1994 continued

I'm really going through my big folder of emails, faxes, scribbled notes of phone calls etc. and trying to unpick what actually happened, so this narrative might seem a bit disjointed. Hopefully, others will now chip in with their own recollections to help fill in the gaps (hint).

For me personally, the big thing that happened with regard to this story was that I started building the Pompe Group in the AGSD-UK. There are several letters from people I met at the Newcastle conference, giving information, other contacts to follow up and so on. Email was not really widespread at this time, so most contact was by letter.

The main things I have are:

I persuaded the AGSD-UK to set up a Scientific Advisory Board, onto which Arnold Reuser and Ans van der Ploeg were invited, amongst others. This helped to provide some professional ballast for the AGSD-UK, while increasing its profile amongst medical and scientific professionals. You know, I still think that was a good move. Well done me;-)

The second thing was that the AGSD-UK set up a specific Pompe fund. This was to become a focus for fund-raising by the Pompe families (and still is).

The creation of the SAB was followed up by inviting Dr Ans van der Ploeg to speak at the next AGSD conference, to be held in Birmingham in May 1995. This invitation was in September 1994, so 8 months in advance. I'm flagging that up for a reason, so pay attention.

There was so much happening that I started a Pompe-specific newsletter - The Pompe's Bulletin - to use a a tool to keep people in touch and to spread the word. Initially 4 sides of A4 text, it has since become a high-quality, professional production. Of course, that only happened once I stopped having anything to do with it. You may see the start of a recurring theme here. Having said that, those newsletters, alongside the US equivalent produced by the AMDA (about to enter our story) are a pretty good historical record of events.

However, I can't let the round-up of 1994 pass without mention of the fact that we knew we were going to have another child and that our child would not have Pompe disease. chorionic villus sampling (CVS) is a technique that allows a sample of placenta to be tested for the presence of (in our case) alpha glucosidase. We had the test at 11 weeks. Not a great experience because you see the foetus on the screen, just like a normal ultrasound. We were trying not to look because, after all, we might have had to terminate the pregnancy. We knew that the sample was to be sent to Manchester and the test carried out there and were told to expect a result in a week or so. The hospital phoned the next day to give us the all clear. They must have had a courier waiting right there and then to take that sample to Manchester, where someone was waiting to - right there and then - start work on it.

The staff at the hospital were wonderful with us - though I don't think I've met anyone employed by the National Health Service who treats it as 'just a job'. They did everything they could to make things as easy for us as possible and treated us with great kindness. Hopefully we were able to show our gratitude at the time. However, there were a lot of people in that chain from Edinburgh to Manchester and back, who did well by us, and who we'll never know. People who are doing the same thing day in, day out for others. Our thanks to all of them from the very bottom of our hearts.

Euan was born in January 1995. The knowledge that we were having a healthy child made the last part of 1994 a very happy time for us.

So, the UK Pompe group was beginning to stir in 1994. This was only the start - the next year would see the start of an international network.

A visit to Rotterdam

Give a guy a big nose and some weird hair and he is capable of anything. Frank Zappa*

I have previously talked about the scientific research into Pompe disease. However, one of the things I hope to do in this story is to try to give a picture of some of the people involved, as they appeared to me. As you might gather from the Frank Zappa quote above, this is a personal and slightly irreverent account of my first meeting with Arnold Reuser.

In late June 1994, I went to Amsterdam, to attend a scientific conference (the 4th International Congress of Plant Molecular Biology, since you ask). Elaine came with me. Of course, I immediately thought that it might be possible to combine this with a visit to the laboratory in Rotterdam which was carrying out Pompe research. So I wrote to Arnold Reuser saying that I would be in The Netherlands and hoped that it would be possible to come and visit him, though I understood that it might not be convenient.


He called me up to say that he would be happy for me to visit and when he heard that my wife was coming to Amsterdam with me, he invited us both to his house for dinner. And so, on 25 June (after the conference session, lest my employers be reading this) , we found ourselves taking the train to Rotterdam. Bear in mind that Arnold and I didn't know what each other looked like - no websites with photos in those days. However, Arnold gave some helpful advice as to how to identify him: "Well, people do say that I have a big nose. And I will be wearing a pink scarf." He was right - we spotted it from the other side of the railway station. The scarf I mean. It was enormous and circled him several times - an excellent ice-breaker.

