Science IBM research staff members Michael D. Miller and Shirley Chiang, and Philip H. Lippel, a physics professor at the University of Texas, Arlington, and Christof Wôll of the University of Heidelberg, West Germany. Details of the research were reported in a recent issue of Physical Review Letters [20,171 (1989)]. The research produced three surprising results, Wilson says. It turns out that the substrate is very important in producing the images. Copper-phthalocyanine molecules can only be seen adsorbed onto the copper(100) surface. Images obtained from silicon(lll) and gold(lll) surfaces were blurred, which may be due to chemical interactions with the silicon surface or low binding forces to the gold surface. Another surprise is that the molecules do not arrange randomly on the copper surface. Instead, the molecules prefer two mirror-image orientations in which the central copper atom sits between four copper substrate atoms, and the four outer nitrogen atoms of phthalocyanine (those not ligated to the central copper) sit directly atop copper substrate atoms. An axis of the phthalocyanine molecule is thus at a 26.5° rotation angle relative to the grid of the copper substrate atoms, Wilson says. In addition, copper-phthalocyanine molecules adsorbed near step edges in the copper substrate surface prefer a different binding geometry, with the molecules centered on the step rather than on either of the flat surfaces adjacent to the step. Wilson points out that molecules occupying such sites can become more active in catalytic reactions, and further examination of molecules at these sites may help to explain the causes of such selective enhanced catalysis. "This is an example of how STM imaging may be useful in understanding a molecule's chemical behavior/' Wilson says. A number of factors enabled the IBM researchers to produce the high-resolution images, including the use of an ultrahigh vacuum STM system and deposition of the copper-phthalocyanine onto a clean copper surface. Rudy Baum 28
February 6, 1989 C&EN
Africa. Since that time, some 2000 more samples of tissue have been examined with consistent results. The method originally used to make the measurements was restriction analysis of DNA, from which Genetic evidence continues to accu- it was possible to build a genealogimulate that all humans today are cal tree. Since then, a technique related to one woman who lived in called polymerase chain reaction has an African population about 200,000 been developed at Cetus Corp. that years ago. Since first announcement allows a researcher to make multiof that finding two years ago, the ple copies of a specific piece of DNA sample base supporting it has in- from a reference sequence. Since creased significantly and the ana- the mitochondrial genome has been lytical technology behind it has ad- sequenced, it provides a reference. vanced considerably. But, according Now for anthropological sampling, to University of California, Berke- a single hair is sufficient. ley,.biochemistry professor Allan C. One basis for the Wilson group's Wilson, the results have remained work goes back to the late 1950s. At consistent. that time, several prominent proIt was Wilson's g r o u p at UC tein biochemists, who had an interBerkeley that reported in 1987 its est in molecular evolution, made estimate of the age of different hu- two major discoveries. One was the man lineages based on measures of discovery of a new class of mutapresent-day diversity in a set of tions that later became known as genes passed down only from moth- neutral mutations. Neutral mutaers to their children. In a plenary tions don't have an effect on the lecture at this year's AAAS meet- performance of an organism, but ing, Wilson sketched in the accu- they are visible to molecular biolomulation of genetic evidence—and gists, who can study the DNA or continuing speculation—that adds proteins encoded by them. support to the view that Homo sapiens The second major finding was that emerged only in Africa and may neutral mutations accumulate at have replaced more "archaic" spe- much the same rate in all organcies about 100,000 years ago with isms, ranging from bacteria to plants no intermixing. to animals. There is thus a sort of The focus of Wilson's work is mi- timepiece ticking away in the genomes of organisms, and this protochondrial DNA. In the nucleus of cells, humans have perhaps some 100,000 genes concerned with specifying most traits. But the mitochondria contain other genes that have a vital function in energy metabolism. Mitochondrial DNA is circular and tightly packed with 37 genes. There are thousands of copies per cell. The molecule has a further characteristic—it is inherited only from the mother. Hence, it provides a pedigree. Each individual is connected by an unbroken chain of mothers back into the past. Wilson's group has constructed genealogical trees by comparing nucleotide sequences of mitochondrial DNA isolated from d o n a t e d placentas—the terminal twigs, so to speak. The group's first report was based on measurements of mitochondrial gene diversity from the tissues of 147 people in the U.S., Wilson: consistent results New Guinea, Australia, and South
AAAS SAN FRANCISCO
Evidence accrues for specific female ancestor
