And also why Israel lags behind in genetic engineering
By Zvi Naor
Dougie swam in the murky water looking for a surface to sit on. Just don't swim, he thought, I hate swimming, and hurried to the protruding surface, finding his way to it with the help of the paintings on the four walls of the laboratory.
Dougie is not an ordinary mouse: he is a super-mouse, and he was no longer the star of the cover story of the weekly magazine "."Thanks to his new skills, he finds the surface in the Morris water maze (a memory test for rats and mice) faster than his peers. He also passed other memory and learning tests with great success.
Using transgenic methods - inserting a synthetic gene into a fertilized egg - Joe Tsian and his colleagues from Princeton University (with researchers from MIT in Massachusetts and Washington University in St. Louis) created a new strain of mice. They are called Doogie and their brains have an overexpression of the NR2B gene associated with learning and memory. This gene is one part of a receptor in the brain called NMDA, which is able to bind the neurotransmitter glutamate to it. Miraculously, nature takes the amino acid glutamate (amino acids are the building blocks of which proteins are built) and assigns it a completely different role - to serve as a neurotransmitter in the brain. The researchers believe that the molecular mechanism responsible for creating the memory is mediated by the glutamate system.
When Dougie was tested in the water maze named after Morris, into which he was put time and time again, he probably used the various paintings on the walls of the room to learn and remember the way to the surface. Every time he and his friends, or peers who didn't get the extra gene, are put into the maze, they can improve their time of arrival at the surface based on their past experience; Therefore, the Morris test is an excellent measure of memory and learning.
Eric Kendall, winner of the Wolf Prize, who studied the memory mechanisms of the Aplysia cochlea for many years, contributed greatly to the understanding of the molecular basis of memory. Since all the neurons in the body of the cochlea are recognized, Kendall and his colleagues were able to discover memory mechanisms and copy them to much more complicated animals such as the mouse and the rat. The interesting thing about the results of Kendall and his colleagues' research is that it turns out that the memory mechanism is like the action mechanism of many hormones in the body; For example, the ovulation hormone (LH) in the ovary. These mechanisms, of intracellular communication, are common to all living things and the same signal can cause ovulation in the ovary and memory in the brain. But the first is activated by the ovulation hormone LH and the second by the neurotransmitter glutamate.
The intracellular communication system affects the electrical activity of neurons in the area of the brain called the hippocampus and the electrical recording of the cells creates the short-term memory. The same intracellular communication system responsible for the electrical activity of the brain cells - the neurons - continues on its way and activates a series of genes in a way that affects the structure of the neurons and creates new connections between them. Creating new connections between neurons is the foundation for long-term memory and involves the synthesis of proteins. Since the dog was injected with an excess of the NMDA system (compared to what is expressed in the brain of a normal mouse), its ability to activate both short-term memory (more extensive electrical activity) and long-term memory (change in the structure of neurons) was improved.
This impressive study by Tessien reinforced the principle that learning and memory are based on adjustments in the strength of synapses between active neurons. The cells of the human brain (numbering about a thousand billion) are not connected to each other and therefore an electric current cannot pass between them; It stops at the intercellular space known as a synapse. Those who still manage to cross the synapse are the neurotransmitters (neurotransmitters including glutamate): they cross the gap and bind to receptors in another nerve cell. For example, glutamate will bind to NMDA, which only recognizes it, like a key fit to a lock.
Tessian and his colleagues write in their article, published in the journal "Nature" (on September 2 of this year), that the results of their research imply that "it is possible to influence the intelligence and memory in mammals using genetic methods." They also added that their research "lays the foundation for a new technological strategy that will make it possible to produce other animals from the mammal family with improved intelligence and memory." These far-reaching determinations led to the fact that the cover photo of "Time" (on September 13) showed a beautiful, chubby baby playing with coils of DNA (the genetic material in cells, from which genes are made), and the title was: "The IQ Gene."
Did Tessian discover the gene for IQ? The answer is of course negative, but at first it became clear that it is possible to improve memory and learning in mammals with genetic methods. In contrast to the genetic duplication of Dolly the sheep, here the life sciences scientists create a transgenic animal into which a foreign gene has been inserted, or a gene similar to its own gene only in greater quantity. The gene is produced in the laboratory and inserted into a fertilized egg that absorbs it in its genome. Following the introduction of the fertilized egg into a simulated pregnant female (surrogate), offspring are born, some of which carry the synthetic gene and these are called transgenic animals.