We had a very nice meal with Arnold and his wife Mariette.  During this, I learned a lot about Arnold and his work and about Pompe disease in general. As I had guessed, funding was precarious. However, he was clearly a determined and dedicated man. His Head of Department used to visit his office every few months or so and say, in effect, "Hey, when are you going to stop working on a disease no one has ever heard of?" I suspect that doesn't happen now. Yet he persevered, on a shoestring, but was at something of an impasse. He wanted to take ERT to the next stage and yet knew that this would more resources than had been available to him so far. He said that Ans van der Ploeg was now a medical doctor at the nearby Sophia Children's Hospital and was also still very much interested in Pompe disease.

Naturally, we wanted to help but, at that stage, had very little to offer except encouragement. I hope that the knowledge that there were people outside of The Netherlands interested in his work did make a difference, however small.

As Elaine and I made our way back to Amsterdam, we reflected on the evening. Of course, it was fascinating to speak with someone who was so knowledgeable about Pompe disease, the condition that had become so important to us. And it is one thing to be familiar with someone's work through their scientific publications and quite another to meet a living, breathing human being. However, there was something else too. The sad fact is that, when you lose a child, some people you know will cross the road to avoid you. It's not because they are bad people and mean to be unkind - it's just that they don't know what to say and, well, it isn't a pleasant thing to speak to grieving parents. Yet here were two strangers who had invited us into their home and had wanted to know about Calum. It must have been difficult for them, particularly since their youngest child was then the same age as Calum. It's a kindness that we've never forgotten.

One other thing. When leaving, I had handed Arnold a copy of a pamphlet I'd written for patients called Recent Advances in Research into Pompe Disease (correct, a snappy title - soon changed to Pompe Disease - a Guide for Families, still available from a website near you). I asked him if he wouldn't mind giving me some comments sometime. When we got back to our hotel in Amsterdam, there was a fax waiting, with encouraging comments in it. This had been sent at 10.30 pm. As I was to discover, Arnold's routine was often to work all day, go home to have dinner with the family and put the kids to bed - and then go back to the lab to do even more work.

So, what had I learned? I knew that there was a small but very determined group in Rotterdam who deserved our support - financial (though we had little in the way of that) and moral. For the first time, I had a sense that this was not a hopeless cause, that there was a battle going on that the AGSD-UK could try and play a part in - and that we had an ally. There would soon be others.

*Sorry Arnold, it was too good a quote to miss:-) This was from one of Frank Zappa's last interviews - fellow Zappa fans can find it here

My first AGSD-UK conference

When Calum was diagnosed, one of the few things the hospital could do for us, was to give us a leaflet for an organisation called the Association for Glycogen Storage Disease (UK) (and also for the Research Trust for Metabolic Diseases in Children, now Climb) .

We called Ann Philips, the President, and she put us in touch with other families who had had a baby with Pompe's. It was an enormous comfort to speak to them - other people who understood what it was like to have lost a child to this rare disease. So we decided to go to their annual conference, which was being held in Newcastle on 29 May, 1994.

The organisers, Henry and Janet, couldn't have been kinder to us and they - and Ann - made us feel very welcome. Most of the conference dealt with the other types of glycogen storage disease - reasonably enough, as that reflected the membership. However, at some point, the Pompe families met together. I don't have a note of everyone who was there, however it certainly included the Harringtons (who had also lost a child to Pompe's and became good friends of ours) the Critchleys and Allan and Barbara Muir. Allan is the current UK Pompe supremo and (I'm jumping the narrative gun a bit here) has made a much better job of it than I ever did. If you are doing a job that really matters to you, then I can wish you no greater blessing than to have a successor who does it better. It's certainly been a source of great happiness for me - cheers, Allan!

But I digress. At that small gathering I spoke about the ERT research and we gave ourselves a target to raise funds to help it. I also found myself on the executive of the AGSD, representing the Pompe group.

