AN ORGAN SYSTEMS APPROACH TO EXPERIMENTAL TARGETING … · AN ORGAN SYSTEMS APPROACH TO EXPERIMENTAL TARGETING OF THE METABOLIC SYNDROME Funded by the National Institutes of Health

AN ORGAN SYSTEMS APPROACH TO EXPERIMENTAL TARGETING OF THE

METABOLIC SYNDROME

Funded by the National Institutes of Health (GM-086771)

Lecture Outline

• Introduction and Business • NIGMS: Short Course Program • Outline of Vanderbilt Short Course • Responsible Conduct in Research

Who are we?

• Owen McGuinness (Course Director) • Masakasu Shiota (Associate Director) • Fiona Harrison(Associate Director) • Fran Tripp (Course Coordinator)

Housekeeping Items

• Parking • Accommodations • Food • When you work with animals

– Wear gloves and a disposable gown

• Course web site: • http://www.mc.vanderbilt.edu/diabetes/mssh

ortcourse/index.php

Lecture Outline


Background

• NIGMS-Sponsored Integrative and Organ Systems Pharmacology: Short course – demand for researchers with experience in the use of

isolated organ systems and whole animal methods in pharmaceutical industry

– Limited training using isolated organ systems and animal methods in core graduate student curriculum

– Lack of physiological training limits ability to translate to human disease

– NIGMS funded four Courses in 2005

Other Short Courses • Michigan State University

– June 3-15 – autonomic, renal, gastrointestinal, computer modeling,

cardiovascular, respiratory, and neuropharmacology • University of Nebraska

– June 4-15 – Neuro and cardiovascular pharmacology

• University of North Carolina at Chapel Hill – June 10-15 – Preclinical skills with emphasis on rodents

www.aspet.org/public/public_affairs/pa_NIGMS_shortcourse_awards.html

Vanderbilt Short Course

• Disease focus – Obesity Epidemic – Disease that crosses multiple disciplines

• Hypertension (cardiovascular system) • Diabetes (endocrinology and metabolism) • Behavior • Dyslipidemia and atherosclerosis • Cancer

– Many coexist • Metabolic syndrome

Metabolic Syndrome

Risk Factors • Insulin resistance • Central obesity • Dyslipidemia • Hypertension

Vanderbilt’s Core

• Diabetes Research and Training Center (DRTC) – Metabolic Physiology Shared Resource Core (Human,

Rat and Dog) – Islet Procurement and Analysis Core

• Mouse Metabolic Phenotyping Center (MMPC) – Metabolic Pathophysiology Core – Subcore: Lipids, Lipoproteins, and Atherosclerosis

• Murine Neurobehavioral Laboratory (MNL) • Institute of Imaging Science

– Small animal imaging

Lecture Outline


Our course

• Lectures • 10 Laboratories • 9 Group Discussions

Outline (Week 1) • Monday –Tuesday

– Animal behavior (rat and mice) – Animal care

• Wednesday –Thursday – Glucose metabolism – Glucose tolerance tests (mice and dog)

• Friday – Islet physiology – Islet isolation and Characterization – Load Animals into CLAMS

• Saturday – Cardiovascular/renal system – CV and glucose lab

Outline (Week 2) • Monday

– Lipid metabolism – Student presentations

• Tuesday – Pharmacology 101 – Liver perfusion lab – Group Dinner at “Wildhorse Saloon”

• Wednesday – Energy balance

• Thursday – Advanced Imaging Technology

Lecture Outline


Adnan Hajj’s Smoking City Photo

• Data Manipulation in 2006

http://www.news.com.au/heraldsun/story/0,21985,20045367-663,00.html

Presenter

Presentation Notes

Reuters’ photographer Adnan Hajj doctored the photo on the left using photo editing software to show more intense smoke and destruction in Beirut. Reuters admitted to the manipulation and apologized, fired Hajj, and removed the doctored photo from its archives. The original photo appears on the right.

Computers and Data

• The number of reported ethical problems involving publications of American Physiological Society (in 14 separate journals) rocketed from an average of less than one a year before 1999 to more than 50 a year in 2004, when all of the society’s publications became available online

Benos, D. J. et al. Adv. Physiol. Educ. 29, 59–74, 2005.

Rossner and Yamada, JCB 166: 11-15,2004

Responsibility comes with authorship

• A paper in Nature co-authored by Nobel prizewinning scientist Linda Buck has been retracted after the researchers were unable to reproduce the results. The authors now report that they have found “inconsistencies” between the original data and the data published in 2001.

Nature 452, 13 (2008)

“Too good to be true” “Nature …(1 April 2009) is retracting a 2000 paper that promised an

advance in diabetes treatment using gene therapy.“ • Nature 458, 561 (2009) • We used a recombinant adeno-associated virus (rAAV) that

expresses a single-chain insulin analogue (SIA), which possesses biologically active insulin activity without enzymatic conversion, under the control of hepatocyte-specific L-type pyruvate kinase (LPK) promoter, which regulates SIA expression in response to blood glucose levels. Here we show that SIA produced from the gene construct rAAV-LPK-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for a prolonged time without any apparent side effects.

• a patent was pending

It takes a long time to purge fraudulent material.

• Thioridazine and withdrawal dyskinesias on workshop performance of mentally retarded young adults Brunning SE

• Retracted 1989. • After nearly 20 years citations still exist

Current Med Res 26:843,2010

Scientific Record Keeping

• Collection

• Storage

• Ownership

• Sharing

Presenter

Presentation Notes

There is no uniform agreed-upon way of best record keeping, and this has nothing to do with legible hand-writing or calligraphy. There are numerous styles and permutations in tracking data collection Every method, however, is crucial for the INTEGRITY of our data, and raw data is what everyone falls back on to prove beyond any doubt that the experiments were done and the results presented are real not fabricated. Keeping data well, in a rational and consistent manner is a hallmark of a good investigator.

