Frayer WC, Frayer WJ. Fish Stories and Clinical Trials. Arch Ophthalmol. 2004;122(7):1049-1051. doi:10.1001/archopht.122.7.1049
Copyright 2004 American Medical Association. All Rights Reserved.Applicable FARS/DFARS Restrictions Apply to Government Use.2004
In this era of ever-increasing printed and electronic publications,we often take for granted the accuracy of the information provided. As themeaning of the presentation is debated, we assume that the data on which webase our judgment have been honestly and accurately developed. Occasionally,it is wise to remember that editorial lapses may lead to false conclusions,as the following story will illustrate.
The American Association for the Advancement of Science, along withits weekly publication, Science, had served for morethan a century as a dependable public source of scientific information. Itwas no surprise, therefore, that when an article appeared in the September12, 1952, issue of the magazine claiming success in the prevention and treatmentof cataracts by the administration of fish lens protein, the proposal receivedwidespread attention. Soon, an estimated 1000 volunteers had been treated.Within a few months, however, severe complications were being reported bycompetent ophthalmologists and there were calls for an investigation. Theentire matter was quickly settled by the National Research Council, whoseCommittee on Ophthalmology concluded that the proposed treatment was not onlyuseless but also dangerous.
The article that had aroused such consternation was authored by RalphF. Shropshire, Jacob R. Ginsberg, and Mendel Jacobi,1 butincluded none of the authors' qualifications. The idea of treating cataractswith lens protein was not new; previous researchers2,3 hadtried it without success, using beef lens and human lens injections. Eventhough the organ specificity of lens protein had already been established,4,5 Shropshire and associates claimed thatthe protein in the lenses of fish differed from that found in the lenses ofmammal and could be administered safely. They made no mention of the possibilitythat they might be inciting a hypersensitivity in their patients.
In their meandering and vaguely worded article, Shropshire et al describedan indeterminate number of rats, which under dietary stress developed cataracts.The stress later proved to be caused by galactose. After a subcutaneous injectionwith a secret vaccine prepared with fish lens protein, the cataracts disappeared,especially when the galactose was discontinued. They also described the findingsin 14 human patients between the ages of 35 and 70 years, all having receivedseveral fish lens protein injections. They claimed spectacular results, althoughthey gave no details describing their method of evaluating visual improvement.There were no control subjects, and no mention was made as to whether visionwas tested with or without correction. In the end, they believed it unwiseto withhold this wonderful news from the anxious public. Ginsberg's officeaddress was prominently displayed at the bottom of page 1. Treatment was availablefor a price.
The 2 junior authors, Ginsberg and Jacobi, were indeed physicians, butneither of them had any experience or training in ophthalmology. They wereapparently naive, and certainly gullible, but provided a degree of legitimacyto the project. They admitted later that they would have been more usefulhad they taken the time to learn how to use a slit lamp.
Shropshire, the leader of the team, had no scientific qualificationswhatever and, apparently, no scruples. He had been appointed to the US NavalAcademy in 1920, but resigned after 2 years. He went with Richard Byrd tothe Antarctic in 1928, with the impressive title of scientific coordinator,but was dismissed before the expedition ended. He later tried to convincepeople that the commemorative medal struck for the Byrd expedition was, actually,a Congressional Medal of Honor. In the early 1930s, he showed up in Buffalo,NY, where he convinced the elderly F. Parke Lewis, an ophthalmologist, thathe had a good idea about a treatment for cataracts and went to work as anassistant. He was soon able to persuade his employer to try the fish lensantigen he had developed for the treatment of cataracts. Lewis6 introduceda paper at the XIV International Congress of Ophthalmology in Madrid, Spain,in 1933, in which he reported the results of treatment in 100 patients. Thepaper was generally ignored by the ophthalmologic community, which attributedits shortcomings to the age of its author.
