12 May

By the 1880s, it was recognized that  the virulence of infectious diseases varied with many factors, including the means and duration of exposure, the way in which the germ entered the body, and the physiological status of  the  host.  By  the  turn  of  the  century,  the  fundamental  question

concerning scientists investigating the immune response was: is the mech- anism of innate and acquired  immunity humoral  or cellular?

When Behring was awarded  the first Nobel  Prize in Medicine for

his work  on serum  therapy,  he made  a special point  of reviewing the history of the dispute between cellular and humoral pathology.  He considered  antitoxic  serum  therapy  ‘‘humoral  therapy  in the  strictest sense  of  the  word.’’  Humoral theory,  Behring  predicted,  would  put medicine on the road  to a strictly scientific etiological therapy  in con- trast  to  traditional, nonspecific,  symptomatic remedies.  The  scientific debate  often  degenerated   into  vicious  personal   attacks,   but  Joseph Lister,  ever the gentleman,  delicately referred  to this controversial era as the ‘‘romantic chapter  in pathology.’’

As serology was transformed into immunology,  scientists saw the

new  discipline  rapidly  outgrowing   its  parental   disciplines  of  micro- biology  and  toxicology.   Studies  of  cellular  mechanisms   of  defense seemed to be a relic of a less sophisticated era of biology closely asso-

ciated  with  old-fashioned   ideas  such  as  those  of  E´ lie  Metchnikoff

(1845–1916). Other  immunologists  of this  period  were primarily  con- cerned with serum antibodies  and  tended  to ignore the role played by cells, but Metchnikoff, discoverer of phagocytes  (the ‘‘eating cells’’ that devour invading microorganisms) and the process of phagocytosis,  was more  interested  in the  defenses of the  host  than  the  depredations of the  pathogen.  While  most   scientists   argued   that   specific  chemical entities in the blood defended the body from bacteria and toxins, Metchnikoff  followed his own idiosyncratic hypotheses concerning evolution,  inflammation, immunity,  senility,  and  phagocytosis.  When he shared  the 1908 Nobel  Prize for Physiology or Medicine  with Paul Ehrlich,  Metchnikoff  was praised  as the  first  scientist  to  establish  an experimental  approach to the fundamental question  of immunity,  that is, how does the organism  overcome  disease-causing microbes?

Through  personal  experience Metchnikoff  knew how little physi- cians could do for victims of infectious diseases. His first wife had been so weakened  by consumption that  she had  to be carried  to their wed- ding. When she died five years later, Metchnikoff  tried to end his own life by swallowing  a large dose of opium.  With  his second  wife close to death  from  typhoid  fever, Metchnikoff  inoculated  himself with the spirochetes  thought to  cause  relapsing  fever so that  his death  would be of service to science. Fortunately, the excitement  generated  by the discovery of phagocytosis  rescued Metchnikoff  from the depression that had driven him to attempted bacteriological  suicide. From  1888 on, the Pasteur  Institute  provided  a refuge in which Metchnikoff  could pursue research problems that  were creative and original to the point of eccen- tricity. Primarily a zoologist, influenced as much by Charles Darwin  as Pasteur or Koch, Metchnikoff’s theories of inflammation and immunity grew out of his evolutionary vision of comparative  pathology.

Studies of inflammation that began with starfish larvae led Metchnikoff  to the conclusion that phagocytosis was a biological phenomenon of  fundamental importance. While  observing  the  inter- action between phagocytes and bacteria, Metchnikoff discovered that phagocytosis  was greatly  enhanced  in animals  previously  exposed  to the same kind of bacteria.  He, therefore,  concluded that  mobile phago- cytes were the  primary  agents  of inflammation and  immunity.  In  his Nobel  Prize lecture, he expressed hope that  people would see his work as an  example  of the  ‘‘practical  value  of pure  research.’’ Inspired  by Metchnikoff’s  ‘‘phagocyte  theory,’’  some  surgeons  attempted to  rush white corpuscles  to  the rescue by introducing various  substances  into the abdominal  cavity or under  the skin. Another  follower of Metchni- koff’s theories  systematically  applied  cupping-glasses  and  rubber  liga- tures around the site of abscesses and similar infections.  The localized edema produced  by these procedures  was supposed  to attract  an army of protective  phagocytes.

