In September 1997 one of those twists took place. Duke University announced that YT Chen's group would also be conducting clinical trials of ERT, in collaboration with a company called Synpac Pharmaceuticals. They would be using the more 'traditional' method of producing the enzyme in Chinese hamster ovary (CHO) cells engineered to produce the human enzyme.
This just seemed incredible - not one but two pharmaceutical companies, competing to conduct a clinical trial and bring a product to market.
In a pretty strange and complicated saga, Synpac were one of the more mysterious participants. They were (probably still are) a Taiwanese company, very private, whose main line of business was the bulk production of generic pharmaceuticals like penicillin. How they became involved with Pompe disease is a story that I suspect only YT Chen knows.
Anyhow, by the end of 1997 we had two teams racing to stage a clinical trial of ERT, something which seemed impossible just a few years before.
However, this was just a taste of what was to come...
Saturday, 12 December 2009
The 1997 AGSD-UK conference: an international gathering
The 1997 AGSD-UK conference took place on 25 May, in Slough, near London. Coincidentally, I used to live in Slough and managed to get the Mayor, Lakhbir Minhas, to come an open the conference, which ensured some local news coverage and also gave a suitable sense of occasion. I also managed to blag a few boxes of chocolate bars from my old employer. Let's just say that we were well prepared for work, rest and playing. And just as well, for this was to be a remarkable conference, for all sorts of reasons.
A report from the Slough Observer! Photo shows Mayor Minhas, Me, Elaine & Euan, Arnold Reuser and Ann Philips. It also contains my embryonic daughter, Catriona who was born in December. We got the CVS all-clear on the drive down.
Firstly, there were a number of international attendees, mainly from the Pompe field. From memory, Gerd Hassler from Germany, Bob Morrison from Australia, Ross Harvey (jr's brother),Randall House and YT Chen from the USA and Gerben Moolhuizen and Arnold Reuser from the Netherlands. Many of us had 'met' online, so in a way it was a GSDNet conference too! In retrospect, this really helped to cement the development of a Pompe community.
There were a series of remarkable presentations too. Arnold Reuser gave a talk on the latest developments in ERT and was helped in the following Q & A session by Gerben Moolhuizen.
That was obviously exciting. However, the following presentation by YT Chen was a real show-stopper. Yt presented his work involving Japanese quails, an unusual choice of experimental animal, explained by the fact that they have the bird equivalent of Pompe disease.
The affected birds were unable to move their wings, or to right themselves after being turned over. After 3 weeks treatment with enzyme produced in YT's lab (at Duke University USA) one of the birds was able to fly - and was only stopped after it hit a light stand! Analysis showed that their heart and liver had returned to normal and that their skeletal muscle, while still containing some glycogen, showed obvious signs of improvement - and, more to the point, fairly spectacular evidence of recovered function!
It was a remarkable double-whammy for everyone in that room. ERT was being developed - and there were the people developing it, right in front of us, answering questions. Not only that but a researcher had come from the US with dramatic evidence that it would actually work. This work was published in 1998 and the paper - well worth reading - is online. To my continued astonishment it manages to avoid all mention of the pioneering series of papers published by the Rotterdam group that demonstrated that ERT was a runner. I guess this was a sign that things were about to become competitive (the paper acknowledges funding by Synpac). Aside from the fact that the reviewers should have picked the omission up, it was just plain bad form.
However, just like a TV drama, there were twists and turns ahead that we could not conceive of. And speaking of TV, do I get a prize for an article involving Slough that does not mention The Office?
A report from the Slough Observer! Photo shows Mayor Minhas, Me, Elaine & Euan, Arnold Reuser and Ann Philips. It also contains my embryonic daughter, Catriona who was born in December. We got the CVS all-clear on the drive down.
And the rival Sough Express was not to be outdone!
There were a series of remarkable presentations too. Arnold Reuser gave a talk on the latest developments in ERT and was helped in the following Q & A session by Gerben Moolhuizen.
That was obviously exciting. However, the following presentation by YT Chen was a real show-stopper. Yt presented his work involving Japanese quails, an unusual choice of experimental animal, explained by the fact that they have the bird equivalent of Pompe disease.
The affected birds were unable to move their wings, or to right themselves after being turned over. After 3 weeks treatment with enzyme produced in YT's lab (at Duke University USA) one of the birds was able to fly - and was only stopped after it hit a light stand! Analysis showed that their heart and liver had returned to normal and that their skeletal muscle, while still containing some glycogen, showed obvious signs of improvement - and, more to the point, fairly spectacular evidence of recovered function!
However, just like a TV drama, there were twists and turns ahead that we could not conceive of. And speaking of TV, do I get a prize for an article involving Slough that does not mention The Office?
Pharming
Pharming were - and are - a fantastic company. They were pioneers in the field of transgenic animals. Relatively small, young and adventurous. That's why they were willing to take a risk on a product for a disease that no-one had heard of. I am of the belief that without Pharming the development of ERT for Pompe disease would have been much delayed. Certainly, Genzyme had not shown any interest when I had written to them regarding the Rotterdam work.
Over the years they were involved with the Pompe project, I always got the impression that this was more than just a job - they believed in this project. That high level of motivation made for good relations with the patient community and undoubtedly helped progress. They were the right company, with the right product at the right time. And the fact that they were nearly destroyed by later corporate chicanery does not detract from that one bit. I hope that all those from Pharming look back on their involvement with the patient community with pride. We owe them our thanks.
No-one exemplified the Pharming commitment to the Pompe project better than Gerben Moolhuizen, the Project Director. Gerben got in touch in early 1997, to bring me up to date with the project. That established a relationship between the AGSD-UK and Pharming based on openess and trust. They knew that confidential and commercially sensitive information could be shared without it going any further.
Pharming were taking a novel and potentially controversial approach. They had genetically engineered animals by adding the human alpha-glucosidase gene to them, along with a marker that meant that the resulting human enzyme was expressed in the animals' milk. This cleverly did away with the need for complex bioreactors, with all their special growth mediums, difficulties in keeping sterile. Just feed grass in and get alpha-glucosidase-rich milk out.
One problem though was that the animal Pharming were not producing the milk in cows, or even sheep or goats - but rabbits. At first this seems odd, not to say bizarre. However the reasoning was solid - the rapid generation time allowed production to be increased quickly due to the relatively short time taken for the animals to reach breeding (and milk producing) maturity. The downside was that it was going to take an awful lot of rabbits to produce the required volume of milk.
