Meet the Researchers Making a Difference in Our Lives

In the “Meet the Researcher” series, the Research Society on Alcoholism (RSA) and the ATTC Network have partnered to introduce you to some of the scientists working hard to make an impact in the lives of individuals battling the disease of addiction. Each quarter, RSA and the ATTC Network will profile a researcher whose work has made a difference in our lives. These profiles will be featured in the ATTC Network publication, Eye on the Field, on the ATTC Network website, and on the RSA website.

JANUARY, 2010

Professor Clive Harper, M.D., FRCPA

Winner of the Begleiter Research Award at the 2009 annual meeting of the Research Society of Alcoholism held in San Diego.  Writer Sherry Wasilow interviewed Dr. Harper via e-mail while he was en route from Oman to his home country of Australia for this profile.

“It is critical for us to take our research out of our laboratories
and apply the lessons to health programs.”

SW: What has been your research focus?

CH: My colleagues and I have established a “brain bank.”  We have gathered a wide cross-section of the population – that is, people who have brain disorders as well as people without disorders (controls).  In 2002, we started a brain donor program called “Using our Brains” (http://www.braindonors.org/about_us.html).  People commit to donate their brains to medical research after they die, in much the same way as you might commit to donate your organs for transplantation. Consented donors have repeat neuropsychological assessments throughout their life with health, lifestyle, and clinical work ups. The detailed profiles that result from this program are extremely useful for researchers using the New South Wales Tissue Resource Center (TRC) tissues. This brain bank is an important resource that will become even more valuable as new techniques are developed for the study of neuropsychiatric diseases. The TRC encourages neuroscience research, particularly into alcohol-related brain damage.

SW: How did you arrive at this research focus?

CH: I first became interested in alcohol research when I worked in Glasgow University and the Southern General Hospital, in Scotland, in 1972. I had finished my medical degree and postgraduate training in pathology in Australia and had just begun to train as a neuropathologist. As many readers may already know, a neuropathologist specializes in the study of disease of the brain and spends most of his/her time studying brains from autopsies or looking down a microscope at samples of brains taken and processed in a laboratory. Part of my job in Scotland involved the study of the brains of people who had become Coroner or Medical Examiner’s cases.

I was astounded by the number of cases that we saw that had severe, permanent brain damage caused by, what was presumed to be, thiamine (vitamin B1) deficiency. This disease is known as the Wernicke Korsakoff Syndrome (WKS).  (See http://www.nlm.nih.gov/medlineplus/ency/article/000771.htm). When I returned to Australia, I took up the position of neuropathologist in Perth, Western Australia and was again involved in the study of the brains of thousands of cases each year from the Coroner’s office and public hospitals. There were even more cases of chronic brain damage caused by thiamine deficiency in Australia. We published these data in peer-reviewed articles in national and international journals; thus began my research career. I had made a scientific observation about the apparent high prevalence of a particular disease in Scotland, taken this knowledge back to Australia, and made the same surprising observation. WKS was even more common in Australia than in Scotland. Why was this so? The critical issue that we identified was that more than 90 percent of the Australian cases were associated with alcohol abuse.

Subsequently, my colleagues and I reviewed all of the hospital files of these cases and were able to show that the diagnosis of approximately 80 percent of the WKS cases had been missed or overlooked in major teaching hospitals. Although the standard textbooks of the day indicated a particular pattern of clinical signs for WKS, we showed that these were rarely all present in our cases. We suggested that clinicians needed to be very alert to make the diagnosis of WKS and that, if cases were admitted where there was a history of alcohol use/abuse, they should be treated with thiamine “just in case.” It could do no harm and thiamine supplements have been shown to quickly reverse the clinical signs and symptoms of WKS and reduce the brain damage. There are still many people each day developing this type of preventable brain damage (WKS), particularly in countries where alcohol use/abuse is becoming more common, and clinicians still need to be alert and consider the possibility of this diagnosis.

These prevalence studies provided the main impetus for 1991 Australian legislation that mandated thiamine supplementation of foodstuffs (bread flour).  (See http://www.gograins.com.au/grainsnutrition/ns/ns7_7.html). This has led to a dramatic reduction in the prevalence of WKS in Australia.  It is, however, important to realize that the research is just the beginning. Translation of research outcomes to clinical practice and effective public-health measures is probably more difficult than the original research. One must be prepared to debate with health-care professionals and politicians to achieve these goals. I feel that this has been one of my major career achievements. We were able to take our research out of the pathology laboratory and into the clinic and public-health arena.

