Reading ‘the Book of Life’ – The Human Genome Project

A Little History Of Science: Reading ‘the Book of Life’ – The Human Genome Project

Humans have about 22,000 genes (the exact number is history in the making). How do we know this? Because scientists in laboratories all over the world collaborated on the Human Genome Project.

This hugely ambitious project counted our genes by using DNA sequencing, and answered a question left hanging when Crick and Watson revealed the structure of DNA. The ‘sequencing’ meant the position, on the chromosomes, of every one of the three billion ‘base pairs’ of molecules that make up our genome. That’s an awful lot of molecules of adenine and thymine, cytosine and guanine arranged in their double helix in the nucleus of each of our cells.

If understanding DNA had given us ‘the secret of life’, the Human Genome Project was about reading ‘the book of life’. For that is what your genome is, the genes for everything about you, from the colour of your hair to the shape of your little toe. It is also about things that cannot so easily be seen: the instructions for one fertilised egg cell to become two and then four and all the way up to a whole baby in the womb. It controls the biological programmes in cells that produce proteins like the hormone insulin to regulate our blood sugar. It runs the programmes for chemicals in the brain that transmit messages from one nerve to the next.

The Human Genome Project began in 1990 and was supposed to be finished by 2005. But in a moment of science drama, on 26 June 2000, five years ahead of schedule, an unusual thing happened. Amid great fanfare, on live television, the President of the United States of America and the Prime Minister of Great Britain announced that the first draft of the project had been completed. They were accompanied by some of the scientists who had done the work, but the presence of these two world leaders was an indication of just how important it was to understand the genome.

It would take another three years, until 2003, to produce a much better version of this book of life – filling in the big gaps and correcting most of the errors. Even so, that was two years sooner than originally planned. During the years of the project the methods and technology used by the scientists, particularly the assistance provided by computers, had also advanced.

The genome project had developed from decades of research that followed the discovery of DNA. After Crick and Watson’s revelation in 1953, an important thing to do was to ‘clone’ strands of DNA, to get more of the particular part of the DNA molecule you wanted to investigate. In the 1960s molecular biologists worked out that this could be done using enzymes and bacteria. Enzymes are proteins that can do all sorts of things depending on their individual structure. They were used here to do one of their natural jobs: cutting DNA into little sections. These little sections were then inserted into bacteria in a special way. Bacteria reproduce very quickly, and as these modified bacteria reproduced they also made copies of the added sections of DNA. These copies, the clones, could then be harvested for further research. The process created a lot of excitement but it was only a beginning. Whole cells as well as bits of DNA can be cloned. A sheep called Dolly was the first mammal to be cloned from an adult sheep cell. She was born in 1996 and died in 2003. Cloning techniques continue to develop and are one of the most newsworthy areas of molecular biology research.

Now that the scientists had lots of the bits of DNA to experiment with, they began to try to solve the problem of DNA sequencing: to reveal the order of the base pairs of molecules in DNA. This was a job for the English molecular biologist Frederick Sanger (b. 1918), working in Cambridge. Sanger had already won one Nobel Prize in 1958 for working out the order of the amino acids of the protein insulin.

One of the key differences between amino acids and DNA is that the DNA molecules are much longer, and have many, many more base pairs than proteins have amino acids. Also each amino acid is less chemically similar, whereas the DNA bases were much like each other, which makes them harder to sort out. Building on his own earlier work, and that of others, Sanger found a way to prepare short strands of DNA using radioactive labels, chemicals and enzymes.

He adapted various biochemical methods to find a way of separating out the adenine, thymine, cytosine and guanine from each other. To do this, he exploited the fact that as chemical compounds they have slightly different chemical and physical properties. The best results came with a process called electrophoresis.

To make sure the results were accurate enough, Sanger and his team processed multiple copies of each strand several times and compared the results. It was a very time-consuming, repetitive process. But by using lots of the short strands of the long molecule and then looking to see where they started and ended, they managed to match up the strands and produce a readable DNA sequence. In 1977 they had their first success in reading the genome of an organism. It was a humble one, a bacteriophage called phi X 174.

Bacteriophages are viruses that infect bacteria, and phi X 174 was one often used as a tool in molecular biology laboratories. In 1980 Sanger won his second Nobel Prize for this valuable work.

The next genome targets were also laboratory organisms. Despite how hard it was to produce a readable DNA sequence, molecular biologists carried on with their research. Meanwhile, innovations in computing helped with analysing the patterns of the bases on the short strands. The scientists pressed on keenly. If they knew exactly which genes an organism had, and which proteins each gene could manufacture, they would be able to understand very basic things about how the organism was made, literally cell by cell from fertilised egg to adult.

