Tag Archives: health

Interview with David Bowtell

By rivqa Posted in Interviews, Science Tagged , , ,

This article was originally published in issue 3 of the MMIM newsletter.

Professor David Bowtell is the Director for Research at the Peter MacCallum Cancer Centre. Although Prof Bowtell studied veterinary science, he has never worked as a vet. Instead, he found himself in biomedical research, initially working as a cell biologist. Here he talks about his work and how the MMIM database can help.

The Peter MacCallum Cancer Centre, or ‘Peter Mac’, as it is affectionately called, is unique in Australia, with an all-inclusive approach to cancer treatment. It is a specialist cancer hospital, where research, support and care are fully integrated. As well as boasting one of the largest cancer research facilities, Peter Mac runs clinical trials and offers state-of-the-art services and care, including medical imaging. Peter Mac is the only centre of its kind in Australia, with very few similar institutions existing outside of the United States.

Prof Bowtell likens his position as Director to the ‘captain of a footy team’ – he has a leadership role but also needs to kick a few goals himself. As well as working in his own lab, he coordinates other aspects of the Centre, including writing grants for the research division as well as the genomics program specifically.

In addition to his role as Director, Prof Bowtell runs a large medical genomics laboratory, which has a focus on ovarian and gastric cancers as well as carcinoma of unknown primary (CUP). CUPs are cancers that do not have a known point of origin, but their sources can be detected by taking biospecimens and testing samples. One test that is extremely useful for CUPs is microarray testing, and it is this data that is present on the MMIM database.

Prof Bowtell became involved in MMIM through his lab. He feels that MMIM is important for cancer research as it allows scientists to gather clinical information, which can then be related to known genetic information. This facilitates the development of predictive models for oncology as well as for other areas.

His lab started working with spotted microarrays in 1999. They now use microarrays (specifically Affymetrix microarrays) to classify different cancers into patterns of gene expression. For example, the primary source of CUPs can be determined by using microarray technology to compare it to cancers with known primary locations.

Tumours from patients with the same type of cancer, but different outcomes, can also be compared to analyse for risk of reoccurrence of tumour formation after remission. This can help doctors plan long-term treatment, as an increased risk would indicate more aggressive treatment.

When asked about his thoughts on a ‘cure for cancer’, Prof Bowtell said that at Peter Mac, researchers are studying the molecular basis for different types of cancer. They are looking at the individual molecular pathways involved and treating each one separately. It seems that there are multiple cures for cancer, rather than the single one that we were previously searching for.

Molecular genetic information can help at all stages of cancer development: diagnosis; staging (determining how advanced the cancer is); planning treatment; implementing treatment; assessing family risks; and managing these family risks.

Peter Mac is involved in cutting-edge research into chemoprevention, which can be likened to vaccination – chemotherapy can be used to prevent cancer ever forming in high-risk patients. And while early detection of cancer is important, genetic information can indicate how aggressively to treat a tumour that has been found promptly. This type of individualised treatment may be the way of the future, and comprehensive organisation and sharing of the information, in a format such as MMIM, is a vital tool for this type of research.

Spotlight on diabetes

By rivqa Posted in Science Tagged , ,

This article was originally published in issue 2 of the MMIM newsletter.

Associate Professor Colman is a consultant endocrinologist and is the head of the Royal Melbourne Hospital’s Diabetes and Endocrinology Clinics and Services. After completing his medical degree, he undertook research training in Melbourne and then Boston, before returning to Melbourne to work. He now researches early diagnosis of Type 1 diabetes and still treats patients as a consultant. In this role he tests how diabetes treatment is progressing, and looks for problems or complications.

Although this work focuses on young children, adults can also develop type 1 diabetes. When asked why he chose to work with Type 1 diabetes, Colman cited the greater knowledge of the genetics of Type 1 as one factor. With Type 2, we know there must be genetic causes but we don’t really have a clear idea of what they might be. With Type 1, however, the genetics are much clearer.

Colman is researching the possibility of detecting type 1 diabetes before symptoms are seen. Type 1 diabetes has a strong genetic background, putting relatives of sufferers at increased risk. However environmental factors affect whether it will actually develop. Some researchers have suggested the possibility of a particular viral infection acting as a determining factor.

In order to study this, Colman’s research group is running several different projects with people who don’t (yet) have Type 1 diabetes, looking for antibodies to pancreatic cells.They are studying risk factors that may cause it to develop.

Colman and his colleagues decided to work with MMIM because it allows a spectrum of many different people to be put together, giving the big picture. For the first time, relatives of type 1 sufferers; children with a parent with type 1; and randomly selected school children can be compared directly. They wanted to compare data on a large scale, and as Colman states, ‘MMIM has given us this opportunity’. Hopefully, putting it all together will help determine risk factors and thereby prevent diabetes.

