As a geneticist, Im going to change the theme here quite considerably.
I think many of you over the last decade have been quite aware that the word gene, genetics even the word genome is coming into quite common usage.
You can hardly pick up a newspaper or a weekly magazine now without hearing about genes, either human genes or plant genes or animal genes; without hearing about the discovery of new genes, or without hearing about manipulation of genes to improve crops or other things.
Many people, however, who are reading about these advances dont really have a fundamental understanding of what a gene is, other than that theyre important and that they determine many characteristics, not only of humans, but of all species.
Genes, of course, are relatively simple things and genes, themselves, dont have any specialized functions, other than to provide the genetic code to make proteins.
Its really the proteins in the cells that do the work of the cell.
Proteins have a very broad variety of functions. If I can give you two or three very simple examples.
Theres a number of genes that provide the code for proteins called keratins. And they make up the major protein in your hair and in your fingernails and things like that. Theyre structural proteins.
Sir John mentioned hemoglobin, which is made up of protein chains of globin molecules and they are also are encoded by genes. The function of hemoglobin, of course, is to act as the carrier of oxygen throughout your body and its the major protein in red blood cells.
Enzymes are another class of protein that are involved in catalyzing reactions in your body and helping you to digest food and create new macromolecules that are part of your cell system.
The importance of genes is the fact that they make proteins and that these proteins are all essential for life in one way or another and to varying degrees.
Another important aspect of genes that I want to emphasize, before I start talking about human genetics, is their remarkable conservation.
We all know that DNA is the genetic material. The conservation of that DNA, from very simple organism, like bacteria, up to slightly more complicated single cell organisms, like yeast, through simple worms and fruit flies and other organisms that have become popular in the study of genetics, is remarkable.
In fact, a lot of the genes that we are now identifying and are trying to understand; [genes] that are involved in early human development and, therefore, critical to our understanding of how humans develop, are genes that are very closely related to genes first discovered in fruit flies and studied in fruit flies.
So, that kind of remarkable conservation is really quite important in our understanding and it raises another issue that has been mentioned by our two previous speakers and that is the importance of fundamental science, or basic science.
I think its fair to say that all of the major advances weve made in the field of genetics in the last couple of decades is a direct outcome of earlier advances that were made in fundamental biology and the understanding of basic science which, at the time it was done, had no connection, had no practical application.
And, therefore, one of the questions that came up last night was: why spend money on certain aspects of very basic science, when that money could perhaps be better spent on more practical kinds of research with more direct impact on human health and human welfare?
I think the answer to that is that the study of basic science is absolutely fundamental to everything that we do and without that basic science we simply wouldnt be able to make the advances we do make.
The importance of the basic science is that it leads to fundamental discoveries and you cannot predict in advance how those fundamental discoveries are going to play out in terms of more practical, more applied science.
The other point I want to make is that the rapid progress in the course of science over the last two or three decades has been absolutely stunning in the speed with which fundamental discoveries in genetics have been made.
Starting perhaps in the late 1940s with the discovery that, in fact, DNA was the genetic material. People before that knew that chromosomes carried the genetic material and were made of two basic kinds of materials, DNA and protein.
The discovery that DNA, in fact, was the genetic material was a little bit of a surprise in the late 40s. Then the understanding of the structure of that DNA, the Watson and Crick model that Sir John referred to earlier, was the next major step.
And then the understanding of how genes work was conducted through the 1960s and early 70s with the development of an understanding of the genetic code. We now know exactly what the code letters are. We know that DNA is made up of four chemicals that are usually referred to as A, C, T and G and that the sequence of those provides the genetic code.
But a lot of that was worked out in very simply organisms, in viruses, in bacteria and later applied to humans.
Again I come back to the fact that this remarkable conservation is what allowed us to do that. The lessons learned in very simple viruses actually pertain, with some exceptions, to more complicated, multi-cellular organisms, like plants, animals and humans.
Having developed some of that basic technology and understanding with simple organisms, it was still very difficult until the mid-70s to study humans or to study mice in a meaningful way at the molecular level, at the level of the gene, because our genomes are so complex.
You heard that we have approximately 100,000 genes in our genome and that these genes are very complicated. To isolate them and study them was virtually impossible until the mid-70s with the discovery of something called recombinant DNA technology, [which allowed you to] recombine DNA from one organism with DNA from another organism.
As soon as it was possible to do that people were able to take DNA from humans, break it up into tiny pieces each piece carrying perhaps one or a small number of genes recombine that DNA with, lets say bacterial DNA, to make a recombinant DNA molecule, put it back in the bacteria and let the bacteria divide into a small colony of millions of bacteria [so that] each one, of course, carries that little piece of human DNA.
Then you have millions of copies of that piece of human DNA and you can begin to study it; you can begin to determine sequences of the As, Cs, Ts and Gs.
You can begin to ask whether it contains a gene along that stretch of DNA, what that gene is, what does it encode, what protein does it make and so on.
So, by reducing the human genome into tiny bits and pieces and studying them in bacteria, it became possible to study one gene at a time.
Having done that and knowing where these genes are in the genetic map, its possible then to reconstruct and build back, at least in our minds, to build back what the whole human genome looks like.
All this technology and development, which was the product of the 50s, 60s and 70s, [led in the 1980s] to the beginning of gene cloning; cloning simply meaning making multiple copies. And Ive just referred to cloning pieces of DNA.
People began to clone genes. First simple genes, like the ones that make hemoglobin or growth hormone. Then cloning the genes for enzymes and beginning to understand how those enzymes work, and then disease genes.
In the mid-to-late 80s, we saw the earliest studies of cloning disease genes by knowing their position in the chromosome, without knowing even what protein they made.
