News of the Week
GENE SPLICING YIELDS HUMAN INTERFERON In what may be the most far-reaching success in recombinant DNA technology so far, scientists working for the two-year-old company, Biogen, based in Geneva, Switzerland, have put a gene for human leukocyte interferon into a bacterium to produce a biologically active protein. Charles Weissmann of the University of Zurich, who led an international team of scientists to this success, announced his findings in Boston. He was joined by other members of Biogen's "scientific board," including Walter Gilbert of Harvard University and Philip A. Sharp of Massachusetts Institute of Technology, and by company president Robert B. Cawthorn. ScheringPlough Corp., a pharmaceutical company and a minority shareholder of Biogen, has been given an exclusive license to market bacteria-produced interferon, Cawthorn says. , Many scientists close to the rapidly developing field of recombinant DNA technology have considered interferon as possibly one of the most valuable and certainly one of the more difficult mammalian gene products to make in bacteria. Interferon is a protein (actually a glycoprotein) made in response to challenges, such as virus infections. Though interferon's mode of action isn't known, the protein is thought to be involved in many of the body's immune reactions, possibly including efforts to fight cancer. Provocative hints about interferon have percolated through the scientific and medical communities, prompting clinical trials of interferon in cancer patients. But the cost of such treatments is extremely high, ranging well over thousands of dollars per patient, befcause of the cumbersome means available for obtaining interferon. Those means, which have improved steadily (C&EN, Aug. 13,1979, page 24), depend on obtaining the protein from human cells. Finnish scientist Kari Cantell, who now supplies much of the interferon for the current clinical trials in the U.S., was among the contributors to Biogen's effort to develop a more efficient means of making that protein. Recombinant DNA technology offers the potential for just such a means. And Weissmann's group now has shown that an interferonlike 6
C&EN Jan. 21, 1980
protein can be made in bacterial cells—though there are still many technical difficulties to be worked out before such a means proves commercial. For example, the bacteria harboring the interferon gene make extremely low amounts of the protein, only about two molecules per bacterium, Weissmann estimates. Moreover, thé molecule is probably an "untrimmed" version of interferon, still having a few too many of the amino acids that normally are shorn from the protein when it is made in mammalian cells. Moreover, the bacterial version of interferon lacks sugar molecules, which could be important for biological activity. Thus, Weissmann explains, the synthetic interferon has been tested for biological activity only in vitro so far. Whether such interferon will function when tested in vivo still is unknown. Despite these shortcomings, Weissmann says, "this is the best demonstration so far of recombinant DNA techniques' providing active molecules." Arid with all of its biochemical handicaps, many of which can be improved using routine tricks, the bacteria-made interferon is surprisingly active. Weissmann attributes that to the potent activity inherent to the molecule. Progress toward understanding
Gilbert: research challenge met
interferon has been slow because of the difficulties in obtaining enough of it at reasonable prices. "A true goal of recpmbinant DNA research," says Harvard's Gilbert, "is to make it easily obtainable—and available as a cheap material. This is the challenge that Weissmann has taken, and met." The Biogen achievement, at the very least, will speed those research efforts, among other things, making it easy to learn the protein's aminoacid sequence. Meanwhile several other groups, which also have been working on interferon in Israel and Japan, as well as in Europe and the U.S., undoubtedly will be dogging Biogen's heels before any of them wins the race to make the protein commercially available. But the Biogen result has quickened the pace considerably. D
OSHA sets final rules regulating carcinogens The Occupational Safety & Health Administration has issued final rules on its comprehensive policy for identifying and regulating cancercausing chemicals in the workplace. OSHA hopes that the policy will allow it considerably to improve its record of having issued regulations on only 20 cancer-causing substances in its first nine years of existence. OSHA's cancer policy has been the subject of intense debate since it was first proposed in 1977. OSHA says it made a number of significant changes in the policy as a result of the more than 250,000 pages of testimony it received. But as usual the changes didn't satisfy everyone. At press time it was uncertain whether labor or industry woujd win the race to the courthouse to challenge a policy that neither side is satisfied with, albeit for different reasons. According to Grover Wrenn, director of health standards programs for OSHA, the new policy provides an explicit framework for OSHA's standards-setting process and thus will permit industry to forecast far more accurately than in the past what the agency's probable actions will be in dealing with a particular substance. This likely would encourage volun-
category. Available evidence on these substances is only suggestive, with the question left open of whether to set a permissible exposure limit. Sometime this summer, Wrenn says, OSHA will issue a candidate list of substances for regulation. Following that, and at six-month intervals thereafter, OSHA will issue a priority list of 10 substances in each category on which it intends to act. According to Wrenn, issuance of the priority list is not a regulatory action and thus a substance's placement on the list cannot be subject to challenge. However, he says, proper classification of a substance in the first category will meet the Occupational Safety & Health Act's test of "grave danger" for issuance of an Emergency Temporary Standard to control exposure while a final standard is being developed. However, in response to Wrenn: changes increase flexibility testimony on the proposed policy, OSHA has made issuance of an ETS tary compliance even before OSHA discretionary rather than mandatory. takes any official action. In the policy OSHA defines the Testimony on the proposed policy scientific evidence necessary to clas- has led to other changes, Wrenn says, sify a substance as a potential car- that are aimed at increasing the flexcinogen. It also establishes two cate- ibility of OSHA's regulatory response gories in which potential occupational on specific substances and providing carcinogens are classified, depending for careful and competent scientific on the nature and extent of the evaluation of the animal and human available scientific evidence. data used to determine whether a The first category covers sub- substance is a potential occupational stances for which the best evidence of carcinogen. Thus, in its final policy, carcinogenicity is available and OSHA provides for scientific review which, thus, are assumed to pose a panels, a system of priorities to assure grave danger. OSHA will have little that the agency deals with the most discretion in regulating these sub- hazardous substances first; and spestances; for the most part it must cific procedures to assure that the follow a model standard set forth in policy can be amended to reflect sigthe policy. A more flexible regulatory nificant scientific and technical adD response is permitted for the second vances.
