June 1, 2007

Research Integrity and Everyday Practice of Science

Fred Grinnell Department of Cell Biology Ethics in Science and Medicine Program UT Southwestern Graduate School of Biomedical Sciences Focus on Research Integrity

Lab meeting each year to discuss research integrity case studies Laboratory policy on authorship Laboratory policy on how to keep a notebook

Attend Ethics Grand Rounds (at least one) Lectures: Practice of Science; Human research & genetics

Web Exercise on Plagiarism 1988 – NIH requires all trainees to receive training on the RESPONSIBLE CONDUCT OF RESEARCH

Research Integrity Regulatory Awareness and Compliance

Primary Examples of Misconduct

Fabrication (lying): Reporting experiments never carried out.

Plagiarism (stealing): Reporting as one’s own the work of another. Research Misconduct: An International Problem

Stem cells: Hwang Woo-suk (Korea) Oral cancer: Jon Sudbø (Norway) Menopause: Eric Poehlman (U.S.) FEDERAL DEFINITION OF MISCONDUCT

Research misconduct is defined as fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results.

A finding of research misconduct requires that there be a significant departure from accepted practices of the relevant scientific community. US Office of Science and Technology Policy December 6, 2000 Cell (1988): If you have wanted a book to recommend to science students that will explain what being a scientist actually involves, this is it.

(Available in the UT Southwestern library) Moral Climate •University • Government • Society

Managing a Laboratory • Research Director Regulatory • Personnel Manager • Business Manager Framework Everyday Practice of Science

world Individual community

DISCOVERY CREDIBILITY The Linear View of Science 1. Scientists observe and collect facts about the world. 2. Scientists use the scientific method to make discoveries (justify discoveries). 3. Scientists are dispassionate, impartial, and altruistic observers. The Ambiguous View of Science Responsible Science, Vol I: The selective use of research data is another area where the boundary between fabrication and creative insight may not be obvious. (National Academy Press, 1992) Nobel laureate Robert A. Millikan selected 58 out of 140 oil drops from which he calculated the value of the charge of the electron. Discovery

Discovery is hard to accomplish. Failure is frequent. The pressure to produce is great. Meno: How will you look for it Socrates, when you do not know at all what it is? Noticing 1. It’s one of them. 2. It looks like one of them, but I’m not sure. 3. I don’t know what it is. I’ve never seen one before. 4. I didn’t notice anything. Where? Calvin’s Photosynthesis Machine

Wilson, A. T. & Calvin, M. (1955) The photosynthetic cycle: CO2 dependent transitions Journal of the American Chemical Society 77, 5948-5957. Thought Style Previous knowledge and experience determine what can be noticed and what it will appear to mean. Seeing things one way means not seeing them another.

adapted from Ludwik Fleck, Genesis and Development of a Scientific Fact Choosing a Problem/ Hypothesis to Study Is is unsolved? Is it worth solving? Can I do it? Experimental Design Explicit assumptions determine the question. Implicit assumptions determine the methodology and therefore limit the possible results. (Plato revisited) The principle of limited sloppiness Max Delbrück Because of ambiguity we sometimes do more than we intend (serendipity). The Meaning of Data At the edge of discovery, how does one distinguish data from noise? Heuristic principles helpful but in the end experience and intuition (creative insight) determine what counts and what does not. DATA 1

Data 1 DATA 2

Data 2 DATA 3

Data 3 DATA 4

Data 4 Saint Matthew by Michelangelo 1. Scientific discovery is like artistic creativity. 2. The artist can stop with his/her completed piece. 3. For the scientist, completing the piece is only the beginning. Credibility

Objectivity is a goal, not a condition, for science. Individual investigators do proto- science.

Scientific communities accept or reject the work as being scientific. The Problem of Subjectivity

The False Mirror, René Magritte, 1928

Individuals aim to be objective but their observations may be illusions or instances of self-deception. Seeking Objectivity Transcend subjectivity by becoming intersubjective - reciprocity of perspectives – you can do/see/think it too. Making a discovery claim public invites verification and validation. Perspicacity René Magritte, 1936

Albert Szent-Györgyi’s prescription for discovery -- seeing what everybody else has seen and thinking what nobody else has thought. Ignoring Collegial Skepticism

