The earliest medicines were folk medicines based on plant extracts, but by the mid-19th century chemists were purifying the active components, often small organic chemicals, and synthesising them as medicines.
Soon they were chemically tweaking the compounds for improved medicinal properties. They even discovered medicinal properties in the new compounds they were learning to synthesise. It was not uncommon for synthetic chemists to taste their compounds, as well as measure their melting points.
During the 20th century the pharmaceutical industry made spectacular advances from its bedrock of synthetic organic chemistry, and medicines became synonymous with chemicals. You get medicines from a chemist, and will usually be given a bottle of chemicals compressed into small pills, each to be taken daily by mouth.
However, in recent years, you may have become aware of a class of new pharmaceuticals based on antibodies. These are transforming the treatment of cancer, and inflammatory diseases such as rheumatoid arthritis or Crohn’s disease.
In nature, antibodies are produced by our immune system as complex mixtures, to attack virus and bacteria. But the new antibody pharmaceuticals are single antibodies (termed monoclonal antibodies), largely directed against human targets and injected, typically every fortnight, month or even six months. It has been a revolution for medicine and for the pharmaceutical industry.
I was lucky enough to witness and to participate in this revolution. I found myself with the right skills, in the right place and at the right time. You might be curious to hear how I came to be in this position.
I was brought up in the West African country that became the Republic of Ghana. My father was at the University there. He struggled with his research into Norman-French, and finally gave up and became an administrator.
Nonetheless, his struggles may have predisposed me to the Life Academic.
My mother tells of when my brother and I were toddlers and she discovered us in our father’s study. We were scribbling on his papers with great flourishes, swearing horribly, crossing out the scribbles, crumpling the papers up, and throwing them in the bin. When she shrieked, ‘What do you think you are doing?’ I looked up and said, ‘Be quiet mummy, you are disturbing us, we are doing daddy work.’
The nudge towards science came at the little primary school on the edge of the University campus, under the huge palm trees. I remember a physicist bringing in a Geiger counter. It clicked feverishly at the teacher’s radium coated luminous watch hands, and so alarmed her that she took the thing off.
I remember the marine biologist bringing a huge sea turtle lashing about in a bath tub, and being warned by the African labourers that it could bite off our fingers.
A few years later at home my brother and I would play with our chemistry sets, and make wasps buzz furiously in a test tube by passing in oxygen, and then sedate them for release with a puff of carbon dioxide. I think it was the wonder of discovery that drew me to science.
My teens were spent back in England. We brought back two West African Royal pythons and my brother and I bred mice to feed to the snakes, and for sale to the pet shop. For piebald mice we got 9d, white mice 8d and others 6d (old money). So, the piebald mice went to the pet-shop for the mouse fanciers, and we fed the others to the snakes.
My profits went to buy a science magazine, and in there, prematurely, I discovered the world of chemistry underpinning biology.
In essence we are all chemical reactors, in which thousands of different chemical reactions are taking place simultaneously. Yet the chemical reactions are taking place under conditions that would defeat chemists – in water, at around room temperature, and in the presence of many other chemicals which could potentially react.
The secret is that these reactions are catalysed on the surface of proteins called enzymes, and the reactions coordinated by turning on and off the enzyme activity. This world was a revelation.
I discovered that all proteins are built from strings of amino acids, each protein with its own precise sequence, and can adopt remarkable structures and functions, every bit as exotic as the plants and animals of a tropical jungle.
Not only that, but the strings are created by tiny machines directed by instructions from another polymer, DNA. As well as coding for the proteins, the DNA codes for itself. You couldn’t make it up if you tried!
The teenage years are when one wonders about all kinds of existential questions and I was no exception.
This teenager wondered, ‘was this molecular jungle the answer to the question of, What is Life?‘
To cap it all, several of the chemical building blocks of proteins and DNA can be generated in the laboratory from the gases and conditions thought to prevail in pre-biotic Earth.
I wondered, ‘was this chemical soup the answer to the question How did Life begin?
And so, at school, when asked to choose between Oxford or Cambridge University, I chose Cambridge.
Cambridge was the Mecca for research in DNA and proteins. It was where Watson and Crick had discovered the structure of the DNA double helix, where Sanger had devised methods for sequencing proteins (and later DNA), and where Perutz had solved the first three-dimensional structures of proteins.
All Nobel laureates. Like a medieval pilgrim I wanted to walk in their steps. But like a medieval apprentice I knew I would first have to learn the tools and practices of the trade.
So, after graduating from the University, I worked at the Medical Research Council’s Laboratory of Molecular Biology in Cambridge. I learned how to sequence proteins and DNA. It was a skilled trade, with strange resonances of the occult one minute and the everyday the next.
We would use recipes with hints of a witches’ brew, cutting up proteins with the digestive enzymes of cows or of honey fungus, or treating the split ends of DNA with enzymes from snake venom.
We would use equipment capable of jolting Frankenstein into life, to apply a high voltage across the ends of blotting paper and fractionate the components of protein digests.
