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Keynote Address of Dr. David Hill, Scientific Director Lawson Health Research Institute

2010 Annual Community Meeting
Tuesday, June 22

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The legacy of LHSC is more than 130 years old, dating from 1875, when the London General Hospital, opened on Ottoway Avenue, now South Street. In 1899, London General Hospital expanded and changed its name to Victoria Hospital in honour of the Queen. On November 16 some 15,000 Londoners jammed onto South Street to celebrate the opening of the Hospital, an impressive new building that commemorated the 60th anniversary of Queen Victoria’s accession to the throne.

Victoria Hospital filled almost an entire city block, and its distinctive bell tower instantly became a London landmark. In May 1941, an addition was opened to the north side of Victoria Hospital—the now-familiar South Street building façade.
It was not long until our doctors and researchers were innovating and changing the way patients were cared for.

Discovery of the Barr body – new era of research into genetic disorders

Dr. Murray Barr was born in Belmont Ontario. After serving in the Second World War, he studied the effects of fatigue on the central nervous system. In 1949, with a $400 research grant, he used an electrical device to stimulate the nerve cells of cats. He was puzzled at a mass of chromatin in nerve cells in some cats but not in others, and concluded that this could be attributed to the sex of the animals. He published his findings on the “sex chromatin” later that year. Later studies by Barr revealed that the single Barr body in normal cells is one of the two X-chromosomes in a highly condensed and genetically inactive state. The other X-chromosome is in the diffuse state and is genetically active.

The discovery enabled Barr and his co-workers to devise a relatively simple diagnostic test for certain genetic abnormalities, in which cells rubbed from the lining of the mouth cavity (a buccal smear) were stained and examined microscopically.

For instance, individuals suffering from Turner's syndrome, which affects females who have only one X-chromosome, lack the Barr bodies. In contrast, males affected by Klinefelter's syndrome possess an extra X-chromosome and exhibit Barr bodies in their cells, where they would normally be absent.

This marked the start of genetic testing, even before the discovery of DNA, and it was done here at LHSC.

Up until the late 1940s patients diagnosed with kidney failure had a death sentence. Dr. Kolff, working in Holland, was quoted as saying after seeing several patients die of uremia he became frustrated by the profession's ignorance of this disease. So he began investigating the kidney with the prospect of mechanically replicating its functions and in the end he built two different artificial kidney machines.

In the spring of 1948, Dr. Jacobus van Noordwijk, who had worked under Dr. Kolff in Holland, decided spend a year in London instructing physicians how to build and operate the first artificial kidney machine in Canada. The device consisted of 120 feet of special cellophane tubing stretched around a drum, which in turn revolved in a special solution designed to remove the blood impurities.

Dr. van Noordwijk began work on the machine at Victoria Hospital in August 1948, and by the following January Canada’s first artificial kidney was put on public display.

Just three years later, in 1951, Victoria was the site of the first cancer therapy using the so-called cobalt bomb. There are two types of cobalt bomb. The first has the destructive power to destroy all human life, and thankfully has never been tested. The second was designed to save lives.

On October 27, 1951, the first treatment in the world with Cobalt-60 radiation took place at the Ontario Institute of Radiation at Victoria Hospital with Dr. Ivan Smith as the attending physician. Developed by Dr. Smith and built in Saskatoon, the machine was known as the “Cobalt Bomb” or the “Peace Bomb”. Its first use was recorded by the CBC.

Its technical name was the “Eldorado A” and the machine treated 16 new patients per month. In 1955, the first radioactive isotope laboratory was established and the first researcher, a radiobiologist, joined the London Clinic team. Additions to the clinic were undertaken until 1966, when a new radiobiological research laboratory was added. In July 2001, the last Cobalt radiation treatment unit at the London Regional Cancer Centre was removed. It was replaced by a Tomotherapy unit. At that time, LRCC was one of only 2 cancer treatment centres in Canada to have that new technology. The unit has the capability to plan and provide treatment at the same time, treating in slices that are designed to “hit the tumour” and spare the surrounding healthy tissue.

Moving now to 1958 and the Surgical treatment of aneurysms Dr. Charles Drake was born in Windsor, Ontario and was Chief of Neurosurgery at Victoria Hospital from 1953. It was here that he developed and perfected his techniques for the diagnosis and repair of brain aneurysms, which gained him international recognition. In 1958, he had a patient with an aneurysm which was generally believed to be inoperable. But Dr. Drake was confident in his abilities, and was successful with a new approach.

Four years afterwards he documented aneurysm surgery, perfected his technique and taught it to other surgeons. Patients from every corner of the world sought his care, medical organizations everywhere sought his leadership and expertise, and Canada awarded him the Companion of the Order of Canada.

The Grapefruit effect was first observed in 1989. Drs. David Bailey, Malcolm Arnold and David Spence were interested in a possible interaction between alcohol and a blood pressure medicine called felodipine. Dr. Bailey was given the task of finding some way to disguise the flavour of the alcohol and decided on double strength grapefruit juice.

What they found was that grapefruit can markedly reduce the activity of the intestinal drug metabolizing enzyme CYP3A4, thereby markedly elevating the percentage of the drug that reaches the circulation, possibly attaining toxic levels.

Sixty per cent of drugs that are commonly prescribed are metabolized to some extent by CYP3A4. The result of the inhibition of this enzyme can be significant. Their research determined that taking certain medications with a glass of grapefruit juice is the same as taking 12-15 tablets of the same medication with a glass of water. The team’s subsequent study was published in the Lancet in 1991 and was the first reported clinical food-drug interaction.

