PROBES GO DEEPER IN BALTIMORE CASE
WITH FOUR INVESTIGATIONS NOW UNDER WAY, A BIG QUESTION IS WHO
KNEW WHAT, WHEN?

Author: By Judy Foreman, Globe Staff

Date: 04/01/1991 Page: 37
Section: HEALTH AND SCIENCE

RESEARCH ETHICS

Eleven days after a National Institutes of Health investigatory panel dropped a bombshell with its finding that a former MIT immunologist had fabricated data concerning a 1986 research paper, the dragnet around her and her famous colleague, Nobel laureate David Baltimore, continues to widen.

Sources say there are now four federal probes delving ever deeper into the 5-year-old mess that some call "the Baltimore affair" and others have likened to a "scientific Watergate."

Among the core questions facing investigators are these: What did Baltimore know about the veracity of his colleague's data, and when did he know it? And did Massachusetts Institute of Technology and Tufts University School of Medicine botch their inquiries into the affair?

Baltimore and his colleague, Thereza Imanishi-Kari, both worked at MIT at the time they and several colleagues published their now-infamous paper in the journal Cell in April 1986. Baltimore is now head of Rockefeller University and Imanishi-Kari works at Tufts.

Outside the official investigations, scientists buzz with other questions: How could Baltimore, who won a Nobel Prize at age 37, have gotten himself into a mess that has tarnished an otherwise brilliant career? And why did he continue for five years to defend a colleague whose veracity was being challenged with each new revelation.

And why, with a few notable exceptions, did the scientific old-boy network rally so vehemently to Baltimore's case?

The whole thing "is a Greek tragedy. It's hubris that brings down the tragic hero. The most charitable thing to say is that Baltimore took some arrogant view that 'I can do no wrong,' that 'whatever I write in science is true.' He couldn't admit to a mistake. If he had, this wouldn't have happened," says Harvard University biology professor and Nobel laureate Walter Gilbert.

As for the "sheep-like" behavior of fellow scientists, Gilbert says, ''What's being triggered here is the we/they mentality: 'We' are the chosen establishment, 'they' are the unwashed barbarians attacking. The line was drawn . . . and it was 'which side are you on?' Outside looking in? Or peace and safety and the old-boy network?"

In 1989, for instance, one of Baltimore's staunchest supporters, Phillip Sharp, the director of MIT's Center for Cancer Research, sent a "Dear Colleague" letter urging scientists to rally to Baltimore's defense. Sharp still thinks that "a congressional hearing is not a productive way to debate scientific truth."

But, he adds, "if Thereza fraudulently modified her notes, it's a great disappointment. But I am absolutely confident that if that occurred, David did not know of it."

Mark S. Ptashne, professor of biochemistry and molecular biology at Harvard, was another who "got involved initially to defend David against what I thought was an unwarranted attack on science. I then came to realize that what was construed as the central claim of the paper was almost certainly wrong. I could not therefore understand why the authors were refusing to correct or retract it, . . .so I knew something was wrong."

On March 20, the NIH investigatory panel concluded in a draft report leaked to the press that Imanishi-Kari had fabricated data in response to its questions about her work, which has been under fire since shortly after the paper was published in 1986 because of questions raised by a junior colleague, Margot O'Toole. The NIH report said Imanishi-Kari had committed "serious scientific misconduct" and "repeatedly presented false and misleading information to the NIH."

Only after the NIH report was leaked did Baltimore take the action that many scientists say he should have taken five years ago: He retracted the paper.

The report did not accuse Baltimore himself of fabricating data. But it labeled Baltimore's handling of the case "difficult to comprehend" and ''deeply troubling." It also criticized him for suggesting, in interviews with NIH investigators, that if data "were fabricated, the NIH was somehow responsible for this act of scientific misconduct."

The report some of Baltimore's statements to investigators ''extraordinary," including this one: "In my mind, you can make up anything that you want in your notebooks, but you can't call it fraud if it wasn't published. Now, you managed to trick us into publishing -- sort of tricked Thereza -- into publishing a few numbers and now you're going to go back and see if you can produce those as fraud."

Neither Baltimore nor Imanishi-Kari would discuss the case last week, and their Boston lawyers, Normand Smith, Jr. and Bruce Singal, respectively, declined to get into the specifics of the case. Singal did say, however, that, ''It has been and continues to be our position that there is absolutely no credible evidence from which broader sweeping conclusions of fraud can be drawn."

The ongoing federal investigations into the Baltimore affair include two at NIH, one by a congressional subcommittee headed by US Rep. John Dingell (D- Mich.), which held hearings on the case in 1988, 1989 and 1990, and a fourth, sources say, by the US attorney's office in Baltimore.

The NIH investigations represent the third attempt by the agency to get to the bottom of the affair. The first three-person panel named in early 1988 was almost immediately disbanded when critics pointed out it was virtually packed with Baltimore's colleagues. A second NIH panel concluded in February 1989 that there was "no evidence of fraud, manipulation or misrepresentation of data."

But that finding collapsed quickly when Dingell held hearings in May, 1989 to present forensic evidence compiled by Secret Services agents showing that certain pages in Imanishi-Kari's key laboratory notebook had been created after O'Toole challenged the paper in 1986. (Since then, the NIH has concluded that these and other experiments were simply faked.)

