biotech PHARMACEUTICALS and BIOTHERAPY

AMERICAN COUNCIL ON SCIENCE AND HEALTH Biotech Pharmaceuticals and Biotherapy

by Fredric Murry Steinberg, M.D., M.B.A., and Jack Raso, M.S., R.D.

Project Coordinator Simona C. Kwon, M.P.H.

Art Director Yelena Ponirovskaya

Cover Design Larry Anderson

May 1998

AMERICAN COUNCIL ON SCIENCE AND HEALTH 1995 Broadway, 2nd Floor New York, NY 10023-5860 Tel. (212) 362-7044 ¥ Fax (212) 362-4919 URL: http:/www.acsh.org ¥ E-mail: [email protected]. THE AMERICAN COUNCIL ON SCIENCE AND HEALTH (ACSH) APPRECIATES THE CONTRIBUTIONS OF THE REVIEWERS NAMED BELOW.

Christine M. Bruhn, Ph.D. Cindy F. Kleiman, M.P.H. University of California, Davis Sisters of Charity Medical Center Staten Island, NY Dale J. Chodos, M.D. Kalamazoo, MI Manfred Kroger, Ph.D. The Pennsylvania State University Ilene R. Danse, M.D. University of California, San Francisco and Floy Lilley, J.D. Davis The University of Texas at Austin

Henry G. Grabowski, Ph.D. James D. McKean, D.V.M., J.D. Duke University Iowa State University

Saul Green, Ph.D. Gilbert Ross, M.D. ZOL Consultants, Inc. ACSH New York, NY Martha Barnes Stone, Ph.D. Richard M. Hoar, Ph.D. Colorado State University Williamstown, MA Elizabeth M. Whelan, Sc.D., M.P.H. Rudolph J. Jaeger, Ph.D. President, ACSH New York University

Ruth Kava, Ph.D., R.D. ACSH

ACSH accepts unrestricted grants on the condition that it is solely responsible for the con- duct of its research and the dissemination of its work to the public. The organization does not perform proprietary research, nor does it accept support from individual corporations for specific research projects. All contributions to ACSH—a publicly funded organization under Section 501(c)(3) of the Internal Revenue Code—are tax deductible.

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April 1998-02000. Entire contents © American Council on Science and Health, Inc. Table of Contents

Reviewers...... 2 Executive Summary...... 5 Introduction...... 6 I. Types of Biotech Pharmaceuticals ...... 9 Cytokines...... 9 Enzymes...... 12. Hormones...... 13. Clotting Factors...... 14. Vaccines...... 15. . Monoclonal Antibodies...... 16. . Some Biotech Drugs Undergoing Investigation...... 17 . Gene Therapy...... 18. . II. Safety and Effectiveness...... 22. . Drug Delivery...... 22 . . Biotech Pharmaceutical Purity...... 23. . Biotech Pharmaceutical Stability...... 23. . III. Regulation of Biotech Pharmaceuticals ...... 24 . Conclusion ...... 25 . References ...... 26. . Glossary...... 28. .

List of Tables

Table 1: Some Approved Biotech Drugs...... 10. . Table 2: Miscellaneous Biotech Pharmaceuticals Undergoing Clinical Investigation...... 19 .

List of Figures

Figure 1: Antibodies...... 7 Figure 2: A DNA Model...... 8 Figure 3: Example of Gene Splicing...... 13 . Figure 4: Phagocytosis...... 16. . Figure 5: A Typical Human Chromosome...... 20. . Figure 6: Telomerase and Cell Division...... 21 . Executive Summary in clinical use are biotech pharmaceuticals. Special A biotech pharmaceutical is simply any Report In a culture where words like “arti- medically useful drug whose manufacture

ficial,” “synthetic,” and “man-made” are involves microorganisms or substances that Biotech Pharmaceuticals and Biotherapy and Pharmaceuticals Biotech often used as slurs and the masses increas- living organisms produce (e.g., enzymes). ingly applaud so-called natural healing, a Most biotech pharmaceuticals are recombi- revolution in what might reasonably be nant—that is, produced by genetic engi- termed “unnatural healing” is proceeding neering. Insulin was among the earliest almost full blast—yet so quietly that the recombinant drugs. public has scarcely noticed it. Genetic engineering—also known This revolution—the “biopharm” as bioengineering, gene splicing, and revolution—stems from major advances in recombinant DNA technology—comprises biotechnology, or biotech, a field that altering genetic (DNA) molecules outside encompasses such disparate processes as an organism and making the resultant DNA winemaking, bioconversion (a means of molecules function in living things. Many- recycling organic waste), and cloning. The celled organisms that have been genetically medical repercussions of advances in engineered to produce substances that are biotech have been impressive, but the or may be medically useful to humans implications of those advances for human include cows, goats, sheep, and rats and well-being are no less than staggering. corn, potato, and tobacco plants. “Biotherapy” refers to any treat- In general, recombinant drugs ment that involves the administration of a approved by the U.S. Food and Drug microorganism or other biologic matter. Administration (FDA) are safer than com- Biotherapy’s name may be spanking new, parable natural-substance derivatives: but biotherapy itself is not: Administering Recombinant-DNA processes are precision living things or biologic matter is an techniques that inherently limit contamina- ancient approach to disease. Crude vac- tion. Moreover, many biotech agents are cines were used in antiquity in China, identical to, or differ only slightly from, India, and Persia. Vaccination with scabs proteins the human body produces natural- that contained the smallpox virus had been ly; thus, biotech pharmaceuticals tend to a practice—a dangerous one—in the East have a lower potential for adverse reac- for centuries when, in 1798, English coun- tions. In contrast, most conventionally pro- try doctor Edward Jenner demonstrated that duced pharmaceutical agents designed for inoculation with pus from sores due to treating humans are foreign to, or not nor- infection by a related virus could prevent mally present in, the human body. smallpox far less dangerously. Humankind Genetic engineering is central to has benefited incalculably from the imple- modern biotherapy’s backbone: pharma- mentation of vaccination programs. ceutical biotechnology. Pharmaceutical Another form of biotherapy, insulin biotechnology involves using microorgan- replacement therapy, has been in use for isms, other organisms (e.g., sheep), or decades. Before Canadian physiologists hybrids of tumor cells and white blood Frederick Banting and Charles Best discov- cells: ered and isolated insulin in 1921, nearly all ¥ to create new pharmaceuticals; persons diagnosed with diabetes died with- ¥ to create safer and/or more effective ver- in a few years after the diagnosis. In the sions of conventionally produced phar- mid-1960s several groups reported synthe- maceuticals; and sizing the hormone. ¥ to produce substances identical to con- Virtually all biotherapeutic agents ventionally made pharmaceuticals more 5 Special cost effectively than the latter pharma- Genetic engineering is revolution- ceuticals are produced. izing medicine: enabling mass production Report For example, before the develop- of safe, pure, more effective versions of ment of recombinant human insulin— chemicals the human body produces natu- which became the first manufactured, or rally. Through gene therapy, the potential commercial, recombinant pharmaceutical of biotech pharmaceuticals for curing in 1982—animals (notably pigs and cat- chronic and “incurable” diseases and tle) were the only nonhuman sources of improving the human condition is limit- insulin. Animal insulin, however, differs less. With sensible regulatory require- slightly but significantly from human ments and expeditious product review by insulin and can elicit troublesome the FDA, biotech pharmaceuticals can immune responses. Recombinant human within decades become unprecedented insulin is at least as effective as insulin of relievers of human suffering. animal origin, is safer than animal-source insulin, and can satisfy medical needs Introduction more readily and more affordably. The FDA approved more biotech In the movie Phantoms (1998) a drugs in 1997 than in the previous several scientist, a physician, and a sheriff use a years combined. The laundry list of genetically engineered bacterium to kill a human health conditions for which the Vaselinelike monster. Their use of the FDA has approved recombinant drugs bacterium saves lives in the short term, includes AIDS, anemia, certain cancers but the monster survives. (Kaposi’s sarcoma, leukemia, and †Such In Phantoms biotechnology, or colorectal, kidney, and ovarian films include biotech, was a benign factor, cancers), certain circulatory Island of Lost Souls though not decisively so. Few problems, certain heredi- (1933) and its two remakes (both titled The Island of Dr. major films have depicted tary disorders (cystic Moreau), The Manster (1961), biotech as clearly beneficial. fibrosis, familial hyper- The Cassandra Crossing (1977), Mary Shelley’s horror novel cholesterolemia, Gaucher’s Star Trek: The Wrath of Khan (1982), Species (1995) and Frankenstein: or, The Modern disease, hemophilia A, Species II (1998), and Prometheus, first published in severe combined immunodefi- Alien Resurrection 1818, may have set the tone for (1997). ciency disease, and Turner’s syn- the public’s perception of biotechnol- drome), diabetic foot ulcers, diphtheria, ogy. Since the release of the first screen genital warts, hepatitis B, hepatitis C, version of that classic, in 1910, filmmak- human growth hormone deficiency, and ers have portrayed biotechnology, or what multiple sclerosis. amounts to it, almost invariably as a †† Pharmaceutical Certain Pandora’s box.† In Mimic (1997), for episodes of Star biotechnology’s great- Trek: Deep Space Nine, example, a bioengineer creates a est potential lies in Star Trek: Voyager, The X- cross between a cockroach and a gene therapy. Gene Files (a government-conspir- mantis to control an infectious acy tale about xenotransplan- therapy is the inser- tation, for example), and The childhood disease that has become tion of genetic mate- Outer Limits (both the original epidemic in New York City. Her rial into cells to pre- series and its 90s incarna- plan succeeds, but her creation tion) have represented Biotech Pharmaceuticals and Biotherapy vent, control, or cure biotech as harmful overmultiplies and evolves into tall, disease. It encompasses or deadly. winged subway dwellers that kill chil- repairing or replacing defec- dren. Televised fictions that have dealt tive genes and making tumors more sus- with biotech have also tended to portray it 6 ceptible to other kinds of treatment. as dangerous.†† In short, the entertainment industry has made biotech fodder for horror sheep. Broadly, the word “biotechnology” stories. means “applied biological science.” In the Special †For But biotechnology’s further details context of this report, “biotechnology” Report scope and potential are on biotech and infor- refers to the use of living things or vaster than Hollywood mation on its utility in parts of living things: Biotherapy and Pharmaceuticals Biotech agriculture and food pro- movies suggest. Biotech cessing, see Huttner SL. ¥ to create or modify drugs and ranges from brewing, Biotechnology and Food. other substances; cheesemaking, and the New York: American ¥ to modify food crops and other Council on Science yeasting of dough to make and Health; organisms that are perceptible leavened bread,† to bioconver- 1996. sion* (a means of recycling organic *Terms followed by an asterisk are waste), gene therapy, and the cloning of defined in the Glossary (page 28).

