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.

Stranger than Fiction

Urologist Michael du Preez is credited with unearthing the true identity of the legendary Dr James Barry – finally solving a mystery that had persisted for over 140 years. He talks to Scope about his years of research and efforts to have Dr Barry’s remains exhumed in a tireless crusade to pluck the Victorian doctor from semi-fictional sensation to the rightful ranks of medical history’s greatest minds.

The secret 19th century love affair between Irish-born Dr James Barry - one of the British Army’s highest-ranking doctors – and the governor of Cape Town, Lord Charles Somerset is sure to add a shake of Hollywood spice to the $15 million film “Heaven and Earth”, which is due to commence filming in South Africa. But regardless of artistic licence in the retelling of the enigmatic Dr Barry’s story, the truth remains far stranger than fiction.
Four decades after this illicit dalliance, charwoman Sophia Bishop was sent to lay out the body of the medical pioneer Dr Barry at his lodgings in London on the morning of 25 July 1865. The diminutive physician had served in garrisons across the globe for a long, illustrious and occasionally controversial career. Stripping away the nightclothes in order to wash his body, Bishop discovered the corpse of “a perfect female”.
The ensuing scandal astounded the conventional sensibilities of Victorian society. The declaration that one of the military’s top doctors was actually a woman became fodder for gossip press throughout the British Empire. Appalled army officials locked away Dr Barry's service records for almost a hundred years in the hope that the story would simply go away.
Quite the reverse was the case. More than 140 years of speculation as to the true identity of the mysterious Dr James ‘Miranda” Barry has cemented the doctor’s place in history, regrettably, more for Barry’s elaborate subterfuge than her skills as a doctor and surgeon, and her outstanding work as a humanitarian.
As speculation persisted over the years, books were written by historians and romantic novelists alike, however, even the most promising research proved inconclusive. Who was the infamous Dr Barry? Where did ‘he’ hail from? Could a woman of that era really hide her true identity for decades while living and working in a thoroughly masculine profession?
It was only after years of meticulous detective work by South African urologist Michael du Preez that Barry’s true identity was finally known. His research, published last year in the South African Medical Journal, revealed that the pint-sized doctor with the sandy curls and squeaky voice, who fought for better conditions for troops, shot a man in a duel, reached the top of "his" profession, had in fact began life as the daughter of a grocer from Cork.
Dr Barry’s real name was Margaret Bulkley.
Dr du Preez says he first heard the story as a boy in Cape Town, where Barry had introduced sweeping health reforms while he was an assistant surgeon to the local garrison. The young doctor also made medical history there by becoming the first surgeon to perform a successful Caesarean section in the British Empire.
“That, in itself, was an astonishing event in 1826,” remarks Dr du Preez, speaking to Scope from his home in Cape Town. “It would be about forty years before the next Caesarean section with survival on mother and child was performed. Apparently, according to the family tradition, the operation took place in the bedroom and not in the kitchen as one would have expected,” he notes, his attention to detail in conversation as apparent as it is in his acclaimed research paper.
Dr du Preez explains that when he retired in 2001 he set about gathering evidence to solve the mystery of Dr Barry once and for all. Isabel Rae, in researching her authoritative 1958 biography of the doctor (The Strange Story of Dr James Barry), gained access to army records that indicated Dr Barry may have been a niece of James Barry, the celebrated Irish artist and professor of painting at London's Royal Academy. It was this angle that Dr du Preez pursued; deducing that if Barry the doctor was a close relative of Barry the artist, then papers linked to the artist's family might provide some leads.
And he was correct.
Buried among a large collection of papers relating to Mr James Barry, Dr du Preez discovered evidence that the enigmatic doctor had started life in Ireland as Margaret Ann Bulkley, the daughter of Jeremiah, a grocer in Cork, and Mary-Ann, sister of the artist Barry.
Several key letters, some penned by the teenage Margaret and some by Barry the student doctor, were analysed by Alison Reboul, an expert on document analysis with the UK's Forensic Science Service, who confirmed they were all written by the same person.
“A representative selection of these letters has been subjected to document analysis and combined with other evidence conclusively established the identity of Dr James Barry, leaving no doubt that the doctor started life as Margaret Ann Bulkley,” says Dr du Preez.
These documents also revealed a conspiracy between Margaret's mother and some of her uncle's influential and liberal-minded friends to get her through medical school, after the teenager and her mother had moved to London having been left destitute through hapless family circumstances.
These powerful friends were the family solicitor Daniel Reardon, Dr Edward Fryer, an academically inclined physician, and General Francisco Miranda, a Venezuelan revolutionary, no less.
“It would not have been surprising if the grand idea had emerged of putting the nineteen-year-old through a medical education, to enable her to participate in his (Miranda’s) vision for the future Venezuela,” Dr du Preez muses.
But this would have involved nothing less than three years’ study at a medical school during an era when only men were admitted to study medicine in Britain.
Margaret would have been obliged to take the extraordinarily bold step of altering her appearance and her persona to that of a young man and sustaining the deception until after the final examinations.
“If this construct is correct, the young doctor could have resumed her female identity once qualified and on her way to Caracas, Venezuela,” says Dr du Preez.
The disappearance of Margaret Bulkley and the appearance of a young medical student called James Barry was carefully orchestrated. The Bulkleys were unknown in Scotland, so they planned to establish themselves there as aunt and nephew while Margaret studied medicine in Edinburgh.
Most exciting of all was the discovery of a letter the budding doctor had written to the family solicitor Reardon on arrival in Edinburgh in 1809. "Reardon was a meticulous man," stresses Dr du Preez. "On the outside of all the letters he received he wrote the date and the name of the sender. This letter was signed "James Barry" but on the outside Reardon had written "Miss Bulkley, 14th December".
“It is thus possible beyond any doubt to identify the individual who was to become Dr James Barry, neatly confirming the result of the handwriting analysis – a particularly significant discovery,” says Dr du Preez.