The MMIM project is very exciting for diabetes research, as it allows the possibility of ‘building of resources that would last forever’. The group can ‘already ask questions across the database that we hadn’t been able to do previously’.

When deciding what data to include in MMIM, Colman also included diabetes patient data. This allows a study of the risks of insulin treatment. For example, different types of cancer are suspected to be linked to this type of treatment. Also included is data from the diabetes clinic – there is now ten years’ worth of information about treatment, patient’s cholesterol levels, blood pressure, kidneys and eyes. The possibility for new discoveries are endless and as Colman says, MMIM is ‘pretty unique actually’.

A/Prof Colman is obviously passionate about his work, as he explains how it was originally thought that pancreatic cells don’t regenerate. Now it is believed that they do, which is important for stem cell research. If they do regenerate, it means that the immune system continues to attack the pancreatic cells, so stem cell transplants may not be effective. However it also hints that prevention could also be cure – if the auto-immune reactivity can be halted, then the pancreatic cells can be saved. He also touches on the ‘interesting crossovers’ between Type 1 and Type 2 diabetes.

In summary, though, he agrees that people often think diabetes is a disease where you’ll have to have insulin shots for the rest of your life, but says, ‘it’s not very satisfactory to think that diabetes is something that you just have to deal with’. Hopefully joining the MMIM database will open up more possibilities to change that.

MMIM: an introduction

By rivqa Posted in Science Tagged , ,

This article was originally published in issue 1 of the MMIM newsletter.

How often do you worry about your health – the conditions you might develop or inherit? Imagine being able to have your DNA analysed for potential diseases, and dealing with them before they become serious. Or, for those with conditions that are already present, being prescribed medication to match your unique genetic profile.

Many diseases are known or thought to be affected by genetic predispositions. A person is much more likely to develop type 2 diabetes if other family members have the condition. However, diabetes is even more dependent on environmental factors, mainly diet and exercise. People living a Western lifestyle are far more likely to develop diabetes than non-Westernised people, regardless of genetic predisposition. If a person with at risk of developing diabetes is aware of it, he or she can make lifestyle changes to avoid this outcome.

Similarly, several types of cancer are known to have genetic factors. Breast cancer is probably the most famous example. Women with a close relative with breast cancer are more likely to develop it themselves. Certain variations in two genes, BRA1 and BRA2, are associated with breast cancer. DNA testing can be used to identify these variations in individuals.

It is likely that other genes are involved in breast cancer, and that other types of cancer have similar genetic associations. These connections can be made by studying the genetics of past and present cancer patients. Melbourne Health is working to link the relevant genetic data and clinical information for patients with colorectal cancer, diabetes and epilepsy, with more diseases to be added in time.

This project, the Molecular Medicine Informatics Model (MMIM), is a collaborative effort between scientists studying genetic aspects of disease; epidemiologists (researchers of public health); and IT specialists. They are combining their expertise and results to create a virtual database of genetic and clinical data from several different sources (Melbourne Health; Austin Health; the Peter MacCallum Cancer Centre; and the Ludwig Institute for Cancer Research). Scientists can use this database to help them study how certain genes relate to specific diseases.

This is where the benefit to patients, or people who might become future patients, comes in. With the identification of more genetic factors that cause diseases such as cancer, people in higher risk groups, or the general population, can have their genetic make-up tested. If they carry genes that are associated with disease, they can make lifestyle choices to reduce their risks, as well as undertake regular screening so that if they do develop a disease such as cancer, it can be treated at an early stage.

The MMIM database will also help doctors to understand why particular drugs work for some patients and not others. Within one disease, one drug may suit people with one genetic profile, while another works for those with a different profile. This type of information can assist in selecting currently available medication, as well as helping match patients with suitable clinical trials, if the drugs that are obtainable are unsuitable. In this way, treatment is tailored for each individual’s needs.

Prevention is always better than cure, and customised treatment is more accurate than generalised therapy. The MMIM database is forming a network to make this type of medical treatment a reality.

Career profile: Dr Bryce Vissel

By rivqa Posted in Interviews, Science Tagged , , ,

This article was originally published in OnSET.

Dr Bryce Vissel is a scientist who believes that if you make smart choices, you can guide your own destiny. Rather than taking the ‘easy route’, he has consistently chosen to work in the place where he felt he could do the best science.