Without really thinking about it, I'd made a decision that whatever efforts I made regarding Pompe disease, it would be as part of this group. In retrospect absolutely the right decision (how I wish they were all like that). The alternative was to start a new group specifically focused on Pompe disease. However being part of a larger group brought the advantages of critical mass (for example, tagging on to a group big enough to organise a proper conference) and opened me up to the constructive criticism of others. Both important things.

Of course, I didn't realise then quite how much of my life this was going to take up for the next 10 years or so... It is not an exaggeration to say that this was a meeting that changed my life.

The very next month, I was to have another important meeting.

Tidying up before the next phase

Before I get into the story of the patient community and its involvement in the development of ERT, there are a few loose ends to tidy up.

Back in 1993, there were three groups looking at ERT. Arnold Reuser's in Rotterdam (of which more soon), Y T Chen's at Duke and Frank Martiniuk's in New York.

Frank Martiniuk had some interesting work and always gave me the impression of someone who was prepared to push things forward. For some reason (luck, politics, who knows) his group was not one of those that eventually participated in trials of ERT. I met him briefly - just to shake his hand really - at a Pompe conference some years later. However I'd like to thank him, not only for his efforts at pushing forward research into what was then a deeply unfashionable field, but also for an act of generosity that was much appreciated by me at the time.

Following my trawl through the literature, as described earlier, I wrote to him and asked him how his work was going. I didn't get an immediate reply, however I did receive in the post a large bundle of papers related to his work. It must have cost a fortune to post from the USA, never mind the time and trouble it took to put it together for me. I read it all avidly and still have it. Thanks, Frank.

The story so far...

Sitting down to write this up has brought back many, many memories. Consequently, it's taking me longer than I thought to sift though files of letters, emails etc.

While I do that, here's a quick summary of where we've got to so far:

Pompe discovered the disease
Hers explained it
Reuser and van der Ploeg worked out a way to treat it with enzyme replacement therapy.

That is the main narrative. Anything you read that purports to be the story of the development of ERT and doesn't have those names in it is not an accurate account. Simple as that.

Now, before I get into the patient group stuff (which is where I really will need some help, as we will be entering a more subjective realm) let me take the scientific story one step further.

As I showed in my last post, the Dutch team had shown that ERT could be made to work. What was needed though, was a supply of phosphorylated enzyme (because it has to be the phopshorylated version to work - you remember that, right?). It turns out that they had the start of the answer to that problem because Arnold Rueser's laboratory had cloned the gene for the enzyme.

This was a huge step forward because once you have the gene in a test tube, you can work at inserting it into other cells. For example, a standard type of cell used in laboratory and other work are chinese hamster ovary cells. These are the type that are used by Genzyme in their huge fermenters. Imagine huge amounts of those cells, all producing that vital enzyme. That's what cloning the gene opened up.

So having cloned this gene - and opening the way to eventual commerical production of the enzyme - the Dutch did a remarkable thing. They gave it away.

They gave it to Y T Chen's team at Duke University and to John Hopwood in Australia (with whom they had a continuing collaboration). That led to the creation of two cell lines producing phosphorylated alpha-glucosidase.

Thanks to an act of scientific generosity, the future was opening up.

The Turning of the Tide

Writing about Calum brought back a lot of memories. It was the saddest time of our lives. However, from now on, the story becomes brighter. Not that there isn't pain and sadness ahead for many - to this day, in fact. But from here on in, I'll be talking about the development of a treatment for Pompe disease. This is where hope first appears in this narrative. This, my friends, is the turning of the tide.

To quickly recap: Pompe discovered and described the disease. Hers explained it. What follows is the story of how Arnold Reuser and Ans van der Ploeg worked out how Pompe disease could be treated - and went on to demonstrate that their theory actually worked.

As we have seen, following Hers' discovery of lysosomal storage diseases, many attempts were made to treat Pompe disease by enzyme replacement therapy. None worked because enzyme was simply soaked up by the liver - it did not reach the muscles, which is where it needs to go, in order to shift glycogen. The whole concept of enzyme replacement therapy therefore fell out of favour. The situation seemed hopeless.