Novelty challenges intersubjectivity. Consequence can be rejection of papers and grants. Success requires becoming an advocate for one's work. Rejection of manuscripts reporting Nobel Prize-winning methods: Science rejected radioimmunoassay and polymerase chain reaction. Cell rejected site-directed mutagenesis. Nature rejected monoclonal antibodies although agreed to publish a markedly shortened version of the work as a letter. When the evidence in support the cycle seemed sufficient, I believed that the work might be of general interest and on 10 June 1937 I sent a ‘letter’ to the Editor of Nature. The paper was returned to me five days later accompanied by a letter of rejection… Two weeks later, I sent the full paper to the journal Enzymologia in Holland and it was published in two months. Hans Krebs on Nature’s rejection of his paper describing the citric acid cycle (Reminiscences and Reflections, 1981), Nobel Prize in 1953 Credibility Happens to a Discovery Ribozymes Prions Cold fusion Transposable elements N-rays Polywater Prions Ribozymes Cold fusion Transposable elements N-rays Polywater Credibility of discovery claims are judged first (initial peer review) according to quality, interpretation, relevance. Subsequently, credibility happens to a discovery claim. The discovery becomes credible, is made credible by events … Its verity is the process of veri-fication. Its validity is the process of valid- ation. (adapted from W. James, Pragmatism) The Scientific Method In Practice • Choosing to test a hypothesis means making an investment of time, energy, and money. • Doing the studies and collecting the data doesn’t mean that the important results will be noticed. What counts for data one day may appear to be noise the next. • If results don’t agree with expectations, it may be because the hypothesis is wrong or because the method is wrong. Don’t give up a good hypothesis just because the data don’t fit. •Just because a discovery claim is greeted with skepticism (rejection) doesn’t mean that it is wrong. Success requires commitment and entails risk. (T)here is no such thing as a Scientific Mind. There is no such thing as The Scientific Method. The idea of naïve or innocent observation is philosophers’ make- believe. Peter Medawar (1982) Pluto's Republic What about the idea that science advances by falsification of hypotheses? An intellectual rather than practical commitment – being open to the possibility that one’s discovery claims/hypotheses are wrong. Science gives up Truth for credibility. Where does the linear view of science originate? Research Papers : Scientific Short Stories Different Types of Experiments

Don’t work: Learning what not to do next time Heuristic: Learning something new Demonstrative: Convincing others it’s correct The Discovery of mRNA

We were to do very long, very arduous experiments . . . But nothing worked. We had tremendous technical problems . . . Full of energy and excitement, sure of the correctness of our hypothesis, we started our experiment over and over again. Francois Jacob, The Statue Within The Beach Our confidence crumbled. . . . we found ourselves lying limply on a beach, vacantly gazing at the huge waves of the Pacific crashing onto the sand. Only a few days were left before the inevitable end. But should we keep on? What was the use? . . . Suddenly, Sydney gives a shout. He leaps up, yelling, "The magnesium! It's the magnesium!" . . . (We) race to the lab to run the experiment one last time. . . The Paper - Results The bulk of the RNA synthesized after infection is found in the ribosome fraction, provided that the extraction is carried out in 0.01 M magnesiun ions12 Lowering of the magnesium concentration in the gradient, or dialyzing the particles against low magnesium… the radioactive RNA leaves the B band …

(Brenner et al., 1961) (W)riting a paper is to substitute order for the disorder and agitation that animate life in the laboratory . . . To replace the real order of events and discoveries by what appears as the logical order, the one that should have been followed if the conclusions were known from the start. Francois Jacob, The Statue Within Is the Scientific Paper a Fraud?

(The scientific paper is) a totally mistaken conception, even a travesty, of the nature of scientific thought. . . . The inductive format of the scientific paper should be discarded.

Sir Peter Medawar Research papers: Edited scientific record Research notebooks: Historical scientific record (To) get some work accepted and a new way of thinking adopted, it is necessary to purify the research of all affective or irrational dross. To get rid of any personal scent, any human smell. F. Jacob, The Statue Within The Objective and Anonymous Discoverer

In their papers, investigators become reporters of discoveries rather than discoverers in presenting the work to the community -- the objective observer. Any scientist would found the same results (typical); any scientist could have made the discovery (anonymous). Conflicting Interests and Conflict of Interest Conflicting Interests of Students and Fellows and the Laboratories in Which They Work There is a difference between teaching and research. For instance, allowing a student or fellow to struggle is often the best teaching method but inefficient for laboratory progress. Conflicting Commitments of Investigators PI’s time/position/salary directly dependent on grant funding Study Section vs. Institution (Research vs. Teaching/Clinical Service) Conflicting Values of Academic and Industrial Research

Biomedicine Biotechnology Public Ownership Board of Directors Sharing Licensing Rapid Publication Editorial Control

In entrepreneurship, what is in the best interests of the individual is not necessarily in the best interests of science. Scientists adhere to the norms of science so well because, more often than not, it is of their own best self interest to do so. (David Hull) • Being right means increasing one's credibility -- getting ahead, having influence. • Being wrong means becoming uncredible, getting ignored, disappearing. But “publish or perish” and “patent and prosper” have different rules. (Howard Schachman) Transition of the Research University

Teaching Teaching

Research Research Biotech & Service & Service Responsible Conduct of Science

Personal Integrity

Inherent Conflicting Ambiguity Interests