One question I often used to get asked was "But how do you milk a rabbit?" To which the obvious answer was "You sit on a very small stool." However the true - and only slightly less amusing answer - is that you buy a rabbit-milking machine. Apparently cheese made from rabbit milk is considered to be a delicacy in some quarters. Who knew?
As a postscript to the above, I once asked Gerben Moolhuizen what precautions were taken to preserve these very valuable rabbits, in the case of some catastrophic accident. he replied that I shouldn't worry because samples of semen from the genetically engineered rabbits were deep frozen so that, in such an event, the breeding line could be quickly restored. I mention that simply to point out that there are worse jobs than milking rabbits.
Over the years they were involved with the Pompe project, I always got the impression that this was more than just a job - they believed in this project. That high level of motivation made for good relations with the patient community and undoubtedly helped progress. They were the right company, with the right product at the right time. And the fact that they were nearly destroyed by later corporate chicanery does not detract from that one bit. I hope that all those from Pharming look back on their involvement with the patient community with pride. We owe them our thanks.
No-one exemplified the Pharming commitment to the Pompe project better than Gerben Moolhuizen, the Project Director. Gerben got in touch in early 1997, to bring me up to date with the project. That established a relationship between the AGSD-UK and Pharming based on openess and trust. They knew that confidential and commercially sensitive information could be shared without it going any further.
Pharming were taking a novel and potentially controversial approach. They had genetically engineered animals by adding the human alpha-glucosidase gene to them, along with a marker that meant that the resulting human enzyme was expressed in the animals' milk. This cleverly did away with the need for complex bioreactors, with all their special growth mediums, difficulties in keeping sterile. Just feed grass in and get alpha-glucosidase-rich milk out.
One problem though was that the animal Pharming were not producing the milk in cows, or even sheep or goats - but rabbits. At first this seems odd, not to say bizarre. However the reasoning was solid - the rapid generation time allowed production to be increased quickly due to the relatively short time taken for the animals to reach breeding (and milk producing) maturity. The downside was that it was going to take an awful lot of rabbits to produce the required volume of milk.
One question I often used to get asked was "But how do you milk a rabbit?" To which the obvious answer was "You sit on a very small stool." However the true - and only slightly less amusing answer - is that you buy a rabbit-milking machine. Apparently cheese made from rabbit milk is considered to be a delicacy in some quarters. Who knew?
As a postscript to the above, I once asked Gerben Moolhuizen what precautions were taken to preserve these very valuable rabbits, in the case of some catastrophic accident. he replied that I shouldn't worry because samples of semen from the genetically engineered rabbits were deep frozen so that, in such an event, the breeding line could be quickly restored. I mention that simply to point out that there are worse jobs than milking rabbits.
Thursday, 3 December 2009
1997: Lift off!
Looking back, 1997 was an absolutely pivotal year.
Browsing the email archive, I see that this was when many leading lights of today's patient community first made contact with each other - for example, Thomas Schaller, Helmut Erny, Juan Magdaraog, Bet Cook, Helen Walker and Bob Morrison. The international network was growing and starting to become a community. Increasingly, this included scientific and medical professionals from around the world too.
I have to make a small confession here. Researchers and doctors are often, for entirely understandable reasons, uncomfortable about talking with individual patients or parents. That's one reason why patient groups are such a good idea. However it did occur to me that my own scientific background would be of use in making initial contacts. Seldom has a PhD been so shamelessly exploited - and to such good end.
I was kept also busy by a whole range of people getting in touch from all over the world. This could be quite difficult at times, such as speaking with someone who had just been told their child had a terminal illness. No matter how many people I spoke with, that never got easier. I guess some things should never be easy.
However towards the end of 1996, came some news that was like a dream come true. A Dutch pharmaceutical company, Pharming, announced a £14 million collaboration with the Rotterdam group to run a clinical trial of ERT for Pompe's. Fantastic! They also announced that were going to produce it in the milk of genetically engineered animals - a novel method. More on that, and on Pharming, later.
Arnold Reuser and Ans van der Ploeg kept us well informed of developments, of course. The March 1997 edition of the Pompe's Bulletin included this article by them (note that the fruits of the conference organised by the Houses are already obvious):
Enzyme Therapy for Glycogen Storage Disease Type II: Dream or Reality?
by Arnold JJ Reuser, Biochemist, Clinical Genetics Erasmus University, Rotterdam and Ans T van der Ploeg, Paediatrician, Sophia Children's Hospital, Rotterdam
Browsing the email archive, I see that this was when many leading lights of today's patient community first made contact with each other - for example, Thomas Schaller, Helmut Erny, Juan Magdaraog, Bet Cook, Helen Walker and Bob Morrison. The international network was growing and starting to become a community. Increasingly, this included scientific and medical professionals from around the world too.
I have to make a small confession here. Researchers and doctors are often, for entirely understandable reasons, uncomfortable about talking with individual patients or parents. That's one reason why patient groups are such a good idea. However it did occur to me that my own scientific background would be of use in making initial contacts. Seldom has a PhD been so shamelessly exploited - and to such good end.
I was kept also busy by a whole range of people getting in touch from all over the world. This could be quite difficult at times, such as speaking with someone who had just been told their child had a terminal illness. No matter how many people I spoke with, that never got easier. I guess some things should never be easy.
However towards the end of 1996, came some news that was like a dream come true. A Dutch pharmaceutical company, Pharming, announced a £14 million collaboration with the Rotterdam group to run a clinical trial of ERT for Pompe's. Fantastic! They also announced that were going to produce it in the milk of genetically engineered animals - a novel method. More on that, and on Pharming, later.
Arnold Reuser and Ans van der Ploeg kept us well informed of developments, of course. The March 1997 edition of the Pompe's Bulletin included this article by them (note that the fruits of the conference organised by the Houses are already obvious):
Enzyme Therapy for Glycogen Storage Disease Type II: Dream or Reality?
by Arnold JJ Reuser, Biochemist, Clinical Genetics Erasmus University, Rotterdam and Ans T van der Ploeg, Paediatrician, Sophia Children's Hospital, Rotterdam
A number of recent events have brought the answer to this question near. When Dr. Kevin O'Donnell asked us for the latest news, we thought it would be nice to put these recent events in a historic perspective.I can hardly describe the sense of excitement at this time. It really seemed that the fledgling Pompe community could, at last, dare to hope.
