Dr J C Pompe

Dr J C Pompe
Discoverer of Pompe disease

About this blog

What you can read here is the story of the development of enzyme replacement therapy (ERT), the first effective treatment for Pompe disease. It is an incredible story, rich with events, characters and science. Above all, it is the story of an international community of scientists, doctors, patients and companies, working together towards a common goal.

It is not a story that features in Geeta Anand's book, The Cure , or the film based on it, Extraordinary Measures despite the fact that they are ostensibly about the development of ERT for Pompe ( you can link straight to the relevant articles covering the events described in the book and film here, here and here).

This blog represents my small attempt to set the record straight and to give the story back to its rightful owners - the international Pompe community. It is written here in roughly chronological order i.e. you'll need to start at the bottom of the April 2009 archive page and work your way up.

It is also a personal account and, although I've tried to make it as objective as possible, there is an inevitable degree of subjectivity. For that reason I have included contributions from other members of the worldwide Pompe community and would be delighted to receive more. Feedback is also welcome.

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Friday 24 April 2009

Calum

The morning glory that blooms for an hour, differs not at heart from the giant pine that lives for a thousand years.

Buddhist proverb
It was Friday 28 May, 1993 and one of the happiest days of my life. I was driving across the border from England into Scotland, to a new home in Edinburgh - the city I had always wanted to live in - and to my dream job, running my own molecular biology laboratory. Best of all, I had my family in the car with me - my wife Elaine and our two-month old baby son, Calum. Life was sweet. Yet within a few short months that sweetness turned to dust in my mouth.

Everything was fine for a couple of months. I busied myself with settling in to my new job, while Elaine and Calum went house-hunting. Then Calum seemed to be getting a lot of colds and sniffles, which took longer and longer to go away. It never occurred to us for one moment that something could be seriously wrong. Even when, at six months old, Calum was hospitalised with pneumonia we didn't think it was anything other than a temporary blip. In hindsight we were incredibly naive - but what does anyone know with their first child?

An x-ray showed an enlarged heart and, even then, we didn't think anything other than "So he shouldn't play rough sports? Guess he'll just have to be geeky like his dad!" Unknown to us though, alarm bells were beginning to ring at the hospital and blood tests were taken "Just routine, nothing to be concerned about..." And we weren't concerned. We found a house (next to a park - and a school - perfect!) and started fixing it up prior to moving in.

Then we got the news that brought our world crashing down around our ears. On a follow-up hospital visit we were told that the blood tests showed Calum had something called Pompe disease which was a type of glycogen storage disease. It was untreatable and fatal; children with this disease did not usually live beyond their first birthday.

We just couldn't believe it. We thought that there must have been some terrible mistake. Our beautiful child, the light of our lives, going to die? How could such a thing be possible? And whoever heard of an untreatable disease in this day and age - those doctors really needed to keep up with what was happening in the world of medicine!

For the next two we weeks we frantically found out everything we could about Pompe disease and what little information there was available was not good. Everything confirmed what the hospital had told us; there was no hope. None. While we were still in shock, Calum declined quite rapidly and he went back into hospital. He died at the Sick Children's Hospital in Edinburgh, on 18 November 1993, just two weeks after we were given the diagnosis.

We used the Buddhist proverb from the beginning of this article as his epitaph. We both think of him every day and will always mourn the life that was lost. But we will always be grateful for the life that we had.

...

The hospital hadn't been able to help us with a treatment however they did one thing for us that was very helpful, both then and in the years ahead, and which was life-changing. They passed us details of two patient groups that helped families in our position. One was the Research Trust for Metabolic Diseases in Children (now known as Climb ), an umberella group for metabolic diseases, and the other was the Association for Glycogen Storage Disease UK, which dealt specifically with the glycogen storage diseases. Both organisations founded by remarkable women who responded to the illness of their own children by creating organisations that helped others. We will be forever indebted to Lesley Greene (Climb), Ann Philips (AGSD-UK) and the families they put us in touch with, for helping us through the darkest time of our lives. More of them later.