The paper first had to be wetted with spray bottles in a vile smelling solution of pyridine, and then immersed in a huge tank of white spirit to keep it cool during the electrophoresis. If the paper was too wet it would fall apart, too dry it could catch fire and set light to the white spirit. After electrophoresis, the sheets were pegged out to dry with clothes pegs on a little washing line inside our fume cupboards.
By contrast, with nucleic acid sequencing, we had to use radioactively labelled DNA, and we worked to the frenzied clicks of Geiger counters. Instead of test tubes we used the drawn tips of fine glass capillary tubes as tiny reaction vessels.
Instead of test-tube racks we stuck the capillary tubes into sausages of plasticine rolled by hand like children do in primary school. Both ends of the capillaries had to be sealed by melting the glass with a flame – hesitate, or too long in the flame, and the radioactive liquid could shoot out over the bench or your fingers.
By the end of seven years working at the Laboratory of Molecular Biology (hereafter referred to as LMB), I had become a master craftsman.
It was the late 1970s, the era of recombinant DNA technology had arrived, and biotechnology companies were cloning proteins for use in medicine. They had already isolated the insulin gene from human cells, and added instructions to the DNA so that bacteria would produce human insulin.
But I wanted to go one better, and to use recombinant DNA technology to alter proteins, and to create those with novel activities.
In the protein world, activities require binding sites – that is the region on the surface of a protein where molecules come together. In enzymes these are pockets, where the reactants are brought close together, so accelerating reactions between them. I started work on tweaking the binding sites of enzymes.
But I soon had to change tack. Fred Sanger, the Head of the Division, supported my work, but would be retiring. I would now have to clear my plans with Cesar Milstein, the new Head. But Cesar didn’t want me to work on enzymes. Cesar was more interested to see what I would do with antibodies. And so I wondered, what could I do with the binding sites of antibodies…?
Then disaster struck. In January 1984, I was attacked on the way to work and my shoulder was dislocated. This resulted in a lesion of the brachial plexus lesion. My right arm was paralysed, from which it has slowly recovered over the years, albeit incompletely. I could no longer work at the bench.
As a distraction from the pain and worry caused by the nerve damage and the possibility that I might have flail arm for the rest of my life, I immersed myself into the 3D world of protein structures using an advanced computer graphics system. Among the structures were a few antibodies.
For months I looked at the molecular architecture of these antibodies, and the sequences of many more.
The binding sites for their targets were thought to lie in a small region at one end of the antibody. This region consisted of loops of different sizes, shapes and sequences mounted on what seemed to be a large protein scaffold.
The structure of the scaffold was rather similar in different antibodies. It got me wondering if we could transfer the binding site from one antibody to another by transferring these loops.
And then, Eureka! But I need to explain something first.
Cesar Milstein had invented a method to make mouse and rat monoclonal antibodies in the mid 1970s, and would soon be awarded the Nobel Prize for Physiology or Medicine.
His method had produced rodent antibodies that attacked human tumours, but when given to patients for more than a week, they were recognised as foreign by the human immune system and rejected. Human antibodies were needed but were apparently impossible to make.
But…if I could lift a tumour binding site from a mouse antibody and drop it into a human antibody, the antibodies would be almost human, and might be tolerated by the human immune system.
The experiments were more complicated than anything we had tackled before, but we managed to transfer the binding site from one antibody to another.
I filed an application for a patent, as there had been a big rumpus about the failure to file a patent on Milstein’s discovery of monoclonal antibodies.Mrs Thatcher had blamed the Medical Research Council (hereafter abbreviated MRC), the MRC had blamed the National Research and Development Corporation (hereafter NRDC), and who were responsible for the MRC’s patents. And a committee of the Royal Society had blamed Milstein.
In the meantime, Milstein simmered with a suppressed fury whenever patents were mentioned. And then the troubles started with my own patent application.
The biotechnology company Celltech approached MRC Head Office, and requested my patent be assigned to them. I understood that this was planned as a highlight of a forthcoming funding pitch to investors.
However, I was warned by other companies that this could cut them out of the humanising technology. I was also uneasy that my work, which had been publicly funded, was being hijacked for the profit of a single company on the say-so of a nest of bureaucrats who had messed up with Milstein.
I therefore argued that the MRC should retain the patent, and licence it to many different companies under standard and easy terms, so as to stimulate the creation of therapeutic antibodies for the common good.
Milstein supported these arguments, and by now, with the Nobel Prize under his belt, and the supressed anger of years, a furious argument exploded between us, and what we now saw as a Celltech-MRC Head Office cabal.
Nevertheless, Head Office over-ruled us and prepared to hand over the patent to Celltech. I was so angry, that I pressed the nuclear button; I wrote a letter to Celltech, warning them that as the inventor I could, and would, destroy my own patent application during prosecution. They would be left with a ruin – perhaps they should tell that to their investors.
MRC Head Office wanted to fire me, as they were entitled to do, but it wouldn’t have solved anything, and the Director of the LMB, Sir Aaron Klug refused.