Figure 1: Antibodies

Antibodies against bacterium

antigen

A B lymphocyte (B cell) identifies an antigen on the outer surface of a bacterium and produces an antibody specific to the antigen. The next time the antigen is present in the body, the antibody “rec- ognizes” and attaches to it. Antigens attached to antibodies cannot affect cells adversely. 7 Special to the naked eye; or pharmaceuticals; and ¥ to adapt microorganisms to agricultur- ¥ to produce substances that are identi- Report al, medical, or other purposes. cal to conventionally made pharma- Perhaps biotech’s greatest poten- ceuticals more cost effectively than the tial lies in pharmaceutical biotechnology, latter pharmaceuticals are produced. which centers on using microorganisms, A biotech* pharmaceutical is any other organisms (e.g., sheep), or hybrids medically useful drug whose manufacture of tumor cells and white blood cells: involves microorganisms or substances ¥ to create new pharmaceuticals*; that living organisms produce (e.g., ¥ to create safer and/or more effective enzymes*). versions of conventionally produced Broadly, the history of pharma-

Figure 2: A DNA Model Biotech Pharmaceuticals and Biotherapy

8 ceutical biotechnology includes Alexander and effectiveness relative to the safety and Fleming’s discovery of penicillin in a com- effectiveness of conventionally produced Special mon mold, in 1928, and the subsequent pharmaceuticals; and the regulation of Report development—prompted by World War II biotech pharmaceuticals. injuries—of large-scale manufacturing Biotherapy and Pharmaceuticals Biotech methods to grow the organism in tanks of broth. Pharmaceutical biotechnology has I. Types of Biotech changed enormously since then. Pharmaceuticals Two breakthroughs of the late 1970s became the basis of the modern The word “drug” has different defi- biotech industry: (1) the interspecies trans- nitions, but any substance that significantly plantation of genetic* material; and (2) the affects bodily function when it is present at fusion of tumor cells and certain white certain concentrations at cellular recep- blood cells. The cells resulting from such tors—specific sites on the surface of a fusion, called “hybridomas,”* replicate cell—is reasonably definable as a drug. (divide) endlessly and can be used to pro- Such substances include pharmaceuti- duce in bulk specific disease-fighting pro- cals—drug preparations and products that teins called “antibodies”* (see Figure 1, are used preventively or in the diagnosis or page 7, and pages 15 and 16). treatment of adverse physical, mental, or Biotech is also far more complicat- behavioral conditions. Many biotech phar- ed than Hollywood movies suggest, and maceuticals are similar or identical to pro- the degree of its complexity may partly teins that the human body produces rou- explain the public’s suspicion of it. tinely (typically in very small amounts) Modern pharmaceutical biotechnology and that are necessary for normal physiolo- encompasses gene cloning and recombi- gy. And many can affect target cells nant DNA technology.* Gene cloning com- directly. prises isolating a DNA* molecule segment Table 1 (page 10) lists biotech (see Figure 2, page 8) that corresponds to a pharmaceuticals that the U.S. Food and single gene* and synthesizing (“copying”) Drug Administration (FDA) has approved. the segment. Recombinant DNA technolo- gy, or gene splicing, comprises altering genetic material outside an organism—for Cytokines* example, by inserting into a DNA mole- Cytokines are immune-system reg- cule a segment from a very different DNA ulators. The prefix “cyto-” means “cell”; molecule—and making the altered material the suffix “-kine” essentially means “to function in living things (see Figure 3, move.” Cytokines activate immune-system page 13). The altered, or recombined, cells such as lymphocytes* and material is called “recombinant DNA.” macrophages* (large phagocytes*; see Recombinant DNA technology Figure 4, page 16). Cytokines that have enables getting microorganisms, animals, recombinant variants or versions include and plants to yield medically useful sub- those described below. stances, particularly scarce human proteins (by giving them human genes, for exam- ¥ Interferons* are potent cytokines that ple). This report, however, focuses not on act against viruses* and uncontrolled cell pharmaceutical biotechnology’s methods proliferation, which is the primary hall- but on its products, notably recombinant* mark of cancer. Virtually all conventional pharmaceuticals. It describes various types chemotherapeutic agents act directly on of biotech pharmaceuticals; their safety cancer cells. When interferons act on can- 9 Special Table 1: Some Approved Biotech Drugs Year of Report Product First U.S. Approved for Approval

recombinant human insulin 1982 diabetes mellitus

recombinant somatrem (human growth 1985 human growth hormone (hGH) hormone) for injection deficiency in children

recombinant interferon alfa-2b 1986 hairy cell leukemia 1988 genital warts 1988 Kaposi’s sarcoma 1991 hepatitis C 1992 hepatitis B

recombinant interferon alfa-2a 1986 hairy cell leukemia 1988 Kaposi’s sarcoma

Muromonab-CD3 1986 reversal of kidney transplant rejection 1993 reversal of heart and liver transplant rejection

recombinant hepatitis B vaccine 1986 hepatitis B prevention

recombinant somatropin for injection 1987 human growth hormone (hGH) deficiency in children

Alteplase (recombinant) 1987 acute myocardial infarction (heart attack) 1990 acute massive pulmonary embolism

Epoetin alfa (rEPO, Epogen) 1989 anemia of chronic renal failure

recombinant hepatitis B vaccine 1989 hepatitis B

interferon alfa-n3 1989 genital warts

adenosine deaminase 1990 severe immunodeficiency in infants

interferon gamma-1b 1990 chronic granulomatous disease

filgrastim (rG-CSF) 1991 neutropenia caused by chemotherapy 1994 bone marrow transplantation 1994 chronic, severe neutropenia

sargramostim (yeast-derived GM-CSF) 1991 Bone marrow transplantation

Aldesleukin (interleukin-2) 1992 renal cell carcinoma

Staumonab pendetide (OncoScint) 1992 colorectal and ovarian cancers

recombinant antihemophiliac 1992 hemophilia A factor (rAHF)

recombinant interferon beta-1b 1993 relapsing, remitting multiple sclerosis

dornase alpha (Pulmozyme) 1993 cystic fibrosis

Pegaspargase 1994 lymphoblastic leukemia Biotech Pharmaceuticals and Biotherapy imiglucerase for injection (Cerezyme, 1994 Gaucher’s disease recombinant lucocerebrosidase)

abciximab (ReoPro) 1994 prevention of blood clotting 10 Table 1 Continued Special Year of Product First U.S. Approved for Report Approval

Humulin 70/30 (biosynthesized 1996 diabetes mellitus Biotherapy and Pharmaceuticals Biotech human insulin)

Humatrope 1996 adult- or childhood-onset growth hormone deficiency

Serostim 1996 AIDS wasting associated with catabolism, weight loss, or cachexia

Saizen 1996 human growth hormone deficiency in children

Nutropin 1996 Turner’s syndrome

Infanrix (vaccine) 1997 diphtheria and tetanus toxoids absorbed coagulation factor IX (recombinant) 1997 factor IX deficiencies (Christmas disease)

Novolin 70/30 (biosynthesized 1997 diabetes mellitus human insulin)

Velosulin human (semisynthesized 1997 diabetes mellitus purified human insulin)

Genotropin 1997 human growth hormone deficiency in adults

Oprelvekin (Neumega) 1997 prevention of thrombocytopenia

Rituximab (Rituxan) 1997 follicular B-cell non-Hodgkin’s lymphoma

Becaplermin (Regranex Gel) 1997 diabetic foot ulcers daclizumab (Zenapax) 1997 acute renal allograft rejection

Nutropin AQ 1997 human growth hormone deficiency in adults

Sources include:

(1) Biotechnology Industry Organization (BIO). Biotechnology Drug Products. Washington, DC: BIO (undated, received in January 1995).

(2) Pharmaceutical Research and Manufacturers of America (PhRMA). 1995 survey: biotech- nology drug research has come of age. In: Biotechnology Medicines in Development; Washington, DC: PhRMA; 1995: 20Ð21.

