Success in Clinical Investigation: Benefits and Pitfalls of Collaboration

1. GI Education Series: Key Elements of Academic Life Success in Clinical Investigation: Benefits and Pitfalls of Collaboration  Ray E. Clouse, M.D. Professor of Medicine and Psychiatry

2. Research mentors….. • Need not be experts in all your fields of interest • Provide examples in their areas of expertise • Prevent mistakes in your early efforts • Offer a foot in the door to accelerate your course Investigative Career Evolution Mentoring by Dr. David Alpers 1978 Psychiatric disorder in GI illness Collaboration with Dr. Patrick Lustman Mind-body relationships 1981 Defining esophageal motor disorders Collaboration with Dr. Annamaria Staiano 1982 Spastic disorders as a functional marker Description of antidepressants for FGIDs 1985 Limited industry funding Origin of high-resolution manometry Co-investigator, NIH funding 1990 Treatment trials for diabetic depression Industry partnerships 2002 Depression and insulin resistance 2004 Creation of high-definition manometry Patent applications

3. Select broad themes in need of research • Parallel clinical and investigative interests • Begin a simultaneous goal of clinical expertise • Narrow the clinical focus as early as possible Investigative Career Evolution Mentoring by Dr. David Alpers 1978 Psychiatric disorder in GI illness Collaboration with Dr. Patrick Lustman Mind-body relationships 1981 Defining esophageal motor disorders Collaboration with Dr. Annamaria Staiano 1982 Spastic disorders as a functional marker Description of antidepressants for FGIDs 1985 Limited industry funding Origin of high-resolution manometry Co-investigator, NIH funding 1990 Treatment trials for diabetic depression Industry partnerships 2002 Depression and insulin resistance 2004 Creation of high-definition manometry Patent applications

4. Let discoveries help refine research directions • Orient research questions to funding sources • Capitalize on perseverance • Combine clinical and investigative notoriety to • reach “thought leader” status Investigative Career Evolution Mentoring by Dr. David Alpers 1978 Psychiatric disorder in GI illness Collaboration with Dr. Patrick Lustman Mind-body relationships 1981 Defining esophageal motor disorders Collaboration with Dr. Annamaria Staiano 1982 Spastic disorders as a functional marker Description of antidepressants for FGIDs 1985 Limited industry funding Origin of high-resolution manometry Co-investigator, NIH funding 1990 Treatment trials for diabetic depression Industry partnerships 2002 Depression and insulin resistance 2004 Creation of high-definition manometry Patent applications

5. Investigative Career Evolution Mentoring by Dr. David Alpers 1978 Psychiatric disorder in GI illness Collaboration with Dr. Patrick Lustman Mind-body relationships 1981 Defining esophageal motor disorders Collaboration with Dr. Annamaria Staiano 1982 Spastic disorders as a functional marker Description of antidepressants for FGIDs 1985 Limited industry funding Origin of high-resolution manometry Co-investigator, NIH funding 1990 Treatment trials for diabetic depression Industry partnerships 2002 Depression and insulin resistance 2004 Creation of high-definition manometry Patent applications

6. Great Collaborations Rodgers & Hammerstein Capitalize on disparate skills of the collaborators Masters & Johnson Collective momentum to accomplish a difficult project Antony & Cleopatra Joining forces to conquer otherwise insurmountable hurdles Sherlock Holmes & Watson Complementary roles or personalities The Lenon Sisters The power of similarity James Kilpatrick & Shana Alexander Energy of dialogue and dissimilar views

7. The Successful Clinical Investigator Must Write • Your ideas are not known or valuable unless they are exposed for consideration and discussion • Publication track record is essential to remain competitive for sustained funding • Reaching “thought leader” status requires a broad sphere of influence • Successful evolution of your own thoughts requires critical feedback

8. Collaboration and Productivity

9. Collaboration and Productivity

10. Academic Expectations Can Deter Collaboration • Independent ideas • Research identity • Independent funding • His or her “own” lab • Principal investigator

11. Science Increasingly Depends on Collaboration * *Articles published in Science Mussurakis, 1993, Khan et al. 1999

12. Rise in Collaborations Has Resulted from Many Factors • No single person has skills, knowledge, resources to address all research problems (judicious choice of collaborators can save considerable time and money) • Funding/structure of science favors programs with authorities in each key area • Breakthroughs are more likely from collaborations across disciplines • Academia/private sector collaboration favored by legislation, industry, and academia • Collaborations are easier than they once were

13. Assessing a Collaborative Opportunity • Do I need this collaboration in order to move my own work forward? Is there a missing piece that I must have? • Even if not strictly necessary, will a collaboration help me make a significant scientific contribution? • Do I have the expertise or resources sought by the other collaborator? • Can this collaboration be conducted efficiently? • Is there funding for the work envisioned? • Can I afford the time?

14. Is this person someone with whom I want to collaborate? • Are our professional and scientific interests compatible? • Will this person be accessible to me and consistently interested in the project? • What exactly is being asked of me? • Can I exclude potential conflicts, either professional or institutional? • Before making a decision, consider all factors. A good collaboration can take your research in an unexpected course; a bad one will siphon off energy and demoralize you. McGovern V, et al. Setting Up Collaborations. In: BWF, HHMI. Making the Right Moves: A Practical Guide to Scientific Management for Postdocs and New Faculty, 2004

15. Personal Qualities of a Good Collaborator • Honesty • Openness • Fairness • Industry • Respect • Reliability Disclosure, constructive criticism Availability, problem resolution Giving credit where credit is due Effort, carrying ones weight Appreciation of each contribution Delivering on time McGovern V, et al. Setting Up Collaborations. In: BWF, HHMI. Making the Right Moves: A Practical Guide to Scientific Management for Postdocs and New Faculty, 2004