Vissel decided to get into research after a year as a pharmacist, mainly because he felt dissatisfied with the work, but also, he says, because “I was not very good at wearing a tie”. He completed his PhD at the Murdoch Institute in Melbourne, which lead to major fellowships at the Garvan Institute and the Salk Institute in California, where he received the prestigious Hereditary Disease Foundation Lieberman Award for his work in neuroscience. Vissel now runs a lab in the Garvan Institute that conducts stem cell research and research into synaptic plasticity, the ability of neurons to modify their connectivity in response to experience, which is important in learning, memory, drug addiction, and thought to be significant in schizophrenia.

For Vissel, his career is rewarding on both scientific and humanitarian levels. Teaching is fun and it is always gratifying to have research published in high-impact journals and recognised by other scientists through citation. However, the best part is the opportunity to interact with the community. His work relates to people with spinal cord injury, stroke, and Huntington’s disease and he finds it “rewarding when you can tell them things that may have a real impact for them in the immediate future”.

Nevertheless, a research career also has its downside, particularly when things do not work. A drawback is that funding depends on good results. Often, the lack of results is no one’s fault, but rather due to the tricky nature of science itself. “Science is not something that you just do as a job,” says Vissel. “It is a passion, and if you have invested yourself in something personally, when things fail, it is more personally frustrating and disappointing.”

Although those times are daunting, “determination, hard work, commitment and doing things a bit out of the ordinary can get you through”. Once sufficient basic knowledge is gained, science becomes a progression of thinking creatively about what discoveries are needed to push a field forward and then beginning to think laterally about what needs to be done, rather than rushing ahead and doing the first thing that comes to mind. “Doing that forced creative thinking can save of time and get you through some great hardships,” says Vissel.

Science in Australia

Many people travel overseas thinking that being at a top institution will turn them into a great scientist. However what they fail to realise is that people do better there because they work harder. “The reality is that you will be working 12 to 14 hours a day, six to seven days a week and you will be exhausted and straining yourself. But after three or four years of that, you will come out with a major publication that will impact the field,” says Vissel.

The same results can be achieved in Australia provided the commitment and conscientiousness is there. According to Vissel, funding for research science in Australia is slowly improving in response to public pressure and the quality of science here is comparable to other leading countries. Often people say that Australians “punch above their weight” because they do so well with so little. Also many people here put their social lives first, whereas “investment early on and hard work pays off enormously”.

In any case, the key to a financially rewarding career in research science is being good at what you do, as in any career. “If you are good at what you do, once you are at a more senior level you will be asked to consult, or be on committees or boards of pharmaceutical companies, and these things add to your salary,” says Vissel.

Science Education

A key part of enthusing young people about science is letting them know that getting to the truly exciting phase of the field takes time. It is important to get the basics in place first no matter how tedious compared to cutting-edge research.

“Science is first taught as a series of facts, and the truth of science in practice is that it is a series of unknowns,” says Vissel. There are many ambiguities and contradictions in science, because no one knows the right answers to any question. Although science is assessed with multiple choice questions even at university level, experts in the field are constantly debating what is the right answer.

Vissel believes that students need to be taught that once they get past the stage of learning the boring “alphabet” of science (the basics), they can start “reading” by understanding the scientific process of studying the unknown, and getting involved in it. Once that stage is reached, science becomes fascinating.

“Unfortunately, many scientists do not transmit this excitement effectively,” says Vissel. “But many of scientists don’t get to experience the excitement of it – they get bogged down in the realities of the day-to-day experiments. But I think it is important, if you are going to be a scientist, to find people who inspire you and who are inspired.”

From Village Healer to Scientist: The History of Natural Product Chemistry

By rivqa Posted in Science Tagged ,

This article was originally published in OnSET.

(Note: for definitions of bolded terms, see glossary below)

Whether we are aware of them or not, natural products are ubiquitous in our lives. Many pharmaceuticals, pesticides and herbicides, food additives, and even some plastics are natural products, or derived from them. So what exactly are natural products?

Although in theory the term could be used to describe any substance derived from a microorganism, plant or animal, it is usually confined to describing secondary metabolites (Cannell, 1998). Natural products have recently become big business, but people have used them since ancient times.

Natural products in ancient times

Early cultures used specific products to cure specific diseases. Chances are that the ancient Egyptians had no idea that the Vitamin A in ox liver was what cured nyctalopia, but liver was used as a cure for this disease. In ancient Mesopotamia, Egypt and other countries, a wide variety of plants, animal products and even stones were used as treatments for various ailments. These cures were discovered by trial and error (Porter, 1997).

As early as 800 AD, the Benedictine monks were using many natural medicines, including the poppy (Papaver somniferum), which was used to alleviate pain as well as an anaesthetic. The active ingredient, morphine, was only extracted in 1806… almost 1000 years later. It was marketed by Merck in 1826. Many other natural products such as quinine, which was the only effective anti-malarial at the time, were also isolated in the nineteenth century (Grabley & Thiericke, 1999). However, these drugs were also characterised largely by random experimentation, and many other structures could not be isolated until much later.