(3) U.S. Food and Drug Administration (FDA). Center for Drug Evaluation and Research web- page: http://www.fda.gov/cder/

(4) U.S. Food and Drug Administration (FDA). Center for Biologics Evaluation and Research webpage: http://www.fda.gov/cber/ 11 Special cer cells, however, they do so indirectly— produce leukocytes adequately without by affecting the functioning of the such stimulation. By keeping leukocyte Report immune system. The FDA has approved levels high enough to control infections, certain recombinant interferons for the sargramostim can hasten recovery. treatment of several diseases, including AIDS-related Kaposi’s sarcoma, hairy cell leukemia,* hepatitis B (see page 15), Enzymes Below are descriptions of recom- and genital warts. binant enzymes and diseases against which they are effective. ¥ Interleukins* function as messengers between leukocytes,* or white blood ¥ Alteplase. The process of dissolving cells. Interleukin-2 (IL-2) stimulates blood clots in the circulatory system leukocytes called “T lymphocytes” or “T involves the conversion of a protein cells.” The FDA has approved a recombi- called “plasminogen” to a protein-split- nant variant of IL-2—aldesleukin ting enzyme called “plasmin.” A recombi- (Proleukin)—for treating renal cell carci- nant version of one of the enzymes that noma, a serious form of kidney cancer. accelerate this conversion can contribute The antitumor effect of IL-2 and its to the treatment of heart attacks, strokes, recombinant variant is directly propor- and clots that form in the blood vessels of tional to how much of the agent is admin- istered. Endogenous* IL-2 is scarce; the lungs. This recombinant enzyme is aldesleukin can be mass-produced but called “recombinant tissue-type plasmino- has adverse side effects at relatively low gen activator” or “alteplase.” The effects levels of administration.1 of alteplase are more localized than those of other enzymes used to dissolve blood ¥ Granulocyte-colony stimulat- clots (streptokinase and urokinase); thus, ing factor (G-CSF) stimulates the in theory, alteplase would cause less 2 bone marrow to produce neutrophils*— bleeding throughout the body. antibacterial white blood cells. The FDA has approved a recombinant variant of G- ¥ Dornase alfa. Cystic fibrosis (CF) CSF, filgrastim, for controlling infections is a genetic disorder marked by excessive in patients on anticancer drugs that sup- mucous secretions and frequent lung press immune responses, in patients infections. About half of those with CF 3 undergoing bone-marrow transplantation, live fewer than 29 years. In 1995 approx- and in patients who lack neutrophils. imately 20,000 to 25,000 people in the U.S. had the disease.4 A DNA-splitting ¥ Granulocyte-macrophage enzyme produced by the body, deoxyri- colony-stimulating factor (GM- bonuclease I (DNase I), can break down CSF) stimulates the bone marrow to pro- DNA that is outside cells, but not DNA duce neutrophils and macrophages (see that is within intact cells. In contrast, dor- Figure 4, page 16). The FDA has nase alfa (Pulmozyme), a recombinant approved its recombinant equivalent, sar- variant of DNase I in aerosol form, can gramostim (Leukine), for administration break down intracellular DNA. And

Biotech Pharmaceuticals and Biotherapy to cancer patients who, because intensive decomposition of the intracellular DNA chemotherapy and/or radiation therapy in the excessive mucous secretions that destroyed their bone marrow, have under- dispose persons with CF to lung infec- gone a transplant. Sargramostim is admin- tions can make the secretions less adhe- 12 istered until the transplanted marrow can sive to airways. Dornase alfa can thus 5 decrease the incidence and duration of both a cost of $160,000 annually —and every- Special lung infections and hospital stays in CF one with the disease has a lifelong need for patients. It is the first new drug in 30 years such an enzyme. The FDA has approved a Report to be approved by the FDA for the manage- recombinant variant of glucocerebrosidase, ment of CF. called “imiglucerase,” that should end the Biotherapy and Pharmaceuticals Biotech supply problem. ¥ Imiglucerase. Gaucher’s disease, characterized by bone destruction and enlargement of the liver and spleen, is due Hormones* to an hereditary deficiency of the enzyme Recombinant human insulin became the glucocerebrosidase. A variant of this first manufactured, or commercial, recom- enzyme is obtainable from human placen- binant pharmaceutical in 1982, when the tas. But 20,000 placentas would provide FDA approved human insulin for the treat- only a year’s supply for a single patient—at ment of cases of diabetes that require the

Figure 3: Example of Gene Splicing

DNA segment “B” is deemed undesirable and removed. Then segments “A” and “C” are joined. 13 Special hormone. Before the development of contamination with slow viruses* that recombinant human insulin, animals attack nerve tissue. Such infective agents Report (notably pigs and cattle) were the only caused fatal illnesses in some patients. nonhuman sources of insulin. Animal Recombinant hGH has greatly improved insulin, however, differs slightly but sig- the long-term treatment of children whose nificantly from human insulin and can bodies do not produce enough hGH. elicit troublesome immune responses. The therapeutic effects of recom- Clotting Factors* binant human insulin in humans are iden- Inadequate bodily production of tical to those of porcine (pig) insulin, and any of the many clotting factors can pre- it acts as quickly as porcine insulin, but vent effective clotting. The FDA has its immune-system side effects are rela- approved two clotting-related recombi- tively infrequent. Unlike the derivation of nant drugs: (1) abciximab—the so-called insulin from animals, biotech production super-aspirin, useful against heart dis- of the hormone virtually precludes conta- ease—for the prevention of blood clotting mination with other hormones. Further, it as an adjunct to angioplasty,* and (2) can satisfy medical needs more readily recombinant antihemophiliac factor and more affordably. (rAHF) for the treatment of hemophilia Other recombinant hormones A. Hemophilia A is a lifelong hereditary include those described below. disorder characterized by slow clotting ¥ Lispro. Regular insulin ordinarily and consequent difficulty in controlling must be injected 30 to 45 minutes before blood loss, even from minor injuries. meals to control blood glucose levels. About 20,000 people in the United States Lispro—a recombinant insulinlike sub- alone have this condition, which is due to stance—is faster-acting than regular a deficiency of antihemophiliac factor insulin. Because injection of lispro is (AHF, or factor VIII). Before the intro- appropriate within 15 minutes before duction of rAHF, treatment of hemophilia meals, using it instead of regular insulin A required protein concentrates from may be more convenient for some human plasma. Such concentrates could contain contaminants (e.g., HIV), and the patients.6 lifetime treatment of a single patient required thousands of blood contribu- ¥ Epoetin alfa. Erythropoietin (EPO), tions. a hormone produced by the kidneys, stim- Persons with hemophilia B lack ulates the bone marrow to produce ery- factor IX. They require either (a) factor throcytes, or red blood cells. The FDA IX concentrates from pooled human has approved recombinant EPO, called blood or (b) factor IX from cell cultures “epoetin alfa,” for the treatment of ane- (some of which are genetically engi- mia due to chronic renal* failure. neered). In July 1997 Scotland’s Roslin Institute announced the birth of the first ¥ Recombinant human growth genetically engineered sheep clone.7 The hormone. Human growth hormone clone carries a human gene for factor IX, (hGH) is used to counter growth failure in and it gives milk that contains the factor.

Biotech Pharmaceuticals and Biotherapy children that is due to a lack of hGH pro- (Other many-celled organisms that have duction by the body. Before the introduc- been genetically engineered to produce tion of recombinant hGH the hormone substances that are or may be medically was derived from human cadavers. useful to humans include cows, goats, and 14 Cadaver-derived hGH was susceptible to rats and corn, potato, and tobacco plants.8,9) Vaccines* an experimental recombinant vaccine Special In every modern vaccine the main against the virus had proved effective in or sole active ingredient* consists of: (1) mice and guinea pigs. Report killed microorganisms, (2) nonvirulent Because of immune-system inade- microorganisms, (3) microbial products quacy, some groups—infants and young Biotherapy and Pharmaceuticals Biotech (e.g., toxins), or (4) microbial components children, for example—tend to respond that have been purified. All these active poorly to vaccination against certain bacte- ingredients are antigens*: substances that rial infections (e.g., streptococcal pneumo- can stimulate the immune system to pro- nia). Preliminary research suggests that duce specific “anti-antigen” proteins, antibacterial vaccines that contain specific called “antibodies.” Such stimulation antibodies are more effective against such leaves the immune system prepared to diseases than are comparable conventional destroy bacteria and viruses whose anti- vaccines, which do not contain antibod- gens correspond to the antibodies it has ies.11 learned to produce. Although conventional- Although vaccines traditionally ly produced vaccines are generally harm- have been designed to prevent only infec- less, some of them may, rarely, contain tious diseases, the development of individ- infectious contaminants. Vaccines whose ualized vaccines—vaccines made from the active ingredients are recombinant antigens cancer cells of each patient—to restrain, do not carry this slight risk. prevent the recurrence of, or cure some More than 350 million people forms of cancer is promising.12,13 worldwide are infected with the virus that Melanoma* is the deadliest form of skin causes hepatitis B, a major cause of chronic cancer. Researchers at the U.S. National inflammation of the liver, cirrhosis of the Cancer Institute have demonstrated that liver, and liver cancer.10 Hepatitis B kills a administration of a special vaccine plus million people each year worldwide. About interleukin-2 (see page 12) can shrink 1.25 million Americans harbor the hepatitis tumors in patients with melanoma that has B virus (HBV); 30 percent of them will spread.14 The vaccine used in this study eventually develop a serious liver disease. contained a melanoma-antigen variant About 300,000 children and adults more effective than the original antigen at in the U.S. become infected with HBV attracting to cancer sites T lymphocytes each year, and 5,000 Americans die annu- that are destructive to tumors. ally from liver disease caused by the virus. Another prospect is effective inocu- The first hepatitis B vaccine available in lation by ingestion. In February 1998 U.S. the U.S. was made with derivatives of plas- researchers announced that they had genet- ma from persons with chronic HBV infec- ically engineered potatoes to produce a tions. A recombinant vaccine—whose sole “vaccine” against cholera15—an infectious active ingredient is a recombinant (and thus gastrointestinal disease usually caused by uncontaminated) antigen—has replaced it. drinking water contaminated with bacteria. Use of this vaccine is very cost effective— Every year five million people contract the especially in North America, since interfer- disease and 200,000 die from it. The “vac- on treatment of hepatitis B is very costly. cine” is a nontoxic, relatively heat-stable The Ebola virus, first identified in protein that can elicit an immune response 1976, causes Ebola hemorrhagic fever, one even when it is ingested as a potato con- of the deadliest viral diseases known. stituent. About 50Ð90 percent of patients infected with the Ebola virus consequently die. In 1997 American researchers announced that 15 Special Monoclonal Antibodies* All the antibodies the immune system Report Antibodies (see Figure 1, page 7) normally produces in response to a specif- are various proteins that mark foreign ic antigen are capable of marking (bind- material in the body, such as bacteria and ing to) that antigen, but these antibod- viruses, for removal or destruction by ies—called “polyclonal antibodies”—are other components of the immune system varied, not identical. Monoclonal antibod- (e.g., macrophages; see Figure 4, below). ies (MoAbs) that share a specific anti-