However, Arnold Reuser, a researcher at Erasmus University in Rotterdam, and his then PhD student, Ans van der Ploeg, had other ideas. They looked again at enzyme replacement therapy. In particular, they made use of the recent discovery that enzymes made their way into the lysosome using a receptor for the sugar mannose-6-phosphate. They reasoned that enzymes with this sugar attached - phosphorylated enzyme - might be more efficient at getting to the lysosome than the enzyme previously used in enzyme replacement therapy. The mannose-6-phosphate would effectively act as an address label, ensuring that the enzyme reached the lysosomes in the muscles. An interesting theory - but was it right?

Their first experiment was to take cell lines isolated from Pompe patients - human muscle cells grown in a dish in the laboratory. These cells showed the classic Pompe symptom of glycogen accumulated in the lysosomes. Reuser & Van der Ploeg added the phosphorylayed enzyme - and the glycogen was degraded.

This was obviously an important step forward, however it was not enough to demonstrate that this approach would work. After all, cells growing in a thin layer in a laboratory dish are one thing - living organisms with blood, liver and muscle are quite another. And this presented a seemingly imovable obstacle. The phosphorylated enzyme was difficult to produce and only small amounts -extracted from bovine testes - were available. This was not enough to treat a child, even if permission had been obtained for such a speculative approach. The only animal model known at that time was a type of cattle - which would require even more of the enzyme. How could this be resolved?

The answer came in a series of experiments which I can only describe by using one of the highest words of praise in the scientific lexicon: elegant.

Reuser and Van der Ploeg realised that they only had enough enzyme to use on mice. However, these mice did not have Pompe disease and therefore had normal levels of alpha-glucosidase and no glycogen accumulation. So how could they be used to demonstrate uptake of the enzyme? The solution was to use antibodies that reacted with the phosphorylated enzyme produced from bovine testes but not against the normal mouse enzyme.

The bovine enzyme was administered to the mice, and the increase in alpha-glucosidase activity in different tissues measured. It was possible to work out how much of this activity was due to the bovine enzyme using the bovine-specific antibodies. Firstly the whole tissue activity was measured, and then the activity when the antibodies had reacted with the bovine enzyme. By comparing these two figures, it was possible to see how much of the activity was caused by the mouse enzyme and how much was due to the added bovine enzyme. This also showed that the bovine enzyme had made its way to the various tissues, including heart and muscle.

Reuser and Van der Ploeg found that the addition of the bovine enzyme to the mice resulted in a 43% increase in enzyme activity in muscle and 70% in the heart.

They noted that even after 6 days, enzyme activity in mice was 10-20% above normal. As enzyme activity of more than 20% of normal does not usually result in Pompe symptoms, they concluded that, in some cases at least, a slight increase in alpha-glucosidase activity might be enough to prevent glycogen storage.

These results were published in February 1991. The paper is entitled Intravenous Administration of Phosphorylated Acid Alpha-Glucosidase Leads to Uptake of Enzyme in Heart and Skeletal Muscle of Mice. Thanks to the wonder of the internet, you can read the whole paper online at the website of the Journal of Clincial Investigation

The paper also notes that the amounts of enzyme required would be very large - beyond what it was then possible to produce. However the speculated - correctly - that it might be possible to produce it using the cloned human gene for the enzyme.

With characteristic understatement, Reuser and Van der Ploeg concluded that "...we think that the original idea of enzyme replacement therapy for treatment of lysosomal storage diseases deserves new attention."

I'll say! While the paper was in preparation, results showing the success of such an approach on Gaucher disease (another lysosomal storage disease) were published. Gaucher disease was something of a special case, for reasons too complicated to go into here, however it underlined the feasibility of the approach.

Here's a suggestion. If you are affected by Pompe disease, follow that link and print out that paper. Read it and try and understand it (go on, it's not as difficult as it might look). Put it in a nice folder. Even better, frame it and put it on your wall. That paper is an important part of your life story because, building on what went before, it made a treatment for Pompe disease a real possibility for the first time. Cherish it.

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.

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.

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.

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.