Following Calum's death we wanted to raise some funds for research into Pompe disease and I also had the idea that, as there was so little information available on Pompe disease, I would use my scientific background to write something aimed at parents. I felt that this was important because we had been desperate to understand what was happening to Calum and as I had watched Elaine (a bright person without a science background) struggle with concepts like genes, enzymes and lysosomes it was brought home to me what a privilege it is to be a scientist. It now gave me the opportunity to make a contribution that others were not in a position to make. I had thought that I would pull together what information there was and write up something for the AGSD. A sort of 'thank you' that would also be of a help to any future parents in our position. I didn't really see that there would be much that could be done beyond that.

The librarian at my work, Lynda, pulled a few strings to get me into the medical library at Edinbugh University and so I started carrying out a literature search on Pompe disease, helped by my cousin Aidan, who was a med student at the time. It was just the kind of mind-numbing, time-consuming task that I needed. In the far off days of 1993, younger readers may be surprised to learn, this was all done as a paper chase - looking up entries in publications like the citation index, then walking to shelves of actual hard-copy journals to look up the articles and see if they were of any interest. And if they were useful, you wrote the reference (by hand) on an index card and put it in a little desk file. Describing this to anyone under the age of 30 elicits a response that can only be compared with the old 'For mash get smash!' advert. But I digress.

And then something astonishing happened. Right then, in that library, amongst those dusty shelves of journals, I felt the sun come out. Because there, in my hands, was a paper that showed that Pompe disease was not the hopeless case that I had thought. A team of people in The Netherlands had been carrying out some ground-breaking research. They had worked out how Pompe disease could be treated and had designed some ingenious experiments to show that their idea could work.

I realised that I would be able to do more than just write an article for other parents to help them understand how their child was dying. I could write something explaining how this disease could be beaten. This was no longer a hopeless cause - it was a cause that could and must be won.

And the first step was to try to explain to other people just why what this Dutch group had done was so important. Which is something that I am going to do again in the next article.

Monday 13 April 2009

The long plateau

Following Hers discovery of lysosomal storage diseases - the second great milestone in the Pompe disease story - there followed a long period where there were no major advances. That's not to say that work was not being carried out. Research continued and small but important additions were added to our store of knowledge.

It was discovered that Pompe disease could affect older children and even adults (where it was at that time given the name acid maltase deficiency) with progressive muscle weakness but no heart enlargement. Diligent, essential work (such as that by Christa Loonen) described the 'natural history' of Pompe disease patients. There were important advances in related fields too - lysosomes became better understood and better molecular biology tools and techniques were developed. The world was moving on.

There were attempts at a treatment too. Soon after Hers discovered lysosomal storage diseases, it had been suggested that enzyme replacement therapy might be a potential treatment. As early as 1965, this was tried for Pompe disease, firstly using enzyme prepared from the fungus Aspergillis niger and later with enzyme derived from human placenta. All attempts failed; the enzyme was simply soaked up by the liver and did not reach the muscles.

I would like to make a tangential point here that I may return to later. It is often said by animal rights proponents that if scientists were not able to use laboratory animals, they would soon find alternative methods. Well, there was clearly a tremendous will amongst the scientific and medical community to find a treatment for Pompe disease, as evidenced by the pretty desperate attempts at enzyme replacement therapy. Yet for a quarter of a century, there was no progress. Looks like absence of animal models does not, after all, magically lead to progress by other methods.

But I digress. By the late 80s, the stage was set for the third great leap forward - one that would lead to a treatment for Pompe disease. Once again, it would take place in the Netherlands.

However, before I get to that, in the next instalment I'd like to leap ahead to 1993, with some personal background. It's an indulgence, I know, however it will also help me to tell the story.

Tuesday 7 April 2009

Christian de Duve, Henri-Gery Hers and serendipity

"In the field of observation, chance favours only the prepared mind"
Louis Pasteur
J C Pompe had described a disease which had the symptom of glycogen accumulation, particularly in the heart, due to an 'inborn error of metabolism'. In the years that followed, further research on glycogen metabolism made the cause of the disease more mysterious, rather than less.