Confident  that  science would  eventually  free human  beings from

the threat  of disease, Metchnikoff  applied  his theory  of the phagocyte to  the  specter  of senility. Reflecting  on  the  principles  of comparative pathology,   he  concluded  that  phagocytes  were  primarily  responsible for the signs and  symptoms  of senility. From  gray hair  and  baldness to  weakness  of bone,  muscle, and  brain,  Metchnikoff  saw the telltale footprints of myriads of motile cells ‘‘adrift in the tissues of the aged.’’ Noxious influences, such as bacterial toxins and the products  of intesti- nal putrefaction, allegedly triggered the transformation of friendly phagocytes  into fearsome foes. Even though  Metchnikoff  believed that phagocytes  caused senility, he warned  that  destroying  these misguided cells would  not  prolong   life,  because  the  body  would  then  be  left defenseless in the struggle against  pathogenic  microbes.

After  comparing  the  life spans  of various  animals,  Metchnikoff

concluded that the organs of digestion determined  length of life. Specif- ically, the problem resided in the large intestine where microbial mischief produced  ‘‘fermentations  and putrefactions harmful  to the organism.’’ Stopping  just short  of a call for prophylactic  removal  of this ‘‘useless organ,’’  Metchnikoff   suggested  that   disinfecting  the  digestive  tract might  lengthen   life.  Unfortunately,  traditional  purges   and   enemas seemed to harm the intestines more than the microbes. Since acids could preserve animal and vegetable foods, Metchnikoff  concluded that lactic fermentation might prevent  putrefaction within the intestines.  In prac- tical terms, his advice could be summarized  by the motto:  ‘‘Eat yogurt and  live longer.’’

Although  scientists generally ignored Metchnikoff’s  theory  of the treacherous phagocytes  and  the useless large intestine,  his ideas about the  positive  and  negative  activities  of  phagocytes  and  the  ambiguity of  the  inflammatory response  were  remarkably prescient.  When  the

body responds to noxious stimuli, the site of the injury exhibits what the Roman   writer  Celsus  called  the  cardinal  signs  of  inflammation and becomes red, swollen, warm,  and  painful.  Although  the inflammatory response  is most  noticeable  on  the  skin,  it  also  occurs  internally,  in response to viral invaders or spoiled food. Thus, although  inflammation is the body’s normal  protective  reaction,  in many  cases, inflammation can harm the tissues it is meant to heal. This occurs in diseases like rheu- matoid  arthritis  and  multiple  sclerosis. In  the  elderly, the  destructive effects of inflammation may be involved in other  common  chronic dis- eases, such as arteriosclerosis, diabetes, Alzheimer’s disease, osteo- porosis,  asthma,  cirrhosis of the liver, some bowel disorders,  psoriasis, meningitis, cystic fibrosis, and cancer. Indeed, some researchers suggest that the use of anti-inflammatory drugs like ibuprofen  or naproxen  may prevent or delay the development  of some of the chronic and debilitat- ing diseases of old age, such as Alzheimer’s disease.

Of course the body’s failure to mount  an effective defense against some pathogens  was well known,  but the discovery by Charles  Robert Richet (1850–1935) and Paul Jules Portier (1866–1962) that the immune system could react to certain  antigens  with life-threatening hypersensi- tivity was unexpected.  Richet, who won the Nobel Prize in 1913, coined the term ‘‘anaphylaxis’’ to describe this dangerous  response.  Based on the Greek  word  phylaxis meaning  protection, anaphylaxis  referred  to

‘‘that state of an organism in which it is rendered hypersensitive, instead

of being protected.’’  Violent itching, vomiting,  bloody  diarrhea,  faint- ing, choking,  and convulsions  characterized this state of hypersensitiv- ity.  In  its  most  severe  form,  anaphylactic shock  could  cause  death within  a  few minutes  of  exposure  to  the  offending  antigen.  Further investigations proved that just as it was possible to transfer passive immunity,  it was also  possible  to  transfer  the  anaphylactic condition via serum.

Anaphylaxis  seemed  to  be a  peculiar  exception  to  the  generally beneficial  workings   of  the  immune   system.  Thus,   many   scientists believed that immunology would provide the key to establishing powerful new approaches to therapeutics. A good example of the optimism characteristic   of  this  early  phase  of  immunology  is provided  by  Sir Almroth  Wright (1861–1947), a man who was expected to take the torch from Pasteur and Koch and illuminate new aspects of experimental immunization and  medical bacteriology.  Wright  expected  his work  in the Inoculation Department at St. Mary’s Hospital  to bring about  a rev- olution  in medicine, but he is generally remembered  only as Alexander Fleming’s mentor.

