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1979: Biochemistry
Genetics. Research on DNA (deoxyribonucleic acid) has virtually exploded during the past two years. Perhaps the most important development has been the synthesis of many new products in "bacterial factories," but there have also been surprising findings about the structure of the gene.
Recombinant DNA. Following up on their previous successes in causing cultures of the bacterium Escherichia coli to produce the hormones somatostatin and insulin, scientists have "tricked" the bacteria into producing first a rat growth hormone and then the corresponding human growth hormone (HGH). Insertion of the gene for the rat hormone into E. coli and production of the rat hormone were reported this January by a team at the University of California at San Francisco, headed by Howard M. Goodman and John D. Baxter. In July, the UCSF team and a second group headed by David Goeddel and Peter Seeburg, of Genentech Inc. in San Francisco, independently reported the production of HGH in the same strain of bacteria. Furthermore, researchers at the University of California also inserted biochemical components of the HGH gene into E. coli, which was then induced to produce a so-called fusion protein, 70 percent of which consisted of amino acids coded by the HGH gene.
These experiments should prove useful in the commercial production of significant amounts of HGH for medical purposes. HGH isolated from the pituitary gland of cadavers is used at present to treat pituitary dwarfism in about 2,000 children in the United States, but some investigators argue that as many as 5,000 more could be helped if more of the hormone were available. Some preliminary work also suggests that HGH could be useful in healing wounds and in controlling gastrointestinal bleeding, but there has not been enough available to follow up these leads.
Hormones are not the only substances that can be prepared by recombinant DNA techniques. In November 1978, a group of investigators headed by Stanley N. Cohen and Robert T. Schimke of the Stanford University Medical Center induced E. coli to produce a mouse enzyme, known as dihydrofolate reductase, that is involved in DNA metabolism. This event marked the first time that a biologically active protein was produced in bacteria by transferred mammalian genes.
In November of the same year, Paul Berg and his colleagues at Stanford University transferred a rabbit gene into cultured monkey kidney cells—the first time that recombinant DNA techniques had been used to transfer a gene from one mammalian species to another. The gene coded for one of the polypeptide chains of rabbit hemoglobin, and the monkey cells subsequently produced that subunit.
In January 1979, Thomas H. Fraser and his colleagues at the Upjohn Company, Kalamazoo, Mich., reported that they had successfully produced chicken-egg ovalbumin in E. coli. The achievement had no immediate commercial application, but it was the first demonstration that large proteins could be successfully produced in bacteria. Ovalbumin has a molecular weight of about 43,000, compared with only 6,000 for insulin.
Production of an even larger protein, with a molecular weight of 249,000, was reported in May by Arthur J. Hale and a team at the G. D. Searle and Company laboratory in High Wycombe, England. The protein is a hemagglutinin, one of the large proteins that determine the antigenic specificity of the influenza virus. The company hopes that hemagglutinins produced in bacterial culture can be used in the preparation of a new influenza vaccine. To judge from these first attempts, recombinant DNA techniques may be simpler and more versatile than anyone had previously expected.
The last few years have also seen a decline in concern that recombinant DNA research might result in possibly dangerous genic material escaping from the laboratory. In 1976 fairly strict federal guidelines had been imposed on federally funded recombinant DNA experiments. This September, however, in accord with the latest scientific thinking, a National Institutes of Health advisory committee recommended that the guidelines be relaxed substantially.
Introns. Perhaps the most surprising development in molecular biology in recent years is the discovery that the genes of higher organisms are segmented. Several teams of investigators have discovered that the DNA sequence of each gene is interrupted one or more times by "introns," or intervening sequences that seem to have no meaning in the genetic code. The gene for an egg protein known as conalbumin, for example, contains 17 introns, and some evidence indicates that less than 10 percent of the gene for the enzyme dihydrofolate reductase actually codes for the amino acids in the enzyme.