At the basis of enzyme therapy for lysosomal storage diseases, such as GSDII, is the discovery of lysosomes in the mid fifties by the later Nobel price winner Dr. Christian De Duve. Lysosomes form a compartment inside the cell in which large sized biological substances from inside and outside the cell are degraded by over 40 different enzymes.
In the early sixties a deficiency of one of these enzymes, namely acid a-glucosidase, also known as acid maltase, was discovered by Dr. H.G. Hers as the cause of glycogen storage disease type II. Together, these discoveries have led to the concept of lysosomal storage diseases and given rise to the idea that patients could possibly benefit from administration of the lysosomal enzyme they are deficient in. Why did it take more than 30 years before enzyme therapy was successfully put into practice, and only so far for a single disease, Gaucher disease?
One major cause of delay was the technical inability to produce lysosomal enzymes pure and in sufficient amounts for clinical application. The second was the initial unawareness that cell type specific receptors can be used to target the administered enzyme to the affected cell and promote uptake by lysosomes.
In late onset (juvenile and adult) GSDII the target tissue is skeletal muscle. In infantile GSDII skeletal muscle and heart has to be reached, and it is possible that other tissues are also in need of therapeutic enzyme. Both heart and skeletal muscle have cell surface receptors that can be utilised for enzyme targeting, and a-glucosidase can be made to fit these receptors. Thus, it was demonstrated in an artificial system with cultured muscle cells, that glycogen stored in cells of patients was degraded by the a-glucosidase added to the culture media. Mice receiving a-glucosidase intravenously, showed an increase of a-glucosidase activity in muscle and heart tissue. But, these mice were healthy so that the therapeutic effect of enzyme therapy could not be tested.
In parallel to these studies, there has been a search for natural sources of a-glucosidase and biotechnological production methods. The latter activity has been successful, as many of you will know. Chinese hamster ovary cell lines suitable for human a-glucosidase production were developed by Dr. J.J. Hopwood and colleagues from Adelaide, Australia, and by Dr. Y-T. Chen and colleagues from Durham, North Carolina, in collaboration with our research group in Rotterdam. The production capacity of the "Hopwood" cell line was tested in a bioreactor, designed and built by BioCell Technology with financial support from the AGSD (UK).
With this reactor we have now produced enough human recombinant a-glucosidase to perform the necessary preclinical tests, but we have learnt that the production capacity of the cell line in this reactor is too low to enter safely into a clinical test in humans. Does this mean that the project is bound to fail? On the contrary, the activities developed in conjunction with the CHO production line and the promising results obtained have stimulated other parties to join and support the project. Very importantly, the Dutch based biotechnology company Pharming B.V. has now set its goal on the production of human recombinant a-glucosidase in the milk of transgenic rabbits and has entered into a collaboration with our research group at the Erasmus University and the Academic Hospital Rotterdam to realize a clinical test within two years.
This news was made public by Pharming B.V. at a press conference held in November last year in Geel, Belgium, where a production facility will be built. The collaboration program foresees in development of a complete production process. With financial support of the Prinses Beatrix Fonds (a Dutch charity fund for neuro-muscular diseases) we have already demonstrated that human recombinant a-glucosidase produced in milk of transgenic mice has all the required characteristics, including a targeting signal. Importantly, the concentration of human recombinant acid a-glucosidase in the mouse milk is far higher than in the CHO cell culture medium.
Production in rabbit milk will solve the problem of production capacity. In the research program it is further planned to generate a mouse model of GSDII. To our knowledge at least three laboratories world wide are pursuing this goal, and the first mouse models may become available this year. The therapeutic effects of human recombinant a-glucosidase produced in CHO cells and in rabbit milk can then be tested. If the test results are positive, the clinical trial in humans can start as soon as the a-glucosidase production process is ready.
Although the final results of this technical, costly and emotional adventure are still uncertain we should feel encouraged that after so many years of waiting a realistic and promising attempt at enzyme therapy for GSDII will be taken.
Wednesday, 2 December 2009
The AGSD-UK
As well as ever-expanding email contacts, I was also involved with the flesh and blood GSD community in the form of the AGSD-UK.
I was a member of the AGSD-UK Executive and I'll try and give some small flavour of that here. When I joined in 1993, the AGSD-UK was already an organisation in transition. From meeting in scout huts, it was growing in size and professionalism, with all the accompanying strains. The 1994 conference, organised by Henry and Janet Thomson, was the first which had gathered people in the same hotel overnight, with the conference proper in a nearby hospital. My wife and I took that to its logical conclusion in 1996, by organising the conference in Edinburgh and making it entirely hotel based - and so it has been ever since.
The AGSD-UK Executive used to meet in London, at the rather grand offices of a firm of solicitors, Winckworth and Pemberton, just round the corner from the Houses of Parliament. This was courtesy of the late Nick Owston who was a partner in the firm. Nick had Mcardles disease (GSD type 5) and represented those patients on the Executive. Nick was a real gentleman. He could have bought and sold the lot of us but you'd never have guessed - he was entirely unassuming. He was happy to host the AGSD-UK meetings and, on occasion, to provide top notch legal advice, all the while quietly encouraging things along from the sidelines. He also organised a robust international survey of Mcardles patients which remains the gold standard for information about that disease. It's a cliche, I know, but he really is much missed by everyone who knew him.
In my time, the husband and wife team of John and Sue Del Mar were chairman and treasurer respectively. Sue is charm personified and absolutely unflappable. She has always reminded me, as she will now be surprised to read, of Lady Penelope from Thunderbirds. I suspect that Sue will not find the comparison with a puppet to be a very flattering one. However, I can assure her that it is, as all men of a certain age will agree. John will be relieved to hear that he bears no resemblance to Lady Penelope's side-kick, Parker. John brought a business-like approach to the chairing of meetings and helped smooth things along, when they got sticky. As they did. Again, a successful businessman who cheerfully gave his free time to helping a small charity. John and Sue were two of the original founders of the AGSD-UK and have a son, Hugo, who has type 1.
