Author: By Judy Foreman, Globe Staff

Date: 05/23/1988 Page: 31


Nobel laureate David Baltimore, director of the Whitehead Institute for Biomedical Research in Cambridge, in order to "set the record straight," last week sent a 9-page letter to scientists across the country in which he offers his view of a dispute that has become the subject of investigations by a Congressional subcommittee and the National Institutes of Health.

The dispute, which was the focus of a day-long hearing April 12 chaired by Rep. John Dingell (D-Mich), concerns a paper about genetic control of the immune system published in the scientific journal Cell in April 1986.

In addition to Baltimore, the authors of the paper were David Weaver, the lead author, of the Whitehead Institute and the department of biology at Massachusetts Institute of Technology; Moema H. Reis, Christopher Albanese and Thereza Imanishi-Kari, at the time all at MIT's biology department and Center for Cancer Research; and Frank Costantini, of the department of human genetics and development at Columbia University. None of the six was invited to the Dingell hearing.

The dispute centers on work by Imanishi-Kari; at the hearing, a former graduate student in her lab testified that he suspected Imanishi-Kari had committed fraud in representing her data, a charge her lawyer denies.

Last week, a four-person team from NIH began its investigation of the case in the Boston area. The week before, a three-person team from Dingell's subcommittee on Oversight and Investigations of the committee on Energy and Commerce also conducted interviews here.

In his letter, Baltimore attacked what he called "a small group of outsiders" who, he said, were out to "catalyze the introduction of new laws and regulations that I believe could cripple American science.

"What we are undergoing is a harbinger of threats to scientific communication and scientific freedom. The halls of Congress are not the place to determine scientific truth or falsity. NIH must put in place procedures that will protect us from such investigations and that will neutralize the activities of such as Mr. Walter Stewart and Dr. Ned Feder by quickly responding to charges of fraud and misconduct."

Feder and Stewart are NIH scientists who have developed a reputation as ''whistle blowers" on issues of scientific error, misconduct and fraud. It was concerns relayed by a junior scientist in Imanishi-Kari's lab to Stewart and Feder about the accuracy of the Cell paper that triggered the two government investigations.

The role of Stewart and Feder, who began as unofficial whistle blowers within NIH and are now officially "on loan" to the congressional investigators, is a subject of intense controversy among scientists. Some, like Baltimore, feel they are a serious threat to science.

Others agree with scientists like John T. Edsall, emeritus professor of biochemistry at Harvard University, who at the Dingell hearing praised the role of the two in a fraud case that came to light several years ago. In prepared testimony, Edsall said: "I greatly respect what they Stewart and Feder have done; I think they have performed an important public service."

The chief concern of Dingell's subcommittee is that academic institutions are not willing to conduct thorough self-policing on matters in which scientific misconduct, fraud or error may be involved, and that NIH, which
funds biomedical research at many institutions, is not capable of doing so either.

After the Cell manuscript had been submitted early in 1986, Baltimore wrote, "Dr. Margot O'Toole, a post-doctoral fellow in Dr. Imanishi-Kari's laboratory, questioned the interpretation of some of the data emanating from that laboratory." Her concern led to two inquiries, one at MIT, headed by Dr. Herman N. Eisen, a biology professor, and one at Tufts University School of Medicine, where Imanishi-Kari now works, led by Dr. Henry Wortis, professor of pathology.

Eisen concluded that although one of O'Toole's allegations was ''disturbing" and she was correct "in claiming that there was an error in the paper," the error was not flagrant. He added that "a correction would be too minor to rate a letter to the journal."

Wortis concluded that there was "no evidence of deliberate falsification and no evidence of deliberate misrepresentation. Alternate interpretations of existing data can be made, but that is the stuff of science."

In his letter, Baltimore noted that "Dr. Imanishi-Kari and I had somewhat different interpretations of these experiments. . .. We wrote the discussion of the paper reflecting the various opinions and indicating that more studies would be necessary to fully understand what was going on."

He also wrote that "the investigation did turn up one clear overstatement in the paper," adding, "There never has been any effort by me to discourage Dr. O'Toole from pursuing her questions, nor have I done anything to affect her career."

After the MIT and Tufts inquiries, he added, "the controversy, I thought, was settled."

O'Toole, for her part, testified to Dingell's subcommittee that this ''dispute has halted my career. . .and had a devastating effect on my life." She said she continued to be troubled by the fact her attempts to duplicate the experiments published in the Cell paper resulted in discrepancies. She has never alleged fraud, but at the hearing she testified, ''It is extremely counterproductive to current scientific investigation, however, that known errors remain published as truths."

O'Toole told the subcommittee that Imanishi-Kari did not let her see the original data for comparison. Imanishi-Kari declined to discuss particulars of the case last week, but said she agreed with Baltimore's letter.

