How to Get It Started

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    Running Out of Room Admissions offices at state universities and land-grant colleges are faced with the prospect of rejecting more qualified freshman applicants than ever before. Already overcrowded, the institutions have 6.9% more applications this year than they had the same time last year.

    Data released last week by the Na-tional Association of State Universities and Land-Grant Colleges put total ap-plications received by 84 of the as-sociation's 101 member universities as of March 15 at 579,370, compared with 541,757 a year earlier. In pro-viding results of an annual admissions survey conducted by its office of insti-tutional research, the association notes that although the percentage increase in applications was the lowest since 1964, when the baby boom hit cam-puses, the numerical increase equaled or exceeded that for any past year.

    The association estimates that alto-gether its 101 members will enroll more than 350,000 freshmen this fall. An increase of 6.5% new, first-time freshmen would result from expected increases by 86 association members.

    The application pattern varies re-gionally. Applications are up 12.4% in the Northeast, 8.7% in the South, and 8.6% in the West (which has later admissions deadlines).

    In the Midwest, however, there has been a decline of 5.3%, primarily be-cause of fewer out-of-state applica-tions. The association attributes this drop to large tuition increases for non-residents and to percentage quotas for out-of-state students set and widely publicized by many of the midwestem schools. In-state applications at eight of 22 mid western institutions surveyed also declined for essentially the same reasons.

    Among 93 survey participants, State University of New York had the lar-gest number of applications89,415. The largest numerical decrease 2450was posted by University of Michigan. A special problem arises at City University of New York, which, under a new open admissions plan, will expand its freshman class by 11,441, a 58.5%? increase.


    Once-a-Month Pill A female contraceptive agent consist-ing of a once-a-month pill with aborti-facient or luteolytic (menses-inducing) properties appears to be the most sci-entifically feasible development in the area of orally ingested birth control agents during the coming decade. Emergence of a male contraceptive pill is less likely. And development

    Stanford's Djerassi

    A better Pill, with government aid

    of a birth control chemical that could be added to water supplies or food is outside the realm of possibility during the remainder of this century.

    That's how Stanford University's Dr. Carl Djerassi appraises contraceptive developments through the 1980\s. The chemistry professor, who is also president of neighboring Syntex Re-search and is an undisputed authority in the area of steroid chemistry and steroid-based antifertility agents, fore-sees enormous research and develop-ment costs associated with the crea-tion of new and effective safe chem-ical contraceptives for oral ingestion.

    Private pharmaceutical firms are ideally suited to carry out such work, Dr. Djerassi maintains, because of their "unique ability to organize, stim-ulate, and finance multidisciplinary re-search covering the entire gamut of scientific disciplines required in con-verting a laboratory discovery into a practical drug. To assure the con-tinued possibility of the development of [novel antifertilityl drugs we must decide either to create an effective partnership between Government and industry on the model of other major technological efforts such as the space program, or to undertake the dif-ficult and even more costly steps that would be involved in the socializa-tion of the drug industry in areas re-quiring long development cycles," he told the 200 delegates who showed up at Beckman Auditorium last week for a three-day symposium on technolog-ical change and population growth.

    Dr. Djerassi estimates that $68 mil-lion was spent between 1965 and 1969 on reproductive physiology studies by Eli Lilly, Johnson & Johnson's Ortho Pharmaceutical division, G. D. S ear le, Syntex, and Upjohn. The figure would probably exceed $100 million

    were the expenditures of European and other U.S. companies included, he sug-gests.

    Using a detailed scheme that he has drawn up to map the steps needed to develop a once-a-month contraceptive pill, and the probable cost and tim-ing involved, Dr. Djerassi arrives at a final minimum cost in the $7 million to $18 million range. But, he main-tains, this sum "should probably be doubled because, as has already hap-pened with the presently used types of oral contraceptives, an agent may be rejected at a late date of clinical trial/' Moreover, he estimates that if existing regulations have to be ad-hered to, it could take between 10 and 15 years of premarketing research and development to ensure that a drug that is to be administered to large portions of the population has a minimum of risks. A suitable male contraceptive would very likely take even longer to develop, maybe as much as 20 years, he believes.

    Because of the special time element involved, Dr. Djerassi suggests that consideration be given to a possible revision of patent lifetimewhich in the U.S. covers a span of 17 years after a patent has been issuedof drugs in the birth control area and other fields that have the same characteristics of very long-term, premarketing investi-gative phases. One possibility he puts forward is that use-patent protection covering such products be offered for 10 years or so after the date that the Government puts its official seal of ap-proval on the drug.

    Another possibility is that a pharma-ceutical company should have the op-tion of applying to a government agency for full financial support of the long-term toxicity studies and most of the clinical trial work. If a commer-cial product results, the company would repay the accumulated financial support to the agency on an annual royalty basis.