A man of broad interests and inflexible opinions, Wright published about  150 books and papers in science, intellectual morality, and ethics. In addition to his scientific articles, Wright often used the British newspapers  to vent his opinions  on issues ranging  from the ignorance

of army  officials to the campaign  for woman  suffrage, which he vehe- mently  opposed.  While professor  of pathology  at  the  Army  Medical School in Royal  Victoria  Hospital,  Wright  developed  sensitive labora- tory methods  of diagnosing  the ‘‘army fevers’’ that  killed more soldiers than bullets. Using a diagnostic test based on what he called the aggluti- nation   effect  (the  clumping  of  microbes  in  response  to  serum  from patients recovering from a disease), Wright prepared a vaccine that apparently protected  monkeys from Malta  fever. In the great tradition of  scientists  who  served  as  their  own  guinea  pigs,  Wright  injected himself  with  his vaccine.  Unfortunately, Wright  was not  as lucky  as his monkeys.

While  recovering  from  Malta   fever,  Wright  began  planning   a

major  study  of  typhoid   fever.  During   the  1890s,  this  dreaded   dis- ease claimed tens of thousands of lives in the United  States and Great Britain. The case fatality rate varied from 10 to 30 percent, but recovery was a slow and unpredictable process. Using himself and his students as guinea  pigs, Wright  found  that  heat-killed  cultures  of typhoid  bacilli could  be used as vaccines. Sir William  Boog Leishman’s  (1865–1926) study  of  typhoid  cases  in  the  British  Army  between  1905 and  1909 provided  the first significant documentation of the value of antityphoid inoculations. According to Leishman, the death rate of the unvaccinated men  was 10 times  that  of the  inoculated  group.  Nevertheless,  at  the beginning of World War I, antityphoid inoculations  in the British Army were still voluntary.

Openly  contemptuous of  the  ‘‘military  mentality,’’  Wright  was happy  to resign from  the Army Medical  Service when he was offered the position  of pathologist at  St. Mary’s  Hospital  in 1902. Although he received only a small salary,  meager facilities, and  was responsible for many  tedious  and  time-consuming  duties, he attracted eager disci- ples and hordes of desperate  patients.  With the fees charged for vaccine therapy,  Wright’s  Inoculation Department became  a  flourishing  and financially  rewarding   enterprise.   According   to  Wright,   ingestion  of microbes  by  phagocytes  required  the  action  of  certain  substances  in the blood that  he called ‘‘opsonins,’’ from the Greek opsono,  meaning,

‘‘I prepare victuals for.’’ Wright’s vaccines were designed to increase the

so-called  opsonic  index of the blood  by making  pathogenic  microbes more attractive  and digestible.

Patients   suffering  from  acne,  bronchitis,   carbuncles,   erysipelas, and even leprosy submitted  to Wright’s experimental  inoculations  and blood  tests.  Doubtless  many  patients  eventually  recovered  from  self- limited infections, despite the therapy rather than because of it. Disdain- ful of statistical  evaluations  of medical interventions, Wright  exhibited great confidence in his methods and warned reactionary physicians that they would be ‘‘degraded to the position  of a head nurse’’ as the art of medicine was transformed into a form of applied  bacteriology.  By the

end of World War II, it was obvious that Wright’s opsonically calibrated vaccines were no more successful than  Metchnikoff’s  attempts  to neu- tralize  the  harmful  effects of phagocytes  with  yogurt.  Even  Wright’s admirers  were forced  to  conclude  that  the  vaccines dispensed  by his Inoculation Department were generally ‘‘valueless to the point of fraudu- lence.’’ British playwright and social critic George Bernard Shaw (1856–

1950)  immortalized   Almroth   Wright’s  eccentricities  in  The  Doctor’s

Dilemma, but scientists remembered  him as ‘‘Sir Almost Wright.’’ Reviewing what was known  about  immunology  in the 1920s, the

eminent  physiologist  Ernest  H.  Starling  (1866–1927) concluded  that

the only thing perfectly clear about the immune system was that ‘‘immu- nity,  whether  innate  or  acquired,  is extremely complex  in character.’’ Further studies of the system have added  more  degrees of complexity and  controversies  at  least as vigorous  as those  that  characterized the conflict  between  humoral  and  cellular  theory.  Immunology is a rela- tively young field, but  its twentieth-century evolution  was so dynamic that  it ultimately  became one of the fundamental disciplines of modern medicine   and   biology.   Discussions   of   AIDS,   cancer,   rheumatoid arthritis, metabolic  disorders,  and  other  modern  plagues  are  increas- ingly conducted  in the arcane  vocabulary  of immunobiology.

