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The impact of medical research is multi-faceted and the road to discovery of new treatments can be long and complex. The productivity of medical researchers is assessed according to professional criteria such as publications in prestigious journals and citations of their work, securing research grants and presenting their results at conferences. However, it is equally important to demonstrate the impact research has on disease. Often the timeframes required to improve patient well-being can involve many years of research.
'New cures don’t fall magically from the sky. Only research will allow us to understand the problems we face and develop new treatments’.
Professor Peter Klinken, Harry Perkins Institute of Medical Research
In the genome
The announcement that scientists have for the first time been able to unravel and read the entire human genome – the DNA instruction manual that underpins all human life – sparked hopes that some of the world’s most deadly diseases could finally be beaten.
The genome is the list of genetic instructions, encoded by the genes within our DNA, needed to make a human. Remarkably, only 20,000 genes were identified, which was much less than predicted. This accounted for approximately 2% of the genome, leaving much to be discovered about the role of the remaining 98% of human DNA.
New sophisticated sequencing technologies have been developed recently called ‘Next Generation’ sequencing. While it took over a decade to sequence one human genome for the Human Genome Project, the revolution in ‘Next Generation’ sequencing now enable researchers to complete an entire genome in a matter of days. Western Australia has become involved in this revolution and is capitalising on the huge amounts of sequencing data that is being generated worldwide.
Connecting the dots
The raw output data from an automated DNA sequencing machine used by the Human Genome Project to determine the complete human DNA sequence. Getty Images
Once all the DNA in the human genome is sequenced, it must be assembled into a complete genome. The process, commonly known as secondary analysis, completes the picture of an individual’s genetic makeup. This is followed by the interpretation phase, where changes in DNA called mutations can be matched with certain diseases or physical traits. The next step is to combine this knowledge with other medical factors, such as the patient’s history, environmental factors and family background. The end result? Researchers can then translate indicators of disease and drug responses into improved treatments, which in turn can be tailored specifically to each patient.
The sequencing of the human genome has ushered in a new era of biology where a one-drug-fits-all treatment is being challenged to one that is personalised depending on the genetic make up of the individual. This has transformed biology where previously one gene was studied at a time, to a world in which whole genomes can be studied simultaneously. By analysing the genome data, researchers will understand better why certain individuals are pre-disposed to diseases, and how they might respond to specific therapies.
Standard laboratory blood tests allow for fewer than 20 variables each measurement. Thanks to the data available from the human genome project and cutting edge measurement tools, many thousands of variables can be measured simultaneously. This new chapter in medical research has opened the door to a better understanding of how our bodies interact with the environment, and how to best target treatment for many complex diseases at a truly personal level.
The genetics of movement
Sufferers with Laing distal myopathy (shown) are unable to lift their fingers and feet. The condition, named after Professor Laing, affects the skeletal muscles needed for movement. Courtesy of Professor Nigel Laing, Harry Perkins Institute of Medical Research.
Professor Nigel Laing’s team has uncovered genetic mutations linked to devastating muscle disorders called myopathies, providing families with important answers and better diagnosis.
Over 20 disease genes have been found so far, including diseases associated with actin and myosin, the two proteins most crucial to movement and muscle contraction. In their most severe forms, these diseases cause the total paralysis of babies at birth.
Professor Laing’s research into this area began with a large family from South Australia that contained ten living affected people with one myopathy called nemaline myopathy. The study led to discovering the mutated gene was a tropomyosin, one of the key proteins in muscle fibres.
This discovery led to studying thousands of DNA samples from patients and families all around the world with other myopathies. The research led by Professor Laing’s group at the Harry Perkins Institute of Medical Research has helped families around the world.
From cancer to fertility
SLIRP in cancer cells. Courtesy of Dr Shane Colley, Harry Perkins Institute of Medical Research
Professor Peter Leedman’s discovery of the SLIRP gene has taken him and his team of cancer researchers into unfamiliar terrain. The initial discovery of SLIRP showed that the gene has the potential to shut down the hormones estrogen in breast cancer cells and testosterone in prostate cancer cells.