SW: Since then …

CH: During the next few years, I developed a more general research interest in the effects of alcohol on the brain. I noted that there was very little scientific documentation regarding structural changes in the brain caused by alcohol, merely comments like “another binge another millionbrain cells killed.” With access to many autopsy brains with well-documented clinical histories of lifetime alcohol intake, it seemed an ideal opportunity to begin to try to document structural changes that might be occurring. My colleagues and I used quantitative methods, including automated systems to count numbers of nerve cells to study the changes in various areas of the brain caused by alcohol and associated factors like thiamine deficiency. We were the first to document that excessive alcohol does cause the loss nerve cells in certain areas of the brain but, more importantly, we showed that the brain shrinkage seen in alcoholics is caused by shrinkage of the “hard wiring” of the brain (the white matter). The importance of this observation is that this type of damage seems to be, at least partially, reversible if the individual reverts to abstinence or “safe” levels of drinking. Most recently we have been studying the protein make-up of the brain to establish mechanisms by which this “hard-wiring damage” occurs and how we might be able to prevent or reverse the process.

I am pleased to see that other researchers have begun to see the benefits of using human tissues for these types of studies, and we are happy to be in a position where we can share our “bank” of tissues – with appropriate ethical clearances – with these groups. The TRC has now been established for 16 years and we have more than 500 brains that can be used by other research groups throughout the world. The brains are stored in freezers and in fixatives for different types of research projects. Tissues have been sent to well over 100 research groups for more than 270 different projects. The frozen tissues can be used for very sophisticated molecular techniques looking at changes caused by alcohol in the genetic makeup and protein structure of the brain.

SW: Describe your current research activities.

CH: We are also addressing the social aspects of brain donation. During scientific and public lectures, I often ask my audience to guess the percentage of families who will agree to donate their loved ones brain to medical research on the day that they have died, often unexpectedly. Our phone call to the families comes out of the blue, without warning. Most of the audience guesses between 10 and 20 percent; the reality is that approximately 60 percent of the families agree to donate. Many say that their decision to donate was helped by the family having previously discussed organ donation. This is a good thing and should be encouraged in all families and societies. Organ donation for research can be just as important, in the long-term, as organ donation for transplantation. The research might lead to the identification of causes and cures of diseases or, even better, prevention of diseases.

I still believe that thiamine deficiency is a relatively common problem in many countries in the world. Prevention is relatively simple with thiamine supplementation and it is cheap and cost-effective. I would hope that the World Health Organization or an equivalent body could learn from our Australian experience, as well as from the experience of other countries that have public-health programs of thiamine supplementation. It should not be too difficult to plan a similar strategy for third-world countries. It is critical for us to take our research out of our laboratories and apply the lessons to health programs.

The same applies to data from addiction research. I think that we have a responsibility to translate our data into lay language. It is important to get the message to the population that alcohol does damage the brain but that, with sensible and safe drinking, damage can be prevented. Even if damage has been done, there is a potential for reversibility of the damage by abstinence or “safe” drinking. Healthy eating programs and adequate thiamine intake are also key issues in preventing alcohol-related brain damage. Education about these matters should be seen as part of our – the researchers – responsibility.

The success of our research and the development of the TRC have been closely linked to the development of collaborative projects with groups of researchers throughout the world, but particularly in the USA, the UK, Sweden, Japan, and Canada. These working relationships have led to close friendships that have made the work particularly enjoyable. Our laboratory, at its busiest, had more than 40 staff and students. It takes a lot of infrastructural and financial support to maintain such a lab and I am particularly grateful to the Australian Government (NH&MRC), the US Government (NIAAA), the NSW State Government, and to many other NGOs who have supported our work.

My personal philosophy has always been to find the best staff to work with regardless of whether or not they are smarter than you … most are smarter! Always be available to staff and to look for opportunities to help staff in their personal development, such as encouraging attendance at conferences, even for junior staff. Always be on the lookout for new opportunities and do not be afraid of the extra work. Go the extra yard and don’t be afraid to ask the hard questions.  Be totally honest and up front with staff and colleagues. I have rarely been disappointed by my staff and consider that I have been blessed in my career.

“Translation of research outcomes to clinical

practice and effective public-health measures

is probably more difficult than the original research.”

Professor Harper profile: http://www.medfac.usyd.edu.au/people/academics/profiles/cliveh.php

Coming in April, 2010 - Meet Edith V. Sullivan, Ph.D.