When we talk about 100,000 genes in the human genome, we are talking about 100,000 different proteins in the body that are encoded by these genes. The big question for the next century is how do these proteins assemble to make the human body work. What are the interactions and interconnections of each of these proteins with each other? How many proteins does it take to
product a heart? How many proteins does it take to produce a liver? And how do they all fit together? This will be the most gigantic jigsaw puzzle that has ever been put together once it is completed-much more complex than creating a map of the city of London, which is a maze of 30,000 streets.
In 1936 there was no map of London. An enterprising individual named Phyllis Pearsall took it upon herself sixty years ago to make the first map of London, the famous A to Z map. She got up every morning at 5 o'clock, walked sixteen to eighteen hours a day for a year-and-a-half, covered over 3,500 miles, and made an alphabetical list of all 30,000 streets in London. This was before the era of computers so Pearsall had to sort all her data in 500 shoe boxes. Her first A to Z listing (before she made the map) did not include Trafalgar Square because the shoe box that began with TR was lost!
Assembling the list of the 30,000 streets of London without an accompanying map that showed all the interconnections and all the interactions-how every street was related to each other street-would be analogous to obtaining the sequence of the 100,000 genes. Having this alphabetical list of 30,000 streets without a street map would be essentially useless to a Texas tourist who comes to London for the first time.
The next one hundred years of biology will be analogous to assembling the first functional street map of London from the alphabetical listing of the 30,000 streets, i.e., taking the gene sequences and the proteins that they encode and figuring out how these proteins interact with each other to form different parts of the body and how these 100,000 proteins relate to each other to orchestrate human life.
So the challenge for biologists of the future will be to learn the structure and the function of these 100,000 proteins. We now know the function and structure of about 4,000 proteins. So we have a long way to go.
When the sequence of the DNA in our genome is completed, we'll have three billion code words, which is equivalent to the information contained in forty Manhattan phone directories. The job of the scientist is to look at all of this information and figure out which regions of this DNA are translated into the proteins that are the workhorses of the body. The challenge to decode and decipher the human genome is truly enormous and approaches the surreal. One has to live in a world of dreams and fantasy to comprehend the enormity of this challenge.
And this brings me to a famous Belgian artist, RenÈ Magritte, our greatest surrealist painter. His paintings, which were done about 60 years ago, capture the style and spirit of the genome revolution. In his painting called Clairvoyance, the artist-this is a self-portrait of Magritte-is looking at an egg and painting a bird. By analogy, the scientist must do exactly what the artist does. He must look at some ill-defined phenomenon of nature (studying the DNA sequence of a gene) and create a thing of beauty (discovering how the protein encoded by the gene works).
Let's assume that scientists have clairvoyance and can look at all 100,000 of these DNA sequences and discover the function of their encoded proteins. This will allow us to answer four central questions of biology.
The first question is how do humans develop from a single egg? This question leads us to ask a sub-question: How is the heart formed from the genes and the proteins that are encoded in our genome? And once you know the answer to this question, then you can begin to say: How can we grow a new heart and transplant it into individuals? And how is the liver formed? Can we grow a new liver and transplant it?
We're beginning to understand how humans develop from a single egg by studying simple organisms like baker's yeast, round worms, and fruit flies. The genomes of these organisms, which are much smaller than that of humans, are being sequenced at the same time that the human genome is being sequenced. Baker's yeast is the first organism whose genome has been completely sequenced. A yeast cell has 6,000 genes compared to 100,000 in the human, and nearly one-half of these yeast genes have an evolutionary counterpart in the human genome.
What we're learning is that the metabolic pathways inside the cell are basically the same in all organisms, whether you're a yeast, a round worm, a fruit fly, an elephant, or a human. What makes a human different from a fruit fly appears to be the regulatory signals at the beginning of a gene that instruct the gene when to turn on and how much of the protein to make. An exciting area in the future is to understand these regulatory signals that instruct the same gene in elephants to express itself differently from its counterpart in humans and fruit flies.
The second question is how do humans differ from one another. Michael Brown has already talked about this topic. Learning about individual genetic differences will lead us to early diagnosis of disease and ultimately to the development of medicines that are tailored to the individual-medicines without side effects, the wonder drugs of the future. The side effects of many drugs that we take today are caused by different responses of individuals to the same drug because different individuals have different genetic makeups that influence the metabolism of the same drug once it gets into the body.
Today we all take the same penicillin. When we get a prescription for penicillin, every one of us will receive the exact same chemical form of penicillin. It will have the same atomic structure. Patients with AIDS all get the same AZT. These are medicines of identity. In the future we will have medicines of variation. Once we understand the genetic differences in the way the body metabolizes the same drug in different individuals, we will then be able to take advantage of that information and design these medicines of variation.
Now to the third question: How do our brains work? The human brain is a small organ with an astonishing complexity, the most complicated machine that exists in nature. No Boeing or General Motors has ever produced a machine that can match the human brain. It contains 100 billion neurons or nerve cells-1011. Each neuron is capable of making 1,000 synapses or connections with a different neuron. And that adds up to be 100 trillion synaptic connections in the brain-1014. That's 100,000 times more synapses in each human brain than code words for DNA in our genome. Counting synapses at a rate of 1,000 per second would take an individual 30,000 years to count them all!