Modern   explanations for  the  induction   of  antibodies  and  their

remarkable diversity  and  specificity can  be divided  into  information, or instructionist theories, and genetic, or selectionist theories. According to  the  information theory  of antibody  synthesis,  the  antigen  dictates the  specific  structure   of  the  antibody   by  direct  or  indirect  means. Direct  instruction  implies that  the  antigen  enters  a randomly  chosen antibody-producing cell and  acts  as a template  for  the production of antibodies  with a configuration complementary to that  antigen.  An in- direct template theory suggests that when an antigen enters an antibody- producing  cell it modifies  the  transcription of immunoglobulin  genes and, therefore, affects the sequence of the amino acids incorporated into the antibodies  produced  by that  cell and its daughter  cells.

A genetic or  selectionist  theory  of antibody  production  assumes

that  information for the synthesis of all possible configurations of anti- bodies  is  contained   in  the  genome  and  that   specific  receptors   are normally  present  on immunocompetent cells. Selectionist  theories  pre- suppose  sufficient natural diversity to provide  ample opportunities for accidental   affinity   between  antigen   and   immunoglobulin-producing cells. In this scenario, the antigen acts as a kind of trigger for antibody synthesis.

One  of  the  first  modern   theories  of  antibody   formation,  Paul

Ehrlich’s side-chain theory, was an attempt  to provide a chemical expla- nation  for  the  specificity of the  antibody  response  and  the  nature  of toxins, toxoids, and antibodies. According to this theory, antibody- producing cells were studded with ‘‘side-chains,’’ that is, groups capable

of  specifically  combining   with  antigens   such  as  tetanus   toxin  and diphtheria toxin. When a particular antigen entered the body, it reacted with its special side-chain. In response, the affected cell committed  itself to full-scale production of the appropriate side-chain. Excess side-chains became detached  and circulated  in the body fluids where they neutral- ized circulating  toxins.  Like  a key in a lock,  the  fit between  antigen and  antibody   was  remarkably  specific,  although   it  was  presumably due to accident rather  than  design.

Karl  Landsteiner (1868–1943) argued  that  Ehrlich’s  theory  was untenable   primarily   because  it  presupposed   an  ‘‘unlimited  number of physiological substances.’’ However, it was Landsteiner’s demon- stration    that   the   body   is  capable   of   making   antibodies   against

‘‘haptens’’ (small  molecules,  or  synthetic  chemical  radicals  that  were linked to proteins) that transformed the supposed number of antibodies from unlimited, in the sense of very large, to unlimited, in the sense of almost infinite. The implications of this line of research were so startling that Landsteiner, who won the 1930 Nobel Prize in Medicine for his dis- covery of the human  blood  groups,  considered  his development  of the concept of haptens  and the chemical approach to immunology  a much greater scientific contribution.

It had always been difficult to imagine an antibody-producing cell

carrying  a large enough  array  of potentially  useful side-chains to cope with   naturally    occurring   antigens.   Imagining   that   evolution   had equipped  cells with side-chains  for the synthetic  antigens  produced  by ingenious chemists was essentially impossible. No significant alternative to  the  genetic  theory  emerged,  however,  until  1930  when  Friedrich Breinl  (1888–1936)  and  Felix  Haurowitz   (1896–1988)  proposed   the first  influential  instructionist theory,  which  they  called  the  ‘‘template theory.’’  According   to  this  theory,  an  antigen  enters  a  lymphocyte and  acts  as a template  for  the specific folding  of an  antibody.  Many kinds  of  objections  were  offered  in  response  to  this  hypothesis,  but proof  that  antibodies  differ in their  amino  acid  sequence  made  early versions of this theory untenable.  A long line of complex clinical puzzles and   methodological  challenges   culminated   in  the   complete   deter- mination   of  the  amino  acid  sequence  of  an  entire  immunoglobulin molecule  in 1969 by Gerald  M.  Edelman  (1929–) and  his associates. Edelman  and  Rodney  R. Porter  (1917–1985) were awarded  the Nobel Prize in 1972 in recognition  of their work on the biochemical  structure of antibodies.