Figure 4: Phagocytosis

antibody-”coated” bacterium

antigen

antibody receptor

macrophage or neutrophil Biotech Pharmaceuticals and Biotherapy

An antibody-“coated” bacterium is attractive to phagocytes such as macrophages and neu- trophils. The receptors on the phagocyte “recognize” the antigen-bound antibody on the sur- 16 face of the bacterium, and the phagocyte engulfs the bacterium. genic target are identical and are more sen- cancer has spread to lymph nodes than if it sitive to that target than are polyclonal anti- has not. Traditionally, determining whether Special bodies for the same antigen. MoAbs are the the lymph nodes have been affected Report products of hybridomas—cells that result involves surgery. But using radiolabeled* from the biotech fusion of bone-marrow MoAbs specific to antigens on malignant Biotherapy and Pharmaceuticals Biotech tumor cells and B lymphocytes.* cells enables locating such cells with an Hybridomas are usable to produce specific instrument comparable to a Geiger counter MoAbs continuously. and may decrease the need for surgery. Theoretically, a MoAb designed for The ability of MoAbs to bind to, a particular antigen on cancer cells can ini- and thus tag, specific proteins also makes tiate an immune response that would them potentially useful in the diagnostic destroy cancer cells without harming nor- imaging of internal organs and tumors. mal cells. At least 26 MoAbs are undergo- ing clinical testing as anticancer agents,16 Some Biotech Drugs but the medical potential of MoAbs extends to many other diseases. Undergoing Investigation For example, the FDA has approved Listed below are a few of the hun- the MoAb drug muromonab-CD3 for the dreds of biotech drugs that are objects of treatment of immune-system rejection of scientific research. transplanted hearts, kidneys, and livers. Muromonab-CD3 restrains immune ¥ Biotech vaccines undergoing investiga- response and thus increases the likelihood tion include vaccines for acellular pertus- that the transplant will function. More sis (whooping cough), AIDS, herpes sim- recently, the FDA has approved the plex, Lyme disease, and melanoma. immunosuppressant* daclizumab (Zena- pax) for the prevention of kidney-trans- ¥ Two new recombinant interferons are plant rejection. Daclizumab’s active ingre- undergoing investigation: consensus inter- dient is a “humanized” MoAb; 90 percent feron, for treating hepatitis C (a form of of the MoAb’s amino-acid structure is viral hepatitis); and recombinant beta inter- human. Thus, the likelihood of an allergic feron 1a, for multiple sclerosis. reaction to it is low. Another MoAb, infliximab (cA2), • Recombinant PTK inhibitors—“PTK” appears effective against Crohn’s disease, stands for “protein tyrosine kinase”—may an immune-system disorder marked by have therapeutic utility against diseases intestinal inflammation.17 Infliximab is spe- marked by cell proliferation, such as can- cific for a factor in the development of the cer, atherosclerosis,* and psoriasis.* disease. Protein tyrosine kinases, enzymes that con- The medical utility of MoAbs is not tribute to cell division, are the targets of limited to therapeutics. Because of their these biotech drugs. ability to bind to specific antigens, MoAbs have been used for many years to identify ¥ Recombinant human interleukin-3 is antigen-carrying disease agents and to undergoing clinical investigation as an locate them in the human body. Recently, adjunct to traditional cancer chemotherapy. British researchers designed MoAbs that may be useful in determining whether can- ¥ Two recombinant growth factors— cer has spread from breast tissue to lymph cytokines that regulate cell division—are nodes at the armpits.18 The spread of cancer undergoing major clinical trials: recombi- to other parts of the body is likelier if the nant human insulin-like growth factor 17 Special (rhIGF-1) and recombinant human grafts, which depended on how much platelet-derived growth factor-BB healthy skin they had, and temporary pro- Report (PDGF). PDGF can contribute to wound tective coverings made of dead cells. healing. Table 2 (page 19) describes sever- al other biotech pharmaceuticals undergo- ¥ In December 1997 the FDA approved ing clinical investigation. clinical testing of a recombinant version of the cytokine myeloid progenitor Gene Therapy inhibitory factor-1 (MPIF-1).19 MPIF-1 Pharmaceutical biotechnology’s can keep certain normal cells, including greatest potential lies in gene therapy. many immunologically important cells, Gene therapy is the insertion of genetic from dividing and can thus protect them material (altered or unaltered) into cells to from anticancer drugs that target rapidly prevent, control, or cure disease, especial- multiplying cells. When such anticancer ly genetic disorders. It encompasses drugs affect normal cells that divide repairing or replacing defective genes and rapidly, hair loss, nausea, and immuno- making tumors more susceptible to other suppression can result. kinds of treatment. Thus, gene therapy’s potential for preventing and curing dis- ¥ Injecting the recombinant protein ease is vast. It has proved somewhat use- fibroblast growth factor, or FGF-1, into ful in the treatment of certain rare genetic the human heart muscle can increase the diseases, such as cystic fibrosis (see page blood supply to the heart by inducing 12) and familial hypercholesterolemia—a blood-vessel formation.20 Such treatment, considerable excess of cholesterol in the called a “biologic bypass” or “biobypass,” bloodstream.22 does not require surgery. FGF-1 can be Carriers for gene-therapy drugs injected nonsurgically by cardiac include: catheterization—a technique in which a ¥ harmless viruses that have undergone tubular device called a “catheter” is intro- genetic alteration and can carry select- duced into a blood vessel in an arm or leg ed genetic material into human cells; and directed to the heart. A biobypass and may benefit persons with coronary artery ¥ liposomes*—injectable microscopic disease (“clogged arteries”) whose arter- fatty globules (see page 22) that can ies cannot be repaired surgically. (A gene- enclose and protect DNA (e.g., a “sui- therapy form of biobypass, VEGF gene cide gene” for insertion into cancer therapy, is described below.) cells23). In January 1998 advisors to the Existing gene-therapy drugs can FDA recommended that the agency restrain the replication of disease-causing approve two recombinant skin-replace- microorganisms, can eliminate defective ment products, one for the treatment of cells, and can increase the resistance of diabetic ulcers and the other for the treat- normal cells to drugs harmful to them ment of leg ulcers due to poor circulation. (e.g., certain anticancer agents).24 For About 800,000 diabetic foot ulcers occur example, the Multiple Drug Resistance in the U.S. annually, and they lead to (MDR) gene enables production of a pro- most of the lower-leg amputations that tein that ejects various foreign chemicals Biotech Pharmaceuticals and Biotherapy approximately 60,000 diabetics undergo from cells. Introduction of the MDR gene each year.21 Traditionally, patients with into the bone-marrow cells of patients chronic skin ulcers or severe burns have with advanced cancer seems safe and may 18 had only two treatment options: skin protect their bone marrow from the toxic Table 2: Miscellaneous Biotech Pharmaceuticals Special Undergoing Clinical Investigation Report

Drug Description Biotherapy and Pharmaceuticals Biotech

recombinant factor VIIa clotting factor for treatment of hemophilia A and B

Pixykine colony stimulating factor designed to contribute to the pre- vention of deficiencies of neutrophils and platelets. (Such deficiencies can result from anticancer chemo- and radio- therapy.)

Auriculin anaritide for acute renal failure

Hirudin for acute heart problems

ILl-2 fusion toxin for cutaneous T-cell lymphoma (DAB389IL-2)

platelet aggregation inhibitor for prevention of complications after angioplasty

recombinant human for fertility enhancement (follicular stimulation) leutinizing hormone

recombinant osteogenic for bone fractures in which the ends fail to unite protein-1

recombinant human thyroid useful in the detection and treatment of recurrent thyroid stimulating hormone cancer

Source:

Pharmaceutical Research and Manufacturers of America (PhRMA). 1995 survey: biotechnology drug research has come of age. In: Biotechnology Medicines in Development. Washington, DC: PhRMA; 1995: 2Ð18. side effects of chemotherapy.25 It may A form of gene therapy that has thus make high-dose chemotherapy safer the opposite effect on blood-vessel forma- and improve recovery. tion has also been developed. Preliminary Another anticancer strategy under- research suggests that “therapeutic angio- going investigation, called “antiangiogen- genesis,”or VEGF gene therapy, may be esis gene therapy,” involves introducing effective against sensory neuropathy27— genetic material to a limited area to specifically, a loss of feeling in the feet— decrease angiogenesis*—the formation of and critical limb ischemia—an arterial blood vessels—in that area.26 Decreasing disease marked by a decrease in the sup- angiogenesis at the site of a tumor ply of oxygen-rich blood to the legs. Such decreases the tumor’s ability to grow and a decrease can result in gangrene and the spread. need for amputation. “VEGF” stands for 19 32 Special vascular endothelial growth factor, a pro- telomerase. Normal cells that tein that can induce angiogenesis. †Viruses lack telomerase can repli- Report Scientists have modified a rela- can elicit an cate (divide) only about tively harmless respiratory immune response, and in any case using viruses to con- 50 times. Each time † virus so that it bears the gene vey genes is not a very accurate one divides, it loses for VEGF. Injection of the means of sending genetic material DNA from its to target cells. In chimeraplasty, an material that corresponds to experimental mode of gene therapy, telomeres—the nat- the VEGF gene directly into chimeraplasts—“repairman” molecules ural, protective defective parts of the heart that are hybrids of RNA * and recom- ends of its chromo- binant DNA—convey the gene. might eventually supersede Chimeraplasty may enable gene somes* (see Figure surgical procedures used to transmission that is more accu- 5). Without telom- treat coronary artery disease.28,29 rate than viral or microbial erase, which is key to Coronary artery bypass grafts, for gene transmission. the synthesis of telomeres, example, necessitate using a heart-lung shortening of the telomeres ulti- machine. As many as 600,000 Figure 5: A Typical Human Chromosome cardiac patients a year might benefit from VEGF gene therapy.30 In January 1998 researchers reported that introduction of the active gene gene for human telom- erase reverse transcriptase (hTRT)—a vital component of the enzyme telomerase— into normal human cells had resulted in a DNA double helix marked increase in the cells’ life span without making the cells otherwise abnor- mal (e.g., can- cerous).31 Most

