Supporting brain tumour research

Professor Clemens Oliver Hanemann is one of our most eminent research scientists and neurologists. I am quite sure he will dislike this being said of him, since he is very much a team player and someone who eschews personal publicity – unless it is necessary to advance his passion, which is research into the causes and treatment of brain tumours. 

Born in 1962 to a family with roots in the city going back many generations, Hanemann qualified in medicine during 1988 at the University of Hamburg. During his training he applied for a student elective at the Johns Hopkins School of Medicine and Harvard Medical School in the USA, which he describes with commendable understatement as: “formative, but extremely tough”. Ward rounds started at 6am, where 3–4 hours sleep a night was the norm. It was a fiercely competitive but stimulating environment, where the best was considered just good enough. 

It was an exercise in survival but nonetheless sparked ambitions to pursue a career in academic medicine. The nervous system fascinated him and back in Germany he was appointed to a research fellowship with Professor Freund in Dusseldorf. This too was an old-style baptism of fire: “It was pretty brutal”, he reflects.

“There were twenty people hanging around to take your job, some would even work unpaid, and if you messed up you were out.”

Although he firmly supports a meritocracy, this is not a leadership style he feels is productive. During his time in Dusseldorf he discovered a new myelin (nerve sheath) protein and the cause of the most common inherited neuropathy.

Evidently, he more than survived and his career progressed through a number of clinical and academic training posts, such that in 2000 he was appointed as consultant neurologist in Ulm. At this point, he was a fully trained bench scientist. Already an expert specialist neurologist, he undertook additional training and qualified also as a medical geneticist. He established a research group, which rapidly earned an international reputation for its research into brain tumours.

Thank you for taking the time to talk to me on behalf of the foundation. I believe people will be particularly interested to hear about your research, but you are also a clinician?

Yes, indeed. I am a consultant neurologist in Derriford. I specialise in the diagnosis and treatment of brain tumours, but also in other pretty devastating conditions such as motor neurone disease.

Why did you select brain tumours for your research?

Several reasons, really. It was and still is a relatively neglected area of cancer research. It often takes away people in their prime and does so in a particularly cruel way. When you think about it, the brain is the most important organ in the body. 

Apart from governing the basic functions such as movement and sensation, the brain is what gives us our intellect and personality; the so-called higher functions. It is what makes us human. Brain tumours, especially the most malignant, destroy these functions. I would hazard a guess that most of us know of someone among our circle of friends and family who has died from brain cancer. 

Importantly, it is also an exciting area of research into cell biology that may well shed light on other conditions. 

Any statistics?

How about it being the commonest fatal cancer in the under 40s? Or that 16,000 people a year develop brain cancer in the UK? 

Or, put another way, that 10 people a day in the UK are diagnosed with the condition. It is a ‘destroyer of potential’.

Indeed. One example close to home is Mo Mowlem, the Northern Island Secretary largely credited with masterminding the Good Friday Agreement in Northern Island (1999). She was diagnosed with a brain tumour just before she took office and despite her treatment is said to have performed brilliantly. She died in 2005.

So, professor, what approach are you taking in tackling this pernicious condition?

Well, first to point out two common misconceptions. A tumour is not necessarily a cancer: it means ‘swelling’ and the word itself is derived from the Latin tumere: to swell.

Sounds a daunting challenge. Where do you start?

It will help if I try to explain first in simple terms what we know about how cells are constructed and function. The basic unit from which our body is built is ‘the cell’. The billions of cells that make up our body each contain a nucleus with DNA, albeit with subtle differences depending on the organ and specific functions. Changes in the DNA can make these cells behave bizarrely and sometimes become cancerous.

We talk glibly about DNA, but I am old enough to remember a time back in the 1950/60s when DNA, its structure and how it worked was largely unknown. It was, I believe, the development of X-ray crystallography, which unlocked the mystery. 

I remember one of my tutors at medical school comparing a molecule of DNA to a tiny but complex piece of machinery such as a mechanical pocket watch. Although parts of it are visible from the outside, imagine having no suitable tools to take it apart and work out how it functions. 

Answer? Shine a bright beam of light into its innards and then painstakingly study the patterns of reflected/diffracted light that emerge. Substitute X-rays for the beam of light, imagine the ‘watch’ is 100 times smaller than a single hair on a flea’s back and you have the concept developed by Maurice Wilkins and Rosalind Franklin – subsequently used by Frances Crick and James Watson to unravel the secrets of DNA. 

I was a schoolboy in Cambridge back in the early 1960s and as it happens my mother was one of the technicians in the Cavendish laboratories working for Francis Crick and the others. At one point, the rest of the family was dimly aware from her excitement that something momentous had happened, but not the details – or that history was in the making. That same laboratory went on to be associated with at least five Nobel prize winners during the space of the next few years. An unprecedented phenomenon.

I believe that this and other similar stories of scientific discovery provide lessons in organisation to which we should pay much heed.

It was back in the early days after WW2 that Lawrence Bragg, a Nobel Laureate himself, became Director of the Cavendish Laboratory in Cambridge. He wanted to redirect its focus from physics into the study of organic molecules. 

Bragg and another scientist, Max Perutz, perceived that this would require a broad mix of scientists from different disciplines and a place where they could come together and work in close collaboration. 

The pair recognised that work needed to be facilitated; that overly zealous bureaucracy was a threat, and also that free and easy communication was vital.