The instructionist theory of antibody  production was challenged in

1955 by Niels Kaj Jerne’s (1911–1994) ‘‘natural-selection theory,’’ which has been described as a revised and modernized form of Ehrlich’s classi- cal side-chain theory. Jerne worked at the Danish  State Serum Institute before earning a medical degree at Copenhagen. He served as the chief medical  officer of the World  Health  Organization from  1956 to  1962

and director of the Institute  of Immunology at Basel from 1969 to 1980. According  to  Jerne’s natural-selection theory,  an  antigen  seeks out  a globulin with the appropriate configuration, combines with it, and car- ries it to the antibody-producing apparatus. Although  Jerne introduced his  theory  in  the  1950s, it  was  not  until  1984 that  he  was  awarded the Nobel Prize in Medicine or Physiology ‘‘for theories concerning  the specificity in development  and  control  of the immune  system and  the discovery  of the  principle  for  production of monoclonal  antibodies.’’ In  his lecture  at  the  Nobel  ceremonies  Jerne  said,  ‘‘My concern  has always been synthetic  ideas, trying  to read  road-signs  leading into  the future.’’ Jerne’s vision of the natural-selection theory  of antibody  for- mation  and  his complex network  theory  of the immune  response  pro- vided the  framework  for  a new phase  in the  development  of cellular immunology. Jerne’s early publications served as a challenge to the instructionist theories that had become the dominant paradigm  of immunology.

The natural-selection theory implied that  the body’s innate ability

to generate a virtually unlimited number of specific antibodies was inde- pendent  of exposure  to foreign antigens.  Normal  individuals  are born with the genetic capacity  to produce  a large number  of different  anti- bodies, each of which has the ability to interact  with a specific foreign antigen.  When  the  immune  system  encounters   a  novel  antigen,  the pre-existing  antibody  molecule  that  has  the  best  fit interacts  with  it, thus  stimulating  the  cells that  produce  the  appropriate antibody.   In the 1970s, Jerne  elaborated his network  theory  as an  explanation for the regulation  of the immune response, essentially through  an antibody cascade  leading  to  anti-antibodies, anti-anti-antibodies, and  so forth, and the ability of the immune system to balance the network  by stimu- lating  or  suppressing   the  production  of  particular  antibodies.   This theory provided vital insights into the body’s response to infectious diseases, cancers, allergies, and autoimmune disease.

Modified  versions of antibody-selection theory solved the primary

difficulty  of  Jerne’s  original  concept  by substituting randomly  diver- sified cells for his randomly  diversified antibody  molecules. That is, cells are subject to selection, not antibodies.  In particular, the cell, or clonal- selection  theory,   independently   proposed   by  Sir  Frank  Macfarlane Burnet  (1899–1985) and  David  Talmage  (1919–), revolutionized  ideas about  the nature  of the immune system, the mechanism of the immune response,  and  the  genesis of immunologic  tolerance.  Burnet’s  clonal- selection  theory  encompassed  both  the  defense  mechanism  aspect  of the  immune  system  and  the  prohibition  against   reaction   to  ‘‘self.’’ During  development,  ‘‘forbidden clones’’ (cells that  could react against self) were presumably  eliminated  or destroyed.  Macfarlane Burnet  and Sir Peter Medawar  (1915–1987) were awarded  the Nobel  Prize in 1960 for their work on immunological  tolerance.

When  Macfarlane Burnet  reviewed  the  state  of  immunology  in

1967, 10 years  after  he proposed  the  clonal-selection  theory,  he was pleased to report  that  the field seemed to have ‘‘come of age.’’ Unlike Ehrlich  and  Landsteiner, who  had  emphasized  the  importance of  a chemical approach to immunology,  Burnet’s emphasis was on biological concepts: reproduction, mutation, and selection. By the 1980s, the cell- selection  theory  had  gone beyond  general  acceptance  to  the status  of

‘‘immunological  dogma.’’  This  transformation was stimulated  by the

explosive  development   of  experimental   cellular  immunology.   Immu- nology  laboratories were awash  with T cells and  B cells, helper  cells, suppressor  cells, killer cells, and fused cells producing  monoclonal  anti- bodies. Throughout the 1970s and 1980s, immunologists  were awarded Nobel  Prizes  for  remarkable  theoretical   and  practical   insights  into organ transplant rejection, cancer, autoimmune diseases, and the devel- opment of new diagnostic and therapeutic tools of great power and pre- cision. A century  of research  in immunology  since the  time of Louis Pasteur had created as many questions as it had answered, but it clearly established  the  fact  that  much  of  the  future  of  medical  theory  and practice would be outgrowths of immunobiology.