Biotech Pharmaceuticals and Biotherapy human cells do not produce hTRT but con- tain all the other 20 components of mately brings cell division to a halt, where- tralizing telomerase or by modifying the upon the cell dies (see Figure 6, below). hTRT gene. Controlling various age-related Special Because the hTRT gene of sperm cells, egg disorders, such as heart disease, with the Report cells, and cancer cells is active, they can hTRT gene may also be feasible.33 divide perpetually. It is theoretically possi- Specific cells from a patient could be reju- Biotherapy and Pharmaceuticals Biotech ble to destroy cancer cells safely by neu- venated and then cultured to replace, for

Figure 6: Telomerase and Cell Division

telomerase (hTRT) immature cell gene active

telomerase (hTRT) gene inactive

adult cell

telomerase (hTRT) telomerase (hTRT) gene active gene inactive

cells keep dividing cells stop dividing

Immature cells make the enzyme telomerase, which greatly increases the number of times the cell can divide. Normal adult cells lack telomerase and therefore can divide only about 50 times. When the telomerase (hTRT) gene is reactivated in adult cells, it removes this limit. 21 Special example, the patient’s hardened arterial tract, for example, hydrochloric acid and tissue or burned or wrinkled skin. digestive enzymes normally break down Report ingested proteins. Thus, therapeutic pro- II. Safety and teins such as insulin and human growth hormone would be ineffective as oral Effectiveness medicines. Even injection of a drug does not In general, FDA-approved recom- ensure that it will work. Pharmaceuticals binant drugs are safer than comparable work by affecting specific parts of target natural-substance derivatives. For exam- cells. To be effective, injected drugs need ple, because recombinant DNA (rDNA) to survive transport through the liver— processes are precision techniques that which deactivates or modifies many inherently limit contamination, both the drugs—and encounters with enzymes; recombinant hepatitis B vaccine and the often, injected drugs also need to pene- recombinant human growth hormone are trate cellular barriers. safer than their natural-source equiva- Drug-delivery innovations rele- lents. Moreover, many biotech agents are vant to pharmaceutical biotechnology identical to, or differ only slightly from, include those described below. proteins the human body produces natu- rally; thus, biotech pharmaceuticals tend ¥ Liposomes. A liposome is a micro- to have a lower potential for adverse reac- scopic fatty droplet designed to carry a tions. In contrast, most conventional- therapeutic substance, especially to spe- ly produced pharmaceutical cific bodily tissues. The liposomal agents designed for treat- †Furthermore, the active ingredients outer membrane and the outer ing humans are foreign of all biotech protein prod- membrane of the target cell to, or not normally pre- ucts consist of levorotatory, or can fuse, whereupon the lipo- sent in, the human “left-handed,” molecules. All natural amino acids are “left- some empties into the cell. 34 † body. handed.” The biological effects of Liposomal encapsulation of a “left-handed” and “right-hand- therapeutic substance enables ed” molecules that are mirror Drug Delivery images to each other—that increasing the accumulation of The term “drug have the same compo- the active ingredient in target nents and structure— tissues and decreasing the spread delivery” refers to both the may differ. form and the way in which a drug of the active ingredient to nontarget is administered or taken. Inappropriate tissues, where it might do harm. drug delivery—for instance, taking by mouth a medicine designed for applica- ¥ Immunotoxins. An immunotoxin is tion to the skin—can render a pharmaceu- a combination of a monoclonal antibody tical ineffective or even harmful. For (see page 16) and a toxic (e.g., anticancer) example, digestive chemicals might substance. Because it responds only to degrade, and thus inactivate, an orally specific antigens, the MoAb component administered drug designed for inhala- limits the toxic effects of the immunotox- tion. Biotechnology enables large-scale in to target (e.g., tumor) cells. production of pure substances with thera-

Biotech Pharmaceuticals and Biotherapy peutic potential. But many such sub- ¥ Prodrugs. A prodrug* is any medical stances lack stability and are not compound designed to work only after it absorbable in a medically useful form has been activated by the body or by a through the gastrointestinal tract, the specific type of tissue in the body. 22 lungs, or the skin. In the gastrointestinal Prodrugs are useful when the “active” drug is too toxic for nonspecific or gener- Biotech Pharmaceutical Special al distribution to bodily tissues, when Purity absorption of the “active” drug is poor, or Report when the body breaks down the “active” Historically, pharmaceuticals 36 drug prematurely. For example, a prodrug whose main ingredients were proteins, Biotherapy and Pharmaceuticals Biotech that only one type of enzyme can activate were not as pure as other pharmaceuti- will work only in tissues that produce that cals. Nearly all biotech agents are pro- enzyme. Such a prodrug can thus spare teins, and the most common impurities in nontarget tissues toxic effects. The intro- recombinant drugs are protein impurities. duction into tumor cells of genes for Protein impurities can render a drug’s enzymes that can activate anticancer pro- effects different from the effects of its drugs—a prodrug-activating gene thera- pure counterpart. Some impurities can py—has been well studied.35 cause allergic reactions. Protein impuri- ties can also render the duration of the ¥ Polyethylene glycol. Frequent drug’s effects different from the expected injections of a therapeutic protein can duration. result in harmful immune responses. A slight difference between a Adding polyethylene glycol (PEG) to recombinant protein and its endogenous therapeutic proteins increases their stabili- counterpart can elicit an adverse immune ty in the body and lengthens the time they response. Recombinant protein prepara- stay in the bloodstream, thus decreasing tions derived from bacterial cultures may the number of injections needed. PEG can also contain small amounts of nitrogen- contribute to the treatment of an heredi- containing bacterial contaminants that can 37 tary disorder called “severe combined elicit an adverse response. But adher- immunodeficiency disease” (SCID). ence to modern standards of manufacture 38 SCID renders even ordinarily trivial can keep such contamination infrequent. infections so deadly to children that insti- Recombinant cell-culture products tutionalization or isolation is necessary derive from a well-delineated, well-moni- for their survival. Neither bone marrow tored source. Thus, microbial contamina- transplants nor daily infusions of white tion is more preventable in such products blood cells—the conventional treat- than in natural extracts. Such contamina- ments—are always effective against tion occurs about as often in the manufac- SCID. Deficiency of the enzyme adeno- ture of products from traditional cell cul- sine deaminase (ADA) causes about one tures as in the manufacture of products third of all cases. Adding PEG to recom- from recombinant cultures. In any case, binant ADA enables effective weekly even low-level microbial contamination infusions, as PEG slows the breakdown of of recombinant cultures is easily 39 ADA in the body. detectable. PEG likewise slows the break- down of another enzyme, L-asparaginase, Biotech Pharmaceutical which the body produces naturally. Stability Pegaspargase, a combination of PEG and Keeping biotech pharmaceuticals recombinant L-asparaginase, can improve stable is more difficult than keeping con- the condition of children with lym- ventional drugs stable. Many biotech phoblastic leukemia. agents consist of protein molecules, which are larger and less stable than the molecules of conventional pharmaceutical agents. A minor unplanned change in the 23 Special amino-acid composition of a biotech erably higher than the temperature and pharmaceutical protein can have unin- humidity recommended for commercial Report tended clinical effects. Often, however, storage. But because heat can affect pro- such minor changes do not make the tein structure, the utility of accelerated effects of a protein significantly different testing for expiration-dating biotech phar- from those of the original protein. For maceuticals is very limited. To establish example, in June 1986 the FDA approved expiration dates for protein-based biotech two recombinant interferons for the treat- pharmaceuticals, manufacturers necessar- ment of hairy cell leukemia (see pages 9 ily conduct real-time stability studies on and 11 and Table 1, page 10). The prod- such preparations under recommended ucts differ in composition by a single storage conditions. amino acid. Stability is particularly important III. Regulation of with larger protein molecules, because Biotech their biologic, or in vivo, effects often depend on their three-dimensional struc- Pharmaceuticals ture.40 Even without a change in the num- ber and kind of a biotech agent’s compo- The U.S. Food and Drug nents, an unplanned or premature change Administration (FDA) oversees sales in in its three-dimensional structure can ren- the United States of “human therapeutics” der it medically useless. and all other lawful products categorized For example, at low concentra- as drugs and presented for application to tions, interferons, interleukins, and certain humans. FDA approval of any such prod- other biotech molecules have a tendency uct must precede its sale. To obtain FDA to adhere to glass and plastic. A loss of approval, manufacturers must submit to potency can result. This is often pre- the agency voluminous information about ventable by coating the insides of contain- the product, including reports of scientific ers used in drug administration with findings concerning medical effective- human serum albumin, a common protein ness, purity, stability, and side effects that can carry the agent, before placing (e.g., due to impurities or high dosing). the drug in the containers.41 By the time approval has been obtained, a The shell of water around a pro- company may have spent five to ten years tein molecule critically affects its struc- and more than $200 million seeking it. ture.42 Removal of all water from a pro- While the public endorses conven- tein usually changes its structure irre- tional pharmaceutical research, it appears versibly. Thus, freeze-drying of biotech apprehensive about biotech.43 But the proteins is complicated. Some biotech consensus of many national and interna- products require both upper and lower tional groups is that biotech risk is pri- limits on water content. Humectants— marily a function of product characteris- glycerin and other substances that pro- tics, and that it is not a function of rDNA mote retention of moisture—increase the technology.44 In other words, these orga- stability of biotech protein powders. nizations have decided that biotech phar- Expiration-dating of pharmaceuti- maceuticals should be judged according

Biotech Pharmaceuticals and Biotherapy cals is based on tests of the drug’s pre- to the components (e.g., active ingredients administration stability. Generally, esti- and contaminants) and the effects (e.g., mates of a pharmaceutical’s shelf life are side effects) of each pharmaceutical—and based on “accelerated” testing, in which not according to how they were made. 24 the temperature and humidity are consid- Consistent with this consensus, the FDA’s approach to recombinant drugs and other releases of recombinant microorganisms biotech pharmaceuticals is the same as its into the environment, and the NIH repeat- Special approach to conventional biologicals.* edly updates biotech research guidelines Report The U.S. Environmental Protection that recipients of federal funds must

Agency (EPA) and the National Institutes follow.45 Many biotech researchers who do Biotherapy and Pharmaceuticals Biotech of Health (NIH) also influence pharmaceu- not receive such funds also follow these tical biotech research. The EPA regulates guidelines.

