A Little History Of Science: Building Blocks
As time went on, scientists tended to specialise in their chosen fields. Still, biologists traditionally did biology, chemists did chemistry and physicists did physics. So what was happening in the 1930s, when first chemists, and then physicists, decided it was time for them to take on the problems of biology? Chemistry was about how substances combine and react. But it was becoming clear that living organisms – the biologists’ subject – were made up of some of the elements of the chemists’ periodic table, such as carbon, hydrogen, oxygen and nitrogen. Physics was about matter and energy, which by this time was full of atoms and their sub-atomic particles. Wasn’t that a way of understanding more about the chemists’ elements? To sum up, couldn’t chemistry and physics explain living organisms as a series of chemical reactions and atomic structures? And might that provide an answer to one of the oldest questions in science: What is life?
In the early decades of the twentieth century, Thomas Hunt Morgan had used his little fruit flies to show that it was the chromosomes in the cell’s nucleus that carried the stuff of heredity. ‘Stuff’ was a good word for it. Geneticists had got very good at showing what this stuff did. They could show how, on different bits of a chromosome, the different genes could result in the development of an eye or a wing. They could even show how mutations produced by X-rays could lead to unusual wing shapes because, they believed, they affected the genes. But they didn’t know what a gene was.
Could proteins be this genetic stuff? Proteins are fundamental to many of the reactions that go on inside our bodies. The proteins were the first group of compounds to be systematically studied by molecular biologists. As the name suggests, molecular biology is a science that seeks to understand the chemistry of the molecules in living things, and how they work. Proteins are mostly very large, complex molecules. They are composed of groups of amino acids, which are smaller and simpler compounds than proteins. Being simpler, it was easier to find out what the amino acids were made of, using ordinary chemical analysis and synthesis. About twenty amino acids are the building-blocks that in different combinations make up all of the proteins in plants and animals.
How these amino acids fit together to make the proteins was a much more difficult question. This was where physics began to play a part – it turned out that X-rays provided clues. The first thing was to make a crystal of the protein you wanted to study. Next, you bombarded the crystal with X-rays. As the X-rays hit the crystal they would be bent as they passed through it, or would be reflected back in a particular pattern, known as the diffraction pattern. It could be caught on a photographic plate.
Reading the patterns captured on the photographic plate is a tricky business. What you see is an intricate picture of lots and lots of dots and shadows. You are looking at a flat, two-dimensional image but you have to think in three dimensions, and just putting on 3D glasses won’t help. As well as being able to visualise the picture, you also need to know your chemistry and understand how elements join together. And be good at maths too. Someone who took on this challenge was the chemist Dorothy Hodgkin (1910– 94) who worked at Oxford University. We partly owe what we know about the structure of penicillin, Vitamin B12 and insulin to her research in X-ray crystallography. She won her Nobel Prize in 1964.
Linus Pauling (1901–94) was also good at using X-rays to work out the structure of complex chemical compounds. In a brilliant series of experiments, he and his colleagues were able to show that if just one amino acid was missing from the haemoglobin molecule in our red blood cells, it produced a serious disease: sickle-cell anaemia. (Rather than being round, the red blood cells that contain this haemoglobin are shaped like a sickle.) This molecular flaw is found mostly in Africa, where malaria is always present. It is now understood to benefit the people who have the flaw, because the sickle cells help to protect against the most serious form of malaria.
This is an example of human evolution in action. People with only the trait (a single gene, inherited in the way Mendel first studied in peas) are moderately anaemic, but they are more resistant to malaria. Individuals who inherit the sickle-cell gene from both parents are seriously ill from anaemia. The symptoms of sickle-cell anaemia had been identified early in the twentieth century. Fifty years later, Pauling used the new techniques of molecular biology to understand what was going on, and his research began a new era in medicine: molecular medicine.
After his success with proteins, Pauling almost achieved the biggest prize: revealing the molecular structure of the genes. His X-ray experiments showed that many proteins, such as those that make your hair and muscles, or carry your oxygen on the haemoglobin molecules, have a special shape. They were often wound into a spiral (helix). By the early 1950s, lots of scientists thought that the genes were made up of deoxyribonucleic acid. This compound is much better known as DNA, and a lot easier to say.
DNA had been discovered in 1869 but it took a long time to under- stand what it might do and what it looked like. In 1952 Pauling suggested that it was a long coiled molecule made up of three strands twisted together – what was called a triple helix. While Pauling was at work in California, two groups in England were hard on his heels. At King’s College, London, the physicist Maurice Wilkins (1916–2004) and the chemist Rosalind Franklin (1920–58) were turning themselves into molecular biologists.
