Monday, May 18, 2009

Cures from the Crypt

After 25 years as a consulting surgeon in Australia, Mark Spigelman switched career. Now the brother of the Chief Justice of New South Wales collects dead bodies. Or more accurately, mummified remains. An acclaimed expert on palaeoepidemiology, Mark believes these ancient bones could hold the key to a cure for TB and other ancient diseases.

Know your enemy. Whether on the battlefield or in the laboratory, this rule of engagement holds true. Prof Mark Spigelman is a surgeon turned archaeologist who believes that knowing what a virus or bacterium did in ancient times will help us understand what it will do as it continues to evolve. And he is confident this crucial intelligence will help scientists develop a new medical arsenal in the form of gene therapy to combat those archaic and virulent disease that plague us still.
A surgeon in Sydney, Australia for 25 years, Mark Spigelman turned a sabbatical to study archaeology in London into a groundbreaking new career. Over the past 15 years Mark has spearheaded pioneering studies of ancient diseases (palaeoepidemiology) found in mummified bodies from Hungary and Korea to Sudan, in his quest to provide answers to the development of diseases affecting us today.
His latest project has the soft-spoken Australian very excited. He has gathered samples from 6000-year old bones found in the biblical city of Jericho that will be examined by a joint Israeli-Palestinian-German research group for clues that could help scientists combat tuberculosis.
Mark is leading the Israeli team as an expert in human remains/anthropology for the Kuvin Centre for the Study of Infectious and Tropical Diseases at the Hebrew University of Jerusalem. The ancient bones, which were all excavated by Dr Kathleen Kenyon between fifty and seventy years ago, will be tested for tuberculosis, leprosy, leishmania and malaria. However, the primary focus will be tuberculosis.
The surgeon and scientist believes the key to curing TB can be found in the past. 
By studying the genetic history of TB and its victims, and mapping it’s evolution, he hopes his work will inspire scientists in the future to develop a gene therapy for this terrible disease. 

And there is urgency to his work. Mark tells Scope that he believes antibiotics are nearly finished in modern medicine. “We are entering what is going to be called the post antibiotic era. The treatment of bacteria is not antibiotics. In fact it’s the worst thing you can do,” he says.
Take TB for example. Dating back thousands of years, tuberculosis was well known in antiquity. But it is still one of the world’s most lethal infectious diseases. Two billion people, or about one-third of the world's population, are infected with TB. Nearly 9 million new cases occur each year and more than 1.5 million deaths are due to TB.
Moreover, tuberculosis is adept at evolving resistance to antibiotics. Drugs must be taken for six months, but many people don't finish the course. Health authorities have helplessly watched the emergence of both a multi drug-resistant strain that survives the two most powerful treatments and an extensively drug-resistant strain that shrugs off the second-line antibiotics as well.
Confronted by such a clever survivor, the human race is losing its battle with TB. A lasting solution is needed urgently.
Mark fervently believes that by understanding the genetic history of TB, he and his colleagues may find a vital weakness in the hardy microbe’s defences.
“Examining ancient human remains for the markers of TB is very important because it helps to aid our understanding of prehistoric tuberculosis and how it evolved,” says Mark, who divides his time as a visiting professor between labs in Israel and at the UCL Medical School in the UK. “This then helps us improve our understanding of modern TB and how we might develop more effective treatments.”
Mark explains that the initial stage of the study will take at least a year. “Firstly, we will extract all of the DNA from the bone specimens. Then we go specifically looking for this bit of DNA that we know is only to be found in Tuberculosis DNA. We use a technique called the polymerase chain reaction (PCR) to amplify it a million times or so and then we’re able to examine it and see whether it looks like today’s DNA from TB or not.
“So the first step will be to look through dozens of bones to see how much TB there was in that community, and then we’re going to see if there is a difference between the Tuberculosis bug in various time periods. And that’s one of the major aims of this experiment is to map the evolution of human TB from it’s very early days until it becomes established as the bug we know today.
“My theory is that early on it was not quite the same bug, and the changes in that will be very important for our understanding of how the bacteria evolved.
“Next we will do the same with the host. We will see certain genes, which are specific for host resistance and susceptibility to the disease. We will start looking at those and see how they evolved in that population because, for instance, those people most likely to have a gene that made them very susceptible to TB are less likely to continue having children in generations. So some of those people will die in childhood before they have children, and I’m interested to know if this one disease affected the evolution of the human population.
“It weeds out the weak, and then when there’s only strong left I believe the bacteria also changed, because otherwise it would die out.
“It is a very exciting project. I believe it is one of the first, if not the first study of the evolution of bacteria and host over time,” he says, rightly proud of this ambitious work being conducted as a team effort between the Hebrew University, Al Quds University, both in Jerusalem, and the Ludwig-Maximilians University in Munich, Germany.
Mark is credited with proving for the first time that the polymerase chain reaction could detect Mycobacterium tuberculosis in ancient skeletons. His research breakthrough was published in 1993 – soon after he graduated with an honours science degree in archaeology from University College London – but it was greeted by widespread scepticism. “When I did my first extractions and amplifications of Tuberculosis DNA, huge doubt. Everybody believed it was artefacts, it was false and it was a false positive. But now 30 40 laboratories world wide have repeated these experiments successfully,” the 68 year old points out.
This technique proved invaluable when in 1997 Mark was invited to the Natural History Museum in Budapest to sample and analyse more than 200 fantastically preserved bodies discovered in an underground crypt in the picturesque Hungarian town of Vac.
"I was very excited by this because I had never heard of 200 specimens. When you are dealing with ancient tissues and mummies, one mummy, two mummies, three mummies is a lot. Two hundred is unheard of. 
 I was stunned. Their clothes, hair, nails, even their skin remained intact. I mean they were gorgeous. These were people with personality,” he chuckles.
This research has progressed remarkably well over the past ten years, and Mark recently presented some of his astonishing results at a meeting in Copenhagen.
“We now know that almost 70 percent of the population studied had evidence of TB DNA in their bodies. I personally believe that all the people in Vac, at one stage or another, had a minor infection of TB, but about 15 to 20 percent of them died from TB, and we know who they are.
“When we sampled them we took lung, we took abdomen cavity, we took muscle, bone, and if they had TB in several tissues we assumed they had active TB, and a significant number of them died from the disease, and in many cases we know that from the excellent and detailed church records, which would state things like ‘died coughing blood’.
“Having done the work on the TB DNA, we turned around and we are now looking at the human DNA, specifically the genes that gives you resistance or susceptibility to TB.
“I cant say more about it because it’s still a work in progress, but we’re getting some very interesting results that suggest there were some genetic differences amongst the people and those people we think died from TB - They have some genetic differences,” reveals Mark.
If he and his colleagues at UCL, who are working with him on this research, identify a genetic variation that could explain why some people got TB and some didn’t in this population, they could well be taking the first historical steps towards finding a genetic treatment for what is the biggest bacterial killer in the world today.
Mark is also eager to talk about “some really exciting mummies” in South Korea, which he has very recently started working on and who fit perfectly into his pattern of research. There is also the added bonus that these mummies now broaden his investigations to include the ancient inhabitants on another continent.
The building boom in South Korea has meant that many cemeteries have had to be relocated. It is this process which led to the discovery of the mummified bodies in 2007. When researchers at Dankook University and Seoul National University identified the Hepatitis B virus in the liver of a 500-year old child they immediately invited Prof Spigelman to South Korea to verify their findings. This is the first time that samples of hepatitis B have ever been found on a mummified body.
“The mummies are remarkably well preserved so we are hoping for some exciting findings. We will study several diseases, including Hepatitis B, but TB specifically.”
And with reference to his on-going study of the mummies from Vac, he adds: “We believe we are going to see a genetic difference between groups of people, those who died from the disease and those who survived. Already there is a certain genetic pattern emerging. Knowing who is or is not more susceptible to TB than others means we can do preventative measures, we can warn these people. There is gene therapy coming along, you can turn genes on, you can turn genes off, you can change the genetic makeup of a person.
“This is highly theoretical. It’s the crazy thoughts of a crazy guy, namely me,” Mark laughs. “You see, somewhere in there our research could fit. It is possible that we may be able to change the genetics of a person and make them less susceptible to TB. And all good doctors know that prevention is the best cure.”