It became possible to clone a disease gene. Two of the first three disease genes to be cloned were Duchenne muscular dystrophy and cystic fibrosis, one in 1987, the other one in 1989.
Just because were here in Canada and many of you are Canadians you should be aware that while both of the stories were international ones they had major Canadian components. The muscular dystrophy gene was discovered approximately simultaneously at the Boston Childrens Hospital and by my own lab at the Hospital for Sick Children in Toronto.
The cystic fibrosis gene was also discovered at the Hospital for Sick Children in collaboration with scientists in the United States, Great Britain and elsewhere.
Where were headed now is a direct outcome of that kind of science.
In the mid 80s and early 90s there was a lot of effort in cloning literally hundreds of disease genes that are responsible for single gene diseases. Cystic fibrosis and muscular dystrophy are just two of those.
What we now understand and are beginning to realize is that its not just the single gene diseases, but virtually all of the major common diseases, while not strictly inherited, are influenced by our genetic component, as well as by components in the environment.
And what the future holds is that we will be able to identify the genes that are involved in your susceptibility to diseases, such as cancer. We already know many, many of the genes that are directly involved in cancer. There are still many more to be discovered.
Heart disease; we know that genes are involved in cholesterol metabolism that directly influence whether or not you develop heart disease. We know now three or four genes that are directly involved in some cases of Alzheimers disease and were beginning to learn about others.
And the neuropsychiatric disorders that you heard Sir John mention, schizophrenia, bipolar disease and so on. All of them are greatly influenced by our genes. Your susceptibility to each of those diseases is related to your genetic makeup, although its also related to other factors, including the environment in which you live.
So, all of this means that the knowledge base is going to grow tremendously.
There is the human genome project you heard mentioned in which the goal is to identify all the 100,000 genes. But its more than that. Its not only to identify the genes, its to sequence the genes to determine the proteins that are made by those genes.
And the sequence of the human genome will be essentially completed in about two years. Some of the sequence of other simpler genomes [like] the work that I mentioned earlier, the fruit fly, are complete now; the fruit fly almost complete and the small worm, called nematode, a favourite organism for study, has been completely determined within the last two years.
The next major phase is whats now called functional genomics. And it will be a much longer phase. Sequencing the human genome, as difficult as it was and as expensive as it was, is relatively simple compared to the next step, which is trying to identify what do each of these 100,000 genes do. Right now, we only know the function of perhaps a few hundred of them.
What does the future hold?
I think the most important thing is what Ive just said: new knowledge; understanding what the genes do, how they contribute to various kinds of disease states and how that knowledge will contribute to developing new therapies.
In some cases it may perhaps be gene therapy; replacing a defective gene with a good gene in the specific tissue in which that gene is required. In other cases, it may be using the knowledge about the protein thats made that gene in order to define drugs that will target the proteins and interact with them and prevent the disease state.
So, we do predict that the future of drug design and the future of treating disease is going to be very heavily related to the understanding of the genes that contribute to these diseases.
DNA testing is already with us. We can already do testing for simple diseases, single gene diseases like the ones Ive mentioned [such as] cystic fibrosis. We can do carrier identification; identify the people who carry those genes and [who], therefore, are at risk for passing them on to their children.
We can even extend that to the population level and do population screening to determine who in the population carries those genes. And the only question is, will we want to do that? Is it cost-effective to do it? Does it create more problems than it solves?
But the economic one is very clear, the cost of doing genetic testing is coming down very dramatically. The ability to detect defective genes cost a few hundred dollars per test in the recent past. In the near future thats going to drop to $10 or $1 per test as were able to put hundreds of genes or thousands genes on to a little chip.
And youll see the genetic technology going the way of the computer technology and, perhaps, Moores Law will apply there [leading to] the doubling of the capacity for gene testing every 18 months. I would predict that it might even be faster than that.
So, genetic testing will be with us.
Thats going to raise some interesting social and ethical problems, as it becomes more and more feasible to test for genes that influence our health.
It may be fairly straightforward to detect a cystic fibrosis gene, because you can say if you have that defective gene then youre going to get the disease.
But, in the case of heart disease and cancer, emphysema, Alzheimers and schizophrenia, its going to be much more difficult to interpret, because there will be multiple genes that influence these diseases and detecting alterations in only some of those genes will allow you to make less precise predictions.
We will see an industry grow up just in the area of genetic testing, in genetic prediction, in interpretation of genetic studies and in genetic counseling to convey the results of those kinds of genetic tests.
This is going to a major challenge for governments around the world to regulate this industry, to determine what genetic testing is going to be done, who is going to pay for it and to determine to what extent those genetic tests will be delivered at the level of the entire population, which ones will only be confined to families where we already know that the genetic disease is relevant.
Ill stop there.
The only other topic I was going to introduce is gene therapy. I think in the short term future we will begin to see gene therapy applied. We will begin to see defective genes replaced in some small number of diseases. I think we still have a long way to go in developing that technology.
Ultimately, of course, we will see the germ line altered. It will be possible to alter the genes in the human germ line. In fact, even right now were close to being able to do that. The only problem is were not able to do it reliably and efficiently and with great confidence and, therefore, that kind study is confined to animals.
But theres no doubt we can now alter the genome of animals pretty much at will. We can create mice that have genetic diseases the same as human diseases. And that same technology could easily be applied to humans in the future.
Then the question will be, do we want to do that? Under what conditions will we want to do that? What sort of regulations will have to be put into place?
But, theres no doubt that we will see a future that is heavily dependent on the results of genetics. Well see very great changes in the way we are able to predict our disease states, predict our own health and well see great changes in our ability to treat diseases, based on the knowledge that come out of genetics.
And all of that is [a] subject for a lot of discussion, because it does carry certain ethical, legal and social implications.