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Cells for life
Cells are the basic unit of any living organism, with each cell containing a complete copy of the organism’s genome, its DNA. Each cell in our body performs a specific task, for example red blood cells carry oxygen, while white blood cells fight disease. All our life processes go on inside these tiny cells that are packed with even smaller organelles, such as mitochondria, which produce energy and nuclei that contains the cell’s DNA.
Cell division produces more cells as the body needs them, either to replenish those with a limited life span, such as blood and skin cells, or replace cells that have been damaged. There are approximately 300 million cell divisions occurring in our bodies every day.
Stem cell research began with the discovery that immature stem cells could generate mature, specialised cells. There are different kinds of stem cells: embryonic stem cells derived from excess in vitro fertilized (IVF) eggs, and adult stem cells produced by adult tissues. Embryonic stem cells can generate all cell types in the body, whereas adult stem cells are more restricted in their capabilities, but act as a repair system replacing worn out or damaged tissues.
Currently, embryonic stem cells are used only for research, while adult stem cells are used are used to treat diseases such as leukemias and lymphomas. Cord blood stem cells are also used to treat certain blood disorders. It was considered for a long time that specialised (differentiated) cells could not alter their appearance or function.
Harry Perkins Institute of Medical Research Professor Peter Klinken showed that it was possible to convert B cells (part of the immune system) into macrophages (scavenger cells) by introducing two genes. In 2012, Professor Shinya Yamanaka was awarded the Nobel Prize for reversing the process of differentiation and turning specialised cells back into stem cells. By introducing four genes into mature (differentiated) cells, he was able to convert them into stem cells which he called IPS cells. This breakthrough has revolutionised our understanding of stem cells and differentiation.
‘We wish to put forward a radically different structure…’
James Watson and Francis Crick, Molecular Structure of Nucleic Acids, Nature Magazine, April 25, 1953
In April 1953 James Watson and Francis Crick presented what was to become one of the most understated breakthroughs in science. Published in Nature magazine, the findings revealed the structure of deoxyribonucleic acid (DNA), the molecule that carries genetic information from one generation to the next. Although by then scientists understood that DNA was most likely the molecule of life, without knowing what it looked like meant that their assumptions could not be confirmed.
The structure, presented by Watson and Crick, and co-discovered with biophysicist and x-ray crystallographer Rosalind Franklin, demonstrated that the DNA molecule was a double helix made up of chemicals called nucleotides. They showed that the genetic information in DNA was encoded by the sequence of four nucleotides – Adenine (A), Cytosine (C), Guanine (G) and Thymine (T).
The precise order of these nucleotides in DNA determines each individual’s characteristics. Nine years later, in 1962, James Watson and Francis Crick shared the Nobel Prize with Maurice Wilkins, for solving one of the most important of all biological riddles. When we are born the DNA in our bodies provides the blueprint for who we are, and who we will become. For example, it will determine our eye colour, our hair colour and a multitude of other factors, which define us during the course of our lives. Half our DNA comes from our father, and the other half comes from our mother, making us the unique individuals that we are.
The central Dogma of Life, first stated by Nobel Laureate Francis Crick in 1958, describes this flow of genetic information in our bodies. The underlying theme of this concept is that DNA is responsible for the storage and transmission of inherited information. It transfers that information via a related molecule called RNA, which then produces proteins, the molecular building blocks of all cells in our bodies.
DNA makes RNA makes protein. This information flow is essential for all functions necessary for life.
How are our DNA instructions ‘read’ and how does this go wrong in cancer?
When the Human Genome was first sequenced, it was a big surprise that only 2% of our DNA was made up of protein-coding genes. The rest was known as noncoding DNA or ‘Junk DNA’, and was thought to be of little importance to a cell’s function. Associate Professor Archa Fox has been involved in a breakthrough discovery that helped show Junk DNA’ is not useless, but can actually form small parts of the cell called ‘paraspeckles’. Associate Professor Fox’s research explores many aspects of paraspeckles and ‘Junk DNA’ function. In particular, she investigates their roles in cancer, how this process works and if they can develop useful anti-cancer diagnostics and therapeutic targets.
