Interview with Recognition Award recipient, Prof Edward Tuddenham

Home / Interview with Recognition Award recipient, Prof Edward Tuddenham

Interview with Recognition Award recipient, Prof Edward Tuddenham

At the EAHAD 2019 Congress, in Prague, Czech Republic, we honoured two professionals for their work for and service to the haemophilia and allied disorders community in Europe and around the world, with the EAHAD Recognition Award for Outstanding Contribution to the Haemophilia and Allied Disorders field. One of the two recipients is Prof Edward Tuddenham, leading haematologist from the Royal Free Hospital in London. We took the opportunity to interview Prof Tuddenham on his beginnings, his thoughts on the shape of the haemophilia field today, as well as his future plans.

 

You are one of the world’s leading haematologists, a pioneer in the field of haemophilia and responsible for the purification of the factor VIII protein leading to cloning of its gene. What impressive achievements! What got you interested in the beginning and made you reach the level you reached today?

My interest in haemophilia sparked back in 1970, as a junior haematologist. One of my tasks back then was to give the treatment to the haemophilia patients. There was a haemophilia A patient I was treating, who despite receiving five bags of cryoprecipitate, did not see an improvement in his bleeds. With no improvement on the horizon, I consulted books to try and find what the problem might be. That’s when I came across inhibitor development. I went back to the lab and said we should check for inhibition. That’s how we discovered that there was a FVIII inhibitor.

 

Two years later, as a lecturer now at the haematology department in Cardiff, I worked with Prof Bloom, running the haemophilia centre there. He had an interest in von Willebrand’s disease and in haemophilia, researching the difference between the two conditions. I learned a lot from him, and it got me very much involved in the possibility of isolating and identifying what was wrong, what was missing in terms of treatment for haemophilia A patients. After I finished my fruitful training with the professor, I went to a research institute in Connecticut, USA. That’s when I decided I wanted to pursue full time research on how to solve the problem of isolating factor VIII. This has been a central point in my career in general: for me, the research problem is of equal value to the clinical problem.

 

What question or challenge were you setting out to address when you started working in the field of haemophilia?
By the time I went to Connecticut, several other clotting factors had been purified, particularly factor IX and prothrombin. These advances inspired me to try to do the same for factor VIII. In Connecticut, I was introduced to the use of antibodies to purify proteins. By immobilising an antibody to von Willebrand factor and pouring blood plasma down the column, the von Willebrand factor would stick and so would the factor VIII. Then, you could “wash” it and bring out the factor VIII without the von Willebrand factor.

 

By the time I left Connecticut in 1978 to go to the Royal Free Hospital, I was able to prepare factor VIII in small quantities without von Willebrand factor. Now I had the plan and intention to take my progress all the way to a completely pure protein. But, at the same time, one has to be ready to take advantage of any new opportunities that may arise. At that time, biochemist Alan Johnson developed a method of making factor VIII with lower amounts of von Willebrand factor At that point, I collaborated with a company called Speywood that was making purified porcine factor VIII using the Johnson method to remove von Willebrand factor, that caused platelet aggregation when given to humans We started using the porcine factor VIII in patients with factor VIII inhibitors with great success. Speywood joined the project to help purify human factor VIII. Another lucky thing that happened, was that, at that time, monoclonal antibody technology was also being developed. We combined this development with what we were doing, took some of the partly purified factor VIIII and made a monoclonal antibody to human factor VIII. By then, we realised that we had a route to final purification if we could make enough factor VIII with the polyelectrolyte column, then use an antibody to the von Willebrand factor, get a further purification and, finally, put it on the column with the monoclonal antibody to human factor VIII. What resulted was completely pure factor VIII that had an activity of 4,000 units per milligram.

 

When we reached that point, the newly set up genetic engineering companies were also keen on going after factor VIII, so they could claim it. We formed a collaboration with one of them – Genentech. By chemically sequencing the pure factor VIII protein we found a peptide from which we could use to genetic code to design an oligonucleotide that could be used to find a clone from a human library, containing part of the human factor VIII gene. This led to mapping the factor VIII gene and completing the cDNA sequence for the whole protein. This was then cloned into an expression vector. After 18 months of work, the team’s efforts came together with the production of active synthetic factor VIII by a cell line. At the time, what we had accomplished was described as a “dramatic technical feat without parallel” and a “moon-shot in the biotechnology industry”.

