in the host tissue (PrP knockout tissue). This indicated that prion pathogenesis is dependent on PrPc. Furthermore, another experiment used transgenic mice which were made to lose the PrP coding sequence after 9 weeks of age. When the mice were inoculated with PrPSc before PrP knockout, they started to develop symptoms of TSE such as spongiosis. However, after PrP knockout, the progression of TSE was halted, early-stage spongiform encephalopathy was healed. The mice survived for their full lifespan, without developing any further disease. This further proved the necessity of PrPc in TSE. Also, an experiment was carried out with transgenic mice with glycosylphosphatidylinositol (GPI) anchorless-PrP. After inoculation with PrPSc, the anchorless PrPc was converted to PrPSc, and highlevel accumulation of PrPSc and amyloid plaques were observed. However, the mice did not suffer any neurodegeneration. This experiment further suggested that cell signalling function of PrPc, is necessary for prion pathogenesis. However, its specific mechanism is yet to be discovered. ARE T H E RE ANY T RE AT ME NTS TO TS Es?

90% of people who have a TSE die within a year after symptoms develop. Furthermore, there are no known cures or reports of survival from prion diseases. However, methods are being studied to elongate survival times.

Enrichment

Throughout this academic year, there have been a plethora of opportunities for students to go beyond their curriculums and extend their scientific understanding. For example, Mr Wells has been directing a superb series of “CATTalks” in which teachers, students and Old Caterhamians have been delving into areas of interest and presenting their findings. One of which on string theory, by Dr Scott, is outlined below. Furthermore, this year’s Senior Independent Research Project was a great success as three of the six finalists were presenting research into scientific fields. One of the finalists, David Poolman, has kindly presented a summary of the extensive research he did for his IRP below.

Unifying the forces of Nature: A road to String Theory Dr Scott

Sharing a crown with rocket science, brain surgery and quantum mechanics, the subject of string theory occupies the throne of ‘complicated science’ in the psyche of the layman. However, the fundamental idea is a rather simple one and as the theory approaches its sixtieth birthday, it remains both as controversial and as beautiful a theory as ever. So, what is string theory, how did we arrive at it and why all the controversy?

In the 19th century, the Danish physicists Ørsted noticed that a compass placed near a currentcarrying wire would be deflected away from pointing north. Michael Faraday too had discovered that a metal conductor, connected to no power source, moving in-and-out of a magnetic field would a generate a current, seemingly out of nowhere. By the middle of the century, the Scottish physicist James Clerk Maxwell had mathematically tied

all of these observations together and demonstrated once-and-for-all that electricity and magnetism are two sides of the same fundamental phenomenon. The theory of electromagnetism as it had come to be known was the first sign that different forces of nature could be unified into a single theory. The desire to seek a ‘theory of everything’ unifying not just two but all laws of nature has been with us ever since.

It is gravity that provides the biggest problem to unifying all of the fundamental forces of nature into a theory of everything, and it is here where string theory enters the story. Einstein’s theory of general relativity (GR) is our best modern description of gravity. GR doesn’t describe gravity as a force per se but rather a bending of the fabric of space and time itself. A notoriously complex theory causing headaches for undergraduate physicists for over a century, it stands alone by not being built out of the framework of quantum mechanics, unlike the rest of physics. To pursue the unification of all of the forces of nature, one needs a quantum mechanical description of gravity. One of a very few number of viable candidates for a ‘quantum gravity’ is string theory. String theory is a quantum theory of nature which disposes with the idea that the fundamental building blocks of nature are point-like particles but rather one-dimensional, extended objects which can vibrate. Essentially, it proposes that everything at its most zoomed-in level is made of tiny vibrating strings. The strings come in two varieties, either open or closed, forming a loop. Just as different vibrating modes on a guitar string produce different pitches, so the different ways in which these strings are allowed to vibrate give rise to all the multitude of particles we observe. The picture is, of course, much more complex and subtle but this is general gist. The reason that (some) physicists

are so excited about string theory is that a certain set of these vibrational states together appear as a single particle vital for a quantum description of gravity which had hitherto not naturally been found in other quantum theories; this is the so-called spin-2 graviton.