At the top of his game – twice!

Born in Poland at the outbreak of World War II, Mark Spigelman says he spent the first years of his life hiding and fleeing from people whose sole ambition, apparently, was to take his. Following the war, Spigelman's family migrated to Australia in 1949. He and his brother Allan studied medicine, both specialising in surgery, while their brother, James studied Law and like his siblings he also ascended to the top of his profession, becoming the Lieutenant Governor of New South Wales and Chief Justice of the Supreme Court of NSW.
For Mark, after 25 years as a consulting surgeon in Sydney, he was ready to turn his attention to another passion - archaeology and anthropology.
“I was working in Australia and my son was accepted to study at the Royal Academy of Music in London. I hadn’t for 25 years taken a lot of holidays so I took a sabbatical. I signed up to do a course as a Bachelor of Science in Archaeology at the University College London. My wonderful wife Rachel came with me.
“Whilst in my first year I got very interested in ancient diseases and I started experimenting with the DNA of disease, it had just emerged at that time the ability to extract and amplify ancient DNA of humans and I thought it would be fun to see if we could do it with bacteria, and within six months we had got quite a good result, published the first paper on the subject.
“So there it is: instead of going back to Australia I decided to stay in England. I was helped by the fact that my younger brother was already here, he’s a Professor of Surgery, and so I was able to continue working with him in surgery, and I still keep right up to date with my skills in surgery.
“I feel very lucky because I’ve had some very good and skilled colleagues at UCL and in Israel who do all the work really, I just hang around and get in the way,” he says with quiet laughter. “Without them I would have done nothing because I am, in the end, a surgeon and I need the skills of such people but we work as a team and we get the results out as a team.”

WHO: Highest rates of drug-resistant TB to date

Multidrug-resistant tuberculosis (MDR-TB) has been recorded at the highest rates ever, according to a new World Health Organisation’s (WHO) latest report that presents findings from the largest survey to date on the scale of drug resistance in tuberculosis.
The document, Anti-Tuberculosis Drug Resistance in the World, is based on information collected on 90 000 TB patients in 81 countries. Extensively drug-resistant tuberculosis (XDR-TB), a virtually untreatable form of the respiratory disease, was recorded in 45 countries – an alarming fact that the WHO warns may “derail 10 years of progress in TB control”.
The health organisation also estimates there are nearly half a million new cases of MDR-TB - about 5 percent of the total nine million new TB cases - worldwide each year. The highest rate was recorded in Baku, the capital of Azerbaijan, where nearly a quarter of all new TB cases (22.3 percent) were reported as multidrug-resistant. Proportions of MDR-TB among new TB cases were 19.4 percent in Moldova, 16 percent in Donetsk in Ukraine, 15 percent in Tomsk Oblast in the Russian Federation and 14.8 percent in Tashkent in Uzbekistan.
These rates surpass the highest levels of drug resistance published in the last WHO report in 2004.

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