Gerty and Carl Cori were pioneers in this field and discovered the missing enzyme in von Gierke's disease. Indeed, they won a joint Nobel Prize for their work on glycogen metabolism. In 1957, G T Cori listed what are now known as glycogen storage disease types 1-4. Only in the case of Pompe disease was the missing enzyme unknown. The key to solving the puzzle of what caused Pompe disease lay in a seemingly unrelated discovery taking place elsewhere.












US stamp issued in honour of Gerty Cori (the formula is wrong, unfortunately...)

In 1955 Christian de Duve and co-workers were investigating the effect of insulin on the liver, when they came across some odd results, in the shape of some intra-cellular particles which seemed to have digestive properties. Intrigued, they stopped their work on insulin and investigated this phenomenon. de Duve named these particles lysosomes and so began a long period of research by his group and others. This was an important discovery. The idea that cells themselves had compartments (now known as organelles) with particular functions was now firmly established. Thus was the idea of the lysosome as the 'recycling plant' of the cell established. Prof de Duve was awarded the Nobel Prize for his discoveries in 1974.

I wrote to Professor de Duve a few years ago, asking him if it had ocurred to him that his discovery of lysosomes might have some medical significance. He replied that it had not - it was curiousity-driven 'blue skies' research. However that connection was made by one of his original co-workers, Henri-Gery Hers.

After the discovery of lysosomes, most of de Duve's team joined him in this exciting direction, however Henri-Gery Hers retained his interest in carbohydrate metabolism and founded his own research group instead. This ultimately led him to become involved in research on glycogen metabolism. Following the death of Gerty Cori, he decided to take up her research on identifying the missing enzymes responsible for the glycogen storage diseases.

In the course of this he examined samples from patients from around the world, including some with Pompe disease. This confirmed the puzzle that in pompe disease all of the known enzymes for the metabolism of glycogen were present and correct - yet there was still massive accumulation of glycogen.

That was still not his main line of research. Hers was trying to develop a test for the enzyme responsible for glycogen storage disease type 3. Unfortunately, his test turned out to be for an enzyme that was at normal levels in his GSD 3 samples. Fortunately, by chance, he had included some Pompe samples in his experiment - and his test showed a deficiency in all of those cases. He had discovered the enzyme deficiency responsible for Pompe disease.

That wasn't all though. Hers knew that his new enzyme, an alpha-glucosidase, worked best at an acid pH. This set him thinking about his previous work on lysosomes which had an acid environment - could this new enzyme be situated there? He went on to establish that it was. He further deduced that the normal function of this enzyme was to break down glycogen inside the lysosomes and that, in its absence, glycogen would accumulate, as it was isolated from the normal enzymes for glycogen metabolism found in the rest of the cell. In 1965 he established the concept of lysosomal storage diseases, based on his Pompe disease research.

All in all, a remarkable piece of scientific detective work. Yes, there was an element of serendipity involved, however Hers was quick to realise the significance of what he found. Truly chance favours only the prepared mind.

Thanks to de Duve and Hers, the cause of Pompe disease was now known over 3o years after its discovery. The next task was to find a way to treat it - that would take an equally long time.

Saturday 4 April 2009

Joannes Cassianus Pompe 1901 -1945

I can think of no better place to start the story of Pompe disease than with Joannes Cassianus Pompe, the scientist who first described the disease which now bears his name. It is important to note that the disease had undoubtedly been around for a very, very long time, prior to its discovery. In fact, I would say (warning: people often look askance when I say this and your attention is drawn to the disclaimer at the right) that it was around in the time of the dinosaurs. "Evidence?", you cry? Well, if it is found in both mammals and in birds (and it is) it's a fair bet that it was found in the common ancestor of mammals and birds - which pre-dates the dinosaurs. All of which makes its eventual discovery all the more impressive as a piece of scientific observation and detective work.