Another regular presence was Phil Lee, a doctor specialising in metabolic diseases at the Institute of Child Health in London. Phil gave a lot of his time to help the GSD, coming to conferences as well as exec meetings and providing some essential medical backbone and advice. He had enormous enthusiasm and, as well as research, was something of a pioneer in establishing clincis for adults with metabolic diseases. Again, a remarkable talent attracted to this small charity, helping it punch above its weight and a good friend to the GSD community. I was sorry to hear that he has recently retired through ill-health and I wish him well.
Which brings me to Ann Phillips, El Presidente. I love Ann dearly, and the fact that the range of talented people described above gave up so much time to such a small charity is a testament to her energy and commitment. She was (still is) a force of nature that the AGSD-UK just gravitated around. All that talent was just drawn in by centrifugal force. But, goodness me, it could be hard work. Ann could be very single-minded and also had an understandable attachment to the organisation she had co-founded. This made for interesting meetings, which could ocasionally get heated. Sometimes she and I argued - she would occasionally try to spend the Pompe fund on other things, for example. However, Ann has a heart as big as the Atlantic that separates her US birthplace from the UK. You could have a stand-up row with her one minute and it was done and forgotten the next. The bottom line is that AGSD-UK simply wouldn't have existed without her and GSD patients in the UK and beyond will always be in her debt.
Ann co-founded the AGSD-UK because her youngest son Peter had GSD type 1. It is a real tragedy that Peter died in 2008, after 3 failed liver transplants. He was a fine young man, who, as well as contributing to the AGSD-UK in his own right, was a paediatric nurse, dedicated to helping others. The apple doesn't fall too far from the tree.
Postscript
The Pompe report stuck out like a sore thumb from the rest of the AGSD-UK business, simply because there was so much going on - research, clinical trials, conferences, meetings with companies and so on. I would give some rather breathless account of what was happening and one of Ann's foibles was to listen and then say "Kevin, that's great but, you know, you should always say 'AGSD-UK' and not 'AGSD' because that will confuse people." Which always seemed like a bit of a non-sequitur and classic Ann. Imagine my huge amusement then, when I'd started writing this blog, to receive an email from Allan Muir, my Pompe group successor, saying "Good blog Kevin - but please remember to say 'AGSD-UK' and not 'AGSD'" Well it amused me anyway. You had to be there, I guess.
I do miss those AGSD-UK Executive meetings. They were a good supportive bunch of people (apologies to those I haven't mentioned - I stuck to the core people who were there all the way through my time on it.) and I always came away from them with a spring in my step.
I was a member of the AGSD-UK Executive and I'll try and give some small flavour of that here. When I joined in 1993, the AGSD-UK was already an organisation in transition. From meeting in scout huts, it was growing in size and professionalism, with all the accompanying strains. The 1994 conference, organised by Henry and Janet Thomson, was the first which had gathered people in the same hotel overnight, with the conference proper in a nearby hospital. My wife and I took that to its logical conclusion in 1996, by organising the conference in Edinburgh and making it entirely hotel based - and so it has been ever since.
The AGSD-UK Executive used to meet in London, at the rather grand offices of a firm of solicitors, Winckworth and Pemberton, just round the corner from the Houses of Parliament. This was courtesy of the late Nick Owston who was a partner in the firm. Nick had Mcardles disease (GSD type 5) and represented those patients on the Executive. Nick was a real gentleman. He could have bought and sold the lot of us but you'd never have guessed - he was entirely unassuming. He was happy to host the AGSD-UK meetings and, on occasion, to provide top notch legal advice, all the while quietly encouraging things along from the sidelines. He also organised a robust international survey of Mcardles patients which remains the gold standard for information about that disease. It's a cliche, I know, but he really is much missed by everyone who knew him.
In my time, the husband and wife team of John and Sue Del Mar were chairman and treasurer respectively. Sue is charm personified and absolutely unflappable. She has always reminded me, as she will now be surprised to read, of Lady Penelope from Thunderbirds. I suspect that Sue will not find the comparison with a puppet to be a very flattering one. However, I can assure her that it is, as all men of a certain age will agree. John will be relieved to hear that he bears no resemblance to Lady Penelope's side-kick, Parker. John brought a business-like approach to the chairing of meetings and helped smooth things along, when they got sticky. As they did. Again, a successful businessman who cheerfully gave his free time to helping a small charity. John and Sue were two of the original founders of the AGSD-UK and have a son, Hugo, who has type 1.
Another regular presence was Phil Lee, a doctor specialising in metabolic diseases at the Institute of Child Health in London. Phil gave a lot of his time to help the GSD, coming to conferences as well as exec meetings and providing some essential medical backbone and advice. He had enormous enthusiasm and, as well as research, was something of a pioneer in establishing clincis for adults with metabolic diseases. Again, a remarkable talent attracted to this small charity, helping it punch above its weight and a good friend to the GSD community. I was sorry to hear that he has recently retired through ill-health and I wish him well.
Which brings me to Ann Phillips, El Presidente. I love Ann dearly, and the fact that the range of talented people described above gave up so much time to such a small charity is a testament to her energy and commitment. She was (still is) a force of nature that the AGSD-UK just gravitated around. All that talent was just drawn in by centrifugal force. But, goodness me, it could be hard work. Ann could be very single-minded and also had an understandable attachment to the organisation she had co-founded. This made for interesting meetings, which could ocasionally get heated. Sometimes she and I argued - she would occasionally try to spend the Pompe fund on other things, for example. However, Ann has a heart as big as the Atlantic that separates her US birthplace from the UK. You could have a stand-up row with her one minute and it was done and forgotten the next. The bottom line is that AGSD-UK simply wouldn't have existed without her and GSD patients in the UK and beyond will always be in her debt.
Ann co-founded the AGSD-UK because her youngest son Peter had GSD type 1. It is a real tragedy that Peter died in 2008, after 3 failed liver transplants. He was a fine young man, who, as well as contributing to the AGSD-UK in his own right, was a paediatric nurse, dedicated to helping others. The apple doesn't fall too far from the tree.
Postscript
The Pompe report stuck out like a sore thumb from the rest of the AGSD-UK business, simply because there was so much going on - research, clinical trials, conferences, meetings with companies and so on. I would give some rather breathless account of what was happening and one of Ann's foibles was to listen and then say "Kevin, that's great but, you know, you should always say 'AGSD-UK' and not 'AGSD' because that will confuse people." Which always seemed like a bit of a non-sequitur and classic Ann. Imagine my huge amusement then, when I'd started writing this blog, to receive an email from Allan Muir, my Pompe group successor, saying "Good blog Kevin - but please remember to say 'AGSD-UK' and not 'AGSD'" Well it amused me anyway. You had to be there, I guess.