Franklin was particularly good at producing and reading the photographs produced by X-ray crystallography. At Cambridge, a young American, James Watson (b. 1928), had given up his earlier interest in ornithology (the study of birds) and teamed up with Francis Crick (1916–2004). Crick had studied physics, and after working as a physicist for the Admiralty during the Second World War, he had gone back to university as a mature student, this time to study biology. Watson and Crick would become one of the most famous double acts in science.
Crick shared his experience on the X-ray analysis of the structure of proteins. He and Watson knew that DNA is found on the chromosomes in the cell nucleus – the same cell components that Morgan had analysed thirty years before. They made paper cut-outs and built models to help them see possible structures of DNA. They also benefited from the photographs that Franklin had produced. Early in 1953 they created a new model that matched all the X-ray data. This one, they said, was the right one. Celebrating in the pub that night, the story goes that they claimed they had discovered ‘the secret of life’.
If the other drinkers that night were a bit in the dark, wondering what they meant, readers of the weekly scientific magazine Nature would soon find out. Crick and Watson published their findings in the issue of 25 April 1953, which also included a paper by the London team of Wilkins and Franklin. But it was Crick and Watson who showed that DNA is made of two twisted strands, not three as Pauling had said. The strands were joined together by cross-pieces – so that it looked like a long flexible ladder twisted into a spiral. The uprights on the ladder are a kind of sugar – the D or deoxyribo part of the molecule and phosphates. Each rung of the ladder is made of a pair of molecules: either adenine with thymine, or cytosine with guanine. These became known as the ‘base pairs’ of molecules. So if that was the structure, how did it explain ‘the secret of life’?
The base pairs are joined together by hydrogen bonds. When cells divide, the coils unwind, almost as if they are ‘unzipping’. The two halves now present the templates for two identical chains to be made by the cell. So Watson and Crick had shown how genes could be passed from parent to offspring and how ‘daughter’ cells would contain the same set of genes as the original ‘mother’ cell. It was simple and elegant, and it immediately seemed obvious. In 1962, when the scientific community had fully accepted the structure and role of DNA, Crick, Watson and Wilkins shared the Nobel Prize. Only three people can officially share a Nobel Prize. But Rosalind Franklin was not ignored: she had died of ovarian cancer, aged only thirty-eight, in 1958.
Francis Crick went on, with others, to explain why genes are so important for living organisms, besides their role in inheritance. What genes do in their daily activity is make proteins. The ‘genetic code’ is made up of three neighbouring rungs on the ladder, and each triplet of rungs (the ‘codon’) is responsible for a single amino acid. Crick showed how little portions of the DNA molecule provide the codes for the amino acids that make up proteins such as haemoglobin and insulin. Geneticists realised that the order of the base pairs within the DNA molecule is crucial, because that determines which amino acids will be built into the proteins.
Proteins are very complex molecules, sometimes with dozens of amino acids, so a long sequence of DNA is necessary to make such a protein. With the basic workings of DNA understood, scientists could now make sense of the kinds of thing that Morgan had seen in his fly room. Morgan had been looking at the visible characteristics of whole organisms – in his case, the fly with its normal white eye or mutant red eye. This kind of visible trait is called a phenotype.
From now on, scientists could begin to work at a level below the whole organism, at the level of the genes – what now became known as the genotype.
Discovering the structure of DNA was a huge turning point in the history of modern biology. It showed that biologists could understand things in terms of the molecules in the cells, previously the domain of chemists. This was now what everyone wanted to do. Later research revealed that the amino acids and then the proteins were made in the cell’s cytoplasm – the liquid bit outside the nucleus. Learning how this little protein factory worked included the discovery of RNA. This is ribonucleic acid, similar to DNA, but with only one strand, not two, and a different kind of sugar. The RNA had an important part to play in the flow of information from the DNA in the nucleus of the cell to the protein factory in the cytoplasm.
Molecular biologists were to transform our knowledge of how diseases originate. They uncovered how proteins like the hormone insulin did their job in regulating blood sugar. They gained a better understanding of cancer, one of our most feared modern diseases. Although all cancers can overwhelm the whole body, and thus become a general disease, they start with a single mutated cell, which misbehaves and doesn’t stop dividing when it ought to.
These runaway cells are greedy. They use up the body’s nutrients, and if they spread to a vital organ, the cancer cells disrupt its functions, leading to further illness. Finding out how this happens at the molecular level was essential before better drugs could be developed to slow the process down, or even stop it.
Studying these dynamic processes is difficult in large, complicated animals like humans, so much of the work of molecular biologists depends on using simpler organisms. A lot of the early research on the actual functions of DNA and RNA was done with bacteria, and cancer research uses animals such as mice. Translating these findings to human beings isn’t easy, but that is the way modern science operates: going from the simpler to the more complex. This method has helped us understand the processes that have driven evolution for millions of years. It turns out that DNA is the molecule that controls our destinies.