Much evidence indicates that an entire gene, including the introns, is converted into messenger RNA (ribonucleic acid). It now appears that one or more enzymes then begin at both ends of the messenger RNA to clip out the introns, splicing the remaining segments together to re-form the RNA, which can then be used as a template for the production of a protein. Postulated functions of the introns are still entirely speculative, but it is clear they must have some role, since mutations in the nucleic acid sequences of the introns have been shown to affect the function of the gene product. One possibility is that some of the introns are promoters—regions of DNA where the enzyme RNA polymerase first binds to a gene before transcribing it. Introns may also play a role in control of gene expression.
Reproductive research. Karl Ilmensee and his colleagues at the University of Geneva in Switzerland have succeeded in transferring the nuclei of cells from one strain of mice into egg cells from another strain and then growing healthy mice from the altered egg cells. If the cells had come from adult mice, this feat would have been cloning in the true sense of the word. In this case, though, the nucleus came from a cell of a blastocyst. (The blastocyst is a stage of growth in which a normal fertilized egg has divided into 64 cells.) The experiment at Geneva is the closest anyone has come to cloning mammals. Ilmensee attributes his success to a new procedure, in which a protective coating of the egg, called the zona pellucida, is left intact; in most previous work, the zona pellucida had been removed.
Cancer. Most molecular biologists have argued that cancer viruses induce tumors in animals by taking over genetic machinery in the nucleus of the host cell and that other changes in the cell are secondary to this process. A small group of investigators, however, have argued that the most important changes in the host cell occur in the cellular membranes and that it is these changes that permit unrestrained replication of the cancer cells.
Support for the latter view has now been provided by one of the chief proponents of the former view. David Baltimore and his associates at the Massachusetts Institute of Technology have found that infection of mouse cells by a leukemia virus produces a large new protein residing in the cellular membrane. The new protein is a "kinase," an enzyme that can transfer phosphate groups from adenosine triphosphate to other molecules and to itself. Other tumor viruses have also been shown to trigger production of kinases, but this is the first instance in which the protein has definitely been shown to exist in the membrane. If the viruses do promote excessive growth by effects on membranes, then the biochemistry of cancer cells might be simpler than had previously been expected.
Chlorophyll. Scientists have long thought that there are only two forms of chlorophyll, termed a and b. The two types are combined in a lipoprotein membrane of plant cells, where they cooperatively convert sunlight, water, and carbon dioxide into food. Now, however, Constantin A. Rebeiz and his colleagues at the University of Illinois have isolated three chemically distinct chlorophyll a's and two chlorophyll b's and have further evidence of at least three other a's and two other b's. Their work suggests that each of the variants has a somewhat different capacity for the conversion of sunlight to food. Rebeiz thus argues that it might be possible to breed plants containing the best variants of the chlorophylls and thereby to increase the photosynthetic efficiency of food crops.
Magnetic bacteria. Certain species of bacteria apparently have the ability to synthesize internal compasses that they use for navigation. These so-called magnetotactic bacteria were first discovered near Woods Hole, Mass., in 1975 by Richard P. Blakemore of the University of New Hampshire, who found that they consistently swam northward and downward. He cultured the bacteria in an iron-deficient medium and obtained a nonmagnetic variant of the same species. The naturally occurring magnetic bacteria were then shown to have more than ten times the iron content of the nonmagnetic variant (and of bacteria generally).
Studies by Blakemore and Richard B. Frankel of the Massachusetts Institute of Technology demonstrated that the iron in the magnetic bacteria is present primarily in the form of the inorganic mineral known as magnetite, or lodestone. They also found that the magnetite is present in particles of exactly the right size to make an effective compass and that there are enough of the particles—generally 22 to 25 strung in a line across the longitudinal axis of the bacterium—to overcome the disorienting effects of thermal energy, or Brownian motion.
Similar deposits of magnetite have recently been observed in the heads of pigeons and the abdomens of bees, where they are thought to be used in navigation. Why the bacteria have developed such a system is unknown, but Blakemore speculates that its purpose is to help them reach bottom sediments, since bacteria in water are too small to distinguish up from down readily on the basis of gravity. At Woods Hole the vertical component of the earth's magnetic field is greater than the horizontal, so that a bacterium which swims toward the north magnetic pole is also swimming downward.
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