They conceived an organisation where equipment was not ‘owned’ but was communal; where the interaction of staff at all levels, essential for stimulating conversation and the development of ideas was facilitated by an informal meeting space at its very heart; the staff canteen!

The MRC ‘Institute’ of Molecular Biology was established and during the next several decades produced an outpouring of brilliant, world-beating research.

I believe I can see where you are going with this...

Of course. Collaboration is the name of the game.

Scientists from different disciplines need to be able to move freely in and out of collaborations as the need arises. This requires a suitable infrastructure. Hence the Institute of Stratified and Translational Medicine (ITSMed) at Derriford.

It works along exactly the lines just described and is a superb facility. All of us in Devon and Cornwall, as well as Plymouth can be very proud of it.

Quite a story – thank you for that. So, you have taken us on a journey describing the basics. Before we focus on your work, is there anything else that we need to understand?

Bear with me for a little longer! I have described how the nucleus is the ‘brain’ of the cell and contains the codes or genes for each different form of life. These are known collectively as the genome, and that which is specific to us as ‘The Human Genome’.

But the majority of the cell lies outside the nucleus and is bounded by its skin or ‘cell membrane’. In how it is organised, a cell can be compared to a factory.

The nucleus is the ‘office’ from where work is directed and it sends its instructions out to different parts of the ‘factory’ where specialised tasks are performed. Much of this will be to do with the processing of molecules to keep us going, but the other main function is to build complicated molecules called proteins from a relatively small number of simple chemical constituents.

The range of protein variants is almost unlimited and each is of course tailored to its particular purpose.

Collectively, the proteins comprising our body are known as the proteome. It equates to the genome, which was mentioned earlier. Many in the team here are studying the proteins of brain tumours – the ‘cellular proteome’ of brain tumour cells.

Right; so the obvious question is how will that help us determine the causes and treatment of brain tumours?

Simple. Well, in principle! The type and nature of proteins within an individual or set of cells tells us everything there is to know about the character and working of a cell. Is it a liver cell? Is it a skin cell? But it also gives us much more detail. 

It can also tell us whether the cell is healthy, ‘normal’ or different from its fellows in some way. Since proteins are produced under the direction of the genes (codes) in the DNA of the cell they tell us, albeit indirectly, what is happening deep in the genome of the cell. A gene is said to ‘express’ itself in this way.

So all you have to do is find the abnormal protein associated with a common brain tumour, use that to identify the ‘faulty’ gene and then either fix the gene or block it from expressing itself or some such?

Not necessarily. It is like looking for a needle in a haystack! There are thousands of these proteins and millions of cells. Some of them are significant; some potentially so, and others not. 

We and other teams are building a huge catalogue of the different proteins present. This catalogue or database is available for analysis by scientists across the world. 

The next step is for scientists to choose a particular group of proteins that are felt worth examining further with the idea that it may provide the answer to the behaviour of cells which are, or will become, cancerous. To test the function of proteins we use different modelling systems, including cells from brain tumours.

You have taken us a considerable way towards understanding the theory behind your approach. What are the practicalities? Could you take us through a typical scenario as an example?

Sure. A patient may present with a low-grade brain tumour affecting the lining of the brain – a meningioma. Often these will be removed surgically and of course with the patient’s consent we will be provided with a sample immediately following removal at operation. 

The individual cells are separated out from the sample and placed in a solution that will permit them to continue living.

That means that they will reproduce. This can happen a number of times before they stop doing so – we can achieve as many as five divisions for brain lining cells, before they ‘run out of steam’ – for reasons we do not fully understand. But it means that we have ‘grown’ a useful volume of cells that we can analyse in the way that has been described.

It sounds hugely laborious.

It is labour intensive but it is made possible by advances in technology that are just amazing.

We have a machine that can analyse hundreds of protein samples a minute. Something that even a couple of decades ago would have been unthinkable.

Can you give us an example of how, in practical terms, your work is already making a difference or will do so?

Yes. For example, while evaluating the cells from a patient’s brain tumour in the manner I have just described, we discovered a new drug target. We then tested a number of different drugs on the cultured cells. 

The best was a drug which was already available for use in other diseases. So we could repurpose that drug and move swiftly into a clinical trial, which we did. Unfortunately, it proved disappointing as the effect was too small and patients experienced too many side effects. 

However, this is a good example of the approach we take; quality scientific work leading as rapidly as possible to improved clinical treatments; the so-called, ‘bench to patient’ pathway.

What do you see as the critical needs for your team here in the Institute?

Ask a research scientist such a question and there will always be a long list of forthcoming. It is clear that people, their expertise, drive, enthusiasm and intellect, are our greatest resource. Focusing on our strengths means that we can build the teams and ensure we achieve a critical mass. 

Reputation is everything and we need to make sure we accept no compromises and maintain the world-class environment which we have developed at Plymouth. 

This ensures that we continue, to attract the best of the best, whether they are scientists or clinicians working next door in the hospital. Another essential element of ‘maintaining a world-class environment’ is being able to provide the equipment researchers need for their work. We are ruthless in defining what we need, ensuring that equipment is used to its full potential and that we obtain value for money. 

For example, we have a need at present for updating the equipment for the proteome analysis at the heart of our programme. It is roughly 10 years old and nearing the end of its life. That will cost approximately £600,000. I desperately need a lottery win as this level of funding is quite beyond anything in my budget or that of the University as a whole.