With  cardiovascular disease  and  cancer  replacing  the  infectious diseases as the leading causes of morbidity  and mortality  in the wealthy, industrialized  nations,  immunology  seemed to offer the answer to the riddle of health and disease just as microbiology  had provided  answers to  questions  about   the  infectious  disease.  In  the  1950s,  Macfarlane Burnet expressed his belief that immunology  was ready for a new phase of activity that  would reach far beyond the previous phase inspired by Paul Ehrlich. Microbiology  and chemotherapy had provided a powerful arsenal of magic bullets directed against the infectious diseases. By combining molecular biology and immunology,  scientists were attempt- ing to create a new generation  of genetically engineered drugs, including so-called smart bombs and poisoned arrows. These new weapons would be designed to target  not only old microbial  enemies, but also modern epidemic conditions  and  chronic  diseases, such as cardiovascular  dis- ease, cancer, Alzheimer’s disease, autoimmune disorders,  allergies, and organ  rejection.

When Cesar Milstein (1927–2002) and Georges Ko¨ hler (1946–1995) shared  the 1984 Nobel Prize with Jerne, they were specifically honored for the discovery of ‘‘the principle for production of monoclonal antibodies.’’  In his Nobel  Lecture,  Milstein stressed the importance of the fact that  the hybridoma technology  was an unexpected  by-product of basic research  that  had  been conducted  to understand the immune system.  It  was,  he  said,  a  clear  example  of  the  value  of  supporting research that might not have an obvious immediate practical application. Monoclonal antibody  production was one of the principal driving forces in the creation  of the biotechnology  industry.  It opened the way for the

commercial  development  of new types  of drugs  and  diagnostic  tests. Monoclonal antibodies  could  be equipped  with  markers  and  used  in the diagnosis of a wide variety of illnesses and the detection  of viruses, bacteria,  toxins, drugs, antibodies,  and other substances.

In 1969, Jerne  had  predicted  that  all the interesting  problems  of immunology   would  soon  be  solved  and  that  nothing  would  remain except the tedious  details involved in the management of disease. Such drudgery,  he suggested, was not of interest to scientists, but would pro- vide plenty of work for physicians. The innovative hybridoma technique developed by Milstein and Ko¨ hler in 1975 falsified that  prediction  and made it possible to explore many unexpected aspects of the workings of the immune system. Contrary to Jerne’s prediction, researchers have not run  out  of questions  to ask about  the immune  system, nor  have there been any complaints  that  the field has become less exciting.

The  characteristic   of  the  immune  system  that   is  so  important

in guarding  the  body  against  foreign  invaders,  that  is, the  ability  to produce  an almost unlimited number  of different antibodies,  represents a problem for scientists trying to understand the system. Immunologists who have struggled with the phenomenon of antibody  diversity estimate that  a mouse can make millions of different  antibodies.  The technique developed   by  Milstein   and   Ko¨ hler  has  transformed  the  study   of antibody  diversity and  made  it possible to order  what  Milstein  called

‘‘antibodies a` la carte.’’ The new generation  of magic bullets that might

be derived from hybridomas could be compared  to creating derivatives of atoxyl and the aniline dyes. Hybridomas are made by fusing mouse myeloma  tumor  cells with spleen cells derived from  a mouse that  was previously immunized with the antigen of interest. The hybrid cells pro- duce large quantities  of specific antibodies,  which are called monoclonal antibodies  (Mabs).  By combining  the  techniques  of immunology  and molecular  biology, scientists expect to design new generations  of magic bullets. As Sir Almroth  Wright predicted,  the healer of the future might well be an immunologist.