The fruit fly was an obvious candidate for their research. Thomas Hunt Morgan and his group had already done a lot on its inheritance patterns, and some crude gene-mapping, before 1950.

Another was a tiny roundworm called Caenorhabditis elegans. At only one millimetre long, it had exactly 959 cells, including a simple nervous system. Now it might not seem like much of a pet, but C. elegans was the favourite laboratory animal of Sydney Brenner (b. 1927), and had been for many years. Brenner had come from South Africa to the Laboratory of Molecular Biology (LMB) in Cambridge in 1956. Since the 1960s he had been investigating its development, since its cells were easy to see. He thought it would be possible to determine exactly what each of the cells in the embryo worm would become in the adult. He hoped that if he could reveal the worm’s genome, he would be able to relate its genes to how the adult worm carries out its living functions.

In the course of their work, Brenner and his team also learned a lot about the ordinary lives of cells in an animal, including one very important job that the cell must do: die when it is time to die.

Plants and animals always make new cells: think of your skin and how it rubs off when you have been in the bath a long time. We get rid of the dead stuff, and new, living cells replace it underneath. All this living and dying within an organism is a regular feature of nature, and the genes programme this process. That is why cancer cells are so dangerous: they don’t know when it is time to die.

Trying to influence the gene that has failed to tell the cell it is time to stop dividing is a major part of modern cancer research. Brenner and two colleagues won the Nobel Prize in 2002 for their work with the lowly roundworm. By this time, one of those colleagues, John Sulston (b. 1942), was leading the British team taking part in the Human Genome Project.

The project stands as a symbol of modern science. First, it was expensive and thousands of people worked on it. The modern scientist is rarely a lone worker, and it is quite normal today for scientific papers to have dozens or even hundreds of authors. The work may require many individuals with different skills. It’s been a long time since William Harvey worked alone on the heart, or Lavoisier in his laboratory had his wife as his only assistant. Several laboratories worked together on sequencing the human genome. They divided up the chromosomes between them, so cooperation and trust were needed, and every lab had to produce the sequences to the same high standards. This needed many smaller portions of the DNA, and then computer analysis to fit them together in a single sequence.

Running these laboratories was expensive, so generous funding was needed. In the United States it was provided by the government-supported labs at the National Institutes of Health (NIH) and else-where. In Britain, first government grants, and then a large private medical research charity, the Wellcome Trust, paid for the research. The French and Japanese governments funded smaller laboratories, making the project truly international.

Second, the project – and indeed, modern science itself – would be impossible without the computer. The scientists had to analyse large amounts of information as they looked at each strand of DNA and tried to see where it began and ended. For humans, it would be overwhelming, but computers do this quickly. Many scientific projects now include people who only look after the computers and computer programmes, not the fruit flies or test tubes.

Third, modern science is big business, with a lot of money to be made as well as spent. The Human Genome Project became a race between the publicly funded groups and a private company established by the American entrepreneur Craig Venter (b. 1946).

Venter, a gifted scientist, helped develop some of the equipment that could speed up DNA sequencing. He wanted to be the first to decode the human genome, patent his knowledge and charge scientists and pharmaceutical companies to use his information.

The final result was a compromise. The whole human genome is freely available, but some of the ways that this information can be used can be patented, and the resulting drugs or diagnostic tests can be sold for profit. And, of course, people today pay to have their DNA sequenced, hoping that what they learn will help them maintain their health and avoid diseases that might affect them in the future.

Finally, the genome project is a telling example of the ‘hype’ surrounding today’s important science. Scientists must compete for scarce funds, and sometimes exaggerate the significance of their research to get their grants. Journalists cover their stories, putting the most dramatic gloss they can on them, since ordinary science is not news. Each fresh announcement of a discovery or breakthrough raises the public’s expectations that a cure or treatment is just around the corner. But mostly science takes longer for its lasting effects to be realised. New knowledge is gained every day, and new therapies are regularly introduced. But most science advances little by little, and media hype is rarely spot-on.

Yet it is a huge achievement to be able to read the human genome, because it can give us a much more precise understanding of health and disease. It will, in time, help us to develop new drugs against cancer, heart disease, diabetes, dementia and the other killers of modern times. We all stand to lead healthier lives as a result of this important work, involving scientists in many fields and many countries.