In putting together this article, I have drawn heavily from information and images supplied by Dr R C C Pottkamp of the Netherlands Institute for War Documentation, whose help I very gratefully acknowledge.

The image above is a contemporary drawing of the great man. I scanned it, with permission, from the 1979 PhD thesis of Christa Loonen (The Variability of Pompe's Disease: A clinical, biochemical and genetic study of glycogen storage disease type 2, or acid maltase deficiency - also drawn on here) one of the dedicated band of Dutch scientists and doctors who did so much to take forward Pompe's work. But more of them later.

Joannes Cassianus Pompe was born in Utrecht on 9 September 1901. He studied medicine at the University of Utrecht and during this time came across the symptoms of what is now known as infantile Pompe disease, which he described in his 1932 publication Over idiopathische hypertrophie van het hart. On December 27, 1930, Dr Pompe had carried out a postmortem on a 7-month old girl who had died of pneumonia. He found the enlarged heart now known to be charactertic of the infantile form of the disease and had some microscope slides prepared. These showed that the muscle tissue was distorted into an oval mesh.

He realised after detailed examination, that this appearance was due to the accumulation of something forcing the muscle tissue to distort in that way. This isn't as obvious as it appears now - when you look at fishing net, would you conclude that it has been forced into that shape by the air filling the holes? He then tried to discover what the accumulated substance was and had the idea that it might be glycogen. Subsequent testing showed that to be the case.

Pompe was perhaps guided in that direction by his colleagues Professor Snapper and Dr van Creveld. They had published a paper in 1928 desribing what is now known as Von Gierke disease, or glycogen storage disease type 1. In fact, the girl on whom Pompe carried out his post-mortem had been the patient of Professor Snapper. You can imagine that these colleagues might have encouraged Dr Pompe in establishing the idea that here was a second type of glycogen storage disease, also an inborn error of metabolism. It is interesting to speculate (and that's all it is, pure speculation on my part) that having missed out on 'naming' glycogen storage disease type 1, Snapper and van Creveld were keen to promote 'Pompe disease' as the name for the new type (there was some competition, as a German pathologist, W Putschar, made the same discovery, just a few months later!).

Dr Pompe graduated in 1936 in the subject 'cardiomegalia glycogenica', indicating that this had been a continuing subject of study for him. After a spell at the St. Canisius Hospital in Nijmegen, he was appointed as Pathologist at Hospital of Our Lady (OLCG) in Amsterdam, where he worked from June 1939 until his death.

The workplace was appropriate as he was known as a very devout Catholic, as well as an admirer of Sophocles and the Dutch poet Vondel. The overall picture is of a 'renaissance man' - a man of both science and the arts, as well as a dedicated family man. He was also, as we shall see, a hero, for Pompe, no doubt led by his strong Christian beliefs, became active in the wartime in the wartime Dutch resistance.


To the right is a photograph of Dr Pompe in the uniform of a Captain of the Dutch army (Medical reserve), thought to have been taken in 1939-40. Following the Nazi invasion of the Netherlands on 10 May 1940, he was mobilised and was involved in the fighting that lasted until 15 May.

Following the fall of the Netherlands, Dr Pompe became involved with the Dutch resistance. At first he was involved in finding hiding places for Jews. Through this he made contact with the operator of an illegal transmitter.

Pompe's laboratory was somewhat isolated from the rest of the hospital. So much so that at least two men who were hidden in the OLVG worked in the laboratory during the daytime! He therefore suggested that it would make a good hiding place for the transmitter and in sometime in November-December 1944 it was installed in the animal house (where the experimental animals were kept) beneath his laboratory. The transmitter was used to send messages to the UK on behalf of the resistance.

The transmitter was eventually detected by the Germans and on Sunday 25 February 1945, at 10 am, 40-50 members of the German Military Police entered the hospital and made straight for the animal house. The wireless operator, Pierre Antoine Coronel, was broadcasting at the time and tried to resist. He was subject to summary execution in the courtyard of the hospital. After the war, a street was named after him in Amsterdam - Coronel Street. Several hospital staff were arrested.