Despite this remarkable and rare feature, string theory in its simplest and even modified forms is riddled with problems. In order to be consistent with the rest of physics, the simplest string theory requires a total of 25 spatial dimensions, rather more than the accepted three we experience. Not only this but this basic theory cannot describe certain particles called fermions, like electrons, which make up everyday matter. An upgrade to the basic theory, called superstring theory, allows us to describe all types of particle and reduces the number of extra space dimensions down to six - six more than we currently have evidence for but still preferable to finding 22! The issue with superstring theory is that, to work, it requires the existence of a whole new array of socalled supersymmetric particles, yet to be found. The last, and, for me, the most crucial issue with string theory is that due to the number of ways in which the extra dimensions must be hidden from view, known as compactification, there are over 10500 different string theories. This is such an absurdly large number that you could have started counting towards this number at the Big Bang, saying one number every nanosecond, and 14 billion years later you’d still have 99.9999 (and 470 more nines) % of the way left to go! It is impossible to therefore falsify any string theory. And a theory which is nonfalsifiable is not a scientific theory; it cannot stand up to experimental scrutiny, always evading the experimental physicist’s spotlight. It might very well be the theory of everything, but what is science if we cannot prove it to be so?

The Rise of Superbugs: Can humans win the race? David Poolman

In World War II penicillin became a life-saving miracle drug, being used to treat bacterial infections. But within just 60 years since then penicillin has become useless against common strains of S. aureus and E. coli bacteria due to the rapid rise of antibiotic resistance. Antibiotic resistant bacteria are already killing 700,000 people a year and this number could skyrocket to 10 million a year if no further action is taken.

In my IRP I sought to understand this rapid change in effectiveness of antibiotics. Then by looking at treatments to resistant bacteria, I researched whether we could deal with the threat and therefore avoid a return to an era where bacterial infections are deadly. In my IRP I looked in detail into bacteriophages as they have a role in both spreading resistance and treating it. Lytic bacteriophages are viruses that infect bacteria in a similar way to how HIV infects helper T cells. They bind to the surface of bacteria via attachment proteins and integrate their nucleic acid into the bacterial genome, using the machinery of the bacterial cells to produce more phage particles. However, in this process they can mobilise bacterial DNA (mobile genetic elements) that could contain resistance genes and integrate it into new bacteriophage particles, therefore acting as a vehicle for spreading resistance. This process is called transduction and is a significant factor behind the spread of resistance in S. aureus as it has a family of mobile genetic elements that have a transduction rate 10,000 times higher than in other species of bacteria. This family typically codes for antibiotic resistance and therefore is a significant reason for penicillin’s ineffectiveness against common strains of S. aureus.

Despite the risk from transduction, bacteriophages also have potential as an alternative treatment to antibiotic resistant bacteria. Lytic bacteriophages produced inside the resistant bacteria through the replication process, secrete proteins that destroy the bacteria cell. However, to initially infect the bacteria, the phage must have attachment proteins specific to the proteins on the surface of the bacterial cell. As a result, a phage will only be effective against a singular strain of a species of bacteria which means they do not kill helpful bacteria in the gut. But this specificity also means phage treatment could not be scaled worldwide, in the same way as antibiotics, as different strains are found in different areas of the world. This coupled with the varied effectiveness of phage treatment means it is not a replacement for antibiotics. The limited scope of effectiveness of phage treatment is a similar problem for alternative treatments such as beta lactamase inhibitors and therefore new antibiotics must be developed to deal with the rising threat. Governments must give economic incentives to pharmaceutical companies to develop new classes of antibiotics. This combined with minimising unnecessary use of antibiotics in animal feed and treating viral based infections should help us in winning the race against antibiotic resistant bacteria.

Olympiads Olympiads provide a great opportunity for some of the most passionate students to test their knowledge against a series of some of the most complex questions they will have encountered to date. This year we had a large number of students step up to the challenge and they can all be very proud of their efforts in a set of papers renowned for their difficulty. Despite how ruthless the questions can be, many students did extremely well and scored high enough to achieve medals. In this year’s British Physics Olympiad, a total of eight students did well enough to place amongst the medals, collectively achieving one gold, one silver and six bronzes between them.

Furthermore, in the UK Chemistry Olympiad, a total of 23 students – four Upper Sixth, sixteen Lower Sixth and three Fifth Years – participated in a paper spanning noble gases to social distancing within molecules. A big congratulations must go to Gleb Iagelskii (L6) who achieved the top score as well as Alex Mylet who got the fourth highest score despite being in Fifth year. In this year’s British Biology Olympiad, 11 students achieved medals obtaining two golds, four silvers and five bronzes collectively. The virtually conducted papers were very well received and everyone who took part can be proud for challenging themselves to apply themselves in these particularly difficult set of questions.

