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Please click on the > to go directly to the page. > Introducing the MRC

>AchievementsIntroducing thetimeline MRC

Achievements>1913 to 1940s timeline >1950s to >1913 to 1940s >1990s to 2006 >1950s to 1980s >1990s to 2006 > Leading research for better health

>NobelLeading Prize resear timelinech for better health

Nobel>1929 Prizeto 1952 timeline >1953 to 1962 >1929 to 1952 >1972 to 1984 >1953 to 1962 >1997 to 2003 >1972 to 1984 1997 to 2003 >MRC research over the decades

MRC> From resear discochvery over to healthcare:the decades translational research > EvidenceFrom discovery for best to pr healthcareactice: clinical — translational trials research > EvidencePublic health for bestresearch practice: clinical trials > PubDNAlic revhealtholution research > ReducingDNA rev olutionsmoking: preventing deaths > ReducingTherapeutic smoking: antibodiespreventing deaths > TherapeuticReducing deaths antibodies from infections in Africa > ReducingPreventing deaths heart fromdisease infections in Africa > PrevMedicalenting imaging: hearttransformingdisease diagnosis > MedicalCutting childimaging: leukaemia transforming deaths diagnosis > Cutting child leukaemia deaths

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The most important part of the MRC’s mission trials, such as those on the use of statins to lower is to encourage and support high-quality research and on vaccines in Africa.The MRC with the aim of improving human health.The MRC is the UK’s largest public funder of clinical trials is committed to supporting research across the and it supports some of the most productive entire spectrum of the biomedical and clinical and ambitious epidemiological studies in the world, . We are proud of our international including the UK Biobank. Figures published in 2006 reputation for achievement – from the introduction by the Office of and Innovation (formerly of and discovery of the structure of DNA, the Office of Science and Technology) showed that to the development of MRI scanners; from the the UK leads the G8 countries in the productivity creation of blockbuster antibody drugs to vital clinical of its biomedical and pre-clinical research.

MRC research has: • Contributed to a reduction in the number • Revealed that a pneumoccocus vaccine tested of people who smoke from 45 per cent in The Gambia could save a million children’s in1974 to 26 per cent in 2003. Half of all lives in developing countries each year. smokers die as a result of their habit. • Led to the development of MRI scanners, • Shown that cholesterol-lowering statins which are used in 60 million medical can save 50,000 lives worldwide every year. investigations worldwide each year. • Shown that folic acid supplements could • Invented monoclonal antibodies, sparking significantly reduce the hundreds of UK a global industry that is expected to be pregnancies affected by neural tube defects worth £16 billion per year by 2010, giving each year – research which has led to rise to some of the UK’s most valuable fortification of 10 per cent of the world’s start-up companies, and earning the flour with folic acid. MRC almost £200 million in licence revenue • Promoted the use of insecticide-treated to be reinvested in medical research. mosquito nets, and revealed that they reduce • Virtually eradicated haemophilus influenzae the incidence of malaria – which causes over type B in Gambian children, with the potential a million deaths a year – by 63 per cent. to save hundreds of thousands of lives • Revealed that magnesium sulphate halves worldwide each year. the risk of eclampsia in pregnant women • Developed DNA chip technology, with pre-eclampsia, a finding that could save tens of thousands of lives globally which has spawned a £1.6 billion each year. a year global industry. • Shown that an abdominal aortic aneurysm • Increased the proportion of children screening programme – now under in the UK who survive leukaemia from consideration by the UK National Health 20 to 80 per cent. Service – could save 2,000 lives each year. < Contents > Benefits for human health The information in this pack is presented in three This pack presents a selection of key achievements different ways: by MRC-funded scientists since the MRC was founded in 1913. All have had major benefits for human health. • Achievements spanning the lifetime of the MRC, presented chronologically on the folder itself. Moving from a discovery to the application of that new knowledge in the form of treatments and interventions • Accounts of important areas of medical research that benefit people’s health can take many years of funded by the MRC, where the positive outcomes further research and development. It often depends are clearly evident today.These often span a long on a number of factors other than just research results. time period, because the key discovery may have For example, with the help of MRC funding, Sir Richard happened many years ago, and it has taken time Doll and his colleagues established the link between and further developments to show the full impact smoking and lung cancer as far back as the 1950s. on human health. Labelling of cigarette packets with health warnings started in 1971 and cigarette smoking began to decline • Details of our Nobel Prizes – 27 MRC-supported a few years later; but it is only now that Doll’s findings scientists have won Nobel Prizes since 1929, are being translated into laws banning smoking in 13 of whom were based at our Laboratory public places in the UK.These benefits to public health of Molecular Biology in Cambridge. stem from research that took place many years ago. Medical science has many other similar examples, some of which are described in this pack.

Many medical advances are the result of research that crosses scientific boundaries. The MRC has always championed such multidisciplinary research, both in its grants to universities and its institutes and units. For example, our winners Dr and Dr were physicists, as is Sir , while Sir John Walker’s original training was in .

www.mrc.ac.uk | © Medical Research Council 2006 < Contents > 1984 Dr César Milstein and Dr Georges Köhler, MRC Laboratory of 1952 1960 Molecular Biology MRC Nobel Prize winners Dr , Sir , The ability of antibodies to bind MRC National Institute Sir MRC National Institute specifically to substances is very for Medical Research for Medical Research, Dr useful in medical research. Since the MRC was set up in 1913, 27 scientists in its units or supported by MRC Director 1962–1971 1972 2001 The invention of partition 1953 Professor Rodney Porter, 1980 Milstein and Köhler suggested Sir grants have won Nobel Prizes, including 13 awarded to researchers at the MRC allowed Sir Hans Krebs, From his studies of skin grafting MRC National Institute Dr Frederick Sanger, the idea of making monoclonal and Dr , mixtures to be separated. to treat soliders with burns antibodies – many antibodies MRC Cell Metabolism for Medical Research MRC Laboratory of Imperial Cancer Laboratory of Molecular Biology in Cambridge.The MRC’s prize winners have been Methods for separating in the Second World War, of the same type – in order to Research Unit, Director Molecular Biology Research Fund substances are fundamental Medawar discovered ‘acquired Porter described the chemical diagnose and treat a wide array spread across the Nobel categories of or and Chemistry; all of 1945–1967 in chemistry; the first thing immunological tolerance’. structure of antibodies – the For his second Nobel Prize, of human diseases.They identified 1997 Nurse and Hunt identified their discoveries have had a momentous impact on human health. a does is isolate the Krebs uncovered the citric acid This is the ability of a living thing body’s defence molecules – Sanger developed a technique a way to produce antibodies by Sir John Walker, elements of the cell cycle, substance that he or she is cycle – a series of chemical to overcome its normal tendency and their interaction with to determine the exact sequence fusing an antibody-producing cell MRC Laboratory of which coordinates processes interested in. Also, the technique reactions that takes place in most to reject another individual’s molecules from outside the of the building blocks – the bases with a tumour cell.This allows involved in cell division, such Molecular Biology These Nobel laureates include Professor , Dr Francis Crick and can be applied to disease plants, animals, fungi and many organs or tissue. Using rabbits, body, called antigens. Antibodies – in DNA. He used it to find out unlimited production of a as growth and chromosome Medawar showed that the are giant molecules in the blood. Walker solved the most complex Professor for their world-famous discovery of the molecular diagnosis and . bacteria.These reactions involve the genetic sequence of a virus, particular type of antibody. duplication and separation. In its simplest form, which is the breakdown of proteins, fats rejection of skin grafts was Porter wanted to find out which was the first fully Antibodies have a wide range structure so far – that of Hunt, working on sea urchins, structure of DNA, and Sir , who discovered penicillin – one of filter-, and carbohydrates into much an immune response. He also exactly how they work. He sequenced genome. Sanger’s of research and commercial adenosine triphosphate (ATP) – discovered proteins that a drop of a mixture is placed smaller molecules.These found that the response could separated the parts of the method was used to determine applications, from treating cancer the major energy currency of are made and destroyed during the first antibacterial agents – virtually by accident. One MRC scientist, Dr Frederick on a piece of filter paper, and molecules are then used as be avoided if, early on in life, molecule that are responsible the sequence of human DNA, and transplant rejection to the cell. ATP captures the the cell cycle. Nurse found the Sanger, even won two separate Nobel prizes for his work on proteins and DNA. the paper allowed to soak up building materials for the cell. mice were exposed to the for the antibody’s ability to react and was the most widely used diagnosing pregnancy and AIDS. chemical energy released by cdc2 gene, which controls cell a combination of liquids, Krebs discovered how certain tissue that would later be grafted. specifically and combine with analysis method in the early 80s. The technique has sparked the combustion of nutrients division.These discoveries, He discovered how to determine the exact sequence of building blocks in these such as water and butyl alcohol. individual reactions are linked The work gave surgeons the a foreign substance: the antigen It was key to the Human an international billion-pound and transfers it to reactions also supported by the Imperial two types of molecule, opening up the new scientific area of molecular biology. The components of the mixture to each other in a cyclic process confidence that the problem to which it is specifically fitted. Genome Project, which has biotechnology industry: that need energy, for example, Cancer Research Fund (now separate on the paper according and how energy is released by of rejection of organs and tissue He also proposed that the increased the understanding monoclonal antibodies are the building of cell components, Cancer Research UK) increased Professor Watson, Professor Wilkins and Dr Crick with to how well they dissolve in the this process for use by the cell could be solved by tackling the antibody molecule is shaped of many genetically-based basis of a third of all biotech muscle contraction and the understanding of cell cycle control Sir Peter Mansfield two liquids. for all its activities. immune response. their model of DNA. like the letter Y. diseases and cancer. products in clinical development. transmission of nerve messages. defects and hence cancer.

