All of us are entangled in life's strands

DNA
October 8, 2004

Knowing DNA's structure has opened our scientific horizons, but its social effects are barely explored, says Ian Wilmut

Few areas of science have had a greater impact on society than our still-developing understanding of the molecular mechanisms of inheritance. One critical step in that development was the recognition of the structure of chromosomal DNA by Francis Crick and James Watson in 1953.

Many meetings and celebrations were held during 2003 to mark the passing of 50 years since their famous paper in Nature . This book is made up of eight essays that were originally presented as lectures at Darwin College, Cambridge.

Darwin, which was founded in 1964, was the first college exclusively for postgraduate students. It is situated along the banks of the River Cam, just a short distance away from the Cavendish Laboratory in which Crick and Watson worked. The connection with the Darwin family is through Sir George Darwin, the second son of the biologist, who became professor of astronomy at Cambridge University. It was he who bought Newnham Grange, the oldest part of the college. Charles Darwin himself studied divinity at Christ's College, Cambridge, after studying medicine at Edinburgh University. At that time, Cambridge did not offer a degree in the natural sciences to which Darwin was to make such a startling contribution.

Darwin went on to publish a theory to account for the extraordinary variety of species found on this planet, almost exactly 100 years before Crick and Watson identified the structure of chromosomal DNA.

These two equally profound advances in biology had very different effects on science and society. The theory of natural selection provoked immediate and passionate debate, and caused outrage in some quarters of society.

Indeed, even today there are some groups who find it impossible to accept that our species is the product of evolution. In fact, the British Government supports schools in which creationism is emphasised. In research, Darwin's theory had limited direct influence except in specific areas, such as palaeontology and classification of species. By contrast, knowledge of the structure of DNA has already led to many developments in research, agriculture and medicine, and has widespread practical uses, whereas it is only now that the social effects are becoming important.

The recognition of the structure of DNA was just one step on a long pathway to understanding the mechanisms of inheritance, and by no means have all of these steps received the public recognition they deserve. Research between these two landmark publications analysed the patterns of inheritance of characteristics, from seed colour to the number of hairs on the leg of a fly. Subsequent work in bacteria established that DNA is indeed the molecular basis of inheritance and focused later work on this molecule. One of the attractions of the double helical structure was that it naturally suggested a means of replication, which was proved to be correct after a great deal of research. The code of three nucleic acids that are the instruction for the inclusion of an amino acid in the protein was revealed mainly by elegant experiments carried out by Crick and Sidney Brenner in Cambridge. Other research identified the role of ribonucleic acid in the production of proteins, in the process summarised by Crick as "DNA makes RNA makes protein".

Practical application of this knowledge also depended on the invention of ever-more sensitive and inventive approaches to the analysis of samples.

Blue-sky investigations into the enzymes of fungi identified those whose ability to cut DNA is restricted to specific sequences of nucleotides.

These "restriction enzymes" are essential for those wishing to cut long strands of DNA at specific sites. One way of revealing those segments is to use electric currents to carry them through plates of gel. The smaller pieces travel farthest. Although invisible in the gel, they can be revealed by blotting samples across onto a thin film and staining the DNA in the process of "Southern blotting", named after the inventor, Ed Southern.

More recently, very powerful methods have been developed for the large-scale copying of DNA samples. This process depends on enzymes isolated from bacteria that thrive in very high temperatures. These enzymes use one strand of DNA as the template for production of a second, before the temperature is increased to separate the strands and allow further amplification. Only proteins from these specific bacteria will tolerate the repeated heating to high temperatures. Amplification is critical not only to a great deal of biological research, but also to the most sensitive methods of analysis that are capable of detecting specific DNA sequences from just one hair.