Scientific Advancements Despite the massive disruption caused by the pandemic, it is reassuring to see that the scientific community has continued to work tirelessly, leading to many developments in our understanding. By far the most well-known developments are those related to vaccines, but it is still important to recognise some of the other discoveries. The following page highlights just a few of these advancements.

RNA Vaccines for COVID-19 Unlike conventional vaccines which work by using an attenuated virus or protein subunit to elicit a primary immune response, RNA vaccines are unique in that they use a molecule known as messenger RNA (mRNA) to produce viral spike proteins within the target cells. It is these spike proteins which the immune system recognises as foreign and ultimately responds to by producing complimentary antibodies and memory cells, thus providing immunity upon secondary infections.

There are two main components to a typical RNA vaccine: the mRNA and the lipid nanoparticle (LNP). Following the sequencing of the SARS-CoV-2 genome in January 2020, it was possible to derive the exact sequence of RNA that would encode the receptor binding domain (RBD) of the virus’ spike protein. This sequence could then be amplified from plasmid DNA before being modified to include a 3’ poly(A) tail, untranslated regions and a 5’ cap, features that both maximise expression and protect the RNA.

The RNA is then encapsulated in the aforementioned lipid nanoparticles which are essential for ensuring the mRNA is not degraded before entering a cell by RNases. Following internalisation of the LNP, the mRNA enters the cytoplasm and binds to a ribosome where its base sequence is deciphered to produce a polypeptide chain in a process known as translation. This polypeptide will fold in this case to produce the RBD from the SARS-CoV-2 spike protein which can then be delivered onto the cell membrane via both MHC class I and II proteins. Following antigen presentation, T cells are activated by a series of complex pathways leading to further B cell activation. These B cells multiply and by a process of somatic hypermutation, B cells are selected for based off their ability to bind to the associated antigen. Some B cells divide to form plasma cells which produce antibodies and a small proportion of these B cells differentiate into memory B cells. Having induced the formation of memory B cells to the SARS-CoV-2 spike protein, it ensures that on infection with the live virus, antibodies can be produced to combat the pathogen immediately and activate an immune response.

Diagram showing the SARS-CoV-2 spike protein primary and tertiary structure

RNA vaccines as such can provide many advantages over traditional vaccines. As seen during the COVID-19 pandemic, these vaccines can be produced in much less time thanks to their relatively simple structure and advances in genome sequencing over the past few decades. Moreover, their production is much less costly and ultimately provides an exciting way forwards for treating infectious diseases.

2020 Nobel Prizes The Nobel Prizes are some of the most prestigious awarded in science. They are presented to those individuals who have provided “the greatest benefit to humankind” and often recognise the work of someone’s entire career. The 2020 prize for Physics was awarded jointly to Roger Penrose, Reinhard Genzel and Andrea Ghez for their collective contributions into the research of blackholes. Roger Penrose, through his mathematical proof, demonstrated that Albert Einstein’s theory of general relativity predicts the existence of black holes whilst both Reinhard Genzel and Andrea Ghez discovered the supermassive object at the centre of our galaxy after studying the region known as Sagittarius A*.

Image showing the crystal structure of Cas9 from S. aureus

The prize in Medicine or Physiology was given to Harvey J. Alter, Michael Houghton, Charles M. Rice following their work into the discovery of the Hepatitis C virus. Previously, a large proportion of blood-borne hepatitis cases were unexplained which prompted the research of these scientists. Having isolated nucleic acids belong to an unrecognised Flavivirus, the work of these individuals ultimately led to the proper treatment of millions of patients. This past year’s Nobel Prize in Chemistry was awarded to Emmanuelle Charpentier and Jennifer A. Doudna for their combined discovery of the CRISPR/Cas9 “genetic scissors”. Having recognised the ability of Streptococcus pyogenes to defend itself against viruses by cutting sections from the pathogen’s genome, the two scientists developed this system in vitro to find they could precisely cleave DNA at any predetermined site, paving the way for future genetic engineering.