During the raid, Dr Pompe had been at Sunday mass and on returning to hospital was warned by patients of what had occurred. He went home to tell his wife that he needed to go into hiding. While leaving the house he was arrested in front of his wife and children, who were threatened with rifles.

While some of the imprisoned staff were eventually released, Dr Pompe, Louis Berben (the man in charge of the animals) and a male nurse, Piet van Doorn, were kept in jail.

On April 14, 1945, the resistance blew up a railway bridge near St Pancras, destroying an army train in the process. As a reprisal, 20 Dutch prisoners, including Dr Pompe and Louis Berben were shot. They were taken in a sealed truck to a meadow near St Pancras and, at around 9pm on 15 April, shot in two groups. The bodies were buried in a mass grave in the sand dunes near Overveen. On the same day, Piet van Doorn was also shot, in retaliation for another attack on a railway.

A monument was erected to the victims after the war (colour photographs below, courtesy of Maryze Schoneveld van der Linde's brother).
















In addition, a tile panel was erected above the main entrance of the OLVG, in remembrance of Dr Pompe and the other employees who were shot. This is currently held in storage, following redevelopment of the hospital.


Apologies if the reader feels I have gone on at too much length here. However, I have to confess that I am in awe of such bravery in the face of seemingly insurmountable evil and so wanted to give a fuller picture of the man who is at the start of our story - his intellect and his courage. Truly, there is much to admire about Joannes Cassianus Pompe.

One last comment. I have been gathering this information for some time and have found myself almost reluctant to write it up. The reason is that the German patient group are amongst the leading lights of the international Pompe community and I would be unhappy if this article were thought to be, in some way, anti-German. It is certainly not intended to be so. It is worth bearing in mind that the first country to fall victim to the Nazis was Germany itself (over 3 million German citizens were imprisoned by the Nazis and around 77,000 executed), that they were aided and abetted by home-grown Nazi movements and sympathisers in other countries and that perhaps the bravest of all the anti-Nazi movements was the German resistance. Lastly, I don't think we need to think too hard to realise the fate of any family touched by genetic disease under a Nazi regime.

Wednesday 1 April 2009

Introduction

Where to begin?

Just 16 years ago, Pompe's disease (glycogen storage disease type 2, acid maltase deficiency) was still an untreatable condition, invariably fatal in infants and relentlessly progressive in older children and adults. That is all changed now. The story of how that change came about is a remarkable one. It's a story that I have been threatening to write a book about for the last 6 years and have signally failed to do so! This blog is an attempt to put that right and to do so in a way that allows the wider Pompe community to add to, comment on and correct what I have written.

I have to confess that this blog is also, in part, a reaction to Geeta Anand's book, The Cure, soon to be the basis for a Hollywood film. It's not a bad book. It's the inspiring story of one man, John Crowley, whom I rather like and admire. What it is not is the story of the development of a treatment for Pompe disease. In fact, in that respect, the book is akin to reading a history of World War 2, told entirely from the perspective of Switzerland: "Skiing good. Apparently the neighbours are fighting about something or other. Most importantly, we have invented Toblerone!"

The Cure misses the main narrative out altogether, along with most of the important milestones in the development of enzyme replacement therapy. However the most glaring omission is the complete absence of any mention - any mention at all - of the role played by the international patient community in bringing about the availability of a treatment. The alliance between patient groups, researchers and industry is a model for the development of treatments for other rare diseases.

This is a story that needs to be told and I will attempt to do that justice here, though I hope I will have some help. I have a large file of material that I intend to work my way through - I know that others have their own archives and I hope that they will contribute from them. The result may not be strictly chronological but I hope that it will be as objective as possible.

Lastly, a quick word about myself. I'll post the story of my involvement later, however, just to be clear at the outset, I have no claim to have played any significant part in the events that will be described here. What I did have, was a ringside seat during what was a very exciting time. What follows is the view from that ringside seat.