Conclusion

Recombinant DNA technology is revolu- within decades become unprecedented pre- tionizing medicine: enabling mass produc- venters and relievers of human suffering. tion of safe, pure, more effective versions Alas, over the last three years the of chemicals the human body produces nat- research budget of the FDA’s Center for urally. Through gene therapy (see page 18), Biologics Evaluation and Research the potential of biotech pharmaceuticals for (CBER)—which is responsible for review- curing chronic and “incurable” diseases ing new biotech (and other biologic) phar- and improving the human condition is lim- maceuticals and for related licensing—has itless. With sensible regulatory require- been halved, and during the next two years ments and expeditious product review by the CBER will lose about one third of its the FDA, biotech pharmaceuticals can research positions.46

25 Special References 14. Rosenberg SA, et al. Immunologic and therapeutic evaluation of a syn Report 1. Sindelar RD. Pharmaceutical biotech- thetic peptide vaccine for the treat nology. In: Foyes WO, Lemke TL, ment of patients with metastatic Williams DA, eds. Principles of melanoma. Nature Medicine. 1998; Medicinal Chemistry. 4th ed. Media, 4:321Ð327. PA: Williams & Wilkins; 1995:637. 15. Arakawa T, Chong DKX, Langridge 2. Sindelar RD. Pharmaceutical biotech- WHR. Efficacy of a food plant-based nology. In: Foyes WO, Lemke TL, oral cholera toxin B subunit vaccine. Williams DA, eds. Principles of Nature Biotechnology. 1998; Medicinal Chemistry. 4th ed. Media, 16:292Ð298. PA: Williams & Wilkins; 1995:635. 16. Miller M. To build a better mousetrap, 3. Reuters. FDA approves inhaled use human parts. JNCI. 1998; cystic fibrosis antibiotic. InfoBeat. 90:14Ð16. December 23, 1997. 17. Targan SR, et al. A short-term study 4. Centers for Disease Control and of chimeric monoclonal antibody cA2 Prevention. MMWR. 1997; 46:2. to tumor necrosis factor a for Crohn’s disease. NEJM. 1997; 327: 5. Kotulak R. A brave, new world 1029Ð1035. emerging at “biopharms.” Chicago Tribune, February 8, 1998:12. 18. Reaney P. New breast cancer test may reduce need for surgery. InfoBeat, 6. The Medical Letter. October 25, 1998; February 2, 1998. 38(986). 19. Reuters. U.S. company gets OK to 7. Reuters. Polly, first designer clone, test drug found in new way. InfoBeat, may help hemophiliacs. InfoBeat, December 18, 1997. December 18, 1997. 20 Altman LK. Injectable heart drug 8. Kotulak R. A brave, new world grows blood vessels. The New York emerging at “biopharms.” Chicago Times, February 24, 1998:F7. Tribune, February 8, 1998:12. 21. Associated Press. FDA panel urges 9. Arakawa T, Chong DKX, Langridge approval of two types of artificial WHR. Efficacy of a food plant-based skin. CNN Interactive, Health section oral cholera toxin B subunit vaccine. (http://cnn.com/HEALTH/), Jan. 29, Nature Biotechnology. 1998; 1998. 16:292Ð298. 22. Sindelar RD. Pharmaceutical biotech- 10. Lee WM. Hepatitis B Virus Infection. nology. In: Foyes WO, Lemke TL, NEJM. 1997; 337:1733. Williams DA, eds. Principles of Medicinal Chemistry. 4th ed. Media, 11. Nature Medicine. 1998; 4:88Ð91. PA: Williams & Wilkins; 1995:646.

12. Reuters. Progress seen in 23. Pharmaceutical Research and biologically-based cancer drugs. Manufacturers of America (PhRMA). InfoBeat, February 19, 1998. 1995 survey: biotechnology drug

Biotech Pharmaceuticals and Biotherapy research has come of age. In: 13. Schiavone L. Unique vaccine shows Biotechnology Medicines in promise in battling ovarian cancer. Development. Washington, DC: CNN Interactive, Health section PhRMA; 1995:1. (http://cnn.com/HEALTH/), March 26 15, 1998. 24. Cunliffe V, Thatcher D, Craig R. Medicinal Chemistry. 4th ed. Media, Special Innovative approaches to gene thera- PA: Williams & Wilkins; 1995:632. py. In: Current Opinion in Biotechnol- Report ogy. 1995; 6:709. 38. Garnick RL, Ross MJ, Baffi RA.

Characterization of proteins from Biotherapy and Pharmaceuticals Biotech 25. Reuters. Gene technique may help in recombinant DNA manufacture. In: chemotherapy. InfoBeat, December 29, Chiu YH, Gueriguian JL, eds. Drug 1997. Biotechnology Regulation. New York: Marcel Dekker; 1991:281. 26. Gene therapy: a new role disrupting tumor’s blood supply? JNCI. 1998; 39. Garnick RL, Ross MJ, Baffi RA. 90:270Ð271. Characterization of proteins from recombinant DNA manufacture. In: 27. Circulation. 97:1114Ð1123, 1998. Chiu YH, Gueriguian JL, eds. Drug Biotechnology Regulation. New York: 28. Reuters. Gene therapy for heart attack. Marcel Dekker; 1991:299Ð300. Yahoo! News, January 7, 1988. 40. Currie BL, Groves MJ. Protein stability 29. Associated Press. Genes are hope as and degradation mechanisms. In: alternative to heart bypasses. The New Pharmaceutical Biotechnology. Buffalo York Times, January 20, 1998:F9. Grove, IL: Interpharm Press; 1992:205Ð217. 30. Preston J. New blood vessels grown in humans—U.S. researcher. InfoBeat, 41. Koeller J, Fields S. The pharmacist’s March 30, 1998. role with biotechnology products. In: Contemporary Pharmacy Issues. 31. Bodnar AG, et al. Extension of life- Upjohn; 1991:8. span by introduction of telomerase into normal human cells. Science. 42. Currie BL, Groves MJ. Protein stability 1998; 279:349Ð352. and degradation mechanisms. In: Pharmaceutical Biotechnology. Buffalo 32. de Lange T. Telomeres and senescence: Grove, IL: Interpharm Press; ending the debate. Science. 1998; 1992:214. 279:334Ð335. 43. Sobel S. Regulatory evaluation of 33. Wade N. Cell rejuvenation may yield biotechnology drugs: current trends in rush of medical advances. The New the United States. In: Chiu YH, York Times, January 20, 1998. Gueriguian JL, eds. Drug Biotechnology Regulation. New York: 34. Bains W. Biotechnology from A to Z. Marcel Dekker; 1991:502. New York: Oxford University Press; 1993:335. 44. Miller HI. When worlds collide: sci- ence, politics, and biotechnology. 35. Looking for synergy in prodrug- Priorities. 1997; 9(4):8Ð13. activating gene therapy. JNCI. 1998; 90:341. 45. Hile JP, et al. A compilation of govern- ment regulation of biotechnology. 36. Sindelar RD. Pharmaceutical biotech Appendix in Drug Biotechnology nology. In: Foyes WO, Lemke TL, Regulation. New York: Marcel Dekker; Williams DA, eds. Principles of 1991: 525Ð544. Medicinal Chemistry. 4th ed. Media, PA: Williams & Wilkins; 1995:624. 46. Marwick C. FDA Funding problems imperil safety of biological products in 37. Sindelar RD. Pharmaceutical biotech the United States. JAMA. 1998; nology. In: Foyes WO, Lemke TL, 279:899Ð901. Williams DA, eds. Principles of 27 Glossary Special Report active ingredient: A product component chromosome: A strand of DNA and proteins responsible for an effect the product was that carries genes. designed to have. clotting factor: Any of a group of chemical angiogenesis: The formation of blood ves- blood constituents whose interaction causes sels. Angiogenesis occurs naturally during blood coagulation. pregnancy and wound healing. cytokine: Any of a group of hormonelike angioplasty: A procedure to alter or repair a molecules that can control reactions between blood vessel (e.g., to unblock a coronary cells. artery). DNA (deoxyribonucleic acid): Any of various antibody (immunoglobulin): Any of various acids that are found in cell nuclei and are the proteins that mark foreign material in the principal components of chromosomes; the body, such as bacteria and viruses, for molecular basis of heredity. removal or destruction by other components of the immune system. endogenous: Originating inside (e.g., natural- ly produced by one’s body). antigen: Any of various substances that can stimulate the immune system to produce anti- enzyme (natural catalyst): Any of numerous bodies. proteins and proteinÐnonprotein compounds that living cells produce and that can initiate atherosclerosis: The most common form of or affect the speed of specific chemical reac- hardening of the arteries. tions.

bioconversion: The conversion of chemicals gene: A unit of chemical information respon- or organic material (e.g., animal waste) into sible for a particular hereditary trait, such as useful or more useful products through eye color. processes that involve living things, dead cells, or enzymes. genetic (genic): Of, relating to, produced by, or being a gene. biological (biologic, biological product): Any preparation made or synthesized from living hairy cell leukemia: A form of blood cancer organisms or their products and used as a named after the hairlike projections of its diagnostic, preventive, or therapeutic agent. tumor cells and marked by the proliferation of Biologicals range from blood to antitoxins lymphocytes. and vaccines. hormone: Any of numerous substances (e.g., biotech (biotechnical, biotechnological): Of adrenaline, insulin, and melatonin) that are or relating to biotechnology. transmittable by the bloodstream to cells dis- tant from their source and that have specific biotherapy: Any treatment that involves the effects on such cells. administration of a microorganism or other