16. Responsible Collaborations are Defined by Openness and Communication • Collaborators should be open about the research • Communal enterprise • Collegiality • Collaborators should be open and clear about the terms of the collaboration • Expectations communicated • Nature of sharing

17. Collaborations Are a Frequent Source of Problems • Failed start-up because of reluctance to share or work together • Misunderstandings of what is to be provided by each participant • Unhappiness with a slow collaborator • Disagreement about what and when to publish • Conflicts regarding authorship and credit Cohen J. Science 1995; Kahn JO et al. JAMA 2000; Wilcox LJ. JAMA 1998

18. Game Theory and the Prisoner’s Dilemma • In game theory, the prisoner's dilemma is a type of non-zero-sum* game in which two players can "cooperate" with or "defect" (i.e. betray) the other player. In this game, as in all game theory, the only concern of each individual player ("prisoner") is maximizing his/her own payoff, without any concern for the other player's payoff. *Situations where participants can all gain or suffer together, such as a country with an excess of bananas trading with another country for their excess of apples, where both benefit from the transaction, are referred to as non-zero-sum.

19. The Prisoner’s Dilemma • Two suspects, A and B, are arrested by the police. The police have insufficient evidence for a conviction, and, having separated both prisoners, visit each of them to offer the same deal: if one testifies for the prosecution against the other and the other remains silent, the betrayer goes free and the silent accomplice receives the full 10-year sentence. If both stay silent, both prisoners are sentenced to only six months in jail for a minor charge. If each betrays the other, each receives a two-year sentence. Each prisoner must make the choice of whether to betray the other or to remain silent. However, neither prisoner knows for sure what choice the other prisoner will make. So this dilemma poses the question: How should the prisoners act?

20. Game Theory and the Prisoner’s Dilemma The dilemma can be summarized thus: The dilemma arises when one assumes that both prisoners only care about minimizing their own jail terms.

21. Tit-for-tat (TFT) Tit-for-tat with forgiveness (TFTF) The Prisoner’s Dilemma – Iterated “Greedy” strategies do poorly “Altruistic” strategies do better Robert Axelrod. The Evolution of Cooperation, 1984

22. The Prisoner’s Dilemma – IteratedAxelrod Conditions for a Successful Strategy • Nice • Mostly important, the strategy must be "nice", that is, it will not defect before its opponent does. • Retaliating • However, the successful strategy must not be a blind optimist. It must always retaliate. An example of a non-retaliating strategy is always cooperate. This is a very bad choice, as "nasty" strategies will ruthlessly exploit such softies. • Forgiving • Though they will retaliate, they will once again fall back to cooperating if the opponent does not continue to play defects. This stops long runs of revenge and counter-revenge, maximizing points. • Non-envious • The last quality is not striving to score more than the opponent.

23. Readily invaded a population of non-altruists and could not be invaded Strategies with Varying Investment in CooperationRoberts G, Sherratt TN. Nature 1998 • Non-altruism (NA): never investing • Give-as-good-as-you-get (GGG): matching what the partner last gave • Short-changer (SC): giving a little less than the partner • Raise-the-stakes (RTS): offering a small amount on first meeting and then, if matched, raising the investment

24. In human models, anecdotal and scientific evidence that cooperation is greater in people who know each other well • Strategies to move from uncooperative strangers to cooperative friends are unknown • Tested RTS and GGG strategies in a varying investment game Proceedings of the Royal Society B: Biological Sciences 2003

25. A x$ I A 2x$ I Matched response, stooge Game Paradigms A B x$ 2x$ I A B 2y$ y$ I Free response, actual partner Roberts G, Renwick JS, Proc Royal Soc B, 2003

26. Cooperation was achieved through a combination of initial escalation (RTS strategy) and quantitative responsiveness (GGG strategy). Playing against a matched response “stooge” Playing against a free response partner

27. The Prisoner’s Dilemma – IteratedAxelrod Conditions for a Successful Strategy • Nice • Mostly important, the strategy must be "nice", that is, it will not defect before its opponent does. • Retaliating • However, the successful strategy must not be a blind optimist. It must always retaliate. An example of a non-retaliating strategy is always cooperate. This is a very bad choice, as "nasty" strategies will ruthlessly exploit such softies. • Forgiving • Though they will retaliate, they will once again fall back to cooperating if the opponent does not continue to play defects. This stops long runs of revenge and counter-revenge, maximizing points. • Non-envious • The last quality is not striving to score more than the opponent.

28. The Mantle of Leadership Belongs to the “Team” • In a complex and technologically sophisticated society, the most urgent projects require coordinated contributions of many talented people • We cling to the romantic idea that great things usually are accomplished by larger-than-life individuals working alone • Despite evidence to the contrary, we still tend to think of achievement in terms of the Great Man or Great Woman, instead of the Great Group Even the Lone Ranger belonged to a team Bennis W, Biederman PW. Organizing Genius: The Secrets of Creative Collaboration. Cambridge, Mass.; Perseus, 1997

29. The Mantle of Leadership Belongs to the “Team” • New leadership paradigms: • Not great leaders alone, but great leaders who exist in a fertile relationship with a great group • Creative alliances wherein leader and team achieve something together that neither could achieve alone • The leader finds greatness in the group and helps members find it in themselves Bennis W, Biederman PW. Organizing Genius: The Secrets of Creative Collaboration. Cambridge, Mass.; Perseus, 1997

30. Summary • Science increasingly depends on collaboration • Responsible collaborations are defined by openness and communication • Successful behaviors in a collaborative relationship can be predicted from game theory strategies for cooperation • Nice, retaliating, forgiving, non-envious • Altruistic strategies are superior to greedy strategies • Collaboration also is necessary for successful leadership by the investigator