1920 1930 1940 1950 1960 1970 1980 1990 2000

1929 1936 1945 He transferred the mould 1958 Sir Frederick Hopkins, Sir Henry Dale, Sir Alexander Fleming, to broth, which he found had Dr Fre Cambridge University MRC National Institute London University, such a strong effect on bacteria Cambridge for Medical Research, Sir that even when diluted Hopkins discovered essential For the first of his two Nobel Director 1928–1932 and Lord Florey, hundreds of times, the penicillin nutrients, now known as , completely prevented bacterial Prizes, Sanger determined the University which are needed in animal diets Dale studied growth.This mould belonged entire sequence of the 51 for growth and for health. Before how nerves Fleming, Chain and Florey to the group of building blocks – called amino his work, most researchers use chemicals discovered the moulds, and he therefore acids – in insulin, a protein, and believed that diet-linked illnesses, to transmit showed how they are linked penicillin and identified how it named the broth, and later Sir Sir such as the scurvy that sailors messages to cures bacterial diseases. Finding the substance itself, penicillin. together. Insulin is an important suffered from during long trips, each other. penicillin was a lucky accident. Chain and Florey went on natural hormone and is used in were caused by a toxic substance When two the treatment of diabetes. B Sir Henry Dale While studying bacteria, Fleming to purify and extract penicillin, in certain foods. But Hopkins nerves cells noticed that some had been enabling it to be produced Sanger’s methods could also be suspected that such diseases meet end-to-end, there is a gap killed and had dissolved away in large amounts to treat many applied to proteins in general, were actually due to something between them called a synapse. around a spot of blue-green different bacterial diseases. and his work showed that all missing in the diet. He studied Chemical transmitters, released mould which by chance had proteins have specific structures. the diets of rats and found that from the end of one nerve, flow contaminated one of his dishes. His method involved separating they would grow well only if he across this gap to the other the different fra added a daily supplement of milk nerve.This is how one nerve cell protein on filter paper and to their diet. He suggested that communicates with another, and moving them with an electric this was because of an is the basis of how nerve cells current according to their electric unidentified organic nutrient. are connected in networks in the charge.This created a distinct Other scientists went on to body. Dale identified a particular pattern on the paper, which identify and characterise the transmitter called acetylcholine. Sanger called a ‘ individual nutrients as vitamins. He also invented ‘Dale’s Principle’, which stated that each nerve releases only one transmitter. Since then, however, some nerves have been shown to use more than one. www.mrc.ac.uk < Contents > | © Medical Research Council 2006 1984 Dr César Milstein and Dr Georges Köhler, MRC Laboratory of 1952 1960 Molecular Biology MRC Nobel Prize winners Dr Archer Martin, Sir Peter Medawar, The ability of antibodies to bind MRC National Institute Sir Hans Krebs MRC National Institute specifically to substances is very for Medical Research for Medical Research, Dr Frederick Sanger useful in medical research. Since the MRC was set up in 1913, 27 scientists in its units or supported by MRC Director 1962–1971 1972 2001 The invention of partition 1953 Professor Rodney Porter, 1980 Milstein and Köhler suggested Sir Paul Nurse grants have won Nobel Prizes, including 13 awarded to researchers at the MRC chromatography allowed Sir Hans Krebs, From his studies of skin grafting MRC National Institute Dr Frederick Sanger, the idea of making monoclonal and Dr Tim Hunt, mixtures to be separated. to treat soliders with burns antibodies – many antibodies MRC Cell Metabolism for Medical Research MRC Laboratory of Imperial Cancer Laboratory of Molecular Biology in Cambridge.The MRC’s prize winners have been Methods for separating in the Second World War, of the same type – in order to Research Unit, Director Molecular Biology Research Fund substances are fundamental Medawar discovered ‘acquired Porter described the chemical diagnose and treat a wide array spread across the Nobel categories of Physiology or Medicine and Chemistry; all of 1945–1967 in chemistry; the first thing immunological tolerance’. structure of antibodies – the For his second Nobel Prize, of human diseases.They identified 1997 Nurse and Hunt identified their discoveries have had a momentous impact on human health. a chemist does is isolate the Krebs uncovered the citric acid This is the ability of a living thing body’s defence molecules – Sanger developed a technique a way to produce antibodies by Sir John Walker, elements of the cell cycle, substance that he or she is cycle – a series of chemical to overcome its normal tendency and their interaction with to determine the exact sequence fusing an antibody-producing cell MRC Laboratory of which coordinates processes interested in. Also, the technique reactions that takes place in most to reject another individual’s molecules from outside the of the building blocks – the bases with a tumour cell.This allows involved in cell division, such Molecular Biology These Nobel laureates include Professor James Watson, Dr Francis Crick and can be applied to disease plants, animals, fungi and many organs or tissue. Using rabbits, body, called antigens. Antibodies – in DNA. He used it to find out unlimited production of a as growth and chromosome diagnosis and forensic science. bacteria.These reactions involve Medawar showed that the are giant molecules in the blood. the genetic sequence of a virus, particular type of antibody. Walker solved the most complex duplication and separation. Professor Maurice Wilkins for their world-famous discovery of the molecular In its simplest form, which is the breakdown of proteins, fats rejection of skin grafts was Porter wanted to find out which was the first fully Antibodies have a wide range structure so far – that of Hunt, working on sea urchins, structure of DNA, and Sir Alexander Fleming, who discovered penicillin – one of filter-paper chromatography, and carbohydrates into much an immune response. He also exactly how they work. He sequenced genome. Sanger’s of research and commercial adenosine triphosphate (ATP) – discovered proteins that a drop of a mixture is placed smaller molecules.These found that the response could separated the parts of the method was used to determine applications, from treating cancer the major energy currency of are made and destroyed during the first antibacterial agents – virtually by accident. One MRC scientist, Dr Frederick on a piece of filter paper, and molecules are then used as be avoided if, early on in life, molecule that are responsible the sequence of human DNA, and transplant rejection to the cell. ATP captures the the cell cycle. Nurse found the Sanger, even won two separate Nobel prizes for his work on proteins and DNA. the paper allowed to soak up building materials for the cell. mice were exposed to the for the antibody’s ability to react and was the most widely used diagnosing pregnancy and AIDS. chemical energy released by cdc2 gene, which controls cell a combination of liquids, Krebs discovered how certain tissue that would later be grafted. specifically and combine with analysis method in the early 80s. The technique has sparked the combustion of nutrients division.These discoveries, He discovered how to determine the exact sequence of building blocks in these such as water and butyl alcohol. individual reactions are linked The work gave surgeons the a foreign substance: the antigen It was key to the Human an international billion-pound and transfers it to reactions also supported by the Imperial two types of molecule, opening up the new scientific area of molecular biology. The components of the mixture to each other in a cyclic process confidence that the problem to which it is specifically fitted. Genome Project, which has biotechnology industry: that need energy, for example, Cancer Research Fund (now separate on the paper according and how energy is released by of rejection of organs and tissue He also proposed that the increased the understanding monoclonal antibodies are the building of cell components, Cancer Research UK) increased Professor Watson, Professor Wilkins and Dr Crick with to how well they dissolve in the this process for use by the cell could be solved by tackling the antibody molecule is shaped of many genetically-based basis of a third of all biotech muscle contraction and the understanding of cell cycle control Sir Peter Mansfield two liquids. for all its activities. immune response. their model of DNA. like the letter Y. diseases and cancer. products in clinical development. transmission of nerve messages. defects and hence cancer.