I do miss those AGSD-UK Executive meetings. They were a good supportive bunch of people (apologies to those I haven't mentioned - I stuck to the core people who were there all the way through my time on it.) and I always came away from them with a spring in my step.
Tuesday, 1 December 2009
GSDNet
I have a huge file of emails, dating from 1995 or so onwards. Looking through 1996, I'm struck by the number of contacts from around the world, many of them nothing directly to do with Pompe disease but with genetic diseases in general. The internet was a much smaller place in those days!
Through hosting the AGSD-UK website, I was gradually amassing a number of glycogen storage disease contacts and I wanted to do something with them, to enable all these people to speak to each other. But what?
For some time the only place where patients could communicate on genetic diseases was an email mailing list called gendisease-j, run by a chap called Wayne Rosenfield. Gendisease-j (now called gaucherdisease) was ostensibly for diseases that have a greater predominance in the Jewish community, which included a number of lysosomal storage diseases. Importantly, this included Gaucher disease, which already had an enzyme replacement therapy. Although I am not Jewish and Pompe wasn't really within gendisease-j's remit, I was welcomed and made to feel right at home in that community. A small but characteristic kindness on Wayne's part. That in turn led to contacts with the Gaucher Society in the UK, which proved important. But I digress.
Having seen at first hand the community that Wayne had created, I thought it would be good to try and create something similar for the glycogen storage diseases. And welcoming as the gendisease-j community were, it's one thing to be a guest and another to invite all your friends and family to stay too. So I asked Wayne how to go about setting up a mailing list and he kindly took the time to put me in contact with someone who could help at St Johns University (which at that time hosted a number of medical lists) and then talked me through the business of setting up and running a mailing list. Wayne has been a source of help and advice over the years since - indeed, I have shamelessly plagiarised many of his ideas. So can I just take this opportunity to say - Wayne, thanks for everything.
I had an accomplice in setting up the new mailing list - John Bird of the AGSD-US. John - inexplicably - didn't think my initial title of Gendisease-gsd was a good one and so a return to the drawing board came up with GSDNet - which was duly launched in June 1996. I thought at the time that it would be great if we could get 50 people to join and hoped that we would have enough to talk to each other about. I needn't have worried. GSDNet quickly grew in size and also, I think, in depth. People from all over the world found that they were no longer isolated but part of a community. A community that has shared successes and supported each other through life's ebbs. It has also provided those affected by GSD with a voice at crucial junctures. I can't better the description from the Australian Pompe Association website:
Along the way, we added Ruth Speary and then Bet Cook as co-owners. Truth be told, it's Bet who does most of the actual work these days. Take a bow, Bet.
Today GSDNet has over 500 members, from all parts of the world and is the leading online resource for glycogen storage diseases. It works so well because it is more than the sum of its parts - and that is down to every one of its members. Well done all.
Through hosting the AGSD-UK website, I was gradually amassing a number of glycogen storage disease contacts and I wanted to do something with them, to enable all these people to speak to each other. But what?
For some time the only place where patients could communicate on genetic diseases was an email mailing list called gendisease-j, run by a chap called Wayne Rosenfield. Gendisease-j (now called gaucherdisease) was ostensibly for diseases that have a greater predominance in the Jewish community, which included a number of lysosomal storage diseases. Importantly, this included Gaucher disease, which already had an enzyme replacement therapy. Although I am not Jewish and Pompe wasn't really within gendisease-j's remit, I was welcomed and made to feel right at home in that community. A small but characteristic kindness on Wayne's part. That in turn led to contacts with the Gaucher Society in the UK, which proved important. But I digress.
Having seen at first hand the community that Wayne had created, I thought it would be good to try and create something similar for the glycogen storage diseases. And welcoming as the gendisease-j community were, it's one thing to be a guest and another to invite all your friends and family to stay too. So I asked Wayne how to go about setting up a mailing list and he kindly took the time to put me in contact with someone who could help at St Johns University (which at that time hosted a number of medical lists) and then talked me through the business of setting up and running a mailing list. Wayne has been a source of help and advice over the years since - indeed, I have shamelessly plagiarised many of his ideas. So can I just take this opportunity to say - Wayne, thanks for everything.
I had an accomplice in setting up the new mailing list - John Bird of the AGSD-US. John - inexplicably - didn't think my initial title of Gendisease-gsd was a good one and so a return to the drawing board came up with GSDNet - which was duly launched in June 1996. I thought at the time that it would be great if we could get 50 people to join and hoped that we would have enough to talk to each other about. I needn't have worried. GSDNet quickly grew in size and also, I think, in depth. People from all over the world found that they were no longer isolated but part of a community. A community that has shared successes and supported each other through life's ebbs. It has also provided those affected by GSD with a voice at crucial junctures. I can't better the description from the Australian Pompe Association website:
GSDNet is an Internet Mailing List for patients, their families and friends, and professionals.
It is a mailing list for all Glycogen Storage Diseases, including Pompe’s Disease, and here you will meet a great bunch of people.
You can email with other Pompe’s patients world-wide. And if you feel alone and isolated with this disease, or if you want to talk with someone who will understand just what you are going through, if you want to ask questions or you just want to receive the latest news, then this is the right place for you.
You can receive email for all Glycogen Storage Diseases or you can set your particulars so that you will only receive mail pertaining to Pompe’s Disease.
And the good thing is - It’s Free!!
Along the way, we added Ruth Speary and then Bet Cook as co-owners. Truth be told, it's Bet who does most of the actual work these days. Take a bow, Bet.
Today GSDNet has over 500 members, from all parts of the world and is the leading online resource for glycogen storage diseases. It works so well because it is more than the sum of its parts - and that is down to every one of its members. Well done all.
Sunday, 29 November 2009
AGSD-UK helps fund Rotterdam group
The UK Pompe patients, organised within the AGSD-UK, had a clear goal. We wanted to raise funds and raise awareness, in order to help the Rotterdam group take their work on ERT forward.
In 1996, there was an opportunity to do exactly that.