NIH, prompted in part by the Dingell hearings and new questions by O'Toole, who had examined information given her by NIH, added members to its panel and reopened the case. It is this panel that recently concluded that Imanishi-Kari fabricated data. (In a minority report, two of the five panel members disputed precisely how many of the experiments were faked.)

Dingell is continuing his probe into the matter and, according to a member of his staff, will have its written report completed "around the first of June." Working with Dingell's staff have been two NIH scientists, Ned Feder and Walter Stewart, who have made a career out of examining cases of alleged scientific fraud and misconduct.

Jeff Garinther of the US attorney's office in Maryland said Friday he could
neither confirm nor deny that his office was involved.

If NIH finds a scientist has committed fraud or made false statements to its investigators, it can turn the case over to the Justice Department for possible criminal prosecution.

Sources said the US attorney's office has met several times with NIH and congressional investigators.

Suzanne Hadley of the Office of Scientific Integrity is heading the ongoing probes at NIH. One, a look at the scientific issues involved, formed the basis of the draft report leaked last month. The principals in the case have until April 22 to submit rebuttals to the draft report.

The final report could recommend penalties, including barring a researcher
from receiving future NIH funding, as has happened in other scientific misconduct cases.

The second NIH investigation is being called informally the who-knew-what- when investigation and will focus, among other things, on the ''institutional response" by MIT and Tufts to the entire affair.

"Who knew what when -- that's the question many people would like to know the answer to," said Hadley last week, though she declined to go into specifics about either investigation.

According to a source close to the investigation, one part of the NIH report that could take on more significance as the case progresses concerns the finding that Imanishi-Kari did not compile her laboratory notebooks at the time of the reported experiments, but only after the investigations began. The report suggests that Baltimore and his lawyer, Normand Smith Jr., were aware that Imanishi-Kari only assembled notebooks in response to the NIH probe, and that Smith may have suggested that she do so.

After the first NIH report in January, 1989, the latest report says, Margot O'Toole asked for access to certain data to review. When O'Toole examined NIH's material, the new report says, she "discovered there were no data in the notebooks for the fourth data point of Figure 1. . .."

"Also during this time," the latest NIH report says, "NIH became aware for the first time that Dr. Imanishi-Kari's notebooks had not been compiled contemporaneously with the conduct of the reported experiments. Rather, the notebooks were assembled specifically to respond to challenges to the paper.

"Subsequent information provided by Dr. Baltimore and his attorney, Normand Smith, Jr., indicated they were aware of Dr. Imanishi-Kari's having organized the notebooks to respond to the NIH and Congressman Dingell's subcommittee," the report says.

It goes on: "During the April 31, 1990 interview by NIH investigators with Dr. Baltimore, Mr. Smith said a meeting was held where 'Thereza came with all of her data and there was a discussion. . .as to whether we should just dump it on the doorstep of the committee . . . or should she go through her data, catalog it and put it in order and try and make it as comprehensible as possible."

Smith, the NIH report says, then said, "I think I may have been instrumental in advising her to do the latter, which I think was, in a large part, her undoing."

Another aspect of the case that is getting new attention is the conduct of the committees named by MIT and Tufts after O'Toole first voiced her concerns in 1986.

The MIT review of the case was headed by Herbert Eisen, emeritus professor of immunology, who listened to O'Toole's questions about Imanisihi-Kari's data and found no need to publish a correction to the paper published in CELL.

Asked last week if he would have handled the case the same way knowing what he knows now, Eisen said, "It's hard to answer. I would have tried to take some kind of measures to have dealt with the issues in a way less tragic and less painful for so many people, like urging Margot O'Toole to write a letter to CELL. I did not urge that strongly enough."

Walter Gilbert, however, took Eisen to task.

"One of the great dangers is that the established community closes ranks against the whistleblower -- that's completely what happened in this case. Eisen is saying he didn't know what he should do, but it was his responsibility to conjecture that there might have been fraud. He should have examined the data.

"He should not have discussed whether the ideas or speculations in the paper were correct. He should simply have asked whether the purported experiment was factually correct, that certain observations were made. That's what the review committee failed to do."

As head of the Tufts review, Dr. Henry Wortis, professor of pathology and immunology, is also on the hot seat. He says now that "there are things I would do differently," including "having made sure there was a more formal process."

Pressed on whether he thinks Imanishi-Kari committed fraud, Wortis responded, "I'll say no, but do I have positive evidence that she didn't? No, I don't have that either."

Wortis' role in the case is being investigated in Washington, according to sources familiar with the case. He testified at a 1989 Dingell hearing that the central thesis of the CELL paper -- that foreign genes inserted into mice cause native or "endogenous" genes to change the type of antibodies they make -- has been confirmed by other researchers.

Others say no one has been able to confirm it. In a recent interview with the journal Science, Wortis insisted that the supposedly confirmatory results exist but are unpublished, but he refused to disclose the name of the scientist or explain why the experiments, supposedly done two years ago, have not been published.

Last modified: Wed Sep 20 19:47:13 EDT 2000