1920 1930 1940 1950 1960 1970 1980 1990 2000

mould 1958 1962 1962 Watson, Crick and Wilkins 1975 1 t found had Dr Frederick Sanger, Dr Max Perutz and Dr Francis Crick, showed how these building Professor Jo s t on bacteria Cambridge University Sir , MRC Molecular Structure blocks interact in three MRC National Institute t uted MRC Laboratory of of Biological Systems dimensions to form a long for Medical Research For the first of his two Nobel the penicillin Molecular Biology Unit, Professor James spiralling molecule with a c ted bacterial Prizes, Sanger determined the double ‘backbone’ made up Cornforth worked on , Watson, MRC Laboratory g belonged entire sequence of the 51 Perutz and Kendrew studied of sugar and phosphate blocks. which are proteins that speed up of Molecular Biology and t group of building blocks – called amino the structures of globular Nitrogen-containing compounds, biological processes, and what is m erefore acids – in insulin, a protein, and proteins such as haemoglobin, Professor Maurice Wilkins, called bases, protrude from known as – the showed how they are linked which carries oxygen in the MRC Biophysics Research geometry o n and later the two halves of the backbone Sir Aaron Klug Sir John Sulston t f, penicillin. together. Insulin is an important blood, and the immunoglobulins Unit and link together in pairs, He found out how C went on natural hormone and is used in (antibodies), which are the body’s The unravelling of the helical so the whole molecule is like work by using radioactive the treatment of diabetes. But natural defence molecules. versions of hydrogen atoms Sir Henry Dale t act penicillin, structure of DNA – the basic a zip.There are only four types e roduced Sanger’s methods could also be They used the way that different building blocks of life – is hailed of bases in humans, represented to identify molecular changes i o treat many applied to proteins in general, proteins cause X-rays to change as one of the most significant by the letters C, A, G and T, that resulted from d diseases. and his work showed that all direction to produce unique landmarks of the 20th century. and they are the basis of action. He studied how proteins have specific structures. patterns that indicated their DNA, which stands for the of DNA. particular enzyme makes His method involved separating structures.The achievement deoxyribonucleic acid, is the This discovery also helped cholesterol in the living cell. the different fragments of the was the result of 25 years’ work. substance that carries heredity in the understanding protein on filter paper and This technique continues to be in living things. It is a large chain of how DNA replicates. moving them with an electric used to determine the structure molecule that is made up of current according to their electric of large molecules. many building blocks. charge.This created a distinct pattern on the paper, which Sanger called a ‘fingerprint’.

www.mrc.ac.uk | © Medical Research Council 2006 < Contents > 1984 Dr César Milstein and Dr Georges Köhler, MRC Laboratory of 1952 1960 Molecular Biology MRC Nobel Prize winners Dr Archer Martin, Sir Peter Medawar, The ability of antibodies to bind MRC National Institute Sir Hans Krebs MRC National Institute specifically to substances is very for Medical Research for Medical Research, Dr Frederick Sanger useful in medical research. Since the MRC was set up in 1913, 27 scientists in its units or supported by MRC Director 1962–1971 1972 2001 The invention of partition 1953 Professor Rodney Porter, 1980 Milstein and Köhler suggested Sir Paul Nurse grants have won Nobel Prizes, including 13 awarded to researchers at the MRC chromatography allowed Sir Hans Krebs, From his studies of skin grafting MRC National Institute Dr Frederick Sanger, the idea of making monoclonal and Dr Tim Hunt, mixtures to be separated. to treat soliders with burns antibodies – many antibodies MRC Cell Metabolism for Medical Research MRC Laboratory of Imperial Cancer Laboratory of Molecular Biology in Cambridge.The MRC’s prize winners have been Methods for separating in the Second World War, of the same type – in order to Research Unit, Director Molecular Biology Research Fund substances are fundamental Medawar discovered ‘acquired Porter described the chemical diagnose and treat a wide array spread across the Nobel categories of Physiology or Medicine and Chemistry; all of 1945–1967 in chemistry; the first thing immunological tolerance’. structure of antibodies – the For his second Nobel Prize, of human diseases.They identified 1997 Nurse and Hunt identified their discoveries have had a momentous impact on human health. a chemist does is isolate the Krebs uncovered the citric acid This is the ability of a living thing body’s defence molecules – Sanger developed a technique a way to produce antibodies by Sir John Walker, elements of the cell cycle, substance that he or she is cycle – a series of chemical to overcome its normal tendency and their interaction with to determine the exact sequence fusing an antibody-producing cell MRC Laboratory of which coordinates processes interested in. Also, the technique reactions that takes place in most to reject another individual’s molecules from outside the of the building blocks – the bases with a tumour cell.This allows involved in cell division, such Molecular Biology These Nobel laureates include Professor James Watson, Dr Francis Crick and can be applied to disease plants, animals, fungi and many organs or tissue. Using rabbits, body, called antigens. Antibodies – in DNA. He used it to find out unlimited production of a as growth and chromosome Medawar showed that the the genetic sequence of a virus, particular type of antibody. duplication and separation. Professor Maurice Wilkins for their world-famous discovery of the molecular diagnosis and forensic science. bacteria.These reactions involve are giant molecules in the blood. Walker solved the most complex In its simplest form, which is the breakdown of proteins, fats rejection of skin grafts was Porter wanted to find out which was the first fully Antibodies have a wide range structure so far – that of Hunt, working on sea urchins, structure of DNA, and Sir Alexander Fleming, who discovered penicillin – one of filter-paper chromatography, and carbohydrates into much an immune response. He also exactly how they work. He sequenced genome. Sanger’s of research and commercial adenosine triphosphate (ATP) – discovered proteins that a drop of a mixture is placed smaller molecules.These found that the response could separated the parts of the method was used to determine applications, from treating cancer the major energy currency of are made and destroyed during the first antibacterial agents – virtually by accident. One MRC scientist, Dr Frederick on a piece of filter paper, and molecules are then used as be avoided if, early on in life, molecule that are responsible the sequence of human DNA, and transplant rejection to the cell. ATP captures the the cell cycle. Nurse found the Sanger, even won two separate Nobel prizes for his work on proteins and DNA. the paper allowed to soak up building materials for the cell. mice were exposed to the for the antibody’s ability to react and was the most widely used diagnosing pregnancy and AIDS. chemical energy released by cdc2 gene, which controls cell a combination of liquids, Krebs discovered how certain tissue that would later be grafted. specifically and combine with analysis method in the early 80s. The technique has sparked the combustion of nutrients division.These discoveries, He discovered how to determine the exact sequence of building blocks in these such as water and butyl alcohol. individual reactions are linked The work gave surgeons the a foreign substance: the antigen It was key to the Human an international billion-pound and transfers it to reactions also supported by the Imperial two types of molecule, opening up the new scientific area of molecular biology. The components of the mixture to each other in a cyclic process confidence that the problem to which it is specifically fitted. Genome Project, which has biotechnology industry: that need energy, for example, Cancer Research Fund (now separate on the paper according and how energy is released by of rejection of organs and tissue He also proposed that the increased the understanding monoclonal antibodies are the building of cell components, Cancer Research UK) increased Professor Watson, Professor Wilkins and Dr Crick with to how well they dissolve in the this process for use by the cell could be solved by tackling the antibody molecule is shaped of many genetically-based basis of a third of all biotech muscle contraction and the understanding of cell cycle control Sir Peter Mansfield two liquids. for all its activities. immune response. their model of DNA. like the letter Y. diseases and cancer. products in clinical development. transmission of nerve messages. defects and hence cancer.