Understanding synapses is the key to understanding how the brain works. Understanding memory, intelligence, emotion will all come ultimately from knowing the function of all the proteins encoded by our genome and comprehending how these proteins influence all the 1014 synaptic connections in the brain. Nongenetic environmental factors also play a crucial role in influencing the activity of our synaptic connections. This is unquestionably the most challenging problem in biology today. The challenge will be to discover the general principles of the brain that simplify this enormous complexity.
That brings me to a famous quotation by Albert Einstein. In 1920, when confronted with the complexities of quantum mechanics, he said, "Everything should be made as simple as possible, but not simpler."
It seems appropriate to follow this subdued quote from seventy-five years ago with a contemporary quote of a bolder nature, made by Walter Gilbert in 1990. Gilbert received the Nobel Prize in Chemistry in 1980 for teaching us how to sequence DNA. In fact, the whole revolution that we're celebrating today would not be possible if it were not for his major contribution. According to Gilbert: "In the year 2020 you will be able to go into the drug store, have your DNA sequence read in an hour or so, and given back to you on a compact disk so you can analyze it." You would then take the compact disk to your physician, and you and he or she together would analyze it and figure out which one-third of the people in this room will be susceptible to heart attacks because they have a cholesterol problem and therefore should eat a low-cholesterol diet and take drugs that lower their cholesterol, and which two-thirds would be immune to the cholesterol problem and therefore would not have to worry so much about cholesterol in the diet. You would also be able to learn whether you would be susceptible to high blood pressure, diabetes mellitus, schizophrenia, etc.
Is this a realistic possibility?
And that brings me to another famous painting by Magritte, entitled The Human Condition, in the National Gallery of Art in Washington, DC. It's a painting within a painting that exemplifies the essence of surrealism. The distinction between illusion and reality is brilliantly called into question in this painting. The tree in the painting hides the real tree behind it outside the room.
This is the way genomic researchers see the world, as a painted dream. Is the tree really outside the room? Will we really have drugs without side effects? Will each of our genomes really be put on a compact disk? Will we really be able to replace organs with cells produced in the test tube?
Let me now come to the fourth and last question. How do we convert genes into drugs? Of the four central questions of biology, this is the one that is furthest along in development, owing to the successes of the biotechnology industry. Drugs are produced by biotechnology through a sequence of events in which a human gene is cloned and then introduced into a living organism (either a bacteria or a yeast). The bacteria or yeast are then induced to manufacture large amounts of the protein encoded by the introduced human gene. This protein, called a recombinant drug or vaccine, is purified and administered to patients for therapeutic benefit.
The biotechnology industry began twenty years ago. It now consists of 1,311 companies, twenty percent of which are publicly owned. It employs 120,000 people, about one-third of whom are Ph.D. scientists. The industry has a market capitalization of $83 billion, product sales of $11 billion, research and development expenses of $8 billion, and an overall net loss of $4.5 billion. In other words, the entire biotechnology industry is about the size of Merck & Co.-without the profits!
To date, the biotechnology industry has developed seventeen recombinant drugs or vaccines that have been approved by the FDA, including insulin, growth hormone, hepatitis B vaccine, and erythropoietin. Erythropoietin is the leading drug produced by biotechnology and one of the top ten selling drugs in the world today. It is given to patients with kidney disease who have low hemoglobin levels. Like erythropoietin, most of the FDA-approved recombinant drugs and vaccines are major contributions to therapeutic medicine, and in this sense the biotechnology industry is a success.
True to the surrealist spirit, biotechnologists are always cooking up new recipes, and I'll tell you about some of the things that are in the pipeline-that you read about in the Wall Street Journal and The New York Times. For example, there are companies working on new growth factors to treat nerve regeneration and chronic neurological diseases like Alzheimer's disease and Lou Gehring's disease. There are companies working on drugs that will slow aging, on hormones to treat obesity, and on inhibitors to prevent the metastatic spread of cancer. There are also companies working on cures for baldness and on novel approaches of gene therapy for treating cancer, AIDS, and inherited diseases like cystic fibrosis.
But let me now try to put all this information into perspective. Here is how I view the biotechnology industry today-from the surreal to the real. These are the real facts. On average, one new gene is cloned and characterized each day, one new biotechnology company is formed each week, but only one new recombinant drug or vaccine is approved by the FDA each year. So in the twenty-year history of the biotechnology industry, only seventeen new recombinant drugs have been approved by the FDA.
Typically, you will read in the newspaper that a new gene for this or that disease has been cloned and that a new drug will be available soon. This is media hype! The available facts suggest that the creation of a drug from a gene takes about ten to fifteen years if the function of the protein encoded by the gene is already known. But to create a drug from a gene when the function of the protein is not known may take twenty to thirty years.
If Magritte, the surrealist, were alive today, he might represent the situation in biotechnology as shown in his famous painting, The Betrayal of Images, in which he reminds us that the image of the pipe is not the same as the pipe itself (Ceci n'est pas une pipe). A modern version of this painting would replace the image of the pipe with the DNA sequence of a human gene to remind us that a gene sequence is not a drug (Ceci n'est pas un mÈdicament).
Let me conclude by reminding you that the cloning of genes is only the first step in putting together the gigantic jigsaw puzzle of human life. The real clues to the puzzle will emerge from learning the function of each of the 100,000 proteins that are encoded by our genes and how they interact and interconnect with each other. This is the goal of biomedical research for the next century.