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Schools’ Day 2008

The theme of the 2008 meeting was How molecular biology shapes our understanding of the living world.

Talks

The afternoon began with presentations by scientists from the Institute who gave short talks about their work. Talks held included:

• Introduction - Dr Michael Sargent

  Mike Sargent introduced the theme of the afternoon "How molecular biology shapes our understanding of the living world."

  Molecular biology is probably the most significant cultural achievement of the last fifty years. Since the first suggestion of what the structure of DNA meant, we have seen an extraordinary growth in our knowledge of the biochemical basis of life. In 2001 the complete sequence of the human genome was published, which we assume is a statement of what it is to be human. It is not easy to comprehend and may take centuries to understand in its entirety, but it surely contains all the answers to the most puzzling aspects of human biology.

  Mike Sargent

  Mike then listed some of the achievements of molecular biology:

  • The significance of the structure of DNA
  • The genetic code, with assignments of codons
  • Discovery of mRNA
  • Role of ribosome as a machine for protein synthesis
  • Enzymes of molecular biology, restriction enzymes, DNA ligase etc
  • Commercial manufacture of proteins in cell factories (insulin and monoclonal antibodies)
  • Chemical basis of acquired immunity (recombination of constant and variable regions)
  • Understanding of chemical basis of mutation and gene rearrangement
  • Their role in genetic diseases, cancer and ageing.
  • Jumping genes (transposons, important in transferable drug resistance)
  • Oncogenes (genes that can cause cancer, formed by DNA rearrangement)
  • Role of reverse transcription in cancer viruses
  • Genetic finger-printing
  • Understanding prion proteins (cause of BSE and Creuzfeld-jacob syndrome).
  • Gene splicing
  • RNAi (interfering RNA). Double stranded DNA that can inactivate genes
  • Significance of transcription for developmental biology. In-situ hybridisation
  • High throughput DNA sequencing . Human genome project.
  • Molecular understanding of classical genetics (dominance, recessiveness and recombination)
  • Epigenetics. Secondary chemical changes to DNA or chromatin that affect gene expression
  • Micro-array technology for RNA for profiling tissues
  • Nuclear transfer (dolly the sheep), demonstrates that a nucleus can be reprogrammed.

• How DNA makes a faithful replica of itself - Andrew Slatter

  DNA and RNA are the only chemicals in the natural world that can replicate themselves. This miraculous process occurs only in cells, for DNA only once in every cell cycle and depends on enzymes found in the cell. These nucleic acids act as 'blue-prints' for the development of a particular organism. Replication of the genome is therefore a highly important process, which ensures that progeny inherit an intact genome.

  During this process, the two strands separate and are used as templates for the assembly of a complementary strand. Strand separation is driven by an enzyme called DNA helicase that unwinds the two strands. The daughter strands are assembled from the four nucleotide triphosphates (the substrates), which are added to an existing DNA strand through the 3_ position of deoxyribose by DNA polymerase. This means replication can occur in only one direction.

  One daughter strand is a continuous replica of a parental strand but the other daughter strand is made in short stretches, replicated in the opposite direction. The parental strands are in an antiparallel configuration which means the 3_ position of the deoxyribose in each strand faces in opposite directions.

  DNA polymerase makes an exact copy of the parent strands of DNA, but how accurate is this process? What would happen if the wrong nucleotide was incorporated? We know that errors do occur in replication resulting in mutations. For example about half of all cases of haemophilia arise through spontaneous mutations.

  How do we study these processes in the laboratory? Modern biophysical techniques have allowed us to measure various parameters involved in DNA replication, and it is now possible to measure the rate of unwinding by a DNA helicase.

• Using molecular biology to study development of embryos: limb formation in chicks - Anna Garner

  Every cell in an organism has the same DNA and yet we know that at least several hundred different kinds of cells make up the mammalian body. How is this possible?

  The answer is that genes produce (or express) products to different extents in different cells. When molecular biologists use the word 'express' it alludes to the optional character of this process. In some cases, expression of a gene is suppressed completely in all cells of the body except for perhaps one cell type. (Example: reticulocytes are the only cell that makes haemoglobin but this red protein persists in the red blood cells that are derived from reticulocytes). This happens because transcription of genes is always selective; a kind of molecular switch regulates each gene. Although RNA polymerase (II) makes almost every protein-encoding mRNA, initiation of transcription is precisely regulated by other factors. Transcription starts at a specific sequence known as a promoter. The use of this site depends on other proteins known as transcription factors that bind to these sequences to create an environment where RNA polymerase can function.

  Once a fertilised egg starts to divide and develop into an organism, certain cells take on distinctive characters that will eventually commit them to becoming particular tissues or organs. Genes switch-on and turn-off at precise times and places in the embryo, and the product of one gene probably turns on other genes in a precise time sequence. This is the basis of an important subject, developmental biology, which is all about how an organism emerges from a collection of undifferentiated cells. A technicque called in-situ hybridisation is used to show where in a tissue the mRNA is located. This employs RNA made in the test tube that is complementary to the message, which "hybridises" to mRNA. A neat chemical trick allows us to see with a microscope where the message is located. The study of specific mRNAs in a chick egg can help us understand how chick limbs develop.