1920 1930 1940 1950 1960 1970 1980 1990 2000

Watson, Crick and Wilkins 1975 1982 2 showed how these building Professor , Sir Aaron Klug, blocks interact in three MRC National Institute MRC Laboratory of dimensions to form a long for Medical Research Molecular Biology spiralling molecule with a double ‘backbone’ made up Cornforth worked on enzymes, Using a new method called of sugar and phosphate blocks. which are proteins that speed up crystallographic electron Nitrogen-containing compounds, biological processes, and what is microscopy, Klug produced called bases, protrude from known as stereochemistry – the a detailed picture of the structure geometry of chemical reactions. of proteins that interact with the two halves of the backbone Sir Aaron Klug Sir John Sulston and link together in pairs, He found out how enzymes DNA. His technique, which so the whole molecule is like work by using radioactive combined conventional electron versions of hydrogen atoms microscopy with the use of Sir Henry Dale a zip.There are only four types of bases in humans, represented to identify molecular changes X-rays, gives an image with by the letters C, A, G and T, that resulted from enzyme enhanced resolution. Klug studied and they are the basis of action. He studied how a a large protein called chromatin, the genetic code of DNA. particular enzyme makes which holds DNA together This discovery also helped cholesterol in the living cell. in chromosomes. He managed in the understanding to break up chromatin into small of how DNA replicates. fragments that could be examined, and then construct a model of chromosomes based on his knowledge of the structure of the fragment. Chromatin affects how the genetic code is read, so investigation of its structure is crucial in the understanding of cancer, in which the control of growth and division of cells by the genetic material no longer works. www.mrc.ac.uk | © Medical Research Council 2006 < Contents > 1984 Dr César Milstein and Dr Georges Köhler, MRC Laboratory of 1952 1960 Molecular Biology MRC Nobel Prize winners Dr Archer Martin, Sir Peter Medawar, The ability of antibodies to bind MRC National Institute Sir Hans Krebs MRC National Institute specifically to substances is very for Medical Research for Medical Research, Dr Frederick Sanger useful in medical research. Since the MRC was set up in 1913, 27 scientists in its units or supported by MRC Director 1962–1971 1972 2001 The invention of partition 1953 Professor Rodney Porter, 1980 Milstein and Köhler suggested Sir Paul Nurse grants have won Nobel Prizes, including 13 awarded to researchers at the MRC chromatography allowed Sir Hans Krebs, From his studies of skin grafting MRC National Institute Dr Frederick Sanger, the idea of making monoclonal and Dr Tim Hunt, mixtures to be separated. to treat soliders with burns antibodies – many antibodies MRC Cell Metabolism for Medical Research MRC Laboratory of Imperial Cancer Laboratory of Molecular Biology in Cambridge.The MRC’s prize winners have been Methods for separating in the Second World War, of the same type – in order to Research Unit, Director Molecular Biology Research Fund substances are fundamental Medawar discovered ‘acquired Porter described the chemical diagnose and treat a wide array spread across the Nobel categories of Physiology or Medicine and Chemistry; all of 1945–1967 in chemistry; the first thing immunological tolerance’. structure of antibodies – the For his second Nobel Prize, of human diseases.They identified 1997 Nurse and Hunt identified their discoveries have had a momentous impact on human health. a chemist does is isolate the Krebs uncovered the citric acid This is the ability of a living thing body’s defence molecules – Sanger developed a technique a way to produce antibodies by Sir John Walker, elements of the cell cycle, substance that he or she is cycle – a series of chemical to overcome its normal tendency and their interaction with to determine the exact sequence fusing an antibody-producing cell MRC Laboratory of which coordinates processes interested in. Also, the technique reactions that takes place in most to reject another individual’s molecules from outside the of the building blocks – the bases with a tumour cell.This allows involved in cell division, such Molecular Biology These Nobel laureates include Professor James Watson, Dr Francis Crick and can be applied to disease plants, animals, fungi and many organs or tissue. Using rabbits, body, called antigens. Antibodies – in DNA. He used it to find out unlimited production of a as growth and chromosome diagnosis and forensic science. bacteria.These reactions involve Medawar showed that the are giant molecules in the blood. the genetic sequence of a virus, Walker solved the most complex duplication and separation. Professor Maurice Wilkins for their world-famous discovery of the molecular particular type of antibody. In its simplest form, which is the breakdown of proteins, fats rejection of skin grafts was Porter wanted to find out which was the first fully Antibodies have a wide range structure so far – that of Hunt, working on sea urchins, structure of DNA, and Sir Alexander Fleming, who discovered penicillin – one of filter-paper chromatography, and carbohydrates into much an immune response. He also exactly how they work. He sequenced genome. Sanger’s of research and commercial adenosine triphosphate (ATP) – discovered proteins that a drop of a mixture is placed smaller molecules.These found that the response could separated the parts of the method was used to determine applications, from treating cancer the major energy currency of are made and destroyed during the first antibacterial agents – virtually by accident. One MRC scientist, Dr Frederick on a piece of filter paper, and molecules are then used as be avoided if, early on in life, molecule that are responsible the sequence of human DNA, and transplant rejection to the cell. ATP captures the the cell cycle. Nurse found the Sanger, even won two separate Nobel prizes for his work on proteins and DNA. the paper allowed to soak up building materials for the cell. mice were exposed to the for the antibody’s ability to react and was the most widely used diagnosing pregnancy and AIDS. chemical energy released by cdc2 gene, which controls cell a combination of liquids, Krebs discovered how certain tissue that would later be grafted. specifically and combine with analysis method in the early 80s. The technique has sparked the combustion of nutrients division.These discoveries, He discovered how to determine the exact sequence of building blocks in these such as water and butyl alcohol. individual reactions are linked The work gave surgeons the a foreign substance: the antigen It was key to the Human an international billion-pound and transfers it to reactions also supported by the Imperial two types of molecule, opening up the new scientific area of molecular biology. The components of the mixture to each other in a cyclic process confidence that the problem to which it is specifically fitted. Genome Project, which has biotechnology industry: that need energy, for example, Cancer Research Fund (now separate on the paper according and how energy is released by of rejection of organs and tissue He also proposed that the increased the understanding monoclonal antibodies are the building of cell components, Cancer Research UK) increased Professor Watson, Professor Wilkins and Dr Crick with to how well they dissolve in the this process for use by the cell could be solved by tackling the antibody molecule is shaped of many genetically-based basis of a third of all biotech muscle contraction and the understanding of cell cycle control Sir Peter Mansfield two liquids. for all its activities. immune response. their model of DNA. like the letter Y. diseases and cancer. products in clinical development. transmission of nerve messages. defects and hence cancer.

1920 1930 1940 1950 1960 1970 1980 1990 2000

2002 2003 Sir John Sulston, Sir Peter Mansfield, Dr Brenner University of Nottingham and Professor Mansfield discovered how the Robert Horvitz, natural magnetic properties of MRC Laboratory of the cell can be used to produce Molecular Biology images of structures.This led to Sulston, Brenner and Horvitz the development of magnetic resonance imaging (MRI), Sir Aaron Klug Sir John Sulston discovered how genes regulate organ development and how cells a breakthrough for medical are programmed to die, which is diagnostics and research because it is safer and can be more Sir Henry Dale critical for the understanding of diseases. By studying a type of sensitive than X-rays. Imaging of worm, they identified key genes human internal organs with exact in its development.The worm has and non-invasive methods is a short lifetime and is transparent, important for medical diagnosis, so it was possible to follow cell treatment and follow-up, for division directly under the example, in cancer and before .The researchers surgery. Now, 60 million MRI induced gene mutations and investigations are performed linked them to specific effects on worldwide each year. organ development.What’s more, Commercialisation has led to corresponding genes were found a multi-billion pound industry. in humans. Sulston, Brenner and Horvitz also studied programmed cell death, which is important in the understanding of how viruses and bacteria invade cells, and in the field of cancer research. Contents www.mrc.ac.uk | © Medical Research Council< 2006 > Improving health through medical research From discovery to healthcare: translational research

During the past two decades, rapid advances in fundamental biomedical science have created a vast body of knowledge and technologies to apply to health problems. Research organisations the world over are working to speed up the translation of this knowledge into clinical practice.

Translational research is the term used for work The team took oral smears from patients attending that links basic research to applied clinical research. outpatient clinics at Guy’s Hospital in London. They Success in this area usually depends on a two-way found that specific proteins, called minichromosome flow of ideas and knowledge between laboratory maintenance proteins (MCMs), are abundant in cells and clinical scientists. Collaboration between from cancers and absent from almost all normal cells. academic research groups from different disciplines, The MCM markers, which indicate that a cancer cell and with the pharmaceutical industry, is vital. Some is about to begin its lifecycle, can be detected using examples of MRC-supported translational research a staining antibody. are detailed below. Last year Cancer Research Technology, Cancer Cancer screening Research UK’s technology transfer company, The MRC Cancer Cell Unit in Cambridge studies announced that it had entered into a worldwide fundamental cell biology and links this to the licence agreement with TriPath Imaging. The licence understanding of cancer. Cancer cells have altered grants exclusive rights to TriPath to several promising properties, and the researchers are identifying genes cancer diagnostic markers from the MCM protein and proteins that are important in this process.The family for the detection of cervical cancer, and an team has found a marker that identifies the presence exclusive option on markers for breast, lung and of cancer in its very early stage.This could uncover colorectal cancers. oral cancer, cervical cancer and cancer of the larynx, Newborn hearing screen in a simple smear test that is non-invasive, accurate, quick and cheap. The NHS newborn hearing screening programme, introduced in 2002, improves the early detection Up to 500,000 new cases of mouth and throat cancer of hearing impairment in babies, allowing earlier are diagnosed annually and approximately 75 per cent and more effective treatment for the 900 babies of these occur in the developing world. The new test born each year in the UK with permanent hearing loss. has the potential to form the basis for an important screening programme for oral cancer, which accounts for more deaths in the UK per year than cervical and testicular cancer combined.

< Contents > Professor David Kemp, an MRC-funded scientist at Prior to deep stimulation (DBS), which has been London’s Institute of Otology and Laryngology, familiar to neurologists and neurosurgeons since the developed the idea for the screen in the late . , a wire is inserted into a particular part of the His technology, the ‘otoacoustic emissions’ test, involves brain. It is then run under the patient’s skin to a small placing a small soft tipped ear-piece in the outer part machine called an implantable pulse generator, which of the baby’s ear and playing quiet clicking sounds. In a is placed under the skin on the chest.The generator hearing ear, the organ of hearing – called the cochlea – sends small electrical currents through the wire to should produce sounds in response to the clicks that the brain. can be recorded and analysed by the computerised screening system in only a few minutes. In the early 1990s, MRC researchers at the University of Manchester identified the part of the brain that Researchers at the MRC Institute of Hearing Research causes PD – the subthalamic nucleus – which is in Nottingham worked on Professor Kemp’s idea and stimulated by DBS. Although this therapy worked for showed that it had the potential for highly sensitive some PD patients, it was ineffective for the 40 per cent screening. of patients who didn’t respond to drugs.

