Graham Russell: A 50-year odyssey with bisphosphonates, bone biology and beyond.

Published: 02 Oct 2020
Category: Editorial


--This blog also appears on the partner ELRIG UK’s website--

It’s difficult to summarize Graham Russell’s contribution to medicine with brevity. The development of bisphosphonates for the treatment of bone disorders has led to life-changing benefits for millions of people and stemmed from Graham’s pioneering work in the late 1960s. This year, he was awarded the prestigious Sir James Black Award, presented by the British Pharmacological Society in recognition of his contributions to drug discovery. If you tell him you’re impressed by his accomplishments, however, you’ll receive an incredibly modest reply and hear multiple mentions of luck.

But don’t just take our word for it: read this blog and register for ELRIG’s Drug Discovery Digital conference to hear directly from this genuine, humble, world-class scientist.

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Chance encounters

Take a step back in time to the 1960s. The hair is big, the music is vibrant, and you’re walking past the Bridge of Sighs at Cambridge University. If you’re lucky, you might happen to meet a man by the name of Graham Russell. He doesn’t know it yet, but the next phases of his career are about to escalate, spurring the development of life-changing drugs that will achieve “blockbuster” status in the pharmaceutical industry. “Cambridge had a fantastically impressive group of scientists around at that time”, Graham recalls. “You know – we had Fred Sanger, James Watson, Francis Crick, Max Perutz and many others around to inspire us as students.”

It’s clear that Graham was influenced by many of the people he came into contact with while at Cambridge University, perhaps none more than his tutor, Gordon Wright. “I planned to study chemistry and biochemistry and never intended to do medicine”, says Graham, “But I had a very good tutor in Gordon who encouraged me to do just that. So, I partially complied and studied anatomy and physiology as well along the way. That actually exposed me early on to pharmacology as an undergraduate, which I found fascinating. It’s therefore a particular honour to receive this award in the name of Sir James Black. He was one of my scientific heroes and I had the pleasure of meeting him many years ago.”

It transpires that, like many others, Graham’s successful career resulted from a combination of tenacity, curiosity, and a series of serendipitous encounters and observations.

Curiosity doesn’t kill the cat

Graham’s fascination with pharmacology, combined with a desire to work in a field with a more ‘human’ element, led him to study kidney stones at Leeds University, “Which were quite a big medical problem back then. I was looking around for projects related to this and stumbled upon work from Herbert Fleisch, who had been working with Bill Neuman in the USA,” he comments. Herbert welcomed Graham to the Medical Research Institute in Davos, where a collaboration ensued. Together, they explored how calcification could be therapeutically controlled – in blood and urine and other places where calcium accumulation would be particularly unwelcome. The collaboration quickly snowballed into a series of discoveries, “Our earlier work focused on inorganic pyrophosphate, a calcification inhibitor present in blood and urine, which we came to realise was. the body’s endogenous water softener” Graham muses.

Their studies showed that urine concentrations of inorganic pyrophosphate were indeed lower in certain groups of kidney stone-formers, which got Graham thinking about other potential roles for this molecule: “In a rare disease called hypophosphatasia, the enzyme alkaline phosphatase is defective, and I thought that enzyme could be removing pyrophosphate and facilitating mineralisation. Interestingly, and thankfully, our work back then wasn’t in vain,” Graham adds, “As now, half a century later, an enzyme replacement therapy with engineered alkaline phosphatase has been developed that can treat this terrible disease.”

A strong sense of gratitude and humour goes a long way

When speaking with Graham, it’s easy to gain a sense of the appreciation he has for the people he has collaborated with on his journey. When asked about the lessons he has learnt during his career, he replies: “There are lots of things in that category I suppose. Who you work with is terribly important, so choose good mentors. I was fortunate enough to work with many great scientists, including Charles Dent, Jack Martin, and Steve Krane, who all had a big influence on my career,” Graham remembers fondly. “And be tenacious, don’t give up”, he adds then with a laugh continues, ”Definitely be very lucky. And this one might sound a bit pretentious, but if you’re going to get into research and science, make sure you choose good topics, choose something that’s going to make a difference.” Looking back, Graham expresses his gratitude: “I feel very fortunate to have been involved with bisphosphonates from the beginning. Osteoporosis and bone cancers affect many people and there’s still nothing that has really supplanted these drugs”.
A lucky accident: how to block bone destruction

Graham recalls what some might consider an “accidental” leap in progress: It became clear that pyrophosphate was too unstable to serve as a viable remedy for unruly calcification, so the search for stable analogues began. “We worked with Dave Francis at Procter and Gamble where they were considering bisphosphonates as potential toothpaste additives to prevent calculus (plaque deposition). We started exploring these in animals and calcification models, and sure enough, they worked”. But that wasn’t half of it. “If you like accidental discovery”, says Graham, “we found that they also blocked bone destruction. And that came out of showing that they (bisphosphonates) would stick onto calcium phosphate crystals and prevent them (the crystals) from dissolving.” Set in the Swiss alpine town, the group confirmed that these findings in crystals translated to bone tissue cultures and animal models, highlighting the therapeutic potential of bisphosphonates in settings of bone disorders. By 1969, Graham’s publications in the Lancet, Nature and Science showed that the pyrophosphate story had evolved significantly, and it has only continued to grow.