action. It suppresses intracellular synthesis of prostaglandin E2 and thromboxane A2 from arachidonic acid by inhibiting the action of cyclooxygenase. Both prostaglandin E2 and thromboxane A2 are partly responsible for the pain associated with inflammation. It also reduces migration of white blood cells into the spaces between joints, thereby reducing release of damaging inflammatory substances from these cells. Feldene's third mode of action appears to be through inhibition of the aggregation of collageninduced platelets. Platelet aggregation is accompanied by an increased release of numerous blood-clotting factors that promote accumulation of fluid in the inflamed joint. D
Justice sues Hercules over nitrocellulose
The Justice Department has sued Hercules for allegedly monopolizing the sale of industrial nitrocellulose in the U.S., a charge the company says is without basis. Hercules is the sole U.S. producer of the material. The Justice Department's complaint alleges that Hercules has exchanged price information with foreign nitrocellulose producers to influence and control the price at which nitrocellulose is sold in the U.S. Justice has asked the U.S. District Court in Newark, N.J., for an injunction prohibiting Hercules from continuing or resuming these alleged monopolistic acts. Hercules became the only U.S. producer of nitrocellulose in 1977, when the only other producer, Du Pont, closed its facilities. Hercules maintains that its limited contact Pfizer sells arthritis pain killer in Europe with foreign producers was aimed at Pfizer has launched a once-a-day pill I 1,1-dioxide. Now made commercially preventing U.S. nitrocellulose users in Western Europe that counters pain at Pfizer's plant in Sandwich, En- from suffering shortages of the maassociated with arthritis. Trade- gland, it belongs to the family of oxi- terial, a synthetic resin used in paints, named Feldene, it has just gone on cams. Edward H. Wiseman synthe- wood finishes, textile and paper sale in the U.K., Ireland, and Swit- sized the first of the oxicam series coatings, and printing inks. In addizerland, and will be put on the market some 15 years ago at Pfizer's research tion, the company says, it sought in other West European countries in laboratories in Groton, Conn. Since legislation to suspend temporarily the next few months. then, he and his associate, Joseph G. duties on imported nitrocellulose to Ian Wilson, Pfizer U.K.'s chairman, Lombardino, have extended the encourage imports so that users would have adequate supplies. describes Feldene as "a unique new range of derivatives. Since the company believes it has drug, the first nonsteroidal anti-inPiroxicairç embodies the best flammatory agent released in the past overall combination of properties of always acted in the public interest in 10 years." A 20-mg dose provides the compounds made to date. It has this matter, a Hercules spokesman 24-hour relief of pain for those af- a plasma half-life of 38 hours. It is says it is surprised by the suit and flicted with the major forms of ar- noncumulative in the body. It passes does not know what prompted it. thritis—osteoarthritis, rheumatoid quickly from the gastrointestinal Justice holds that the exchange of arthritis, and ankylosing spondylitis, tract into the bloodstream, rapidly price information violates Section 2 a disease of the spine. It is also effec- reaching clinically effective blood of the Sherman Act and has the postive in acute conditions of bursitis, levels. sible effect of Hercules' monopolizing tendinitis, and gout. According to John M. Faccini, di- nitrocellulose sales, retarding proFeldene's active agent is piroxicam, rector of pathology at Pfizer's re- duction of the material in the U.S., search center in Amboise, France, and depriving nitrocellulose users of 4-hydroxy-2-methyl-n - (2-pyridyl) 2ii-l,2-benzothiazine-3-carboxamide I Feldene likely has three modes of a choice of suppliers. Jan. 21, 1980C&EN
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