The breakthrough came through work by MRC- “This technology has transformed the whole funded Professor Tipu Aziz, a neurosurgeon at Oxford screening process,” says Professor Mark University’s John Radcliffe Hospital, who identified another target in primate , the pedunculopontine Haggard of the MRC Cognition and Brain nucleus. When this target was stimulated, PD symptoms were alleviated, even in patients who Sciences Unit in Cambridge, former director were not responsive to drugs. The first DBS in this brain region in human patients was recently of the MRC Institute of Hearing Research. performed in Rome.

The DBS device, made by US medical technology Before the introduction of the neonatal screen, there company Medtronic Inc. was approved in Europe were two screens that took place at later stages in 1995 for treating tremor in PD. Estimates are of infancy using different, less effective, technology. that the cost of DBS treatment will be recouped The screen at nine months is now obsolete and the in around five years.The therapy is now used five-year screen is currently under review. worldwide – more than 30,000 people have received it – and is also being used to treat other disorders Deep brain stimulation including dystonia, a much rarer disease than PD A remarkable surgical procedure may relieve the which affects children. Professor Aziz’s team has also symptoms of Parkinson’s disease (PD).The technique, been testing DBS for the relief of chronic pain and which involves electrically stimulating specific parts to regulate blood pressure. Currently, the MRC is of the brain, has recently been shown to help patients carrying out a £1 million randomised clinical trial of who do not respond to drug treatments, and may DBS in different parts of the brain, and Medtronic is offer hope to PD patients worldwide. about to begin a trial of the technology for treating severe depression.

www.mrc.ac.uk | © Medical Research Council 2006 < Contents > Improving health through medical research Evidence for best practice: clinical trials

The MRC is a leading international funder of trials of clinical and public health measures, applying the most advanced evaluation methods to provide health services with proof of what works and what does not.

The MRC’s trials address important areas that industry Developing the gold standard would not normally be expected to tackle, such as: How well a clinical trial is designed is important, as it determines the accuracy and reliability of the • Evaluation of new public health and preventive results. The randomised controlled trial (RCT) design, measures – for instance sex education, nutrition pioneered by the MRC in the 1940s, is the gold or accident prevention measures. standard for clinical trials. In an RCT, the research team • Trials of low-cost or non-patented treatments allocates treatments to patients at random instead of such as aspirin, warfarin or folic acid. the decision being made by their doctor. This helps to • Re-evaluation of, or comparison between, ensure that all of the groups receiving the different well-established treatments. treatments are made up of an equally diverse selection of people, so researchers can be confident that the • Trials of non-drug treatments or diagnostics, trial will reveal the differences between the treatments, including surgery, radiotherapy and psychological rather than the differences between the people therapies. receiving them. High-quality RCTs are very influential • Trials of treatments and preventive measures in changing medical practice.The UK National Institute for use in the world’s poorest countries. for Health and Clinical Excellence (NICE) and the international Cochrane Collaboration, which make recommendations for evidence-based healthcare, place more emphasis on RCTs than any other form of evidence.

< Contents > Pioneering work in clinical trials • Clinical trials revealing that screening for colorectal The MRC has a long history of clinical trials. Some cancer in the general population could double of our key achievements in this vital area of medical detection rates. research include: 1990s 1920s • Clinical trials showing that combining antiretroviral • Identifying ways of combating rickets and other drugs delays the progress of AIDS, but that childhood diseases by improving children’s nutrition. zidovudine (AZT) provides no benefits before symptoms are present. 1930s • Clinical trials of that revealed • Clinical trials of new drugs to treat life-threatening it to be beneficial for many types of cancer. infections including septicaemia, meningitis, erysipelas and pneumonia. • Trials of breast-cancer screening. 1940s • Clinical studies of AIDS treatment for children. • Clinical trials of whooping cough vaccines. • Vaccine trials in The Gambia that wiped out haemophilus influenzae disease and reduced rates • Studies to find treatments for tuberculosis (TB), of pneumococcus and hepatitis B. other serious bacterial infections and hepatitis. • Development of the definitive methology for randomised clinical trials, now accepted worldwide • Clinical trials showing that statins reduce heart as the ‘gold standard’. attacks and strokes. 1950s • Research revealing that magnesium sulphate halves the risk of eclampsia in pregnant women with • Clinical research showing that home-based TB pre-eclampsia. treatment is as effective as sanatorium treatment. • Trials of treatments for diseases of the elderly • Clinical trials of treatments for rheumatism and hormone replacement therapy. and skin disorders. • Research identifying the potential of MRI to 1960s improve breast cancer screening for young • Clinical trials of vaccines for influenza, polio, leprosy, at-risk women. diphtheria, measles and rubella. • Clinical trial showing that cannabis has little benefit • Clinical research into radiotherapy for cancers. for multiple sclerosis sufferers. 1970s • Study showing that dental braces can improve • Clinical trials of chemotherapy and immunology for self-esteem in children as young as eight who have leukaemia. prominent front teeth. • Development and testing of first short-duration TB • Research showing that ultrasound screening treatments. could halve the death rate from abdominal aortic • Studies showing that treating even slightly high aneurysm among older men – as a result, the blood pressure reduces heart disease risk. UK National Screening Committee is currently considering whether a routine screening 1980s programme should be introduced. • Clinical trials revealing aspirin and warfarin • Clinical trial showing that routine corticosteroid to be effective for treating cardiovascular disease. treatment for head injury patients may do more • Studies identifying treatments for childhood harm than good. leukaemia that dramatically improve chance of recovery. • Clinical research showing that folic acid given to high-risk women reduces numbers of babies born with birth defects. www.mrc.ac.uk | © Medical Research Council 2006 < Contents > Improving health through medical research Public health research

The MRC’s public health research addresses the full range of influences on health and disease, such as diet, infection, injury and social and environmental factors. Our genes can also be important in increasing or decreasing the effects of environmental or lifestyle risks.The research is aimed at helping to prevent illness through measures such as education, advice or policy changes. It can also provide the knowledge base needed to plan health services and to develop screening and early treatment programmes.

Fundamental research for Confirming the link between cannabis public health: and psychosis Low birth weight linked to disease Cannabis use among young people is a risk factor in adulthood for psychotic symptoms in adulthood, but not all In 1989, Professor David Barker, director of the former cannabis users go on to develop psychosis. MRC MRC Environmental Epidemiology Unit at investigators uncovered a genetic variation that has Southampton University, put forward the ‘early origins helped to explain why cannabis triggers psychosis in hypothesis’. He suggested that low birth weight due some users but not others. Professor Avshalom Capsi to nutritional deprivation in the womb is an important of the Institute of Psychiatry at King’s College London cause of some of the most common, costly and and colleagues followed 1,000 people from birth to disabling illnesses of adult life, including heart disease, 32 years.They found that those who had a common COMT stroke and type 2 diabetes. Dozens of subsequent variation in a gene called were five times more large-scale studies across the world have confirmed likely to develop psychosis if they used cannabis strong links between low birth weight and chronic frequently in their adolescence than cannabis-users diseases in later life, a list which now includes without the gene. Around 13 per cent of participants osteoporosis, chronic obstructive pulmonary disease, in the first group went on to develop schizophrenia, cancer, schizophrenia and depression. compared with only around five per cent of those in the second group.

< Contents > Evidence to change policy: In 2006, researchers at the MRC Dunn Human Folic acid prevents birth defects Nutrition Unit went on to uncover a mechanism that may explain the link between red meat Neural tube defects (NTDs) such as spina bifida are consumption and bowel cancer.They found that relatively common and often fatal birth defects that DNA damage in the bowel increases after eating red occur during the first month of pregnancy. In 1983, meat, due to a rise in the levels of substances called the MRC began a randomised controlled trial in N-nitrosocompounds. 33 centres across seven countries to see whether folic acid or other supplements could Sex education by peers better than teachers prevent NTDs.The results were published in 1991 A major MRC-funded study by scientists at University and showed that giving folic acid supplements to College London showed that sex education for women who had already had an affected pregnancy teenagers might be better delivered by their peers and were planning another baby reduced the risk than their teachers. Although overall changes in of NTDs by almost three-quarters.The finding behaviour were modest, the research showed that sparked a £2 million public awareness drive in pupils were more satisfied with sex education taught the UK by the Health Education Authority. In 1998, by their peers than by their teachers. And importantly, the US Government brought in legislation compelling there was a change in sexual activity: fewer girls in the manufacturers to add folic acid to breakfast cereals former group reported having had sex by age 16. and wholemeal bread – reducing cases of spina bifida The study involved 8,000 pupils aged 13 to 14 from by a fifth. Many other countries have followed suit, 27 schools in who were randomly assigned and today around 10 per cent of the flour produced to receive sex education from pupils aged 16 to 17 in the world is fortified with folic acid.The UK will or to continue their usual programme with teachers. make a decision in 2006 about also bringing in The peer educators underwent extensive training mandatory fortification of flour with folic acid. with experts to deliver the programme. Red meat increases bowel cancer risk In 2005, MRC-funded scientists confirmed that people who eat a large amount of red and processed meat have an increased risk of developing bowel cancer. Beginning in 1992, they tracked the diet and lifestyle of almost half a million people in 10 European countries who were initially free of cancer. They found that the risk of bowel cancer among people who regularly ate two or more portions per day of red or processed meat was a third higher than the risk among people who ate less than one portion a week.The results also showed that eating fish every other day was linked to a reduced risk of bowel cancer. Professor Tim Key of Cancer Research UK, which co-funded the study, said:“We estimate that more than two-thirds of colorectal cancer cases – 25,000 cases in the UK – could be avoided by changes in lifestyle in Western countries.”

www.mrc.ac.uk | © Medical Research Council 2006 < Contents > Improving health through medical research DNA revolution

Decades of MRC research into the has led to the development of technologies such as DNA sequencing, fingerprinting and chips that have had a huge impact on medical research and medicine. Today, the industry based on genomics, including gene-based services, diagnostics and potential new drugs, is worth around £3.5 billion per year.