By 1980, only five years after Ko¨ hler and Milstein first published an account of their technique, monoclonal  antibodies were well-established tools in many areas of biological research. By 1990, thousands of monoclonal  antibodies  had been produced  and described  in the litera- ture.  Researchers  predicted  that  monoclonal  antibodies  might be used as novel vaccines and in the diagnosis and treatment of cancers. In cancer therapy, monoclonal antibodies might function as smart bombs, targeted against cancer cells to provide site-specific delivery of chemotherapeutic drugs. The concept is simple in theory, but difficult to achieve in practice. In part this is due to the fact that, despite new insights into the etiology of cancer, discussions of ‘‘cancer’’ are rather like nineteenth-century debates about  the nature  of fevers, plagues, pestilences, and infectious diseases. The  complex  constellation  of  disorders   subsumed   by  the  category

commonly called cancer looks quite different to physicians, patients, pathologists, oncologists,  and  molecular  biologists.  There  is a  great gap between understanding the nature  of oncogenes (genes that  appear to induce malignant  changes in normal  cells when they are affected by carcinogenic  agents),  transforming retroviruses  (RNA  viruses that  can transform normal  cells into  malignant  cells), proto-oncogenes, and  so forth, and establishing safe and effective means of preventing and treat- ing cancers.

Studies  of viral infections  and  possible links between cancer  and viruses led to hope that some endogenous agent might serve as a univer- sal viral antidote  and cancer drug.  Interferon, a protein  that  interferes with virus infections, was discovered in the 1950s by researchers study- ing the growth of influenza virus in chick embryonic cells. Despite early excitement about  interferon,  the substance  was very difficult to isolate and  characterize.  By 1983, about  20 distinct  human  interferons  had been identified.  The interferons  were involved in the regulation  of the immune system, nerve function,  growth regulation, and embryonic development.  Experiments  in the late 1960s suggested that,  at least in mice, interferon  inhibited  virus-induced  leukemias  and  the  growth  of transplantable tumors.  Interferon’s  potential  role  in cancer  treatment attracted the  attention of  the  media,  patient   advocacy  groups,  and members of Congress.

Preliminary  tests of interferon’s clinical efficacy against osteogenic

sarcoma  (a malignant  bone cancer) in the early 1970s interested virolo- gist  Mathilde   Krim   (1926–),  who  launched   a  crusade   to  support research  on interferon  as an  antitumor agent.  Krim,  who had  earned her  Ph.D.  in  1953 at  the  University  of  Geneva,  Switzerland,  joined the Sloan-Kettering Institute  for Cancer  Research  in 1962. From  1981 to 1985, she served as Director  of the Institute’s Interferon Laboratory. Interferon was initially promoted as a potential  ‘‘miracle drug,’’ which would presumably  be well tolerated  because it was a ‘‘natural  agent.’’ Clinical  trials  were,  however,  quite  disappointing in  terms  of  effec- tiveness  and  safety.  Adverse  reactions   to  interferon   included  fever, chills, fatigue,  loss of appetite,  decreased  white-blood-cell  counts,  and hair  loss. Through  further  development,  however,  interferon  gained  a role in the treatment of certain  cancers and  viral diseases. In addition to  her  interferon   work,  Krim  became  well known  as  a  health  edu- cator  and  AIDS  activist.  She was the  founder  of the  AIDS  Medical Foundation  (1983),  which  later   became  the  American   Foundation for AIDS Research.  In 2000, President  Bill Clinton  awarded  the Presi- dential  Medal  of  Freedom   to  Krim  for  her  contributions to  AIDS education  and research.

Ever since 1971, when President  Richard  M.  Nixon  (1913–1994)

declared  war  on  cancer,  oncologists  and  cancer  patients  have  been caught  in cycles of euphoria  and  despair.  Since the 1970s, the phrase

‘‘war on cancer’’ has been used to stimulate  spending on research.  Yet the total cancer death rate has not significantly declined since the declara- tion of war. Critics insisted that  the war was profoundly misguided in term of its overly optimistic  predictions  and its implementation. More- over,  the  rhetoric   of  the  cancer  crusade   often  conveyed  false  and misleading  information to  the  general  public.  Premature reports   of

‘‘breakthroughs’’  and  ‘‘miracle  cures’’  convinced  many  people  that cancer is essentially a single disease and that  sufficient spending would soon result in the discovery of a magic bullet. Scientists point  out that the funds and technologies associated with the war on cancer stimulated revolutionary developments  in molecular  biology  and  biotechnology. Congress  and  the public,  however,  prefer  to support  mission-oriented research rather  than  basic scientific investigations.

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