And so to today. Research continues to be an integral part of the LHSC’s strategic plans. We have over 1,200 research personnel involved in all areas of research across London’s hospitals with $70 million in their research accounts on April 1st 2010.

As Terry Fox said, the research has to carry on.

For decades, our view of heredity has been written in the language of DNA -- and genetic mutations which confer risks for disease such as cancers. Yet this is only one way that we look at the genetic basis of disease now, as can be seen from this recent paper from our cancer group looking for a genetic signature to determine if a breast cancer is likely to be metastatic. They not only consider gene mutations but changes in the balance of gene expression, the number of copies of a gene, and in the middle here the epigenetic profile, the degree of chemical modification to DNA, such as addition of methyl groups, that will determine the level of expression of individual genes.

Epigenetics is one of the mechanisms that links our genetics to our environment, and determines where we are on the continuum of risk between health and disease. Unlike genetic mutations, epigenetic changes are potentially preventable and reversible.

These changes in gene expression can be imparted early in life, prior to birth or during childhood, and yet can determine our risk of heart attack or osteoporosis and a host of other diseases in adult life. Epigenetic changes are heritable, so disease risk can be passed across generations. Shown here in a pregnant women are the two future generations, the unborn child and the gametes of that child.

The Children’s Health Research Institute is looking for the critical windows in life where epigenetic patterns can be rewired, and the recurring cycle of disease fundamentally altered.

Personalized medicine takes information from a person’s genetic makeup, along with dietary and environmental influences and clinical disease states, to identify more precise or tailored treatment options.

The benefits are fewer drug side-effects, adverse drug reactions or toxicity, and more customized drug treatment options. Dr. Richard Kim is a pioneer in the field. He and his team were the first in Canada to start a Personalized Medicine Clinic, based at LHSC, for the blood thinner warfarin. Over 200 patients on warfarin have been seen at this clinic since 2008. Dr. Kim is also leading a personalized medicine program for the cholesterol lowering drugs called statins and a personalized medicine program for breast cancer patients on tamoxifen therapy. He received a research Chair for the latter from CCO a couple of weeks ago.

Cancer is now largely looked upon as a chronic disease rather than a fatal diagnosis. However remaining obstacles are early detection, and dealing with metastasis. This is the work of Dr. John Lewis and Dr Ann Chambers, both working in our cancer group.

John Lewis has identified a protein that may be a new target for future cancer therapies. By experimentally blocking the action of this protein, called CD151, he has found he can stop cancer cells from metastasizing and seeding new tumours.

The reasons why some cancers metastasize, and others do not is under active study. Dr. Chamber’s work involves following cancer cells throughout the body after they break off from a primary tumor and begin to move through the bloodstream. Not all of these cells become metastatic. The vast majority will die or disappear fairly quickly, while a small percentage enter a dormant phase from which they may or may not awaken. Only a few continue to proliferate, or to metastasize.

Following this concept of “metastatic inefficiency” Dr. Chamber’s lab, in collaborating with Dr. Paula Foster at RRI to use novel cellular magnetic resonance imaging approaches to track individual cancer cells and study where these inefficiencies happen.

LHSC has a long series of surgical firsts, and in the last 10 years these have increasingly involved minimal invasion and computer assistance. These technologies require incredible skills that traditionally have been racked up over dozens of cases. Surgical training in silico rather than on live patients is the logical answer to skills acquisition, emulating skills training in the airline industry.

CSTAR’s laboratory space at UH is the home of growing simulation training programming, developed for multi-disciplinary teams. CSTAR is supporting the expansion of this programming to encompass and provide simulation training opportunities for critical, team-based, patient care activities at LHSC.

Finally Health informatics. We are now drowning in information, genomic, blood protein signatures, metabolic and other lab measurements, imaging, medical history through the EPR, our travel through the greater health system outside of the hospital, and provincial and national health registries. This is a goldmine in terms of our ability to predict patients who will respond to regular care plans, and those who will not. On a scale of 1 to 10 our ability to use this information is about 0.5 at present. We are building health informatics science and recruiting scientists whose job it will be to let us access and compare information. Information mining will be a key enabler to health research, and to health care.

What of the future? This is what LHSC has to continue to be – Innovation Drive. This is what being one of those elite global centres, the research-intensive teaching hospital is all about. We are building the best research infrastructure we can. What will the future of research look like in these new facilities? Let’s hear it from our research leaders.

This legacy of innovation started here at Victoria Hospital. The locations will change but the spirit of inquiry and the thirst for innovation will continue at LHSC. We market them now through Lawson Health Research, but it is not about a name.

It is about all of our health professionals recognizing there will always be better ways to prevent and treat disease, and to serve our patients, and that they are not going to wait to read about it in books. They are going to create the future for themselves, and do it now. This will be the challenge of our new CEO. Just like Tony and Cliff have embraced innovation and moved all obstacles to allow it the flourish, so their successor must create an environment where new ideas are not stillborn, but are nurtured and tested, and the best ones will flourish.

I watched Stephen Hawking on Sunday and felt the buzz of being part of a free-thinking organization such as the Perimeter Institute. But LHSC is so much better than that. Hawking has had to wait for decades for astronomers to gain the evidence that validated his theories. We can test our innovations tomorrow, and for the immediate improvement of people’s lifes.

It’s because innovation and discovery is in our DNA at LHSC.