Structure of DNA Genome sequencing and the Human Genome Project Working in the MRC’s unit at the Cavendish Laboratory in Cambridge, Professor James Watson Determining the structure of DNA laid the and Dr Francis Crick famously described the foundation for a genetic revolution that went on structure of DNA in the scientific journal to establish in the 1960s that three-letter DNA in April 1953.The work owed a substantial debt ‘codons’ formed the basis of instructions for building to Dr Rosalind Franklin and Professor Maurice proteins. In the 1970s, MRC scientist Dr Frederick Wilkins at the MRC Biophysics Unit at King’s Sanger’s DNA sequencing technique and other College London. methods to manipulate and analyse DNA gave scientists the basic toolkit to begin exploring the It transformed our understanding of human diseases DNA blueprint. Dr Sanger won two Nobel Prizes and treatments and triggered the development of for this and further work on the structure of proteins. new DNA technologies with enormous economic and health benefits. Professors Watson and Wilkins Building on this work, in 1998 UK and US researchers and Dr Crick won the 1962 Nobel Prize in including the MRC Laboratory of Molecular Biology’s Physiology or Medicine for this work; Dr Franklin Dr and Sir John Sulston finished had died four years previously. sequencing the C. elegans genome – the first complete sequence of a multicellular organism.Their work provided the techniques for a vast international project that culminated in 2003 with a team of researchers, including MRC scientists, establishing the DNA sequence of the entire human genome.

< Contents > DNA fingerprinting and its many applications DNA chips: a £1.6 billion global market DNA fingerprinting technology was invented in 1984 In his laboratory at Oxford University, Sir Edwin went by MRC-funded scientist Sir Alec Jeffreys at the on to further develop Southern blotting, culminating University of . His invention has helped in the invention of today’s DNA chip, or microarray, to push forward the fields of and genomics technology. He invented a technique for attaching and has led to research into genetic markers of human ordered arrangements of thousands of DNA diseases. The technique has also revolutionised forensic molecules to the surface of a chip the size of a thumb science, matched donors to patients in need of life- nail. These chips allow scientists to compare the saving organ transplants, and provided an infallible sequence or expression of genes in different tissues method of paternity testing. And it has helped to or individuals, enabling diagnosis of disease and establish family relationships in immigration cases, potentially enabling choice of treatment based on determined human origins and patterns of migration, genetic make-up. DNA chip technology is also used and helped save endangered animal species. in drug discovery to identify potential drug targets, and can be used to study changes in gene expression The technique built on work by MRC-funded scientist in response to drug treatment. The global market for Sir , who invented a novel method for DNA chips reached almost £1.6 billion last year. analysing DNA called Southern blotting. Sir Alec exploited Southern blotting to develop a way to distinguish all humans – except for identical twins – from each other. He discovered that each person’s DNA had a distinct and unique pattern of repeat areas called . Unrelated humans have different numbers of repeats at particular sites on their DNA. DNA fingerprinting can detect the number of repeats in several different locations, making it possible to establish a match that is exceptionally unlikely to arise by coincidence. The patterns in an individual’s genetic fingerprint are a hybrid of patterns from their parent’s DNA.

Revolutionising forensic science

In the UK last year, the UK Forensic Science Service (FSS) used DNA fingerprinting techniques to match 40,000 samples from crime scenes to people’s records on the National DNA Database, including 165 homicides, 100 attempted murders and 570 rapes. Also, the FSS has developed what they describe as a world-leading DNA expert system enabling automatic analysis and interpretation of DNA profiles.The system is now being made available to the international forensic community including the USA, Canada, Europe, and New Zealand, resulting in an important economic spin-off for the UK from the technology.

www.mrc.ac.uk | © Medical Research Council 2006 < Contents > Improving health through medical research Reducing smoking: preventing deaths

MRC researchers first established a link between smoking and cancer 50 years ago.They have recently shown that, on average, smokers die 10 years earlier than non-smokers.

The research has led to national public health campaigns aimed at avoiding millions of unnecessary How many people smoke? deaths. It has also culminated in government decisions • In 2003, 26% of British adults aged 16+ smoked in England, Scotland,Wales and Northern Ireland to cigarettes (28% of men and 24% of women) ban smoking in workplaces and public places, after compared with 45% in 1974. There are around sustained exposure to passive smoking was also shown 12 million adult cigarette smokers in the UK. to be harmful. • Among men, smoking prevalence dropped from Smoking-related cancer deaths among middle-aged 51% in 1974 to 28% in 2003; in women the drop men dropped dramatically after people became aware was from 41% to 24%. of the dangers and stopped smoking in the 1970s, • The biggest falls in smoking prevalence have while the rate of cancer deaths not related to smoking been in the over 35s. stayed the same (see graph). • Young people are most likely to smoke: in 2003, 36% of adults aged 20-34 smoked. Dying from smoking • One in two smokers dies prematurely: of these, nearly one in four will die of lung cancer. • In 2000, there were 42,800 cancer deaths in the UK attributable to smoking: approximately a third of all cancer deaths. • About half of all persistent cigarette smokers are killed by their habit – a quarter while still in middle age (35-69 years). • On average, cigarette smokers die about 10 years earlier than non-smokers. • Stopping smoking at ages 30, 40, 50 and 60 increases life expectancy by around 10, 9, 6 and 3 years, respectively.

< Contents > In 1947, the MRC held a conference to discuss the And for a unique group of men born around 1920 possible causes of a large increase in deaths from lung the odds were even worse, with cigarettes killing two- cancer in the UK. MRC scientists Sir Richard Doll and thirds of those who continued to smoke. The scientists Sir Austin Bradford Hill published a preliminary paper attributed this to conscription into the British army in 1950 that suggested a relationship between tobacco from 1939 onwards. The armed forces provided smoking and cancer. To investigate further, in 1951 they low-cost cigarettes to servicemen, and this intense began a study of 40,000 British doctors who were born early exposure to smoking established their addiction. between 1900 and 1930. Doctors were chosen for the study because they were a relatively simple group to follow through the General Medical Council’s register. They were asked about their smoking habits and those who replied have been tracked ever since to see what illnesses they died of. Among the first results, a paper published in 1956 showed that the death rate from lung cancer among heavy smokers was 20 times the rate in non-smokers, indicating beyond doubt that smoking causes lung cancer.

In 2004, Sir Richard completed the picture by publishing 50-year follow-up results from the study. These showed that the overall risks from smoking were even greater than originally suspected and that, on average, smoking lowered life expectancy by 10 years. By tracking over 34,000 male doctors, he and This pioneering work, alongside other MRC-supported his colleagues found that around half of those who research into the effects of smoking, has led to a smoked were killed by their habit. The results also dramatic reduction in the number of people who showed that stopping smoking at ages 30, 40, 50 smoke in the UK over the past 50 years. and 60 increased life expectancy by around ten, nine, six and three years, respectively.

www.mrc.ac.uk | © Medical Research Council 2006 < Contents > Improving health through medical research Therapeutic antibodies

MRC research stemming from the 1970s has led to the development of monoclonal antibodies – which now make up a third of all new drug treatments for a variety of major diseases.

The invention of methods for producing therapeutic The early applications of monoclonal antibodies monoclonal antibodies has revolutionised biomedical included grouping blood types, identifying viruses, research and sparked an international multi-billion purifying drugs and testing for pregnancy, cancers, pound biotechnology industry. It has given rise to a blood clots and heart disease. However, applications new class of drugs for treating a variety of diseases, in human medicine were limited because mouse including cancer, arthritis and asthma. monoclonal antibodies are rapidly inactivated by the human immune response, which prevents them from In 1975, Dr César Milstein and Dr Georges Köhler of providing long-term benefits. the MRC Laboratory of Molecular Biology devised a way to isolate and reproduce individual, or monoclonal, Monoclonal antibodies began to reveal their full antibodies from among the multitude of different therapeutic potential in 1986, when MRC researcher antibody proteins that the immune system makes to Sir Greg Winter, also at the Laboratory of Molecular seek and destroy foreign invaders attacking the body. Biology, pioneered a technique to ‘humanise’ mouse monoclonal antibodies.This made them better suited They won the 1984 Nobel Prize in to human medical use as they were much less likely to elicit an inappropriate immune response in patients. Physiology or Medicine in recognition Sir Greg’s technology has since been licensed to around 50 companies, which have each paid a one-off of this ground-breaking work. licence fee and agreed to pay royalties on any resulting drugs that reach the market.