This type of research can only be done in laboratory animals: immediately at the end of the experiment, one can examine the brain and determine what changes have occurred in the intensity of gene expression and electrical activity. The accumulated experience in the life sciences and medical research clearly show that it is possible to draw correct conclusions from experiments on laboratory animals about what is happening in the human brain. Otherwise we wouldn't have birth control pills, aspirin and Prozac today. This is why Tessian and his colleagues wrote that their research goes so far as to draw conclusions relevant to humans.
The mention of the letter IQ) I) in the article attracted a lot of criticism - as happened following the book by journalists Charles Murray and Richard Hernstein, "The Bell Curve", in which it was claimed that there is a connection between race and IQ. Today, most researchers believe that there is a connection between IQ and heredity and that success in IQ tests, as in other tests, is related to the ability to realize the potential inherent in genes.
Many are very troubled by the problem of forgetfulness in old age and Alzheimer's disease, which severely impairs memory. Understanding the basic processes of memory is considered a breakthrough, as it leads to the development of new drugs and holds the possibility of gene therapy in the future. Using genetic engineering methods, it will be possible to produce, for example, a fertilized human egg into which the NR2B gene has been inserted to improve memory, let the egg develop in an incubator for a few days until primary brain cells appear - and insert them into the brains of Alzheimer's patients. However, the ways of using this revolution in the life sciences will involve difficult ethical decisions.
Meanwhile, intuitively known facts are reinforced by Tessian's research. We age from the moment we are born and memory capacity decreases with sexual maturity. The appearance of the sex hormones - the steroids, progesterone and estrogen in the female and testosterone in the male - mature us sexually but mark the beginning of the senescence of the memory; A high price for the pleasures of life. They also harm us a second time in our adulthood: testosterone will cause prostate cancer and estrogen breast cancer. And finally, as a kind of gesture, the sex hormones return and support what remains of the memory and even preserve it: now they are even considering using them, and especially estrogen, to treat Alzheimer's. We should therefore not be surprised at the flourishing of methods for teaching languages (one of the most difficult tasks for human memory) that call for teaching them from the age of two and not to wait until the age of nine: according to this study in rats and other studies in humans, the newborn's memory is already in decline (the rat lives up to about three years And her memory begins to deteriorate from the age of 40-30 days).
Is it true that a day is near when it will be possible to instill genes of wisdom, beauty or courage and thus play God's game? Well, the technology is at the gate, but the ethical problems that arise simultaneously with the rapid progress of the human genome project are difficult and require deep thought and the ability to decide on priorities.
Why wasn't Dougie born in Israel?
Dogi is not Israeli, because there is no great science in Israel. Government spending on research per capita is 74 dollars in Denmark, 59 in Japan, 58 in the United States and only 0.4 dollars in Israel. It will therefore not be surprising that Israel dropped to 14th place in the world research ranking in relation to the number of inhabitants in the field of biology and to 16th place in medical research.
When a country sees the revolution in the life sciences that is at the gate and invests its resources in biotechnology, biotech companies such as Amgen, Genentech and others (in the United States) arise, whose products sell for a billion dollars a year per product. The total investment in research and development in Israel is about 70 million dollars per year. Israel has about ten thousand scientists (the largest proportion in the world in relation to the number of inhabitants), so it turns out that it invests about 7,000 dollars per scientist. Just hiring the services of a skilled lab worker costs between 30 and 60 dollars a year, and the cost of a project like Dougi is one million to two million dollars.
The State of Israel must decide that the life sciences (biochemistry, biotechnology and medical sciences) are a national goal, as Japan has done. The revolution in the life sciences is the next opportunity train (that of communication and computers has long since left). It doesn't have free meals and it doesn't have standing places. Its seats are marked and the tickets are sold out. It is appropriate that the decision-makers come up to it at a later date and even call on the neighboring countries to join; Disputes over land, blood, religion and water will be easier to settle in the first class of this train.
The author is a professor of biochemistry at Tel Aviv University
{Appeared in Haaretz newspaper, 24/12/1999{
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