Barry graduated in 1812 and after six months as a pupil at St Thomas' Hospital in London, joined the army - surely a strange choice for someone with such a secret to hide. But Barry's options were limited: General Miranda had just been betrayed by fellow revolutionaries and thrown into a Spanish jail. There was no longer a job for Margaret in Venezuela.
"Put yourself in her position," suggests Dr du Preez. "You've spent all that time maintaining this deception, so what do you do now? If she had come clean and said she was a woman she couldn't have done anything in Britain. The army was actively seeking doctors, so she chose the army."
Dr Barry's rise through the ranks was swift and remarkable. After only two years, she received her first promotion to assistant staff surgeon in 1815 and was soon after posted to the Cape of Good Hope (South Africa). It was here that Barry's emerging personal and professional eccentricities first evoked comment. Her high-pitched voice, effeminate manner and short-fused temper were duly noted by Afrikaners. The epithet "Kapok Doctor" was bestowed when it appeared that the doctor was padding her shoulders with cotton.
But Barry proved herself a highly skilled and respected physician and was soon attending fashionable Cape families. Among them was the family of Barry's great friend and patron, Lord Charles Somerset, governor of the colony. Stories linking the pair romantically form a large part of Barry lore. Isabel Rae’s biography describes the original incident from which these stories may have sprung:
“A placard was affixed to one of the posts of the Hout St bridge [it] was seen and read, to all intents and purposes, by one man only who ‘found it to be a most disgusting anonymous letter reflecting upon the moral character of Lord Charles Somerset; it did, in fact suggest an immoral relationship between the Governor and Barry’.”
This “passionate love affair” is the central theme in the multi-million dollar film “Heaven and Earth”, which will recount the relationship between Lord Somerset (Pierce Brosnon) and Barry (Natasha McElhone). Given his acknowledged expertise on Dr Barry, and his own medical proficiency, Dr du Preez has been retained as historical and surgical advisor to the film.
“It has truly been remarkably interesting. Fortunately we have been able to source period instruments from our local Medical Museum, and I have had several discussions with the actors from whom I have gleaned much information, which would contribute to the interest and readability of any biography that might eventuate.
“Natascha MacElhone, cast as Dr Barry, had researched her character admirably and she always came up with searching questions and suggestions that would never have crossed my mind. That was really good,” he confides.
Although all cast and crew were on set to commence filming in Cape Town mid-February, the project has been temporarily suspended due to a funding shortfall, but filming is expected to recommence shortly.
Barry led a colourful personal life, quite apart from the alleged affair with Lord Somerset. She is reported to have fought a duel in Cape Town, and to have been sent home under arrest on numerous occasions after run-ins with her Army superiors.
But in particular, she made her mark as a medical innovator. When appointed colonial medical inspector, Barry used her power to stop widespread administering of drugs by unqualified persons. She pushed through vast changes in the care given to lepers and other inmates of institutions, regardless of race, arguing the benefits of fresh air and balanced diet long before such measures became standard. With Sherlock Holmesian deduction, she traced the cause of Cape Town's impure water supply, and arranged for a better system.
Dr Barry also instituted regular and detailed audits of garrison medical facilities and hospitals, checking on the health and hygiene of the troops and consulting on the treatment of tropical disease. Above all, she showed a rare compassion for the soldier and his family, devoting considerable energy to improving their welfare, a most unusual practice in those days when the enlisted soldier was poorly fed and treated with little respect. To this day her visionary service reforms – including separate quarters for married soldiers - benefit most modern military services.
Dr Barry was, without question, a pioneer in the fields of health promotion and preventive medicine and these standards became the hallmark of her subsequent postings, following 13 years in South Africa, to garrisons around the globe, including Barbados, Jamaica, St Helena, the West Indies, Corfu and, towards the end of her career 46-year career, Canada.
Eventually, poor health forced Dr Barry - then Inspector General of Hospitals - to return to England in 1864 where she was placed on half pay and retired in almost total seclusion, with her black manservant and dog “Psyche”, to her house in Marylebone, London. Her secret remained intact until her death from “dysentery” in 1865.
“I did make a serious attempt to obtain the opinion of a forensic osteologist about the configuration of Barry's pelvis, as well as DNA analysis for any evidence of Y chromosomal material, but after a year of correspondence with the functionaries in the Home Office, and with the informed interest and intercession of the amazing Boris Johnson - my local MP, Harriet Harman declined permission to expose the mortal remains, stating that it was not in the public interest.
“As far as I am able to judge, the public are very much interested in this extraordinary story of Dr James Barry,” argues Dr du Preez, obviously frustrated by this thwarted attempt to irrefutably confirm Barry’s gender.
“I do plan to continue my work,” he quickly adds. “I would like to be able to put together a proper biography - not one of those novelesque affairs which appear from time to time. I am interested in facts that can be verified, not unfounded speculations. It will require investigating archives in the Caribbean and the Mediterranean, as well as in Edinburgh London and Cork, and possibly Carlisle.
“I am quite excited just at the moment, because I think I have located a collection of books presented to the Public Library here, by Dr Barry, in about 1824. I believe that amongst this collection will be books, which Barry used while a Medical Student at Edinburgh. And there might even be handwritten notebooks - of the type which persisted even into my time, when photocopying was a messy wet and expensive process, and the computer was still a far off dream.
“James Barry is certainly an extraordinarily interesting subject, and I believe that there is much that still remains to be unearthed,” says Dr du Preez.
Through her subterfuge, Margaret Bulkley, as Dr James Barry, secured her place in history by being the first woman in Britain to graduate as a medical doctor and to fulfil an active army career dedicated to medicine and the amelioration of human suffering.
She elected to question every institution and sacred medical tenets of the day and was afraid of no one. But above all, she had a clear understanding of where the great scientific and social revolutions of the early 19th century were leading.
She chose to be a military doctor, not in a crusade for a woman’s right to join the profession, but simply to be one. The quickest course then was to become a man in the eyes of the world.
As they would say in her native Cork, that’s some woman for one woman.