Shropshire, however, was not deterred. In 1937, he succeeded in publishing2 articles7,8 in the Archives of Ophthalmology, both entirely devoid of references and withoutmention of his qualifications. One of these articles attempted to documentthe results of fish lens protein treatment in the same 100 patients describedby Lewis. A few more patients were added to the list. There were no controls.The results were not tabulated, and the methods of evaluation were only vaguelydescribed.
Beginning in about 1935, Shropshire began a series of laboratory jobs,all of which were terminated because of lack of qualifications and, by then,drug addiction. In 1944, he was sentenced to 10 years in prison for posingas a physician and for forging prescriptions for narcotics. He served only1 year, but was soon back to his addictions and to other criminal activities.His parole was revoked in 1948, and he served another year in prison.
Shropshire must have been somewhat charismatic. After his release fromprison, he was adopted by a Mrs M, of South Kortright, NY, who loaned himthe use of her stable as a laboratory. He seemed to have no other source ofincome. Whatever additional emoluments may have been provided by his benefactressare open to speculation. In 1951, she introduced him to Saul R. Gaynes, aNew York businessman who took an interest in the fish lens project and whosaw in it good commercial potential. He recruited a relative, Ginsberg, andhis associate, Jacobi.
Together, the businessman, the ex-con, and the 2 physicians establishedKortright Industries and set about selling the vaccine for clinical use. Inaddition, they founded what they called the Cataract Institute, devoted tofurther advances in cataract prevention. They persuaded Arno Towne, of Philadelphiaand New York, to try the vaccine on a series of patients. Towne reported laterto the National Research Council that the treatment had no merit. They evenattempted to sell the idea to COL Harry King at Walter Reed Hospital, Washington,DC. King did not feel comfortable about using the vaccine, but some of thesolution was tested in the hospital laboratory. Most of the samples were contaminated.At one point, later investigation would reveal, the project took on a cloak-and-daggercomplexion. On one occasion, a call was made to the hospital, stating thata shipment of the vaccine could be picked up in the refrigerator at a certaingas station in Washington, DC.
Within a short time, real ophthalmologists began to see serious inflammatorycomplications in patients who had been treated with the fish lens vaccine,and who had later sought surgical correction. Posner9 andBreinin,10 acting responsibly, reported theirfindings and urged patients to tell their ophthalmic surgeons about any suchtreatment before surgery. No accurate estimate of the number of patients harmedby the treatment is available. Posner estimated that more than 1000 patientshad received the injections. At the request of the Council of the AmericanAcademy of Ophthalmology and Otolaryngology, the matter was referred to theCommittee on Ophthalmology of the National Research Council.
The committee, composed of several prominent and highly respected ophthalmologists,had heard testimony from several people concerning the vaccine and the individualsinvolved in the enterprise. In addition, they had heard testimony from 2 editorsof Science, both of whom had defended their decisionto publish the article by Shropshire et al.1 "TheEditorial Board was too small and had to review too many manuscripts," theysaid. This one had been sent to an unnamed ophthalmologist in New York, whothought it should be published with a few corrections that were never made.The committee promptly published its decision.11 Thecommittee said that the treatment was useless and dangerous and that it didnot recommend further investigation. Shropshire returned to jail in Florida.
Thus ended the saga of the fish lens protein. Was it simply a sordidtale about an unscrupulous unqualified amateur whose activities caused anunknown degree of distress, and whose persuasive manner made it possible forhim to recruit several others to promote his self-centered project, or isthere more to the story? Historians tell us we should learn from past experience.Fifty years have elapsed. Experimental, ethical, and journalistic norms haveundergone enormous changes. What have we learned?