vides the possibility of being able to put a time scale on evolution. Another basis for the Wilson group's work, and key to it, is population genetics. "The most astonishing claim that we m a d e , " says Wilson, "was that all the maternal lineages in a species necessarily trace back to one, and only one, mother in some remote generation. So the one-mother principle was widely misunderstood, or unappreciated." The concept, Wilson says, is one that's basic to population genetics. Life is a statistical process. At any given time, some mothers will have one or more daughters. Some mothers may just have sons. For the latter, from the standpoint of mitochondrial transmission, their lineage has died. At the same time that extinction is going on as a natural process, proliferation is also occurring, with surviving lineages often increasing greatly. If such a process goes on, with no migration coming in from elsewhere, it's inevitable that all of the lineages except one are destined to go extinct. "This is a purely statistical process," Wilson explains. Combining these concepts leads to the genealogical tree. Among the descendants of the one mother, mutations will be arising independently, so that the twigs won't be identical to one another necessarily. "If you're a good enough molecular biologist," Wilson says, "you can reconstruct that branching diagram leading back to the one mother by taking account of the number of mutational differences among the twigs." To draw the tree, the California group divided people into five categories, depending on their aboriginal continent of origin: Africa, Asia (mainly East Asia), aboriginal Australians, aboriginal New Guineans, and aboriginal Europeans. In building the tree, Wilson says, there is an obligation to choose the tree that explains the evolution with the simplest story, the fewest mutations. It is not a proof, he says, but a plausibility argument. Wilson explains that the picture emerging from this construction is of a tree with two primary branches connecting to the common mother. One of the branches leads exclu-
sively to people of African background. The second branch includes most of the people in the world, including many Africans. So Africans are on both primary branches. Moreover, Wilson says, the branches within the all-African group are very deep. So Africa has by far the most diversity of all the continents. The two primary branches in the tree were found upon looking at the first 21 women, Wilson says. As more women were added, it was just adding twigs, no deep branches. Putting a time scale on the tree makes use of the fact that some populations in the modern world result from colonization events that occurred very late. New Guinea is an example. "The point is," Wilson says, "it was hard to get to a place like New Guinea. People got there rather late, and once there, it was hard to get back." Using the genetic mutations, it's possible to estimate the amount of evolution that's occurred in places like New Guinea—Australians and American Indians are other examples—and compare that with the time that is thought to have elapsed on the basis of archaeological evidence. From the agreement between such calibration points, Wilson's group arrived at the 200,000 year estimate. Actually, the range is 140,000 to 290,000 years. From this point, the matter is one of complete speculation. Wilson explains, for example, that there would
presumably have been no genetic barrier to mixing of the Africans with "archaic" Eurasian people, probably descended from Homo erectus, who had evolved in Africa and populated much of the old world already by 700,000 years ago. But there is no evidence for this. The question that then arises is what was the barrier between the resident Asian populations and the incoming Africans? Wilson suggests that language, or skills stemming from language, may have played a key role. He cites research by human population geneticist Luigi Luca Cavalli-Sforza and his colleagues at Stanford University and in Italy who have been reporting evidence that the emergence of language coincided with the emergence of anatomically modern humans in Africa. The linguistic tree devised by the Cavalli-Sforza group shows important parallels with the genealogical tree devised by Wilson's group and others. Wilson further cites speculation in linguistic circles that grammar is in the brain and that one mutation or a small number might be all that would have been required for the critical advance in the kind of memory circuits needed for language. Wilson speculates on the notion that a mutation-caused language ability of the Africans may have been the barrier between them and the resident Asians. James Krieger
Powerful immunosuppressant synthesized Chemists at Merck Sharpe & Dohme Research Laboratories in Rahway, N.J., have achieved the total synthesis of the immunosuppressant agent, FK-506. The compound is about 100 times as potent as cyclosporin A, the leading drug now used to suppress patients' immune systems to prevent rejection of transplanted organs [/. Am. Chem. Soc, 111,1157(1989)]. In the short term, this accomplishment gives Merck a supply of the compound for further research in the U.S. Further, it provides Merck chemists with experience in the chemistry needed to make improved analogs that may have advantages
over the natural substance and to make subunits that may reveal its mode of action. In the long term, chemists everywhere will study the synthesis for knowledge of how to effect changes at one functional group without damage to the wide variety of other groups in such a complicated molecule. The Rahway workers' strategy was to make "northern" and "southern" portions of the molecule, which contained most of the dissymmetric carbon atoms, in high optical purity. They then linked these subunits through additional groups to close the 23-membered ring. Interestingly, the synthesis of February 6, 1989 C&EN
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