The problem for the Dutch group (I am putting words into their mouths here, for which I apologise) was to find a way to make the jump from their ground-breaking experiments that demonstrated that ERT could work in principle, to clinical trials. The funding required for that (£ millions) seemed like an insurmountable problem, however they took the sensible approach of taking one small step at a time. For example, a collaboration with John Hopwood's lab in Australia had resulted in the development of cells which produced alpha-glucosidase (complete with the critical sugar residues attached) and which were suitable for growing in a production vessel.
The strategy was therefore to use the Hopwood cell line to produce enough alpha-glucosidase to treat one or two patients and hope that a pharmaceutical company would then take it up. This was, to say the least, an approach fraught with uncertainty. However it is also true to say that there was no alternative.
To produce the enzyme, it was proposed to use a new company started by a former student (Martin van der Vliet) of Arnold Reuser's, called Biocell technology, who would build a small-scale fermenter. However this work, while being done at a bargain rate, still needed funding- and, despite applications to grant-awarding bodies and biotechnology companies, none was forthcoming. That was where the AGSD-UK were able to step in and fund the building of the fermenter via a grant of £10,000. Here's a photo of it below (that's the old AGSD-UK logo in the corner):
This was a great day for the UK Pompe patients - at last we were taking an active part in shaping our own destiny. At the same time, the AMDA were funding similar work at Y T Chen's lab in the US (along with other projects).
I think that the AMDA had also offered to fund the Rotterdam work, however Arnold Reuser and Ans van der Ploeg opted to receive the money from the AGSD-UK instead, a route that involved them in a bit more hoop-jumping. Why? I don't know for sure but here are my guesses. Firstly, they knew how much it would mean to us to do it. Secondly, it always makes sense to keep a diverse range of funding options open - and they knew that the AMDA route would still be open to them in the future. Thirdly - and this is a complete guess on my part - Arnold had a shrewd idea that by allowing us to become a funder, it would give us a seat in future discussions on the development of ERT.
£10,000 is, of course, in the grand scheme of things a small amount (though it represented a lot of hard work and generosity by many people). However, I believe that it had an effect out of all proportion to the amount. Again, I am departing into the realm of conjecture here - what follows represents my opinion only and I am not going to present any evidence to back it up:-)
The reactor was indeed used to produce enzyme that was used in experimental work. However it also demonstrated to Erasmus University (and Sophia Children's Hospital) that the Pompe group were capable of raising funds from overseas to further their work. I think that would have helped to boost their profile. Most important of all, the Rotterdam group had been in discussions with a biotech company called Pharming, regarding the production of alpha-glucosidase in the milk of transgenic animals. These discussions had been going on for a while and were inconclusive. However the advent of a new funding source (conveniently omitting that it was a small charity with limited resources) may have helped to push Pharming into a decision to commit to the project. It's a great theory - but I have absolutely no idea if it's true!
Soon after, Pharming did indeed commit to the Pompe project. And that decision was the key to making things happen.
In 1996, there was an opportunity to do exactly that.
The problem for the Dutch group (I am putting words into their mouths here, for which I apologise) was to find a way to make the jump from their ground-breaking experiments that demonstrated that ERT could work in principle, to clinical trials. The funding required for that (£ millions) seemed like an insurmountable problem, however they took the sensible approach of taking one small step at a time. For example, a collaboration with John Hopwood's lab in Australia had resulted in the development of cells which produced alpha-glucosidase (complete with the critical sugar residues attached) and which were suitable for growing in a production vessel.
The strategy was therefore to use the Hopwood cell line to produce enough alpha-glucosidase to treat one or two patients and hope that a pharmaceutical company would then take it up. This was, to say the least, an approach fraught with uncertainty. However it is also true to say that there was no alternative.
To produce the enzyme, it was proposed to use a new company started by a former student (Martin van der Vliet) of Arnold Reuser's, called Biocell technology, who would build a small-scale fermenter. However this work, while being done at a bargain rate, still needed funding- and, despite applications to grant-awarding bodies and biotechnology companies, none was forthcoming. That was where the AGSD-UK were able to step in and fund the building of the fermenter via a grant of £10,000. Here's a photo of it below (that's the old AGSD-UK logo in the corner):
This was a great day for the UK Pompe patients - at last we were taking an active part in shaping our own destiny. At the same time, the AMDA were funding similar work at Y T Chen's lab in the US (along with other projects).
I think that the AMDA had also offered to fund the Rotterdam work, however Arnold Reuser and Ans van der Ploeg opted to receive the money from the AGSD-UK instead, a route that involved them in a bit more hoop-jumping. Why? I don't know for sure but here are my guesses. Firstly, they knew how much it would mean to us to do it. Secondly, it always makes sense to keep a diverse range of funding options open - and they knew that the AMDA route would still be open to them in the future. Thirdly - and this is a complete guess on my part - Arnold had a shrewd idea that by allowing us to become a funder, it would give us a seat in future discussions on the development of ERT.
£10,000 is, of course, in the grand scheme of things a small amount (though it represented a lot of hard work and generosity by many people). However, I believe that it had an effect out of all proportion to the amount. Again, I am departing into the realm of conjecture here - what follows represents my opinion only and I am not going to present any evidence to back it up:-)
The reactor was indeed used to produce enzyme that was used in experimental work. However it also demonstrated to Erasmus University (and Sophia Children's Hospital) that the Pompe group were capable of raising funds from overseas to further their work. I think that would have helped to boost their profile. Most important of all, the Rotterdam group had been in discussions with a biotech company called Pharming, regarding the production of alpha-glucosidase in the milk of transgenic animals. These discussions had been going on for a while and were inconclusive. However the advent of a new funding source (conveniently omitting that it was a small charity with limited resources) may have helped to push Pharming into a decision to commit to the project. It's a great theory - but I have absolutely no idea if it's true!
Soon after, Pharming did indeed commit to the Pompe project. And that decision was the key to making things happen.
1996
A quick summary of where we were at in 1996.
In retrospect, this was a pivotal year though it didn't seem so at the time. The patient group in the UK was growing slowly. The Pompe's Bulletin newletter was circulated to any patients, doctors and scientists that we could think of. The patient groups in different countries began to reach out to each other via the internet. Another common link was Arnold Reuser's group on Rotterdam - their willingness to engage with the growing patient community was crucial to its development. They struck a careful balance between their compassion and their professionalism. There was a growing sense of beginning to come together for a common purpose. Little did we know that things were about to kick off in a quite astonishing way. But that's for 1997:-) First a couple of articles on 1996.