SLIRP also has a functional role as a regulator of metabolism, linking it to diabetes. Its most unexpected role, however, is that it is vital to male fertility. SLIRP is a potent regulator of testosterone activity and is expressed in fertile sperm. Professor Leedman’s research suggests SLIRP is present in the head and tail of the mature sperm, and without it fertility becomes difficult. This finding encouraged Professor Leedman’s cancer team, led by Dr Shane Colley, to think more about male fertility, sparking collaborations between research areas. The implications of this research have the potential to lead to more personalised treatments for men with infertility who may have defects in SLIRP.
Energy for life
The green fluorescent markers in this image show the mitochondria in a cell. Mitochondria are microscopic, energy-producing machines found in all human cells. Courtesy of Professor Oliver Rackham, Harry Perkins Institute of Medical Research
Mitochondria are microscopic, energy-producing machines found in all human cells. Defects in genes that make up mitochondria cause debilitating diseases for which there are no known cures. Professor Aleksandra Filipovska’s group at the Harry Perkins Institute of Medical Research have developed new technologies to help understand how defects in mitochondrial genes cause disease, providing insights into new treatments. By creating maps of human mitochondrial genes, knowledge of how these genes work and mutate can be studied, enabling the development of personalised drugs that target the defective genes or proteins.
Professor Filipovska’s research team has discovered how specific mitochondrial proteins regulate the energy requirements of human tissues. This is particularly important since different tissues have varying energy requirements. For example, tissues such as the heart or brain that require more energy have more mitochondria compared to tissues with lower energy demands such as the skin.
|Courtesy Victor Chang Research Institute|
The heart is an amazing organ. It’s the first in the body to start functioning during embryonic life and from that early stage it beats relentlessly – contracting about 70 times a minute, 100,000 times a day, two and a half billion times a lifetime. It pumps 70 ml to 100 ml of blood per beat, carrying oxygen and nutrients to all your body’s organs and tissues. The heart has a left side and a right side, divided by a wall of muscle. Each side has a small collecting chamber called an atrium, and a larger lower pumping chamber called a ventricle. Between each pair of chambers is a valve which only lets the blood flow in one direction. There are also valves between each ventricle and the artery it feeds.
The right side of the heart collects blood that has been depleted of oxygen as it returns from the body. This blood is pumped through the pulmonary artery to the lungs, where the oxygen is replenished. It then returns to the left side of the heart, where it is pumped through the aorta and out to the body again. The left ventricle is larger and thicker than the right ventricle, so it can produce the higher pressure needed to pump blood round the body.
Blood moves through the body along a network of vessels called arteries, veins and capillaries. Arteries carry blood away from the heart, while veins carry blood towards the heart. Capillaries, which are too small to be seen with the naked eye, carry oxygen and nutrient rich blood from the arteries to the tissue cells and then back into the veins. This constant flow of blood – from the heart to the lungs, back to the heart, out to the body and back to the heart – takes about 23 seconds. The whole system is known as your Cardiovascular System, which comes from the Greek word cardiac meaning heart and the Latin word vasculum meaning vessel.
Portrait of a failing heart
Since the completion of the human genome project heart specialists have been searching genome data for genes relating to heart attacks. However, unlike other disease areas, such as cancer, few genes have been found with a link to vascular genetics. This has led to an entirely new research approach where the whole genome is analysed, rather than just the areas that directly relate to the heart. Results of whole genome screening have revealed unexpected associations, for example between heart attacks and cancer. Surprisingly, many of the associations are not related to cholesterol or blood pressure, so the mechanism by which it causes heart disease is unknown. Professor Peter Thompson found a cancer gene with an association to the heart, prompting new research connections between cardiovascular and cancer research teams.