 

What do you think will be the next step in the process of discovery in the field?
Now that we have moved into gene therapy, we have been able to transfer a version of the factor VIII gene, using a modified small virus that will carry an expression cassette into a target cell. Until 2016, this was only successfully implemented in animal studies, but now we have shown that this can work in a human clinical trial. The levels of factor VIII attained are up to and within the normal range of factor VIII, staying at that level for up to two years. This step forward is certainly encouraging and, while we don’t know how long it will last, we hope that we can get a curative level of production for many years to come. Time will tell.

 

We have very encouraging early results, but we still have to grapple with controlling the immune response in a way that is safe and effective and leaves the patient with the benefit of still making their own factor VIII and factor IX. We need to improve our control of the immune response, we need to find better ways to treat older patients and we need to be sure that the effect will be long lasting. Putting these three things together, we could have what could become the therapy of choice. In general, there are a lot of things going on in multiple different channels. My particular choice is to work within haemophilia gene transfer, which we hope we can finally use to control the problem that I first saw in a man with haemophilia back in 1971 – the inhibitor antibody. A final future idea is to move the treatment from just adult patients to younger patients and children, always taking safety into consideration above all.

 

What was your favourite aspect of your research when you were starting and what is it now? Has your perspective changed?

I started with the challenge of defining and identifying what factor VIII was. That was my initial goal until 1984 when we finally had the sequence. Then, I had to stop and think whether I wanted to carry on. But the next challenge was to try and understand more about the genes and the genetics and use that as a way forward. That part of my work was my favourite at the time. Now, my favourite part is working with practical genetics and gene transfer. This is my current target, but I am sure there’ll be another one. Someone said to me “oh, you change what you do every ten years” and it’s true. I move on as science moves on.

 

Could you share a turning point or defining moment in your work as a scientist?
When I arrived in Connecticut, at the beginning of 1976, I was able to put my complete full-time energy and effort on a single goal: how am I going to make clean factor VIII. That was such an exciting time. It was so inspirational, and I could finally see I made real progress.

 

Could you tell us how you felt when you reached that breakthrough point?
I was elated. When we reached that breakthrough point, I was certainly extremely happy. I was pursuing that goal for 10 years, keeping at it. I was certainly on a high! I reached the peak of mount Everest of coagulation!

 

You received the 2019 EAHAD Recognition Award for your contribution to the haemophilia and allied disorders field. You also had a presentation on “Gene Therapy for Rare Bleeding Disorders” at the EAHAD 2019 congress. Do you plan on slowing down anytime soon?
Actually, no. I seem to be speeding up! Gene therapy keeps me very busy and I have no plans of slowing down at all.

 

What do you think are the key issues for haemophilia and allied disorders care in Europe in 2019 and onwards?

The availability of new and different therapies today is unlike any time before in my career in haemophilia. There is a huge variety of choices. We are not yet where we should be in terms of the affordability of treatment. In higher income countries with good levels of funding for haemophilia care, it is good to see a broader selection of choices. Selecting among the choices, testing and using them in a clinic, tailoring the best treatment for each individual patient; these are key issues today. But on a wider, international level, there are many patients that have no access to any of the aforementioned resources. It should be a goal and responsibility for all of us involved to share these resources with our colleagues worldwide and bring these cutting-edge scientific advances to the patients, wherever they live.

 

Do you have any advice for young and aspiring medical professionals entering the haemophilia field?
Look for the exceptions and the unusual cases. They often have the clues to a better understanding. Also, look for ways of combining treatments and look at each patient individually. There is still very much to do and many aspects of haemophilia that deserve further exploration: Women and bleeding disorders, children, the inhibitor problem, haemophilia in older ages…

 

Outside of your work, what gives you the biggest sense of accomplishment?
Seeing my young son playing football for his local team. He is a great left-back.