In retrospect, this was a pivotal year though it didn't seem so at the time. The patient group in the UK was growing slowly. The Pompe's Bulletin newletter was circulated to any patients, doctors and scientists that we could think of. The patient groups in different countries began to reach out to each other via the internet. Another common link was Arnold Reuser's group on Rotterdam - their willingness to engage with the growing patient community was crucial to its development. They struck a careful balance between their compassion and their professionalism. There was a growing sense of beginning to come together for a common purpose. Little did we know that things were about to kick off in a quite astonishing way. But that's for 1997:-) First a couple of articles on 1996.
Saturday, 14 November 2009
House improvements
I have tried to make this a roughly chronological account but I'm going to go off piste here because I can't give a good portrait of Randall and Marylyn without looking ahead.
In front of me is my first written communication from the Houses. Dated 29 August, 1995, it expresses sympathy for our loss of Calum, introduces Randall, Marylyn and their daughter Tiffany (then just a 12-year-old slip of a girl) who has Pompe (they have two other children, who do not), shares their conclusions so far and a sheaf of information on diet, including a paper by Pompe patient Donald Ewers. In hindsight it has all the hallmarks that mark out the Houses: compassion for others, sharp analysis and - above all - a drive to translate those things into action. It's a bit of a cliché but I found a lot of the American pioneer spirit in the Houses.
We talked on the phone and exchanged emails and gradually built up a relationship. My dealings were mainly with Randall, whose no-nonsense approach impressed me. We were fairly guarded with each other at first, as we worked out each other's agendas. It's probably true to say that I respected Randall before I liked him - though I came to like him a great deal. He is straight-talking - not given to exaggeration or soft-soaping. I found that if he said something, he meant it and if he said he would do something, he did it. I quickly realised that the Houses' resources were in a different league and that the most useful thing I could do was to be as open as possible and hope that it was reciprocated (it was).
Randall's words to me were along the lines of "We are not super-wealthy but we do have some means. We would like to use that means to find a treatment for this disease." Little did I realise then how much they would do. I also didn't fully appreciate at the time what those words meant. The Houses owned (still do, I think) a manufacturing business that they had devoted years to building up. That "some means" came from hard work and toil. I think it was, to a significant extent, their life's work up to that point. And yet they unhesitatingly put it at the service of finding a treatment for Pompe disease. In my view, their contribution to the development of a treatment for Pompe disease is as much their life's work as building their successful business.
I think I suggested that to have maximum effect they should found a patient organisation (the AGSD-US was, for whatever reason, less amenable to a devolved Pompe group than the UK version) , rather than act as individuals, and also have a scientific advisory board, to ensure that their money was spent wisely. We were both agreed that enzyme replacement therapy was the way to go. I don't know whether I had any actual influence, however Randall and Marylyn founded the Acid Maltase Deficiency Association (AMDA) as a patient organisation. They used that as their base to do some remarkable things.
Firstly, they built the AMDA as a source of advice and information for hundreds of people affected by Pompe disease. Secondly, they did something that had never been done before. They gathered together, at their own personal expense, Pompe experts from all over the globe and hosted a conference for them in San Antonio, Texas. This was on March 21-22, 1996. The talks read like a who's who of the Pompe world. It was followed by a second, even bigger, conference on June 22-23, 1997.
Organising these conferences was an imaginative and far-sighted act. As important, I think, as the funding that the Houses put into research (again, a significant amount - nearly $5 million to date, according to the AMDA website). They were obviously scientific conferences, not patient ones, however the Houses were kind enough to send me video recordings of each conference, which allowed me to keep right up to date with what was happening. A characteristic piece of generosity on their part.
Looking at the 1996 programme now, I am amused to note that the session started at 7.00 am with breakfast and registration. That's approximately 2.5 hours earlier than most scientists are used to, so I guess Randall and Marylyn were putting their own work ethic stamp on proceedings from the start (1997 had a more leisurely 7.30 am start). The programme was designed by one Tiffany Laurel House, who now heads up the AMDA.
In the founding of the AMDA and the gathering of US patients together, and bringing together scientists, Randall and Marylyn were playing the major role in creating a worldwide Pompe community. In extending those connections to industry (I'm really getting ahead of myself now) they helped found a new model in the development of treatments for rare diseases, one in which patients, researchers, doctors and companies interact. The development of ERT for Pompe was possibly the first instance where an informed patient community said to industry, in effect, "We are your future customers, this is our condition and this is the treatment we would like you to develop." But more of that later.
For now, it's enough to say that Randall and Marylyn changed the game. In a very real sense, they made ERT happen. They made it happen while being part of an international community. And they made it happen not just for Tiffany but for all Pompe patients.
Postscript
I don't think I actually met Randall until 1997, at the AGSD-UK's annual conference. Here's my earliest memory of him. We had introduced ourselves and I noted that he was wearing a formal business suit, unlike my scruffy self. I was fussing about trying to make some sense of the organisation of the Pompe session out of the customary AGSD-UK chaos. There was a group of parents who had found some space on the floor in order to feed/change their young children. Next time I turned around, Randall had hunkered down on the floor, amongst the crumbs, in his business suit, in order to talk with them. That's my abiding image of Randall House. Sorry, I can't tell you what brand of suit it was - or what kind of watch he was wearing.
In front of me is my first written communication from the Houses. Dated 29 August, 1995, it expresses sympathy for our loss of Calum, introduces Randall, Marylyn and their daughter Tiffany (then just a 12-year-old slip of a girl) who has Pompe (they have two other children, who do not), shares their conclusions so far and a sheaf of information on diet, including a paper by Pompe patient Donald Ewers. In hindsight it has all the hallmarks that mark out the Houses: compassion for others, sharp analysis and - above all - a drive to translate those things into action. It's a bit of a cliché but I found a lot of the American pioneer spirit in the Houses.
We talked on the phone and exchanged emails and gradually built up a relationship. My dealings were mainly with Randall, whose no-nonsense approach impressed me. We were fairly guarded with each other at first, as we worked out each other's agendas. It's probably true to say that I respected Randall before I liked him - though I came to like him a great deal. He is straight-talking - not given to exaggeration or soft-soaping. I found that if he said something, he meant it and if he said he would do something, he did it. I quickly realised that the Houses' resources were in a different league and that the most useful thing I could do was to be as open as possible and hope that it was reciprocated (it was).