Natural products in the twentieth century

The trial and error method of discovering new medicines continued into the twentieth century. Alexander Fleming, the British microbiologist who discovered the effects of some fungi on bacteria, essentially made his discovery by being careless and not practicing aseptic technique. He left a Petri dish of Staphylococcus aureus open when he went on a holiday. It was accidentally contaminated with Penicillium notatum¸ which inhibited the growth of the bacteria, apparently by excreting an antibacterial substance. Chemists Earnest Chain, his Australian co-worker, Howard Florey, and their team later purified penicillin and conducted animal and human trials with it, bringing it to the market in 1941 (The Nobel e-Museum, 2003).

Many secondary metabolites that were discovered after penicillin in the 1940s and 1950s were effective antibiotics but too toxic for human use. Some of these were usefully administered to animals. In the 1960s-70s, research turned to improving yields of existing biopharmaceuticals, as well as chemically altering them to reduce their side effects or improve their activity against micro-organisms (Grabley & Thiericke, 1999).

As a result, over 73 different variations of the beta-lactam antibiotics (including penicillin and cephalosporins) are available. Of these, 40 varieties are used to treat human disease in hospitals. The prevalence of beta-lactam antibiotics, coupled with the ease with which bacteria can mutate and share genetic information, has led to widespread resistance to beta-lactam antibiotics. A famous example of antibiotic resistance in bacteria is that of Staphylococcus aureus. Golden Staph, as it is commonly known, causes many problems in hospitals where bacterial infection spreads rapidly and patients may be more susceptible to disease than they are usually (Therrien & Levesque, 2000).

Natural products today

More recently, the competitive nature of the pharmaceutical industry in particular has brought natural product chemistry to a crossroads. Developing new drugs is profitable, and the pharmaceutical industry is constantly growing. New innovations such as High Throughput Screening (HTS), which involves automated, miniaturised assay techniques, have made it much easier to determine the potential uses of a new compound. State-of-the-art HTS machines can test up to 10,000 compounds in one week, a big improvement on the 10,000 per year that were tested in the mid-80s (Grabley & Thiericke, 1999).

These developments are fantastic both for the pharmaceutical industry and the consumer. However, the natural product industry is finding it difficult to keep up with the demand for new compounds to test. This is pushing the industry further, as marine biologists, microbiologists, ecologists, biotechnologists, biochemists and chemists team up to find new organisms with novel compounds, mainly from previously untested environments (Grabley & Thiericke, 1999). Advances in biotechnology mean that it is no longer necessary to collect large amounts of environmental samples in order to test for a new pharmaceutical. Rather, the sample is cultured in the laboratory where biotechnologists can create a clone library. The gene responsible for the production of the natural product of interest can then be isolated more easily, and the natural product itself can be produced in Escherichia coli (Lodish et al, 2000).

Ultimately though, natural product chemistry is still waiting for a breakthrough that will bring discovery of new compounds up to speed with the discovery of potential uses for these compounds.

Glossary

Antibiotics: secondary metabolites that either kill microbes or hamper their growth.

Aseptic technique: maintaining sterility and avoiding contamination of laboratory instruments and microbial cultures.

Biopharmaceuticals: Medicines that are made from compounds produced by living organisms, such as penicillin.

Clone library: an organism’s DNA is fragmented and copied into a laboratory organism such as E. coli, allowing for easier analysis of the original organism’s genes and metabolism.

High Throughput Screening (HTS): robotic and computerised methods of testing samples and analysing data, which allow many samples to be tested in a short amount of time.

Nyctalopia: night blindness, the inability to see clearly in dim light.

Secondary metabolites: compounds produced by an organism that are not essential for its survival but may be useful to the organism.

References

  • Cannell RJP (ed). (1998) Natural products isolation. Humana Press, Totowa, N.J.
  • Grabley S, Thiericke R (eds.) (1999) Drug discovery from nature. Springer, Berlin.
  • Lodish H, Berk A, Zipursky L, et al (2000) Molecular Cell Biology (4th Ed) WH Freeman and Company, New York.
  • The Nobel e-Museum (2003). The Discovery of Penicillin. Available at: http://www.nobel.se/medicine/educational/penicillin/ (accessed Jul 05).
  • Porter, R. (1997) The Greatest Benefit to Mankind: A Medical History of Humanity from Antiquity to the Present. Harper Collins Publishers, London.
  • Therrien C, Levesque RC (2000) Molecular basis of antibiotic resistance and -lactamase inhibition by mechanism-based inactivators: perspectives and future directions. FEMS Microbiology Reviews 24: 251-262