Monoclonal antibodies were initially developed from Sir Greg’s colleague Dr Michael Neuberger invented mice as a tool for studying the immune system. The the ‘Neuberger technique’ for producing humanised method is important because it allows the production monoclonal antibodies.This technology has been of large amounts of highly specific antibodies, enabling licensed to two companies. reproducible research measurements and results.

< Contents > Further patented research by Sir Greg along with scientists at the Scripps Research Institute in California 1975 Method devised to isolate and led to development of the ‘phage display’ method of reproduce monoclonal antibodies. producing monoclonal antibodies.The technique was used in the development of Humira® by Cambridge 1986 Techniques pioneered to ‘humanise’ Antibody Technologies, an MRC spin-out company. mouse monoclonal antibodies. Humira®, the first fully human monoclonal antibody 1990 drug, was launched in 2003 as a treatment for Test-tube production of highly specific rheumatoid arthritis. human monoclonal antibodies. 2003 Today, monoclonal antibodies account for a third of all First fully human monoclonal antibody – ® new treatments.These include therapeutic products for Humira – launched in the UK. breast cancer, leukaemia, asthma, arthritis, psoriasis and 2005 MRC signs deal with Abbott for rights transplant rejection, and dozens more that are in late- to Humira®, worth over £100 million. stage clinical trials.The size of the therapeutic antibody market is projected to more than double to around 2006 MRC spin-out company Cambridge £16 billion per year by 2010. Antibody Technology sold to AstraZeneca for £702 million. Monoclonal antibody technology has not only benefited human health.The UK economy also stands to gain: in 2005, US pharmaceutical company Abbott paid the MRC over £100 million in lieu of future licensing royalties for Humira®. And Cambridge Antibody Technology, of which the MRC is a shareholder, has been sold to pharma giant AstraZeneca. All of this money will be ploughed back into further research to improve human health.

www.mrc.ac.uk | © Medical Research Council 2006 < Contents > Improving health through medical research Reducing deaths from infections in Africa

The MRC has been carrying out pioneering research into infectious diseases in Africa for more than 90 years.Today, we continue to make significant headway in the fight against some of the world’s most challenging illnesses. Much of this work is carried out in partnership with the UK Department for International Development.

Improving HIV treatment delivery reduction in deaths compared with mortality The MRC-supported DART (Development of rates among HIV-positive Ugandans before ART Antiretroviral Therapy in Africa) study is looking at the was introduced. best way to deliver antiretroviral drugs in settings where While the main study continues, other findings from resources are limited. Although antiretroviral therapy DART are also helping to provide answers for AIDS (ART) has dramatically reduced the number of people health policymakers in Africa and worldwide. For who die from HIV-related diseases in developed instance, the study has answered important questions countries, the limited resources within health systems about how to manage anaemia (low red blood cell in many parts of Africa can make it difficult to use. counts) at the beginning of ART treatment, and has In particular, the blood tests needed to check the provided insights into side effects and effectiveness effectiveness and side effects of treatment are of different drug combinations. DART is a successful expensive and require laboratory support, which public-private partnership, with antiretroviral drugs is scarce in Africa. donated by GlaxoSmithKline, Gilead and Boehringer DART is a multicentre trial taking place in Zimbabwe Ingelheim and funding provided by the MRC, the UK and Uganda in collaboration with the MRC Clinical Department for International Development and the Trials Unit and . It is being US Rockefeller Foundation. carried out at three sites: the MRC/Ugandan Virus Vaccines research in The Gambia: Research Institute in Entebbe, the Joint Clinical Research eradicating Hib disease Centre in Kampala, Uganda and the University of Harare in Zimbabwe. The 3,300 DART participants are Sixty years of MRC research in The Gambia has led randomly allocated to either a group that regularly sees to a national vaccination programme that has Haemophilus influenzae a doctor with sophisticated lab support or a group completely wiped out type seen by a doctor without such support.The volunteers B (Hib) disease. One of the most common causes will receive ART during and after the five-year trial, of meningitis and bacterial pneumonia in children, without which half of them would die within a year. Hib is estimated to cause at least three million cases Early results have revealed that after two years 94 per of serious illness and hundreds of thousands of deaths cent of participants are still alive – a staggering 17-fold each year, mostly in developing countries. < Contents > MRC scientists first began work on Hib 20 years ago received a dummy vaccine. Tracking the children for four when they identified the bacterium responsible for the years revealed that the vaccine was 77 per cent effective disease. Between 1993 and 1995, the MRC tested a at preventing infection and resulted in a 16 per cent vaccine against Hib in 42,000 Gambian children. The reduction in the number of deaths and a 37 per cent results persuaded the Gambian Government to begin reduction in cases of pneumonia.The study was funded one of the first country-wide Hib immunisation by international health research funders including the US programmes in Africa. The researchers subsequently National Institutes of Health, and the pharmaceutical examined the vaccine’s effectiveness, looking at the industry. incidence of Hib disease from the start of routine Insecticide-treated mosquito nets: stopping vaccination in May 1997 until April 2002.They found the spread of malaria that Hib meningitis had been eradicated in children aged up to five. The MRC Laboratories in The Gambia demonstrated in 1984 that nets treated with biodegradable insecticides Pneumococcus vaccine: saving millions protect people from malaria, both by preventing of children mosquitoes reaching the skin and by killing them when Meanwhile, scientists at the London School of Hygiene they land on the net. Subsequent MRC studies showed and Tropical Medicine and the MRC Laboratories that use of insecticide-treated mosquito nets resulted in The Gambia have found that vaccinating infants in a 63 per cent reduction in deaths in children under in the developing world against pneumococcus could five. This work triggered large-scale trials in northern drastically reduce rates of death and serious illness. Ghana, Kenya and The Gambia, which led the United Responsible for around one million deaths every year Nations, the World Bank and the World Health among children in developing countries, pneumococcus Organization (WHO) Tropical Diseases Research bacteria invade the lungs and cause the most common Programme to fund research to improve methods type of bacterial pneumonia. They can then infect the for treating nets with insecticide. bloodstream or move into the fluids surrounding the brain and spinal cord, resulting in meningitis. The WHO estimates that malaria causes over a million deaths a year. The disease is a prime factor holding back In the 1980s, MRC scientists worked to find an effective economic and social development, especially in Africa. vaccine against pneumococcus in The Gambia. Between In some countries, malaria may account for 40 per cent 2000 and 2003 they vaccinated nearly 9,000 Gambian of public health spending; its indirect costs include lost children and compared them with children who productivity or income due to illness or death.

A snapshot of some of our ongoing Malaria work in Africa: • Studying the genes that control antibody response to malaria HIV in the Fulani people, who are less susceptible to the disease • Showing why type 1 HIV infection is more deadly than than other African groups. type 2 infection. • Conducting a genetic analysis of thousands of malaria sufferers, • Researching the use of a drug, nevirapine, to prevent which added to the extensive global MalariaGen project. mother-to-child HIV transmission. • Testing a new malaria vaccine, RTS,S/ASO2A, which may • Observing 18,000 people in Kyamulibwa to see whether protect children against the disease for 18 months. the HIV epidemic in Uganda is getting better or worse. Other research • Investigating whether the success of antiretroviral therapy • Research into the effectiveness of a new TB vaccine, MVA 85A. has affected patient behaviour and how being HIV-positive • Monitoring 40 Gambian villages, including births, deaths and is seen by the community. migration information, for a variety of population-based studies. • Testing the use of microbicide gel to prevent HIV • Studying the effectiveness of hepatitis B vaccine in children, transmission in 10,000 women. and its impact on rates of liver cancer in adulthood. • Examining differences in HIV progression, why some people • Researching the effect of counteracting poor nutrition with who are exposed to the virus remain HIV-negative, and what dietary supplements on the reduction of stillbirths and early happens to individuals infected with two subtypes of the virus. deaths of babies.

www.mrc.ac.uk | © Medical Research Council 2006 < Contents > Improving health through medical research Preventing heart disease

MRC research spanning four decades has contributed to vast reductions in the number of people dying each year from heart disease and strokes. Mortality rates today are almost 40 per cent lower than in the 1970s, due to drug and surgical treatments and reductions in risk factors such as smoking.

High blood pressure MRC scientists first carried out population studies into the effects of blood pressure in the 1950s and 1960s. In 1970, the MRC Epidemiology and Medical Care Unit was set up at Northwick Park Hospital in Harrow. Research by the unit revealed that high blood pressure was a major risk factor for heart disease and stroke. In the 1970s and 1980s, MRC scientists conducted two large multi-centre clinical trials into mild hypertension and showed that treating patients with the condition substantially reduced their risk of heart disease and strokes. Aspirin the wonder drug In the 1980s and 1990s, MRC researchers investigated the use of low doses of blood-thinning agents such as aspirin to prevent cardiac conditions. Major studies showed that this significantly reduced the number of deaths and illnesses related to heart attacks and strokes among patients who were at risk of these conditions.The researchers found that combined low doses of aspirin and warfarin could reduce heart attacks in middle-aged, at-risk men by around a third.

