Presentation Speech by Professor Christer Betsholtz, Member of the Nobel Assembly at Karolinska Institutet, 10 December 2007.
|Professor Christer Betsholtz delivering the Presentation Speech for the 2007 Nobel Prize in Physiology or Medicine at the Stockholm Concert Hall.
Copyright © The Nobel Foundation 2007
Photo: Hans Mehlin
Your Majesties, Your Royal Highnesses, Ladies and Gentlemen,
This year’s Nobel Prize in Physiology or Medicine rewards discoveries that have given us new and powerful methods for studying and understanding the role of our genes. These genes carry their information as DNA code, a kind of script which in humans had been fully read for the first time in 2001. But reading genetic script is one thing − understanding its significance is another.
To study the role of a gene, we need to be able to change it in a specific way and then observe what happens or doesn’t happen. This approach is empirical and resembles that of a child as it learns the meaning of words. Small children perform their word experiments by inserting or leaving out words in different contexts and, based on the reactions of people around it, guessing the meaning of the words. As an example: When a child tries out an exciting new word it has heard, and the reaction of its parents is “Shame on you, don’t ever say that!” the child naturally draws the conclusion that this word is very important and also presumably usable.
Doing equivalent experiments with genetic language is of course somewhat more complicated, though similar in principle. We have more than 22,000 genes, distributed among 3 billion DNA “letters”. Making a specific, or targeted, genetic modification can thus be compared to correcting an error in a text document 30 times larger than the Swedish National Encyclopaedia. Nowadays, given computers and word processing software, this is of course no major problem. We merely specify what text we want to remove and what we want to insert in its place, then we let the computer find the right place in the document and make the substitution.
This is a good analogy to what Mario Capecchi and Oliver Smithies discovered in their path-breaking experiments during the first half of the 1980s. Independently of each other, they found that DNA molecules which resemble parts of normal genes, yet differ from them in crucial respects, can be inserted in the right place in the genome.
Their discoveries made it possible to carry out targeted gene modifications in individual cells in a culture, but an important problem remained to be solved. Every cell in our bodies carries our entire genome, so if we want to understand the function of a given gene in its full context − in real life − the same genetic change must be introduced into all the cells of the body. If a targeted gene modification in one cell is comparable to finding a needle in a haystack, then the challenge here is to find a needle in hundreds of billions of haystacks.
Martin Evans solved this problem through his discovery of embryonic stem cells − cells from early embryos that can be cultured, grown and genetically modified in a test tube. Like a fertilised egg cell, these embryonic stem cells can give rise to all the cells of the body, thereby passing their genes, including modified ones, onward to future generations.
But making hereditary, targeted changes in genes is something we are neither able, willing nor allowed to do in humans. Instead we do this in mice, with which we share most of our genes. Here it is important that we apply accepted standards and ethical principles for animal experiments, and that in doing so we weigh the expected benefit to humanity against the number of animals used and any suffering that may be caused. The usefulness of mice with targeted gene modifications can hardly be exaggerated. “Knockout mice”, in which the functions of individual genes have been knocked out, have already shed light on the role of several thousands of our genes and provided us with important new knowledge that, among other things, is being used today in the development of new drugs for treating virtually all important human diseases. The 2007 Nobel Prize in Physiology or Medicine is indeed a real knockout.
Professors Capecchi, Evans and Smithies,
In the early 80s your ideas about how mice with precisely tailored genetic changes could be obtained were met with scepticism. In the beginning of the 90s, reported successful examples of gene-targeted mice were still considered anecdotal. Today, information about the physiological functions of all mammalian genes is within reach. Few discoveries have had greater impact on contemporary biomedical sciences than yours. On behalf of the Nobel Assembly at Karolinska Institutet it is my privilege and pleasure to express our warmest congratulations and our deepest admiration as I now ask you to step forward to receive the Nobel Prize from the hands of His Majesty the King.