The trouble with Barry

It is argued that Dr James Barry received scant recognition for extending the frontiers of military medicine because of her ability to upset the establishment with surprising regularity.
Shortly after being posted to Jamaica in 1829, Dr Barry took unofficial leave of absence and returned to England. The reason for her disappearance was demanded at a subsequent "interview without tea" with Sir James McGregor, the Director General. She answered, "I was fed up with my hair and wanted a proper haircut." To which McGregor replied, "It would seem Sir, that your audacity is equal to the prodigious growth of your hair."
Years later, during a short stint in Crimea, Barry was the only medical officer with the temerity to reprimand another equally formidable woman in the form of Miss Florence Nightingale. According to reports they disliked each other on sight. It was a mutual animosity that lasted throughout Barry's life.
On hearing of Dr Barry’s death Nightingale remarked: "After she was dead I was told she was a woman. I should say she was the most hardened creature I ever met throughout the army."

A question of sex

Dr Michael de Preez’s research has incited comments “from New Zealand to Venezuela and many places in between” - a large volume of which concerned Barry's gender.
“An interesting one was from a person who referred to Barry as transgendered, which I think is valid. Although like those Albanian women who have no more men in their families, I believe that the motivation for the young Margaret Bulkley was entirely career orientated, and had nothing to do with any emotional deviation.
“At the outset, it is my sense that, should the original plan of Miranda's have come to fruition, Margaret would quite likely have resumed her female persona once in Caracas. But that, of course, never happened. We shall never know,” says de Preez ruefully.