< Contents > Statin success Abdominal aortic aneurysms In a dramatic advance in 2002, the Clinical Trials In another breakthrough in 2002, MRC scientists Service Unit at the , which is showed that ultrasound screening could halve the jointly funded by the MRC and Cancer Research UK, death rate from abdominal aortic aneurysm among conducted the largest ever clinical trial of older men. Abdominal aortic aneurysms are balloon- cholesterol-lowering statin drugs. It showed that the like swellings in the aorta – the main artery that runs drugs could prevent around a third of heart attacks from the heart through the abdomen. Often fatal, and strokes in people at risk, as well as reducing the they kill thousands of Britons every year and death need for arterial surgery, angioplasty and amputations. rates in England and Wales have rocketed by 20-fold The study was funded by the MRC, the British Heart in men and 11-fold in women since 1950. Most Foundation and the drug companies Merck & Co Inc. patients die when an aneurysm ruptures, and the and Roche Vitamins. Based on World Health chance of this happening increases sharply with age. Organization estimates of the numbers of people with coronary heart disease, stroke and diabetes, it In 2002 MRC researchers studied 67,000 men aged can be estimated that if an extra 10 million high-risk 65–74 years old and showed that a national screening people were to start statin treatment, this would programme could save 2,000 lives a year and would save about 50,000 lives each year and would prevent be cost-effective for men over 65. As a result, the UK similar numbers from suffering non-fatal heart attacks National Screening Committee is considering or strokes. introducing a routine screening programme.

A subsequent study in 2005 showed that statins benefit people with diseased arteries irrespective of their cholesterol levels.The study combined data from more than 90,000 participants of previous trials of statins.The results also revealed that the greatest benefits occur in patients with the largest absolute reductions in cholesterol following treatment, regardless of their initial levels. Statins are now widely prescribed by UK doctors.

www.mrc.ac.uk | © Medical Research Council 2006 < Contents > Improving health through medical research Medical imaging: transforming diagnosis

Magnetic Resonance Imaging (MRI) and other imaging techniques have opened windows on our bodies and brains. Today MRC scientists are pioneering new imaging techniques that allow scrutiny of the tiniest structures to illuminate the origins of health and disease and help the development of new treatments.

Until 30 years ago, doctors had to rely on X-rays Advances in high speed computing and for showing bones and dense clumps of cells like superconducting magnets have since allowed tumours inside our bodies.Then scientists started researchers to build ever more powerful MRI scanners, using MRI – which makes use of the magnetic capable of producing stunningly clear images, making properties of cells – to create images of the body. it possible to detect early cancers and subtle damage The field took a huge leap forward in 1973 when to tissues including delicate nerve fibres. MRC-funded scientist Sir Peter Mansfield (pictured above) used MRI to produce exquisitely detailed MRI’s offspring, functional magnetic resonance imaging images of soft tissues. He won the 2003 Nobel Prize (fMRI), which also builds on techniques conceived by in Physiology or Medicine for this work. Sir Peter, is helping scientists to gain the first real understanding of how the brain functions by enabling The technique enabled doctors for the first time to them to view the working brain. peer deep inside the body, allowing them to diagnose disease without exposing patients to the trauma of Today MRI is used in research centres and hospitals exploratory surgery. worldwide to diagnose disease and monitor treatment. All major hospitals are equipped with MRI whole-body scanners and more than 22,000 systems in use Sir Keith Peters, President of the Academy worldwide perform at least 60 million investigations of Medical Sciences, called medical imaging every year. In 2005, MRC-funded researchers at the Institute of Cancer Research showed that MRI can “the most important advance in diagnostics improve breast screening for younger women. Their study revealed that MRI was twice as sensitive as X-ray in the twentieth century”. mammography at detecting breast cancer among under-50s who were at high genetic risk of breast cancer. MRI is also safer than traditional mammography as it does not use X-rays.

< Contents > CT scanning PET MRC research also played a role in the origin of Positron emission tomography, also called PET imaging computed tomography (CT) imaging, also known or a PET scan, is a highly sophisticated scanning as ‘CAT scanning’ (computed axial tomography), technology used to create images of molecular events an ingenious way of using X-rays to take images inside the body. As one of the most important tools of parts of the body. in hospital diagnosis, research and drug discovery around the world, it has helped understanding of CT scanning builds up three-dimensional images from disease processes and treatment in areas such as large numbers of low-dose X-rays transmitted across movement disorders, stroke, dementia and coronary the body. In a traditional X-ray film, there is no heart disease. dimension of depth. PET involves the collection of images based on the The principle of this method stemmed from research detection of radiation from the emission of positrons – by Sir Aaron Klug at the MRC Laboratory of Molecular particles emitted from a short-lived radioactive Biology, who put together ‘slices’ – electron microscopy substance given to the patient by injection or images – to form a detailed picture with depth. Sir inhalation.The MRC initiated the development of Aaron combined conventional electron microscopy PET 50 years ago by installing the world’s first medical with the use of X-rays to enhance the resolution of cyclotron, which produces artificially radioactive images of proteins. substances, at Hammersmith Hospital in London.

Sir , an engineer at EMI Central In 2001, a public-private partnership between the Research Laboratories in Middlesex, and Professor MRC and Amersham BioSciences (now GE Allan Cormack, a South African born physicist, Healthcare) established a new company, Hammersmith developed the technology of CT scanning. CT head Imanet, with substantial new funding including money and body scanners were tested separately in the early for a new cyclotron. Now, over 1,000 PET scans a year 1970s, work which the MRC supported. are run there for research purposes.Throughout the rest of the UK there are 10 cyclotrons used in medical Sir Godfrey and Professor Cormack shared the projects, with many hundreds around the world Nobel Prize in Physiology or Medicine in 1979. producing materials for diagnostic scans and medically- Then in 1982, Sir Aaron won the Nobel Prize in related research. In pre-clinical research, such as that Chemistry. The development of the CT scanner has carried out at the MRC Centre for Behavioural and had an explosive impact on diagnostic radiology and Clinical Neuroscience in Cambridge, PET imaging is its principles have been applied to other areas including used to determine where in the various ultrasound imaging. cognitive operations are carried out and can also establish how drugs work to produce changes in brain chemistry, and how these affect behaviour.

As a convenient non-invasive technique, PET imaging is increasingly used in MRC phase II clinical trials to assess changes in the body. For example, a scan can reveal how active a patient’s tumour is or track diabetes by measuring the quantity of insulin-producing cells in the pancreas.

www.mrc.ac.uk | © Medical Research Council 2006 < Contents > Improving health through medical research Cutting child leukaemia deaths

As a result of MRC research, four in five children with leukaemia now recover, compared with only one in five 25 years ago.

MRC studies over the past 25 years have had a major ALL is by far the most common type of leukaemia influence on the treatment of children with acute in children and accounts for around a quarter of all lymphocytic leukaemia (ALL) and have increased the childhood cancers. Around 380 UK children are recovery rate from around one in five children to four diagnosed with ALL every year. This means that about out of five. This advance is the result of many gradual 230 children who would have died each year now go improvements in treatment for the disease, achieved on to lead healthy lives because of the improvements through a series of clinical trials aimed at finding the in their treatment. best therapy. The MRC began research into childhood ALL in the 1950s following recognition that the disease was a virtual death sentence for children.

In the 1970s, the MRC formed a leukaemia steering committee to encourage collaboration between all hospitals and doctors across the UK that were researching and treating childhood ALL. This partnership has enabled the MRC to carry out an ongoing series of ‘rolling’ clinical trials.These are set up so that the most effective treatment in a study is then compared with a potential new treatment in the next study. The Clinical Trial Service Unit at the University of Oxford, which is jointly funded by the MRC and Cancer Research UK, has coordinated the majority of these trials.

< Contents > Increasing a child’s chance of life four-fold Dramatic improvements in the rate of survival started to occur in the 1980s. Today, four in five children recover following treatment. And more than 90 per cent of UK children who are treated for leukaemia take part in clinical trials.This means that they receive either the best therapy currently available or an experimental treatment that may offer even more benefits.

In recent years, the focus of MRC childhood leukaemia research has moved away from improving survival and towards identifying the most appropriate treatment for the individual child. A quarter of children initially fail to respond to chemotherapy and need further treatment, which can be very toxic and expensive. So MRC clinical researchers are now trying to increase the success rate of initial treatment so that the disease is less likely to recur. Some children who are cured may develop treatment toxicity-related problems in later life. MRC scientists are therefore also trying to identify patients who are likely to respond to lower doses of drugs, to minimise their exposure to toxic drugs.

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