• How to find what genes do; knockout mice and interfering RNA - Dr Julia Cocquet

  If we are to use our knowledge of molecular biology and genetics to understand and improve human health, we need ways of finding the role of individual genes. The study of inherited genetic diseases (like haemophilia) tells us about the importance of one group of genes. However, many more genes look potentially interesting and important but we need a method to establish their precise role. It is a relatively easy matter to inactivate (knockout) genes of prokaryotes (bacteria) and see how this affects bacterial physiology. For mammals, the same approach is conceptually far more complicated. Mammalian cells are diploid, and mutations may be recessive, so we can see the full effect of a mutation only if it is present in the homozygous form (ie each set of parental chromosomes carry the mutation).

  Knockout mice

  To address such questions, we use an intricate scheme for manipulating the genomes of laboratory mice, to "knockout" the gene of interest from both sets of chromosomes. Briefly, mutations are made in cultured embryonic stem cells (cells that can make every cell-type in the body). These cells are implanted in the uterus of a mouse where they form a mouse that is heterozygous for the mutation. Subsequently, homozygous mice are obtained from cross of two litter mates. This is now a widely used generic procedure for creating laboratory mice that can be used for, amongst other things, testing drugs that may be useful for treating specific human genetic diseases.

  Interfering RNA

  Another approach to identify the function of genes is to use interfering RNA (RNAi) to destroy the mRNA. This exploits an observation first made in plants and the nematode Caenorhabdidtis elegans. A small piece of double-stranded RNA containing the sequence of the mRNA of interest can initiate a process that destroys the mRNA and allow us to assess the importance of that gene.

• Understanding proteins - Dr Oliver Schenkler

  The study of proteins has a special place in every branch of biomedical research. Proteins are the remarkable group of chemicals that carry out all the important physiological functions of cells and form a large part of all the structures found in a cell. The character of particular proteins are critical to almost every topic and every physiological process studied by biologists. Because they have a linear modular organisation, in which one of 20 amino acids can occupy each position, they can form an almost infinite variety of structures.

  When proteins form on the ribosome they fold up in characteristic ways driven by bonds that create a secondary and tertiary structure. The secondary structure is hydrogen bonds and the tertiary structure includes hydrophobic (water hating) and disulphide bonds that stabilise the secondary structure. Genome sequencing projects identify presumed protein-coding sequences. These include many proteins from many kinds of organisms that have never existed in the laboratory. However, these can now be made in cellular factories using gene technology. They can be purified by a variety of methods, crystallised and their structure determined in atomic detail using X-ray diffraction of the crystals. Understanding the structure of a protein provides profound insights into their cellular or physiological role.

  Some remarkable proteins:

  • Fastest known chemical reaction (rhodopsin). Makes real-time vision possible.
  • The biggest protein (Titin, a huge - 28,000 residues - spring-like protein found in muscle Oxygen transporter in blood (haemoglobin) Transparent crystalline material (crystalin, in eye lens).
  • Most stretchy and strongest (silk fibroin from spiders and silk worms).
  • Most poisonous (ricin from castor oil bean) Contractile proteins (actin-myosin).
  • Coloured proteins (cytochromes, red; caerulein, blue; xanthine oxidase, yellow) Able to recognise chemical groups with great specificity. (Antibodies).
  • Light emitting (luciferase from fire flies) Fluorescent (green fluorescent protein from Pacific Jelly fish).

Demonstrations and posters

A break for refreshments provided students with an opportunity to see demonstrations of some aspects of the development of mice, chicks, frogs, fish and flies. Posters relating to the theme of the meeting and work done by last year's Nuffield Bursary students were also on display. In addition, a poster exhibition of biomedical science news published in 2007 was used as a source for the quiz. Poster topics included:

• Nobel Prize for Medicine 2006 - RNA interference. An extraordinary phenomenon discovered in the humble nematode has provided an unexpected opportunity to develop new medicines. A 20bp double stranded piece of RNA can inactivate an mRNA. This has enormous potential for scientific investigations and possibly in medicine.
• Nobel Prize for Medicine 2007 - The 2007 Nobel Prize for Medicine was awarded for the discovery of a method for modifying the genetic constitution of mice by the use of embryonic stem cells. This includes techniques known as making "knock-out mice", "knock in mice" and the concept of "gene targeting". Mario Capecchi and Oliver Smithies discovered how to introduce genes into cells by homologous recombination (like crossing over in meiosis). Evans discovered mouse embryonic stem cells.
• Extraordinary proteins - There are an infinite number of possible structures and have properties no human could have invited.
• Childhood Leukaemia - and the identical twins Olivia and Isabella. A tragedy that afflicted one of these twins has uncovered some important biology.
• Epigenetic effects. - Changes in gene function occur without a change in DNA sequence) could be the route by which environmental factors affect our life expectancy

Quiz and discussion

The demonstrations were followed by a quiz, based on the day's presentations. The day ended with a discussion panel comprised of scientists and graduate students from the Institute, with science, ethics and careers being the main topic covered.