Bruce Singal, Imanishi-Kari's lawyer, noted Friday that "there have been two reviews by qualified and eminent scientists who concluded there was no problem with the work. This is an issue involving not falsification of data in any way but rather different interpretations of scientific data, which goes to the very heart of what science is about.

"I do think it's important to note that at no time while Dr. O'Toole was working for Dr. Imanishi-Kari did she challenge the premises of the paper. The first time she did so was in May of 1986, after the paper was published, after she had seen a draft of the paper and after she stopped working for Dr. Imanishi-Kari."

O'Toole told the subcommittee, "As my results continued to disagree with those she told me to expect, Dr. Imanishi-Kari became so displeased with me that she told me to stop experimenting altogether and take care of the mouse breeding."

But toward the end of O'Toole's time in Imanishi-Kari's lab, O'Toole testified, "she told me that at least for some of the discrepant results, her actual data agreed with mine and not with her published claims. She also confirmed that some of the experiments were not done as presented in the paper." O'Toole testified that she then found some of the original data, which strengthened her conviction that a number of the paper's "conclusions were actually contradicted by the records."

O'Toole also took her concerns to a young colleague in Imanishi-Kari's lab, Dr. Charles Maplethorpe, who had just finished his doctorate at MIT. Maplethorpe testified at Dingell's subcommittee under a subpoena.

"I suspected that Dr. Imanishi-Kari was committing fraud," he said, adding that he had overheard parts of a conversation in which Imanishi-Kari said she was obtaining the same results O'Toole later obtained.

Maplethorpe, like O'Toole, took his concerns to higher-ups at MIT but concluded, as he told the subcommittee, that "I felt there was no question but that if I were to make a formal charge of fraud, that it would not be taken seriously and then I would be the person who would be worse off for it."

Eventually, however, Maplethorpe revealed his concerns to Stewart and Feder, whose names he had seen in a New York Times article.

Stewart and Feder, Baltimore wrote, "apparently convinced Dr. O'Toole to provide copies of the 17 pages of laboratory notes from Dr. Imanishi-Kari's notebooks, pages that contained data that appeared to be contradictory to the data published in the Cell paper."

Stewart and Feder then asked all the authors to see the lab data to compare with the published data. Baltimore said the scientists declined to comply
because "the two were self-appointed and had no right to the data."

Stewart and Feder eventually aroused the interest of the NIH bureaucracy. Baltimore then suggested to the deputy director of NIH "that a group of immunologists be impaneled to consider whether the paper had been published appropriately."

In his letter, Baltimore goes on to describe his view of the press coverage of the dispute. He notes that in the days before the Dingell hearing, "there were newspaper articles about the O'Toole-Imanishi-Kari dispute throughout the country, including all of the major newspapers." In general, he wrote, "we fared badly," with the exception of articles in the Washington Post and the Los Angeles Times.

He said he had "not yet recovered" from a story in the Boston Globe. He did not mention a long story on the day of the hearing in the New York Times which, unlike the Globe story, quoted Maplethorpe and Dr. Howard Temin of the University of Wisconsin, who shared the Nobel Prize with Baltimore in 1975.

Temin told the Times, "It does appear that the research paper was in error."

A spokesman for Dingell said last weekhe could not comment on the substance of the investigation, nor could he estimate when it would conclude because ''we have been delayed significantly by the attorneys representing these people."

Don Ralbovsky, a spokesman for NIH, said, "We never comment on an ongoing inquiry."

Baltimore concluded, "I believe this is all totally unnecessary. . . .It is hard to know when and how this will end. I am inured to the necessity of public testimony in an atmosphere created by the one-sided publicity and proceedings that have gone before.. . .

"What is now my problem could become anyone else's if circumstances present themselves."


Excerpts of letter from Nobel laureate David Baltimore to colleagues.

I have recently become embroiled in a controversy over some of the data used in a paper published in the journal Cell in April 1987. The controversy has generated widespread press coverage, some of it wrong. I believe that it is of critical importance that I set the record straight to clear the names of the authors who have been compromised by this attack.

This letter contains approximately three single-spaced pages discussing the science of the paper, all of which is deleted here for lack of space.

Early in 1986, Dr. Margot O'Toole, a postdoctoral fellow in Dr. Thereza Imanishi-Kari's laboratory she is a co-author, formerly at MIT, now at Tufts University, questioned the interpretation of some of the data emanating from that laboratory. Dr. O'Toole was not directly involved in the work that led to the Cell paper. A part of her criticism was based on 17 pages of selected laboratory notes, a small fraction of the notes compiled during this project. Dr. O'Toole provided four arguments why the published interpretation was inappropriate. Reviews by Dr. Herman Eisen of MIT and by a panel formed by Dr. Henry Wortis, an immunologist at Tufts, dealt with these four points. The reviews concluded separately that, although alternative interpretations are possible for most data, there was no compelling reason to believe that any one of Dr. O'Toole's four points representated a serious misinterpretation. In the molecular biology data of the Cell paper there is a clear contradiction to the hypothesis of Dr. O'Toole. A more precise reagent now available is corroborating the data from the earlier study.

