A new Golden Age of cell biology?
Ten years ago, the sequencing of the human genome promised many medical advances but, according to Professor Angus Lamond, there are still many steps to go on the scientific journey to decode the secrets of life...…
Sequencing the genome was a great intellectual achievement and technological landmark which will help us to develop new and safer drugs, but it certainly wasn't the last word in biology, and Lamond's quest to understand the underlying chemistry of life and the “near infinite spectrum of proteomes” is part of the continuing story of science.
To understand Lamond himself and the serious nature of what he is seeking to do in his current research, it may be revealing to know that when he was an undergraduate, while other students may have spent their summer holidays picking strawberries or lying on beaches, he was rubbing shoulders with Nobel Prize winners and learning how to clone genes.
Nowadays, Lamond is pioneering new ways of analysing proteins to see what is happening inside cells, using the latest proteomics technologies (see The Science) and creating online databases to communicate the results (e.g. the human nucleolar proteome). Another fundamental aim of his work is to answer key questions such as “how long does a protein live?” and find out why the same protein lives for different lengths of time in different cells and under different growth conditions. But the intellectual curiosity that drives Lamond forward today is the same that he had as a student.
The story starts in Glasgow over 30 years ago. Lamond’s father was a shop steward in a heavy engineering works and the young man was the first member of the family to go to university. At first, he thought of studying chemistry, but after borrowing a textbook on biology, he opted for a degree in molecular biology at the University of Glasgow. Lamond says his interest was to “try to understand living things at the chemical level,” and he soon turned his attention to the world of cell biology and genetics, which “captured his imagination” and steered the course of his future career. “I always studied what interested me most rather than what other people thought I ought to be doing,” says Lamond. Working on a research project for one of his tutors also exposed him to laboratory work, and at the end of his third year he applied for a summer job in Andrew Travers’ laboratory in Cambridge. This was a pivotal moment for the 20-year-old Lamond – and his first “lucky break.” As soon as he arrived, he “entered a completely different world” and realised this was what he wanted to do with his life.
During that extraordinary summer, Lamond met a lot of scientific VIPs, including Nobel Prize winner Francis Crick, who co-discovered the structure of DNA. One day, when Lamond was rummaging around in the freezer looking for some radioactivity to use in an experiment, he bumped into another Nobel Laureate, the biologist Fred Sanger – who had won the Prize in 1958 for his work in insulin and later that year (1980) won it for a second time for work that paved the way for sequencing the genome.
The young undergraduate did not know who Sanger was and imagined at first that he may be a janitor, but as Sanger started probing him with questions concerning his work, it dawned on him the “janitor” may know quite a lot about science.
Returning for his final year in Glasgow, Lamond helped his tutor, Professor David Sherratt, on a piece of research which was subsequently published in the journal Nature, and along with his summer work at Cambridge, he was able to co-author two research papers before he graduated with his BSc degree. “I enjoyed the freedom to create things and test my ideas,” says Lamond, describing his “apprenticeship” in Glasgow with David Sherratt, where he studied transposons (sequences of DNA that move to new positions within the genome of a single cell) and how they develop resistance
Before he returned to Cambridge to work for his PhD, Lamond spent three months in Zurich learning how to clone genes in the “highly disciplined” laboratory of Charles Weissmann, the scientist who first cloned interferon – a protein which was once the “great hope” for the treatment of cancer.
Back in Cambridge, Lamond completed his PhD studies in less than three years, with a thesis on the regulation of bacterial genes. What excited him most was the “adventure” of biology and the excitement of being the first person ever to know a new piece of information about how life works – such as how proteins interact and how drugs make our cells respond in different ways. “I was exploring how molecules behave,” he explains, “working at the frontiers of molecular biology.” In retrospect, he also thinks the fact that he didn’t fear failure was down to the fact that he “didn’t know enough not to do things.” At the same time, he has always loved the “democratic” nature of science and how scientists don’t pay attention to status and judge you by the quality of your ideas, rather than just your title or position. Lamond also stresses the importance of not being frightened of getting the “wrong” results in an experiment. “Research shouldn't be about ‘end-gaming’ – you have to learn from your mistakes.”