In view of the wide range of techniques now available and the number of uses to which they are put, it is clear that eight essays can provide only glimpses into their chosen subjects. Inevitably there are aspects that are not discussed. In this context, it is surprising that there is no essay on methods of sequencing or on the value of the genomic sequences. Current projects to describe the entire genome of different species depend on being able to determine the sequence of nucleotides in a fragment of DNA. Fred Sanger, working in Cambridge, devised the method that is still in use today and for which he was awarded his second Nobel prize in 1980. Within a mere 15 years, an international collaboration obtained the first complete sequence of the nucleotides in a human genome. It will soon be followed by the sequence of other species. This knowledge will create new opportunities to define the role of specific genes in healthy and sick animals.

The nature of the essays varies considerably. They include historical memoirs by those directly involved. The Nobel laureate Aaron Klug describes the events that led to the discovery of the structure of DNA. He worked with Rosalind Franklin and had access to her laboratory notebooks. It is hard to disagree with his judgement that Crick and Watson should have acknowledged their use of the data they obtained from Franklin's work more clearly than they did in the 1953 paper.

Alec Jeffreys records the steps in the development of different methods for DNA fingerprinting at Leicester University and also the first use of the techniques in court. It is well known that these methods are used for the identification of criminals, but it is interesting to learn that they were first used in 1985 to confirm the genetic relationship between would-be immigrants to Britain. Previously, the official decision had depended on a subjective judgement by an immigration officer based on documents and appearance.

Svante Paabo describes how genetic techniques have provided insights into the evolution of animal species, including humanoids, and into the first breeding of agricultural crop plants. Neanderthals appeared 100,000 years ago and persisted for 70,000 years, during which period our own species emerged. The extent of the interaction between the species is unclear.

Studies of variation in mitochondrial DNA suggest that Neanderthal and our species did not interbreed. Comparable analyses of chromosomal DNA of maize and its ancestors in Mexico suggest that some critical traits were fixed by selection several thousand years ago, early in the process of domestication.

The startling improvements in yield achieved by more recent plant breeding relied on a variety of techniques to cause genetic change and to cross species that would not normally reproduce. The armoury of techniques has now been enhanced by an understanding of the role of some genes and the ability to introduce precise changes to genes. Malcolm Grant of University College London is a robust advocate of the potential benefits of modern techniques of genetic modification in plant breeding. He also describes the various organisations that have been involved in the regulation of genetic modification in agriculture and demonstrates the importance of there being an effective public debate rather then the present polarised screaming match.

Other essays deal with the use of modern molecular biology in aspects of medicine ranging from techniques of assisted reproduction (Robert Winston) to causes of cancer (Ron Laskey). Cancers arise as a result of damage to DNA, but, paradoxically, many of our present therapies rely on causing more damage to DNA to induce destruction of the cells. Less familiar is a discussion by Dorothy Bishop of Oxford University of the genes associated with the acquisition of language. Her recent research has begun to identify regions of chromosomes that are associated with the variation in the ability of children to learn new sounds. Difficulty in learning new sounds was associated with an impaired ability to acquire language.

Molecular genetics will contribute so many benefits to society that it is impossible to list them all. But they will certainly include new understanding and, in some cases, treatments for unpleasant diseases.

However, these developments bring with them significant risks to individuals and society. Each country will have to determine the appropriate use of new techniques. In the attempt to curb crime, there would be great benefit in having an international database of human DNA.

Individual countries will have to decide on the appropriate balance between the potential benefit of such a database and the diminution of the freedom of the individual its very existence would entail. It is appropriate that, in the final essay, Onora O'Neill provides a very clear analysis of the ethical issues for many of the uses of molecular genetics. In dealing with the large number of complex situations, there is a great need for wider understanding of both the biology and ethical issues. These essays provide authoritative descriptions of their diverse subjects.

Ian Wilmut is head of the department of gene expression and development, Roslin Institute.

DNA: Changing Science and Society

Editor - Torsten Krude
Publisher - Cambridge University Press
Pages - 193
Price - £25.00
ISBN - 0 521 82378 1

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