The Wright Society Max Fogelman

Patron: Dr Richard EP Wright MB BS (Lond); MRCGP

The Wright Society is the medical society of Caterham School. The Society was formed in the summer of 2020; it is named after our Patron: Dr Richard EP Wright MB BS (Lond); MRCGP who is the school’s GP. The current President is Max Fogelman and Vice President is Louie Steel. The Society helps people applying for medicine, veterinary, dentistry and other allied health professional courses. We do this by offering advice and support for the medics whilst helping them to develop the skills necessary to be successful once they go to medical school. the medics going into their interviews as they got feedback on all of their answers from actual doctors. We also guide and advise the Lower Sixth members on their medical school application, with much of this advice coming from current Upper Sixth students who have just gone through the process. This allows for the Lower Sixth to have a firm understanding of the medical school application process and what to expect. W HAT D O W E DO?

WH O G E TS INVO LVE D?

We enrich our members with challenging scientific talks on different areas of medicine that are delivered by our members to the rest of the Society. These talks are always followed by a period of questioning - this helps the medics improve their communication skills.

The Society involves not only Caterham students but also students from the London Academy of Excellence (LAE) and Oxted School who are given the title of “associate members”. These associate members are of immense value to the Society as they increase the diversity of thought within the Society meaning that the questioning after talks is even more intense and challenging.

We have held UCAT sessions for the Lower Sixth (run by the President and Vice-president) where the medics were taught how to prepare for and tackle the UCAT, the main medical school admissions test that applicants face. We have also run PBL sessions for the Lower Sixth to get the medics used to what it is like to be studying in a PBL environment with a significant number of the Upper Sixth running the medical side and a vet running the vets’ side of the session. The Upper Sixth were also fortunate enough to have two interview prep evenings where they got to experience both an MMI and traditional style of interview. This was an invaluable experience for

Final Reflection Dan Quinton

John Jones started the Moncrieff Society over 50 years ago here at Caterham School to showcase the best in science above and beyond the curriculum, and today the Society is still flying high with those same founding principles. I took over the reins nearly two decades ago and renamed it “The Moncrieff-Jones Society” to acknowledge his massive contribution. The MJS has been a big part of my life here at Caterham and is therefore very dear to my heart, and lockdown and virtual schooling have raised some serious questions over how the Society would function this year. I have heard many times the foolish argument that some people in this world are scientific and others are creative. There is no one more creative than some of the pioneers in science who must devise ways and design equipment to test the hypotheses they are investigating. I would argue that scientists are amongst the most creative people on the planet. No more so than our President and Vice President, Alex Richings and Max Fogelman, who have ensured the MJS has continued to thrive throughout the many challenges of this difficult year. The live talks online have flourished and provided opportunities for pupils from our partner state schools to attend – from Oxted, Warlingham and the London Academic of Excellence in Newham: a development I am extremely proud of. Alex has chaired the meetings and the quality of talks this last term by our Lower Sixth have been as high as ever. In fact, I feel some of the talks have been the best in my time at Caterham School. Thanks to science we live in an extraordinary technological age, but also a dreadful world of Twitter sound bites, where ill formed, self-appointed gurus give their opinion about anything and everything, without really knowing or understanding the facts, or only having superficial knowledge having read the first article that appears in Google. This has been

highlighted more than ever during the pandemic with the spread of false news and has given a platform for the anti-vaccine campaign and those denying the existence or seriousness of Covid. The brave students giving lectures at the MJS meetings not only make me very proud, but also give me hope for the future. They receive no help from staff in their research and normally must present a 30-minute talk before then being grilled by a large audience for another 40 minutes. They teach themselves a vast array of material outside any A level specification and then have to understand it all if they are to survive a MJS lecture. The trendy buzz phrase ‘Independent Learning’ has crept into education in recent years. Although as scientists we loath trendy jargon, the MJS has been doing just this for the last 50 years – a Moncrieff-Jones lecture surely must be the ultimate in ‘Independent Learning’. In delivering a MJS talk pupils are showing a skill the top universities around the world are looking for in their undergraduates. We live in an age of science. There has never been a better time to study science and I am jealous of all our students leaving to go to university to study science degrees at this time. How I would love to sit in on their lectures. Finally, I must thank Alex and Max for the incredible job they have done over the last 12 months and look forward to welcoming them back here anytime. They will always be a part of the Moncrieff-Jones Society.