Dig deeper into a topic: Choose from over 8 main session tracks at Drug Discovery Digital 2020

Hard work and knight’s moves

When looking back, Graham highlights the serendipitous nature of his career. “Like all things, a lot of things aren’t planned – they happen by knight’s moves.” These “knight’s moves”, however, involved a lot of hard work; many qualifications, a lengthy record of clinical and academic appointments, and more than 570 publications to his name. Back at Oxford University, Graham completed his medical degree with distinction in 1970, while concurrently spurring the clinical development of bisphosphonates. Together with Roger Smith, a specialist in bone disorders, remarkable progress was made, says Graham: “One of the first bisphosphonates called etidronate was a spectacularly effective treatment for Paget’s disease. That happened within a couple of years of doing the early work, and then we gradually progressed to other conditions, like the bone destruction that occurs alongside myeloma and bone cancers. Osteoporosis came much later because the technology wasn’t there to directly and easily measure bone mass. If we fast forward to today, there’s about a dozen of these drugs in human use.”

The story is not over

“One thing I’ve always felt”, Graham recalls, “is that you should judge students by how much they have taught you, rather than the other way around.” Indeed, past student Mike Rogers and others in the Sheffield group created a clearer understanding of the molecular mechanisms by which bisphosphonate drugs inhibit bone resorption, by inhibiting the mevalonate pathway responsible for the production of cholesterol, meaning that bisphosphonates impact the same pathway as statins.  Interestingly, and with relevance to the current COVID-19 pandemic, research suggests that amino-bisphosphonates could possibly ameliorate or prevent severe COVID-19 disease. “There are studies showing that people surviving intensive care are better off if they have previously taken bisphosphonates, regardless of their reasons for being in intensive care. This is really, really fascinating, and I think we are beginning to understand the mechanisms, which may include effects on cell survival and preventing DNA damage,” explains Graham.

These are not the only non-bone effects of bisphosphonates. They reduce mortality and expand the life span of osteoporosis patients, with those who have them having fewer fractures, and reduce the number of deaths from pneumonias and heart attacks.” Graham continues with excitement, “But that’s not all, there’s evidence to suggest that bisphosphonates could also improve the survival rate of colon cancer patients, which really is remarkable. And if we further explore the cancer arena, research suggests that bisphosphonates can act as a carrier for anti-cancer drugs for bone cancers such as myeloma, which is in the bone marrow environment. Typically, these drugs have horrible side effects, but when attached to bisphosphonates, the drug is actually released in the bone marrow and significantly reduces the side effects outside bone.”

“Another area that fascinates me is parasitic diseases. There’s a whole load of literature showing that these bisphosphonates could work on protozoan parasites; it’s such an important opportunity but there’s a question of investment. Who’s going to do it?  So, you know, we live in a funny old world, don’t we?”

Who’s going to write the next chapter of the bisphosphonate story?

In 2019, bisphosphonate enthusiasts celebrated their golden anniversary, marking 50 years since the first publication on the biological effects of bisphosphonates. During that time, Graham has accumulated a wealth of knowledge and perspective on drug discovery, which he shares with warmth and humility. And he shows no signs of stopping: “The story really isn’t over for bisphosphonates,” Graham says, “We old dogs are continually learning new tricks.  I’m greatly enjoying still working closely with my long-term chemistry friend and colleague, Hal Ebetino, and with Claire and James Edwards representing the next generation of excellent younger scientists in Oxford. This links in very nicely with the outstanding support we have from Chas Bountra, who leads the newly created Centre for Medicines Discovery. We all hope that these drugs will receive more attention for their many exciting potential and novel medical uses.

On that note, the conversation shifts to the topic of attending events, both virtual and face-to-face. “It’s really about making the most of the opportunities that are there. To me, hearing good science is like going to a good theatre; it informs, enlightens and entertains – and that is a good reason to go and take part”.

To hear more invaluable insights from Graham, be sure to register for Drug Discovery Digital so you can attend his talk and learn more about the lessons he has accumulated since those early days in Cambridge, when the Beatles were taking the US by storm, and that tutor encouraged him to ‘do medicine’.

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--This blog also appears on the partner ELRIG UK’s website--

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