Lamond spent the next two years at Christ’s College, Cambridge, as a junior research fellow, and when he was inducted, he was asked to sign the Fellows’ book, which previously Milton and Darwin had signed. During his time there, he also met his fellow Glaswegian, Lord Todd, who won the Nobel Prize for Chemistry in 1957.
Next stop was postdoctoral studies in Cambridge, USA, and after receiving his BSc and PhD he was able to get his ‘BTA’ (Been To America). In America, he switched his research from studying bacterial to human genes, working at the Massachusetts Institute of Technology (MIT) in the Centre for Cancer Research, where he continued his training. At MIT Lamond studied RNA processing (the splicing of RNA in eukaryotic cells), under the guidance of future Nobel Laureate Phillip Sharp, seeking to “understand how the molecular machinery interprets genetic information to assemble proteins.”
Lamond got “lucky” again when he moved back to Europe and the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, where he “became a born-again cell biologist”. At EMBL he continued to study RNA splicing in human cells and it was at this point that he first got his hands on a new type of fluorescence microscope, called a ‘confocal’, which enabled him to see more clearly the structures inside a living cell, “and how the nucleus of the cell is organised.” He was also introduced at EMBL to mass spectrometry technology and its new application for the identification of proteins, literally by weighing individual fragments of purified cell proteins.
For eight years working in Germany at EMBL and the last 16 years in Dundee, Lamond's work has therefore evolved from analysing the chemical process of splicing to studying the proteins in the nucleus, and now he is taking full advantage of the latest technology to look at all the proteins in cells – the “nuts and bolts” of how cells develop and respond to their environment.
“It's hard to study the proteins in living cells,” Lamond explains, “because you can’t see them.” To solve this problem, scientists fuse human genes with genes which originally came from bright-coloured jellyfish, and the jellyfish genes colour the proteins so they can be seen in a fluorescence microscope– a process known as green fluorescent protein (GFP) tagging. Lamond also compares this “revolutionary technique” to putting a siren on the roof of a police car so people can hear it in the midst of the traffic.
How proteins behave is a key part of Lamond’s research – measuring, for example, where they are located within the cell and how they bind to other proteins and affect them – and he enjoys the detective work involved in measuring and identifying thousands of proteins. “Mass spectometry has changed the way we do experiments,” Lamond explains, “doing things we couldn't imagine before.”
In his view, advances in technology have ushered in a new Golden Age for cell biology, as the science itself evolves from cloning genes to sequencing the genome and beyond. Sanger, for example, made enormous breakthroughs, but most of his ground-breaking methods have now been replaced with more efficient new technologies.
“For 25 years, we've been spending much of our time trying to solve technological problems, but now we have the tools to study what we really want – how cells work,” says Lamond. Bacteria and viruses were the focus of attention in the 1950s and ’60s, with “simple experiments driven by clever ideas.” This was followed by a phase where experimental methods became more complex, with many of the breakthroughs coming from unexpected discoveries, rather than clever ideas. Nowadays, says Lamond, there is “an interplay of ideas and technologies” which is changing the way we do science once again.
Lamond thinks decoding the genome was a major advance but, alone, it has not delivered the host of new drugs and medicines many people expected. He feels instead that proteomics is increasingly important in the drive to understand how cells work and thereby to discover new drug targets and new and safer medicines. Proteomics enables us to study cells at very high resolution, to identify all the proteins and observe what happens to them inside the cell after drug treatments.
“We know what the genome is,” Lamond continues, “so now we have to find out how it works.”We have the right vocabulary to talk about the genome, but that does not explain the complex processes going on inside the cells any more than knowing English can explain the works of Shakespeare. When you also add the “overload of data” involved, the picture gets more and more complex, but recent breakthroughs in biological computing, including new techniques for data visualisation, are helping biologists to cope with the huge data volumes, says Lamond.
Lamond's work can sometimes seem quite complex, but the aims are quite simple – if also ambitious. “I want to understand how complex chemistry changes over time,” he explains, “and pioneer the intellectual framework so we can measure the responses and properties of cell proteins and understand what's happening inside the cell when it responds to its environment.” It’s a long way from his student days in Glasgow but exactly the same sense of wonder and the same determination to understand the “Big Bang” of biology.