Shropshire and his colleagues must have fancied that they had reporteda clinical trial, but even in 1952, their simple and flawed attempt couldhardly qualify as such. Clinical trials have been a favorite method for thestudy of diseases and their treatment for centuries. Controls were deliberatelyincluded in a nutritional study reported in the book of Daniel (Daniel 1:11-16),and later, by James Lind in 1747 in a study of patients with scurvy.12 Clinical trials today bear little resemblance tothose published in the past. Standards for successful trials are outlinedin a recent textbook by Meinert.12 Precisecriteria have been established and widely accepted. Present clinical trialsoften include data collected at numerous academic institutions, monitoredby impartial judges, and subjected to close scrutiny by each member of theteam. Before publication, these studies are further scrutinized, often byseveral impartial referees.
In 1952, the scientific community had few rules by which to judge clinicaltrials. Even so, ophthalmologists recognized the nature of the fish lens scam,and moved quickly to investigate its source and to take measures to bringit to an end. The National Research Council acted with great alacrity, andthe damage was, thus, limited to a few patients.
There remains the serious moral issue regarding human experimentation.Did the patients who received fish lens protein injections know how they werebeing used? Those from the Committee on Ophthalmology who interviewed someof the patients were impressed by the naive acceptance of risk by those whowere anxious for a good result.
In 1952, the doctrine of informed consent had been talked about, butwas hardly a topic of daily discourse. In 1907, Osler13(p1) had contended that "as long as participants had full knowledgeof the circumstances and willingly submitted to the experiment, studies onvolunteers were not only permissible but praiseworthy." Although much discussionhad taken place before 1952, Osler's sentiments could be considered the norm.Lederer,14 in her book Subjectedto Science, reviewed the subject of human experimentation as it occurredbefore World War II, observing that the modern history of human experimentationbegan with the Nuremberg Code, written in 1946. She properly distinguishesbetween therapeutic and nontherapeutic experimentation. She also asks thequestion: "Is it fair to apply the ethical standards of the 1980s and 1990sto researchers working in the 1930s and 1940s when, presumably different ethicalnorms were in place?"14(pXIII)
Publication in reputable journals is the ultimate goal of all investigators.Medical publications number in the hundreds, and elaborate editorial boardssit in judgment on the quality of the manuscripts submitted to them. It seemshardly likely that articles such as those by Shropshire7,8 wouldbe accepted today, either by Science or the Archives of Ophthalmology.
Francis Adler, who was then editor-in-chief of the Archives of Ophthalmology, was a champion of a new movement to improvethe quality of medical journals by insisting on proved valid scientific information.In his address before the 1953 meeting of the American Medical Association'sSection on Ophthalmology,15 he chastised theeditors of Science for accepting the manuscript byShropshire et al,1 but made no mention of theequally flawed articles by Shropshire7,8 thathad appeared in the Archives of Ophthalmology in1937, during the term of a previous editor.
Yet, we owe much to editors like Adler, Derrick Vail, David Cogan, andFrank Newell, who brought ophthalmic journalism from the relatively uncriticalmid–20th century to the excellence we see in the hands of a new generationof superb editors.
It might be assumed that the type of story described herein would beunlikely to be repeated. On October 30, 2002, however, a similar tale wasrecounted in an Associated Press release.16 Onceagain, Science was victimized, this time becauseof false data provided by a physicist in a series of studies on superconductors.In this case, a single physicist had submitted many manuscripts based on fancifulinformation and had convinced several coauthors to lend their names to hisprojects. Once they discovered that the information serving as the basis forthese publications was fabricated, these coauthors demanded retraction of8 of the articles already published. Some reputations were already severelydamaged. Robert C. Haddon, one of the coauthors, stated the obvious: "Whenresearchers combine their studies to produce a single paper, each scientistdepends upon the honesty of work provided by the other co-authors. That isthe way science is supposed to work."16(p3)
Correspondence: William C. Frayer, MD, 910 Weldon Ln, Bryn Mawr,PA 19010 (firstname.lastname@example.org).
Submitted for publication July 9, 2003; accepted September 10, 2003.
This paper was presented at a meeting of the Cogan Society for OphthalmicHistory; April 13, 2003; St Louis, Mo.