In the end it helped that the Secretary of the MRC was about to retire, and the new Secretary negotiated a deal in which both the MRC and Celltech would be entitled to license out the patent widely and with a low baseline royalty, much as Cesar and I had requested.
But Sir Aaron was required to thoroughly reprimand me for insubordination. Somehow, I knew that I would get blamed, but the victory made it all worthwhile.
Anyway, I was busy with more exciting things. I had been working with Dr Herman Waldman in the Cambridge University Department of Pathology to humanise a rat monoclonal antibody that killed human white cells, potentially useful for the treatment of lymphoma.
We created the humanised antibody within the year, and it killed human cells in the test tube just as well as the original rat antibody.
Herman and his clinical colleagues now needed to find the first patient. It was a lady in her 70s, who had non-Hodgkin’s lymphoma, her spleen grossly enlarged with tumour cells. Other treatments had failed and she was expected to die.
After a few days of treatment, there were no adverse reactions, some regression of the tumour, and I was told that the patient wished to see me. I was told to wear a white coat, fling a stethoscope around my neck like a junior doctor and to breeze in.
I found her knitting. She thanked me for what we had done, but wanted to know how long she had left. I told her that I was just relieved that the antibody hadn’t killed her, glad that it seemed to be working but didn’t know if, or when, the humanised antibody would be rejected. I told her that it could be a few weeks, a few months, or a year or more. To my surprise she said firmly, ‘two months is enough.’
Seeing my surprise, she explained that her husband was dying, it wouldn’t be long and she wanted to be with him when he died. Her loving comments continue to haunt me.
In fact, she was lucky: the antibodies largely destroyed the tumour over the 30-day treatment, and were not rejected. After one year the tumour came back and she died. She might have lasted longer if we’d had any antibody left to treat her.
Publication of the clinical work stimulated interest in the patent and the underpinning technology, and the MRC licensed out the technology to more than 40 companies, leading to several blockbuster drugs against cancer, including Herceptin, Keytruda and Avastin. The patent generated a lifetime royalty stream of more than £500m back to the MRC.
After humanised antibodies, I continued to direct my research towards clinical application, but with even greater determination.
My next idea, to create fully human antibodies in the test tube, led to the founding of Cambridge Antibody Technology, the creation of the antibody Humira, for several years the world’s best-selling pharmaceutical drug, and to the Nobel Prize in Chemistry. But that is another story!
I was asked by the Science Director of the Science Museum, to comment on how to keep the UK innovative in pharma. I don’t pretend to be an innovation guru, and most of what I could say has been said by others, so in the spirit of the evening let me say something radical about innovative research.
I am thinking here about breakthrough not incremental innovation, and about research in academia funded by the public and by charities. My comments are not directed to research in industry or collaborative ventures with industry.
My view is that we need to take more considered risks in the funding of innovative research.
Unfortunately, funding decisions are usually made by committees, and there is a fundamental problem in the way that committees work. Committees are rather conservative, and gravitate to the comfort of the consensus.
They can be excellent for managing ‘steady as she goes’, but I am less sure about their handling of radical ideas.
With radical ideas they can act like packs of sharks, one whiff of blood in the water and all members attack. It is just too easy to criticize – radical innovation doesn’t come exquisitely packaged – there are often loose ends and doubts.
At best, committees get paralysed by the question marks, and kick things to a subcommittee and into the long grass.
Perhaps we could try to overhaul the way committees work, but i’m not sure how. Or we could place more funding decisions in the hands of individual experienced scientists, not committees.
This suggestion is based on my experience at the LMB, where my research was entirely at the discretion of the Heads of Division, Fred Sanger, and then Cesar Milstein.
In turn they were personally responsible to the MRC for the quality and coherence of the research emerging from their Division, and the quality of their key scientists.
I am sure I would not have received grant funding for my most innovative work from an external committee. And even committees of top scientists can get it wrong.
Of my own career appointment, which was based on my proposal to engineer enzymes and antibodies, Sydney Brenner, then the Director of the LMB, told me: ‘Don’t thank me or the Executive Committee, we were all against it. But Fred said we had to.’
Furthermore, based on my own experience, if we want to see more innovative work applied, it might help if the ownership of IP were fully vested in the inventor. Not in the employers, not in technology transfer organisations, and not in the funders of the research.
This would allow an inventor to negotiate directly with investors or industry, without all parties having to break through multiple tiers of bureaucracy.
This would stimulate the application of innovative research, and could lead to the growth of a cadre of entrepreneurial inventors.
Nevertheless, you can be sure that both my ideas will be thoroughly savaged should they ever be considered by a committee with University or charity representation, and at best will get kicked into the long grass.
Finally, back to the question that had preoccupied me as a teenager, ‘What is Life?’. After a lifetime of working with the molecules of life, do I have the answer?
Not really, but it helped me to find the answer to my life. It placed me in the right place at the right time and with the right skills to do what I have done.