Computer modelling the human heart
How a research student in 1960 built a virtual heart on a mainframe in the middle of the night.
Denis Noble developed the first computer model of the human heart. As a young research student in 1960, he made a huge breakthrough in computational physiology. Now 85 years old and Professor emeritus and co-director of Computational Physiology at the University of Oxford, he is still using computers to advance our understanding of human life.
In an interview with Archives of IT, Denis spoke about how he achieved every researcher's dream of a world-changing breakthrough, working the graveyard shift with the university mainframe each night from 2am to 4 am. He tells people it worked using "light bulbs - because no-one these days seems to know what a (thermionic) valve is."
Since Denis' work, software simulation of biological structures has grown with advancing technology to address ever more complex structures, inform our understanding of biology, support the development of new drugs and expand our views of evolution.
Before Denis' model, scientists didn't understand how the electrical activity of chemical ions in the cells of the human heart caused it to beat in a self-sustaining, repetitive pattern. In 1952 Hodgkin and Huxley had addressed a similar but much simpler problem of how electrical activity in a squid's axon (nerve fibre) controlled its water jet propulsion system. They did that with a hand cranked, mechanical Brunsviga calculator and many hours of manual work, earning a Nobel prize, awarded in 1963.
Denis - working with his supervisor, Otto Hutter - identified several ion channels that control the flow of electric current in the cells of the heart.
"We made some important experimental discoveries. I was strongly motivated to try to see whether I could do exactly what Hodgkin and Huxley had done just 8 years previously on nerve excitation," he says. Denis' initial idea was to do it by hand using the Brunsviga in the laboratory, but he worked out that a single calculation would take him six months. However, he thought he could speed the work up using a relatively new invention: a computer.
He learned that University College London had access to the only big mainframe computer in London, so he turned to the computer engineers for help. He says: "This machine was extremely valuable, extremely expensive but very slow. Nevertheless, it was capable of doing in two hours what would take me six months to do by hand.
"I didn't know how to programme but I came up with a set of little equations for each of the ion channels, and I thought that if I give these equations to the computer people, they will know how to make the computer give me an answer." The engineers were sceptical that he would be able to do it and allocated him the worst possible time slot to use the computer, in the middle of the night. However, this worked perfectly for Denis. He explains, "I could continue doing experiments during the day and do the computing at night. I didn't sleep for about three days."
Having taught himself Mercury Autocode and spent several weeks debugging the programme, he started getting some promising results.
"They showed something fascinating. After each electrical pulse of this model heart I was building, there was the hint that it would take off again; it was trying to do another pulse. This made me think that if I fine-tuned the equations within the limits of the experimental technique that gave us the results, maybe it would take off again and I would have a model of cardiac rhythm, and that is exactly what happened. So, six months from getting access to the computer, I had a paper in Nature showing that it worked.
"For a young research student looking for a thesis, it was unbelievable. I don't know what bigger problem you could have had in those days than to produce a model of heart rhythm. Nobody knew how the rhythm of the heart was generated. It's like a dream when I think back on it nowadays. Sixty-odd years later, I still find it astonishing that I managed to do what I did."
He continues, "There are other things that came out of it. That early model was very simple, the later models are much more complex, which made me ask, 'Why does nature bother to be so complex?' After all, I could do it with just four channel mechanisms in 1960 - but if I had knocked out any one of those, the heart would stop beating. Your and my heart does not stop when we block major channels that take part in the rhythm. That major discovery has led to the drug ‘Ivabradine', which was developed by the French company, Servier, based on producing a gentle, slower cardiac rhythm for people who suffer from too high a rhythm particularly during exercise, and it is now used worldwide.
In 1960 it took two hours to reproduce two seconds of heart rhythm (two beats); today, it takes milliseconds. Denis says: "Things have become so fast, but I've lost count of the number of Moore's laws I've been through; it must be at least 40. This has enabled us to tackle much greater complexity in nature."
Denis' latest modelling has been in skeletal muscle, calculating the mechanism of a multi-component medication for the relief of cramp. "We were able to reproduce about an hour or so of skeletal muscle activity in 20 minutes of computation on a desktop. Obviously, that would go even faster if you went to one of the big mainframes, but why bother with mainframes anymore? You can bang together a number of desktops or do cloud computing."
The insights gained through the power of modelling have stimulated new thinking on how evolution works and possibilities for our future (see Denis' books, The Music of Life and Dance to the Tune of Life) but that's another - equally revolutionary and fascinating - story.
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