    How to Get It Started Mammalian initiation factorssub-stances necessary to turn on the pro-tein synthesis process in mammalian cellshave been discovered by scien-tists at the National Heart and Lung Institute, Bethesda, Md. The discov-ery, made by a team headed by bio-chemist and pediatrician W. French Anderson, was revealed by coworker David A. Shafritz last week at the At-lantic City meeting of the Society of Clinical Investigation. Other mem-bers of the team are Dr. Jeffrey M. Gilbert and Dr. Philip M. Prichard.

    The discovery is of immediate inter-est to physicians because of its appli-

    22 C&EN MAY 11, 1970


    cation to the study of ^-thalassemia, a hereditary, ultimately fatal anemia afflicting mainly children of Mediterranean stock. More important in the long run, the discovery portends an era when scientists can take a biochemical look at protein synthesis in diseased human cells, see what has gone wrong, and perhaps even treat diseases by direct attack on the genetic translation system.

    Studying protein synthesis at the molecular level, the team tried to make hemoglobin chains in the test tube by mixing components isolated from living reticulocytes (immature red blood cells). The reticulocyte is ideal for such studies, Dr. Anderson says, because it is essentially a sack containing only the cell's genetic translation machinery and because it makes only one primary end product, hemoglobin. A few chains were made, but the rate of production was low.

    The team then followed up an observation made several years ago by Dr. Richard Schweet and coworkers: that a protein fraction isolated from ribosomes seemed to stimulate hemoglobin production. Investigating this fraction, the team found that it contained at least three distinct factors, each of which was necessary to initiate hemoglobin synthesis. By adding the initiation factors to the system, they were able to make hemoglobin at a rapid rate.

    The team also studied the effects of varying the amounts of other components. They found that if one specific group of tRNA molecules was left out, the a and chains of the hemoglobin molecule were made at different rates. This meant that different mRNA molecules can be decoded at different rates, depending on the types of tRNA molecules present.

    Thus, the NHLI scientists have shown two ways to alter protein production in mammalian cell-free systems: by varying the amount of one or more of the initiation factors, or by varying the amount or type of tRNA. Now they are working to determine whether defects in either of these mechanisms might be responsible for causing thalassemia.

    MEMBRANES: High-Energy Shapes Biochemists may be using the wrong suppositions when they try to explain ATP (adenosine triphosphate) formation and ion transport across membranes, using the traditional concepts of chemical reactions in homogeneous solutions. In the view of Dr. David E. Green, codirector of University of

    Wisconsin's institute for enzyme research, changes in the shapes of membrane proteins drive these energy-requiring reactions.

    Dr. Green told the National Academy of Sciences at its annual meeting in Washington, D.C., that he and his coworkersDr. John H. Young, Dr. George A. Blondin, and Dr. Garret Vanderkooihave been led by their studies of mitochondria to propose a conformational model for energy transductions in membrane systems. Mitochondria are organelles within many cells, where the final steps of respiration produce energy from the oxidation of carbohydrates to carbon dioxide. Some of the energy is used to move cations and anions against osmotic pressure, across the mitochondrial membranes, from regions of low concentration to regions of higher concentration. Some of the energy is also used to make ATP, an energy-rich molecule that provides the energy to move muscles and make proteins.

    The energy comes initially from a series of electron transfer steps as electrons "fair to lower free energy levels through a chain of quinones and chelated transition metals within the mitochondrial membrane. ATP formation and ion transport are somehow coupled to this flow of electrons, but a molecular mechanism for this process has eluded biochemists for decades.

    The missing link between electron transport and ATP formation or ion

    transport is energy storage in the membrane itself, Dr. Green says. Free energy released during electron transport may be conserved as proteins in the membrane change their conformations to unstable shapes of higher energy. If an energized conformation has a free energy sufficiently greater than the free energy of the protein's thermodynamically stable conformation, ATP might be formed as the protein relaxes to its stable shape.

    Dr. Green bases this model on a conformational cycle that he and his colleagues observe in electron micrographs of mitochondrial membranes during stages of ATP formation from ADP (adenosine diphosphate) and inorganic phosphate. Membranes and lipid-protein subunits within them both change from "nonenergized" to "energized" conformations as a result of electron transport. When inorganic phosphate is added, Dr. Green observes a third "energized-twisted" conformation. When ADP is finally added to form ATP, the membrane returns to the nonenergized shape.

    Relating ion transport to changes in protein conformation, Dr. Green suggests , that a conformation change would rearrange amino acid groups at the protein's surface, exposing some and burying others. In particular, amino acids that bind anions might be shifted. Cations would follow this redistribution, Dr. Green says, even into regions of higher concentration.

    Wisconsin's Green Missing link between electron transport and ATP

    MAY 11, 1970 C&EN 23

    PROTEIN SYNTHESIS: How to Get It Started