‘Cancer is like a normal kid that mixes with the wrong crowd and turns bad’.
Professor Peter Klinken, Harry Perkins Institute of Medical Research
Growing cells outside the body
To understand how cells work, researchers have developed ways to grow cells outside the body. Within the laboratory small samples of normal or abnormal cells are collected from patients, and grown in an incubator that creates the same conditions as in the body. These cells are given food, water, oxygen and warmth. Waste chemicals and carbon dioxide are removed so the cells can grow in size and increase in number, just as they do in the body. The process of growing cells outside the body is called tissue culture. Importantly, to prevent contamination of the cells by bacteria, fungi or viruses, tissue culture is performed inside cabinets with equipment that has been sterilised to make them microbe free.
Almost a century ago one of the most unexpected medical breakthroughs in human history occurred. Scottish scientist Alexander Fleming discovered a mould growing in one of his petri dishes. Looking closer, he realised that wherever the mould was growing, the Staphylococci bacteria he was culturing had died. He spent the next decade growing the penicillium mould while trying to isolate the antibiotic it secreted. Ten years later Australian scientist Howard Florey and German-born British biochemist Ernst Chain purified and concentrated the compound, transforming penicillin from an interesting observation into a lifesaver. The drug’s success in treating bacterial infections earned Fleming, Florey and Chain the Nobel Prize in Medicine in 1945.
The Harry Perkins Institute of Medical Research has an original display of the miracle mould signed by Alexander Fleming. Make a booking and see the the discovery that changed medicine forever.
Crystals are famous for their beautiful appearance, but it is their internal structure, too small to be seen by the eye, that makes them so interesting to scientists. Crystallography can reveal the three-dimensional arrangement of the smallest entities of matter, including DNA and proteins. Once these molecules have been crystallized, an X-ray source is aimed at the crystal, and the diffraction pattern that is created as the X-rays strike the crystal is then analysed. Approximately 85% of the known protein structures and complexes have been determined using crystallographic techniques. It is a fundamental tool to obtain crucial information in structural biology, as well as drug discovery and design.
Courtesy of Professor Charlie Bond, UWA
The combined use of crystallography and other methods have been invaluable in understanding biochemical processes in the living cell. For example, by combining microscopy and crystallography, Associate Professor Archa Fox from the Harry Perkins Institute of Medical Research and Professor Charlie Bond from UWA revealed a ground-breaking new molecular structure formed by two human proteins involved in turning genes on and off in cancer. While previous studies had shown the importance of these proteins to normal cells and cancerous cells, this was the first time researchers had a picture of what they looked like. The image to the left reveals a tight embrace between the proteins NONO (blue) and PSPC1 (yellow) that explains for the first time how they work together inside cells. Using crystallography the structures of the NONO and PSPCI proteins have been studied. The conspicuous hole in the middle of the structure suggests a possible place for binding key RNA molecules in cells, while the coiled-coil arrangement at the right offers cluses as how to many of these dimers, along with RNA, can interacts to form subnuclear bodies termed paraspeckles.
Luminescence and fluorescence
It takes a leap of faith to believe a jellyfish can help resolve health burdens that disease will place on our society. At the Harry Perkins Institute, Associate Professor Kevin Pfleger and his team are studying how proteins in cells interact, using a technique called Bioluminescence Resonance Energy Transfer (BRET). The green fluorescent protein that is used in these experiments comes from a bioluminescent jellyfish, sometimes called the crystal jelly. When the jellyfish is stimulated a green fluorescence can be seen around its edge.
In BRET experiments, the green fluorescent protein is attached to a protein that is being studied, and a green light is emitted only if the protein is extremely close to another protein. This is important because it allows researchers to understand how proteins interact with each other in normal cells, and how incorrect interactions can cause disease.