Late in June, 1986, Drs. Eisen, Imanishi-Kari, O'Toole, co-author David Weaver and I sat down and went over in detail the questions raised by Dr. O'Toole. At the conclusion of the meeting, Dr. Eisen wrote a memo that includes the following sentences:

". . . These kinds of disagreements are . . . not uncommon in science and they are certainly plentiful in Immunology. The way they are resolved traditionally, and effectively, is by publishing the results and having other laboratories try to repeat and evaluate them. The wonderful transgenic mice that have been prepared for this study are . . . being provided freely to other laboratories, and so within a reasonable period of time we should know the extent to which the authors' interpretations are correct or incorrect. If they are incorrect and require revision, then so be it. This is the way science operates; and in fact it is the kind of contentiousness seen in this dispute that helps drive the science 'engine' . . ."

From all that we had learned so far -- including two reviews and a lengthy meeting among all of the central figures in the dispute -- it was unlikely that Dr. O'Toole's arguments were valid. The only way to go farther was by using new tools of analysis and other transgenic systems.

The investigation followed MIT guidelines for examining charges of improper laboratory procedures. In her later testimony Dr. O'Toole emphasized that she has never claimed that fraud was involved, but that she was upset because she felt that scientific data was being misrepresented.

There never has been any effort by me to discourage Dr. O'Toole from pursuing her questions, nor have I done anything to affect her career.

The controversy, I thought, was settled. But a one-time graduate student in the Imanishi-Kari laboratory, Dr. Charles Maplethorpe, who finished at MIT in the year before the paper was published, contacted Mr. Walter Stewart and Dr. Ned Feder, NIH scientists who have turned their attention to personal not official investigation of issues of scientific fraud. Mr. Stewart and Dr. Feder apparently convinced Dr. O'Toole to provide to them copies of the 17 pages of laboratory notes. Mr. Stewart and Dr. Feder wrote formal letters to all of the authors of the paper asking for all of the laboratory data so that they could compare them to the published data. We discussed this proposal and declined for the following reasons:

1. They are not immunologists and from the types of questions they raised clearly showed a lack of understanding of the complex serology involved.

2. The two were self-appointed and had no right to the data. We believe that for random people, scientists or not, to investigate scientific papers would severely disrupt ongoing scientific activities. On the other hand, duly constituted investigative bodies or colleagues in the same field should be provided the date for investigative purposes without question.

Dr. Feder and Mr. Stewart persisted with letters and phone calls, and I decided to stop responding. I suggested in a letter in March, 1987, to NIH, that a group of immunologists consider whether the paper had been published appropriately. I asked for one condition: that Mr. Stewart and Dr. Feder agree to accept the decision of the panel. They refused, instead asking they they be part of the panel.

Mr. Stewart and Dr. Feder produced a written manuscript on the basis of 17 pages. They circulated it widely within the scientific community. A number of scientists have sent me copies of their comments and all rejected the contentions of the Stewart-Feder manuscript. This is not surprising; a critique of a paper based on a selected, random set of data is extremely unlikely to be accurate. Dr. Feder and Mr. Stewart then attempted to publish the manuscript, but it was rejected. In April, 1988, I learned that they were visiting college campuses and discussing the issue in very explicit and unflattering terms.

A House subcommittee, chaired by Rep. John Dingell (D-Mich), held a hearing at which the witnesses included Mr. Stewart, Dr. Feder, Dr. O'Toole, Dr. Maplethorpe and NIH officials. The authors of the paper were not invited to testify, nor were we even informed that an investigation was underway. Prior to the meeting, Mr. Stewart and Dr. Feder called up certain newspaper reporters. Thus, in the few days before the hearing there were newspaper articles about the dispute throughout the country.

We have not yet seen the end of this. The Dingell subcommittee has asked MIT and Tufts to literally empty their files of everything pertaining to the situation. A letter was sent by the subcommittee to NIH on May 4, 1988, and demanded that all of hte data be supplied the next day.

I believe this is all totally unnecessary. Dr. O'Toole never charged fraud and has avoided that characterization. NIH is finally getting a group of immunologists together to review the paper, as I had asked a year ago and repeated recently. I firmly believe that this panel -- or any other qualified scientists -- who look at all of the records and experiments will conclude that the paper appropriately reflected the state of the science at the time it was written.

What we are undergoing is a harbinger of threats to scientific communication and scientific freedom. The halls of Congress are not the place to determine scientific truth or falsity. NIH must put in place procedures that will neutralize the activities of such as Mr. Stewart and Dr. Feder by quickly responding to charges of fraud and misconduct.

Last modified: Wed Sep 20 20:16:39 EDT 2000