Past Moncrieff-Jones Society Presidents & Vice Presidents 2 007-2 008

2012-201 3

2 01 7- 2 01 8

President: Luke Bashford (University College London)

President: Rachel Wright (St Peter’s College, Oxford)

President: Kamen Kyutchukov (University College London)

Vice President: Edd Simpson (University of Leeds)

Vice President: David Gardner (University of Nottingham)

Vice President: Natalie Bishop (University College London)

2 008- 2 009

2013 -201 4

2 01 8- 2 01 9

President: Tonya Semyachkova (Balliol College, Oxford)

President: Holly Hendron (St Peter’s College, Oxford)

President: Daniel Farris (University of Exeter)

Vice President: Raphael Zimmermann (University of East Anglia)

Vice President: Annie-Marie Baston (Magdalen College, Oxford)

Vice President: Rowan Bradbury (University of York)

2 009- 2 010

2014 -201 5

President: Alex Hinkson (St Catherine’s College, Oxford)

President: Ollie Hull (Merton College, Oxford)

President: Michael Land (University of Warwick)

Vice President: Alexander Clark (Robinson College, Cambridge)

Vice President: Cesci Adams (University of Durham)

2 010- 2 011

2015 -201 6

President: Oliver Claydon (Gonville and Caius College, Cambridge)

President: Thomas Land (University of Southampton)

Vice President: Sally Ko (Imperial College, London) 2 011- 2 012

President: Glen-Oliver Gowers (University College, Oxford) Vice President: Ross-William Hendron (St Peter’s College, Oxford)

Vice President: Emily Yates (University of Birmingham)

2 01 9 - 2 02 0

Vice President: Ben Brown (Bristol University) 2 02 0 - 2 02 1

President: Alex Richings (Imperial College London) Vice President: Max Fogelman (University of St Andrews)

2016 -201 7

President: Hannah Pook (St John’s College, Oxford) Vice President: Vladimir Kalinovsky (University College London)

Past Endorsers of the Moncrieff-Jones Society Dr Jan Schnupp Lecturer in the 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 Max Bodmer Marine Biologist and lecturer at Lincoln and Nottingham University

Dr Alexis Bailey Surrey University, Department of Biochemistry and Physiology Leader of the Drug Addiction Research Team

Dr Jansen Zhao Senior Researcher in the Computer Science Department at ETH Zürich

Dr Nick Lane Reader in Evolutionary Biochemistry at University College London Mike Bonsall Professor of Mathematical Biology at St Peter’s College, Oxford

Mr Shahnawaz Rasheed Consultant Surgeon at The Royal Marsden and Senior Lecturer at Imperial College London

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Rheumatology Network Editorial Staff (2020), Study Confirms Skin Cancer Risk with Methotrexate, Rheumatology Network, Available at: www.rheumatologynetwork. com/view/study-confirms-skin-cancer-riskmethotrexate Daniel H. Solomon et al. (2018), Adverse Effects of Low-Dose Methotrexate: A Randomized Trial, National Centre for Biotechnology Information, Available at: pubmed.ncbi.nlm.nih.gov/32066146/ Akbar k Waljee (2020), Anti-tumour necrosisα therapy and recurrent or new primary cancers in patients with inflammatory bowel disease, rheumatoid arthritis, or psoriasis and previous cancer in Denmark: a nationwide, population-based cohort study, The Lancet, Available at: www.thelancet.com/journals/ langas/article/PIIS2468-1253(19)30362-0/ fulltext Barbara Brody (2019), Older ‘Triple Therapy’ Just as Safe as Methotrexate Plus TNF Inhibitors for Rheumatoid Arthriti, Creaky Joints, Available at: creakyjoints. org/treatment/triple-therapy-safe-asmethotrexate-plus-biologic/ www.intechopen.com/media/chapter/56532/ media/F1.png Future Medicine [Online Image], Available at: www.futuremedicine.com/ cms/10.2217/14622416.9.8.1011/asset/images/ medium/graphic26.gif Creaky Joints [Online Image], Available at: creakyjoints.org/wp-content/uploads/0819_ Triple_Therapy-1024x683.jpg Medical News [Online Image], Available at: www.news- medical.net/image.axd?picture=20 17%F4%2Fshutterstock_390538711_6b3c40fdd 32742caa54307db3553cab1-620x480.jpg Other Articles Daniel Wrapp et al. (2020), Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation, Science [Online Image], Available at: science.sciencemag.org/ content/367/6483/1260 Paul Goldsmith (2015), Zhang lab unlocks the crystal structure of new CRISPR/Cas9 genome editing tool, Broad Institute [Online Image], Available at: www.broadinstitute.org/blog/ zhang-lab-unlocks-crystal-structure-newcrisprcas9-genome-editing-tool

2020 - 21 ISSUE

THE ANNUAL MAGAZINE OF THE MONCRIEFF-JONES SOCIETY

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