Randall's words to me were along the lines of "We are not super-wealthy but we do have some means. We would like to use that means to find a treatment for this disease." Little did I realise then how much they would do. I also didn't fully appreciate at the time what those words meant. The Houses owned (still do, I think) a manufacturing business that they had devoted years to building up. That "some means" came from hard work and toil. I think it was, to a significant extent, their life's work up to that point. And yet they unhesitatingly put it at the service of finding a treatment for Pompe disease. In my view, their contribution to the development of a treatment for Pompe disease is as much their life's work as building their successful business.
I think I suggested that to have maximum effect they should found a patient organisation (the AGSD-US was, for whatever reason, less amenable to a devolved Pompe group than the UK version) , rather than act as individuals, and also have a scientific advisory board, to ensure that their money was spent wisely. We were both agreed that enzyme replacement therapy was the way to go. I don't know whether I had any actual influence, however Randall and Marylyn founded the Acid Maltase Deficiency Association (AMDA) as a patient organisation. They used that as their base to do some remarkable things.
Firstly, they built the AMDA as a source of advice and information for hundreds of people affected by Pompe disease. Secondly, they did something that had never been done before. They gathered together, at their own personal expense, Pompe experts from all over the globe and hosted a conference for them in San Antonio, Texas. This was on March 21-22, 1996. The talks read like a who's who of the Pompe world. It was followed by a second, even bigger, conference on June 22-23, 1997.
Organising these conferences was an imaginative and far-sighted act. As important, I think, as the funding that the Houses put into research (again, a significant amount - nearly $5 million to date, according to the AMDA website). They were obviously scientific conferences, not patient ones, however the Houses were kind enough to send me video recordings of each conference, which allowed me to keep right up to date with what was happening. A characteristic piece of generosity on their part.
Looking at the 1996 programme now, I am amused to note that the session started at 7.00 am with breakfast and registration. That's approximately 2.5 hours earlier than most scientists are used to, so I guess Randall and Marylyn were putting their own work ethic stamp on proceedings from the start (1997 had a more leisurely 7.30 am start). The programme was designed by one Tiffany Laurel House, who now heads up the AMDA.
In the founding of the AMDA and the gathering of US patients together, and bringing together scientists, Randall and Marylyn were playing the major role in creating a worldwide Pompe community. In extending those connections to industry (I'm really getting ahead of myself now) they helped found a new model in the development of treatments for rare diseases, one in which patients, researchers, doctors and companies interact. The development of ERT for Pompe was possibly the first instance where an informed patient community said to industry, in effect, "We are your future customers, this is our condition and this is the treatment we would like you to develop." But more of that later.
For now, it's enough to say that Randall and Marylyn changed the game. In a very real sense, they made ERT happen. They made it happen while being part of an international community. And they made it happen not just for Tiffany but for all Pompe patients.
Postscript
I don't think I actually met Randall until 1997, at the AGSD-UK's annual conference. Here's my earliest memory of him. We had introduced ourselves and I noted that he was wearing a formal business suit, unlike my scruffy self. I was fussing about trying to make some sense of the organisation of the Pompe session out of the customary AGSD-UK chaos. There was a group of parents who had found some space on the floor in order to feed/change their young children. Next time I turned around, Randall had hunkered down on the floor, amongst the crumbs, in his business suit, in order to talk with them. That's my abiding image of Randall House. Sorry, I can't tell you what brand of suit it was - or what kind of watch he was wearing.
Making connections
The UK group was definitely stirring and I had a growing mailing list that I could send paper newsletters to. However I realised that there were probably patient groups and individuals in other countries going through exactly the same process - but how could I contact them?* The answer seems simple now - just use Google, d'oh! Unfortunately, in 1995 Google was yet to be invented. I had internet access at work though and was keen on the idea of using a website as a sort of shop window.
A bit of history/nostalgia. My first web browser was something called Lynx which was entirely text-based. I then started using something called Mosaic which had the startling innovation of allowing you to see pictures and text. I got a hold of it by email - you got sent the code for it in chunks and had to manually piece them together to make a functioning piece of software. Happy days. But I digress.
I put together a rudimentary website for the AGSD-UK and included the full text of my Pompe patients' guide. A friend at work kindly hosted on his webspace (cheers, David). But how could people find it? I emailed it around to anyone I could think of but there were no search engines as such. However a couple of students at Stanford University had used their university account to set up a sort of index for interesting websites, so I listed it there. They had called their site Yahoo. It'll never catch on with a name like that, I thought.
Anyways, I gradually made contact with people from other countries - individuals from Germany and the US to begin with. Then I got a phone call from a guy in the USA that I'd never heard of but who had come to the same conclusions as me and was determined to do something about them. His name was Randall House and he, along with his wife Marylyn, changed everything.
*I realise on looking through my papers that the original list of names I was given by Ann Philips contained one non-UK contact - Helen Walker from Australia. I'm surprised by that and also to find that I've now been in touch with Helen for 15 years! More about the Ozzies later.
A bit of history/nostalgia. My first web browser was something called Lynx which was entirely text-based. I then started using something called Mosaic which had the startling innovation of allowing you to see pictures and text. I got a hold of it by email - you got sent the code for it in chunks and had to manually piece them together to make a functioning piece of software. Happy days. But I digress.
I put together a rudimentary website for the AGSD-UK and included the full text of my Pompe patients' guide. A friend at work kindly hosted on his webspace (cheers, David). But how could people find it? I emailed it around to anyone I could think of but there were no search engines as such. However a couple of students at Stanford University had used their university account to set up a sort of index for interesting websites, so I listed it there. They had called their site Yahoo. It'll never catch on with a name like that, I thought.
Anyways, I gradually made contact with people from other countries - individuals from Germany and the US to begin with. Then I got a phone call from a guy in the USA that I'd never heard of but who had come to the same conclusions as me and was determined to do something about them. His name was Randall House and he, along with his wife Marylyn, changed everything.
*I realise on looking through my papers that the original list of names I was given by Ann Philips contained one non-UK contact - Helen Walker from Australia. I'm surprised by that and also to find that I've now been in touch with Helen for 15 years! More about the Ozzies later.
Subscribe to:
Posts (Atom)