Biotech Pharmaceuticals and Biotherapy biologic matter. hybridoma: A cell that results from the biotech fusion of a bone-marrow tumor cell B lymphocyte (B cell): An antibody-produc- and a B lymphocyte. Hybridomas replicate ing white blood cell. (divide) endlessly and can be used to produce 28 specific antibodies in bulk. immunosuppressant: Any drug or chemical prodrug: A drug precursor (“pro-” means “pre- that can restrain an immune response (e.g., to cursory”); a medical compound designed to Special prevent immune rejection of a transplanted work only after the body, or a specific type of Report

organ). bodily tissue, has converted it. Biotech Pharmaceuticals and Biotherapy and Pharmaceuticals Biotech interferon: Any of a group of small protein- psoriasis: A chronic skin disease characterized carbohydrate compounds that can prevent viral by dry, flaky patches, often on the elbows, replication and can slow the growth and repli- knees, genitals, nails, and scalp. cation of cancer cells. radiolabeled: Distinguished by combination interleukin: Any of a group of protein-carbo- with a radioactive atom or substance. hydrate compounds that function as immune- system regulators. recombinant [adjective]: Produced by recom- binant DNA technology. leukocyte (leucocyte, white blood cell, white blood corpuscle, white cell): One of a group of recombinant DNA technology (bioengineer- colorless blood cells whose function is to coun- ing, gene splicing, genetic engineering, med- teract infection. ical biotechnology, the new biotechnology, rDNA technology): Altering genetic (DNA) liposome: A microscopic fatty droplet designed molecules outside an organism and making the to carry a therapeutic substance. resultant DNA molecules (called “recombinant DNA”) function in living things. lymphocyte (lymph cell): A type of leukocyte (white blood cell) that can detect foreign mate- renal: Relating to kidneys. rial and is primarily responsible for immune responses. RNA (ribonucleic acid): A single-stranded molecule, found in all living cells, that con- macrophage: A large phagocyte; any of a tributes to transferring information from DNA group of leukocytes (white blood cells) that can to the cell’s protein-forming system. engulf bacteria and other foreign material. slow virus: Any of a group of noncellular melanoma: Cancer of pigment-producing skin infective agents—specifically, viruses and/or cells. prions (abnormal protein particles)—whose incubation period is long. An incubation period monoclonal antibody (MAb, MoAb): One of is the time between a pathogen’s entrance into any group of identical artificial antibodies. an organism or organ and the first appearance of the disease it causes. neutrophil: A type of leukocyte (white blood cell) that can engulf and kill microorganisms. vaccine: Any preparation designed to prevent, ameliorate, or restrain a specific disease (par- phagocyte: Any cell capable of the uptake of ticularly a specific infectious disease) in an material (e.g., bacteria) by the formation of a organism by inducing or increasing antibody vesicle, or membranous “pouch.” In mammals, production therein without causing disease. the main phagocytes are neutrophils and macrophages. virus: Any of a group of noncellular parasites that are smaller than bacteria, can multiply pharmaceutical: Any drug preparation or only within living cells, and consist of a strand product used preventively or in the diagnosis or of either DNA or RNA and at least one protein treatment of a physical, mental, or behavioral cover. condition. 29 ACSH EXECUTIVE STAFF Elizabeth M. Whelan, Sc.D., M.P.H. President

ACSH BOARD OF DIRECTORS

A. Alan Moghissi, Ph.D Raymond Gambino, M.D. Kary D. Presten Stephen S. Sternberg, M.D. Chairman Corning Clinical Laboratories U.S. Trust Co. Memorial Sloan-Kettering Cancer Center of the Board, ACSH Institute for Regulatory Science Jerald L. Hill, Esq. R.T. Ravenholt, M.D., M.P.H. Lorraine Thelian Hill & Associates Population Health Imperatives Ketchum Public Relations Norman E. Borlaug, Ph.D. Texas A&M University Roger P. Maickel, Ph.D. Fredrick J. Stare, M.D., Ph.D. Elizabeth M. Whelan, Sc.D., M.P.H. Purdue University Harvard School President, ACSH Taiwo K. Danmola, C.P.A. of Public Health Arthur Andersen LLP Henry I. Miller, M.D. Robert J. White, M.D., Ph.D. Hoover Institution Fredric M. Steinberg, M.D. Case Western Reserve University F. J. Francis, Ph.D. Mainstreet Health Care Inc. University of Massachusetts Albert G. Nickel Lyons Lavey Nickel Swift, Inc.

ACSH BOARD OF SCIENTIFIC AND POLICY ADVISORS Julie A. Albrecht, Ph.D. C. Jelleff Carr, Ph.D. Ralph E. Dittman, M.D., M.P.H. LaNelle E. Geddes, Ph.D., R.N. U. of Nebraska, Lincoln Columbia, MD Houston, TX Purdue University Roslyn B. Alfin-Slater, Ph.D. Robert G. Cassens, Ph.D. John. E. Dodes, D.D.S. K. H. Ginzel, M.D. UCLA University of Wisconsin National Council Against Health Fraud University of Arizona Thomas S. Allems, M.D., M.P.H. James J. Cerda, M.D. John Doull, Ph.D., M.D. William Paul Glezen, M.D. San Francisco, CA University of Illinois University of Kansas Baylor College of Medicine Richard G. Allison, Ph.D. Bruce M. Chassy, Ph.D. Theron W. Downes, Ph.D. Jay Alexander Gold, M.D., J.D., American Institute of Nutrition (FASEB) University of Florida Michigan State University M.P.H. John B. Allred, Ph.D. Dale J. Chodos, M.D. Adam Drewnowski, Ph.D. Medical College of Wisconsin Ohio State University Kalamazoo, MI University of Michigan Roger E. Gold, Ph.D. Philip R. Alper, M.D. Emil William Chynn, M.D. Michael A. Dubick, Ph.D. Texas A&M University U. of California, San Francisco Manhattan Eye and Ear Infirmary U.S. Army Institute of Timothy N. Gorski, M.D. Dennis T. Avery Walter L. Clark, Ph.D. Surgical Research Arlington, TX Hudson Institute Chapman University Edward R. Duffie Jr., M.D. Ronald E. Gots, M.D., Ph.D. Robert S. Baratz, D.D.S., Ph.D., M.D. Dean O. Cliver, Ph.D. Savannah, GA National Medical Advisory Service Boston University School University of California, James R. Dunn, Ph.D. Michael Gough, Ph.D. of Medicine Davis Averill Park, NY Cato Institute Stephen Barrett, M.D. F. M. Clydesdale, Ph.D. Robert L. DuPont, M.D. Henry G. Grabowski, Ph.D. Allentown, PA University of Massachusetts DuPont Associates, P.A. Duke University Walter S. Barrows Sr., Ph.D. Donald G. Cochran, Ph.D. Henry A. Dymsza, Ph.D. Carpinteria, CA Virginia Polytechnic Institute & State University of Rhode Island John D. Graham, Ph.D. Harvard Center for Risk Analysis Thomas G. Baumgartner, M.Ed., University Michael W. Easley, D.D.S., M.P.H. Pharm.D. W. Ronnie Coffman, Ph.D. State University of New York James Ian Gray, Ph.D. Michigan State University University of Florida, Gainesville Cornell University Michael P. Elston, M.D., M.S. Blaine L. Blad, Ph.D. Bernard L. Cohen, D.Sc. Rapid City Regional Hospital William W. Greaves, M.D., M.S.P.H. Medical College of Wisconsin University of Nebraska University of Pittsburgh James E. Enstrom, Ph.D., M.P.H. Hinrich L. Bohn, Ph.D. Neville Colman, M.D., Ph.D. UCLA Saul Green, Ph.D. Zol Consultants, Inc. University of Arizona St. Luke’s Roosevelt Myron E. Essex, D.V.M., Ph.D. Ben Wilsman Bolch, Ph.D. Hospital Center Harvard School of Public Health Richard A. Greenberg, Ph.D. Hinsdale, IL Rhodes College Gerald F. Combs, Jr., Ph.D. Terry D. Etherton, Ph.D. J. F. Borzelleca, Ph.D. Cornell University Pennsylvania State University Gordon W. Gribble, Ph.D. Dartmouth College Medical College of Virginia Michael D. Corbett, Ph.D. Daniel F. Farkas, Ph.D. Michael K. Botts, Esq. Eppley Institute for Cancer Research Oregon State University William Grierson, Ph.D. University of Florida Nevada, IA Eliot Corday, M.D. Richard S. Fawcett, Ph.D. Michael B. Bracken, Ph.D., M.P.H. Cedars-Sinai Medical Center Huxley, IA Lester Grinspoon, M.D. Harvard Medical School Yale University Roger A. Coulombe, Ph.D. John B. Fenger, M.D. George A. Bray, M.D. Utah State University Phoenix, AZ Helen A. Guthrie, Ph.D. Pennington Biomedical Research Center H. Russell Cross, Ph.D. Owen R. Fennema, Ph.D. Pennsylvania State University Allan Brett, M.D. Texas A&M University University of Wisconsin Philip S. Guzelian, M.D. University of South Carolina Charles R. Curtis, Ph.D. Madelon Lubin Finkel, Ph.D. University of Colorado Christine M. Bruhn, Ph.D. Ohio State University Cornell University Alfred E. Harper, Ph.D. Center for Consumer Research Ilene R. Danse, M.D. Jack C. Fisher, M.D. University of Wisconsin Gale A. Buchanan, Ph.D. Enviromed Health Services U. of California, San Diego Robert D. Havener University of Georgia Ernst M. Davis, Ph.D. Kenneth D. Fisher, Ph.D. Solvang, CA U. of Texas at Houston Edward E. Burns, Ph.D. Commission on Dietary Supplement Virgil W. Hays, Ph.D. Texas A&M University Harry G. Day, Sc.D. Labels University of Kentucky Indiana University Francis F. Busta, Ph.D. Leonard T. Flynn, Ph.D., M.B.A. Dwight B. Heath, Ph.D. University of Minnesota Jerome J. DeCosse, M.D. Morganville, NJ Brown University Ogbourne Butler, Ph.D. N.Y. Hospital–Cornell William H. Foege, M.D., M.P.H. Medical Center Norman D. Heidelbaugh, V.M.D., College Station, TX Emory University M.P.H., S.M., Ph.D. Earl L. Butz, Ph.D. Thomas R. DeGregori, Ph.D. Ralph W. Fogleman, D.V.M. Texas A&M University University of Houston Purdue University Upper Black Eddy, PA Zane R. Helsel, Ph.D. William G. Cahan, M.D. Robert M. Devlin, Ph.D. E.M. Foster, Ph.D. Rutgers University University of Massachusetts Memorial Sloan-Kettering University of Wisconsin L. M. Henderson, Ph.D. Cancer Center Seymour Diamond, M.D. Glenn Froning, Ph.D. University of Minnesota Diamond Headache Clinic Elwood F. Caldwell, Ph.D., M.B.A. U. of Nebraska, Lincoln Victor Herbert, M.D., J.D. University of Minnesota Donald C. Dickson, M.S. Arthur Furst, Ph.D., Sc.D. Bronx Veterans Affairs Medical Cemter Gilbert, AZ Barbara N. Campaigne, Ph.D. University of San Francisco John Higginson, M.D., F.R.C.P. American College of Sports Medicine John Diebold Charles O. Gallina, Ph.D. Savannah, GA Zerle L. Carpenter, Ph.D. The Diebold Institute for Public Policy Illinois Dept. of Nuclear Safety Texas A&M University System Studies ACSH BOARD OF SCIENTIFIC AND POLICY ADVISORS

Richard M. Hoar, Ph.D. Daryl Lund, Ph.D. Albert M. Pearson, Ph.D. S. Fred Singer, Ph.D. Williamstown, MA Cornell University Oregon State University Science & Environmental John H. Holbrook, M.D. Harold Lyons, Ph.D. Timothy Dukes Phillips, Ph.D. Policy Project University of Utah Rhodes College Texas A&M University Robert B. Sklaroff, M.D. Robert M. Hollingworth, Ph.D. Howard D. Maccabee, Ph.D., M.D. Mary Frances Picciano, Ph.D. Elkins Park, PA Michigan State University Radiation Oncology Center Pennsylvania State University Gary C. Smith, Ph.D. Edward S. Horton, M.D. Henry G. Manne, J.S.D. Thomas T. Poleman, Ph.D. Colorado State University Joslin Diabetes Center George Mason University Cornell University Myron Solberg, Ph.D. Joseph H. Hotchkiss, Ph.D. Karl Maramorosch, Ph.D. Charles Polk, Ph.D. Cook College, Rutgers University Cornell University Rutgers University University of Rhode Island Roy F. Spalding, Ph.D. Susanne L. Huttner, Ph.D. Judith A. Marlett, Ph.D., R.D. Gary P. Posner, M.D. University of Nebraska U. of California, Berkeley University of Wisconsin, Madison Tampa, FL Leonard T. Sperry, M.D., Ph.D. Lucien R. Jacobs, M.D. James R. Marshall, Ph.D. John J. Powers, Ph.D. Medical College of Wisconsin UCLA School of Medicine Arizona Cancer Center University of Georgia Robert A. Squire, D.V.M., Ph.D. Rudolph J. Jaeger, Ph.D. James D. McKean, D.V.M., J.D. William D. Powrie, Ph.D. Johns Hopkins University Environmental Medicine, Inc. Iowa State University University of British Columbia Ronald T. Stanko, M.D. G. Richard Jansen, Ph.D. John J. McKetta, Ph.D. Kenneth M. Prager, M.D. University of Pittsburgh Colorado State University University of Texas, Austin Columbia Presbyterian Medical Center James H. Steele, D.V.M., M.P.H. William T. Jarvis, Ph.D. Donald J. McNamara, Ph.D. Daniel J. Raiten, Ph.D. University of Texas Loma Linda University Egg Nutrition Center FASEB Robert D. Steele, Ph.D. Edward S. Josephson, Ph.D. Patrick J. Michaels, Ph.D. Russel J. Reiter, Ph.D., D.Med. Pennsylvania State University University of Rhode Island University of Virginia University of Texas Judith S. Stern, Sc.D. Michael Kamrin, Ph.D. Thomas H. Milby, M.D., M.P.H. John H. Renner, M.D. University of California, Davis Michigan State University Walnut Creek, CA Consumer Health Information Research C. Joseph Stetler, Esq. John B. Kaneene, D.V.M., M.P.H., Joseph M. Miller, M.D., M.P.H. Institute Bethesda, MD Ph.D. University of New Hampshire Rita Ricardo-Campbell, Ph.D. Martha Barnes Stone, Ph.D. Michigan State University William J. Miller, Ph.D. Hoover Institution Colorado State University Philip G. Keeney, Ph.D. University of Georgia Barbara K. Rimer, Dr.P.H. Glenn Swogger Jr., M.D. Pennsylvania State University John A. Milner, Ph.D. Duke University Medical Center Topeka, KS John G. Keller, Ph.D. Pennsylvania State University Mark A. Roberts, M.D., Ph.D. Sita R. Tatini, Ph.D. Olney, MD Dade W. Moeller, Ph.D. Medical College of Wisconsin University of Minnesota George R. Kerr, M.D. Harvard School of Public Health William O. Robertson, M.D. Mark C. Taylor, M.D. University of Texas Grace P. Monaco, J.D. University of Washington Physicians for a Smoke-Free Canada George A. Keyworth II, Ph.D. Medical Care Mgmt. Corp. J. D. Robinson, M.D. Steve L. Taylor, Ph.D. Progress and Freedom Foundation Brian E. Mondell, M.D. George Washington University University of Nebraska Michael Kirsch, M.D. Baltimore Headache Institute David B. Roll, Ph.D. Murray M. Tuckerman, Ph.D. Highland Heights, OH Eric W. Mood, LL.D., M.P.H. University of Utah Winchendon Springs, MA John C. Kirschman, Ph.D. Yale University Dale R. Romsos, Ph.D. Joe B. Tye, M.S., M.B.A. Emmaus, PA John P. Morgan, M.D. Michigan State University Paradox 21 Ronald E. Kleinman, M.D. City University of New York Steven T. Rosen, M.D. Varro E. Tyler, Ph.D., Sc.D. Massachussetts General Hospital John W. Morgan, Dr.P.H. Northwestern University Medical School Purdue University Kathryn M. Kolasa, Ph.D., R.D. Loma Linda University Kenneth J. Rothman, Dr.P.H. Robert P. Upchurch, Ph.D. East Carolina University W. K. C. Morgan, M.D. Newton Lower Falls, MA University of Arizona David Kritchevsky, Ph.D. University Hospital, Ontario Stanley Rothman, Ph.D. Mark J. Utell, M.D. The Wistar Institute, Philadelphia Stephen J. Moss, D.D.S., M.S. Smith College U. of Rochester Medical Center Manfred Kroger, Ph.D. David B. Kriser Dental Center Edward C. A. Runge, Ph.D. Shashi B. Verma, Ph.D. Pennsylvania State University Ian C. Munro, Ph.D. Texas A&M University U. of Nebraska, Lincoln J. Laurence Kulp, Ph.D. CanTox, Inc. Stephen H. Safe, D.Phil. Willard J. Visek, Ph.D., M.D. Federal Way, WA Kevin B. Murphy Texas A&M University University of Illinois Carolyn J. Lackey, Ph.D., R.D. Merrill Lynch, Pierce, Fenner & Smith Paul D. Saltman, Ph.D. W. F. Wardowski, Ph.D. North Carolina State University Philip E. Nelson, Ph.D. U. of California, San Diego University of Florida J. Clayburn LaForce, Ph.D. Purdue University Wallace I. Sampson, M.D. Miles Weinberger, M.D. UCLA Malden C. Nesheim, Ph.D. Stanford U. School University of Iowa Hospitals Lawrence E. Lamb Cornell University of Medicine and Clinics Santa Barbara, CA John S. Neuberger, Dr.P.H. Harold H. Sandstead, M.D. Steven D. Wexner, M.D. Lillian Langseth, Dr.P.H. University of Kansas University of Texas Medical Branch Cleveland Clinic, FL Lyda Associates, Palisades, NY Gordon W. Newell, Ph.D. Herbert P. Sarett, Ph.D. Joel E. White, M.D. Larry Laudan, Ph.D. Palo Alto, CA Sarasota, FL Radiation Oncology Center National Autonomous University of Mexico James L. Oblinger, Ph.D. Lowell D. Satterlee, Ph.D. Carol Whitlock, Ph.D., R.D. Brian C. Lentle, M.D. North Carolina State University Oklahoma State University Rochester Inst. of Technology Vancouver General Hospital Richard Oksas, M.P.H., Pharm.D. Marvin J. Schissel, D.D.S. Christopher F. Wilkinson, Ph.D. Floy Lilley, J.D. Medication Information Service Woodhaven, NY Technology Services Group, Inc. University of Texas, Austin J. E. Oldfield, Ph.D. Barbara Schneeman, Ph.D. Carl K. Winter, Ph.D. Bernard J. Liska, Ph.D. Oregon State University University of California, Davis University of California, Davis Purdue University Stanley T. Omaye, Ph.D. Edgar J. Schoen, M.D. James J. Worman, Ph.D. William M. London, Ed.D., M.P.H.. University of Nevada Kaiser Permanente Medical Center Rochester Institute of Technology Fort Lee, NJ Jane M. Orient, M.D. Patrick J. Shea, Ph.D. James Harvey Young, Ph.D. James A. Lowell, Ph.D. Tucson, AZ University of Nebraska, Lincoln Emory University Pima Community College M. Alice Ottoboni, Ph.D. Sidney Shindell, M.D., LL.B. Panayiotis Michael Zavos, Ph.D. Frank C. Lu, M.D. Sparks, NV Medical College of Wisconsin University of Kentucky Miami, FL Loren Pankratz, Ph.D. Sarah Short, Ph.D., Ed.D., R.D. Ekhard E. Ziegler, M.D. William M. Lunch, Ph.D. Oregon Health Sciences University Syracuse University University of Iowa Oregon State University Michael W. Pariza, Ph.D. A. J. Siedler, Ph.D. University of Wisconsin University of Illinois The opinions expressed in ACSH publications do not necessarily represent the views of all ACSH Directors and Advisors. ACSH Directors and Advisors serve without compensation.