DATA COLLECTION

• Why do we need to keep good records? – To record our progress – To build upon for new research – To support our claims in grants and papers – For audit purposes – For the approval process of new drugs or medical devices – To establish intellectual property claims – To establish that appropriate authorization was granted

Good data books: • Are sufficiently legible • Are mostly organized • Are up to date • Allow repetition of your experiments • Are compliant with granting agency and institutional requirements • Are accessible to authorized person, stored properly, and

appropriately backed up • Are the ultimate record of your scientific contributions • Stay in the lab

Francis Macrina: Scientific Integrity, 3rd ed

DATA STORAGE

• Raw data, notebooks and computer files – Safe place – Back ups – Prevent sample degradation – Risk of fire, flood etc

• Confidentiality • Retention periods

– What is a reasonable period of time? – NIH: 3 years after final financial report – Know individual organizations’ rules

WHO OWNS WHAT?

• Those who provide money for research – Government agencies

• grants (institution) • Contracts (government)

– Private sector (generally the funding source) – Philanthropic organizations ( Varies)

Presenter

Presentation Notes

Most of us do not think about details of data ownership while we’re doing experiments. There are, however, clear rules provided by many funding agencies. For example, the NIH (therefore the government) distinguishes very specifically between grants and contracts. For grants, control of the data remains with the institution that received the funds, while the PI is the steward of the funds and the data collection, storage, etc. The PI as an individual never legally has ownership of the data. In the case of contracts, the government retains ownership and control of the product or service the researcher delivered. Private companies usually want to retain the right to the commercial use of the data Philanthropic entities can go either way Here was the answer to question 4 on the test: Under National Institutes of Health (NIH) policy, who owns the research data that result from work funded by an NIH grant? The principal investigator (PI) responsible for getting the grant owns all of the resulting data. Each scientist collecting data under an NIH grant owns any data that he or she personally collects All named investigators, but not graduate students or technicians, own any data that they personally collect under an NIH grant. The federal Department of Health and Human Services owns any data that result from research funded by an NIH grant. The institution that receives the NIH grant owns all of the resulting research data.

DATA SHARING

• Intuitive in the scientific tradition • Supports open scientific inquiry • NIH:

– Data should be made as widely and freely available as possible – Grants usually must contain plan for sharing of data, animals and

reagents • Special circumstances:

– Complexity of projects – Multi-site investigations – National security

Presenter

Presentation Notes

Complexity of projects: Human Genome Project. Massive amounts of information that pose problems in storage, access to data Multi-site projects: Who controls the data? Individual researchers/site maintain control over their “own” data or a centralized depository that collects, stores and interprets? Undecided National security: Many journals censor submissions on critical topics that pertain to national security. Analysing a bioterror attack on the food supply: the case of botulinum toxin in milk -July 12, 2005 PNAS DHHS wanted to embargo the publication Data sharing practices, that is open or secret, also play a role in issues of conflict of interest.

Scientists are INTERESTED in

• Advancing knowledge • Discoveries that benefit society • Professional advancement • Personal gain and satisfaction

• However these often can be in conflict!

Presenter

Presentation Notes

Today’s researchers are interested in All of these are legitimate, responsible, and justifiable interests. However, these can and OFTEN do conflict with one another thereby giving rise to what is termed “conflict of interest”

Types of conflict

• Financial Conflict

• Intellectual conflict

– Grant or manuscript review

• Conflict of Commitment – Percent Effort – Teaching/Advising – Paid Consultant

Presenter

Presentation Notes

Conflict of conscience Science is a values-free process that leads to a greater understanding of nature. Each of us, however, brings his own values, morals, ethics, traditions, beliefs, thoughts and feelings into our job. There are times when deeply felt personal convictions interfere with the objectivity of scientific methods and the practice of science, for example during peer review or study sections. At those times the views of an individual override scientific merit in reaching an objective decision. Example: the use of laboratory animals in research Attempts to resolve such conflicts or regulate them infringe upon the notion of academic freedom Hospital ethics committees Intellectual conflict or bias in research is usually seen as one’s inability to recognize and consider alternative approaches or interpretations Conflict of commitment is a common occurrence resulting from the combination of multiple demands on a researcher’s time and multiple expectations and responsibilities that surround modern academic careers. At any given time a researcher may be juggling A number of funded projects New grant applications Teaching Mentoring Engaging in peer review in study sections or journals or both Attending professional meetings and delivering lectures Membership in advisory boards Being a paid consultant Majority results from enthusiastic aspirations to become nationally or internationally known and to gain acceptance from your peers Furthermore, universities send mixed messages to young investigators since professional recognition is highly valued and prioritized In addition to rules and guidelines, the right way to balance one’s commitments to service, research and teaching is often found through active mentoring and advice from senior faculty.

CONFLICT OF INTEREST

• Exists when an individual (appears to) exploits his position for personal gain or for profit of his immediate family

• Undue use of position or exercise of power to influence decisions (VU guidelines)

• Rule of thumb: if an educated outsider could perceive there is a conflict, then there is likely a conflict

Presenter

Presentation Notes

Conflict of interest is a legal term that encompasses a wide spectrum of actions that involve personal gains or financial interests. The definition of what constitutes COI is variable, but practically all institutions that receive federal funds have a definition in place as well as policies for it A critical component of COI is the undue use of one’s position or exercise of power in order to influence decisions for personal gain It is generally believed that the only effective way to combat perceptions of undue influence is to instigate FULL DISCLOSURE. Conflict of interest, where financial gains are at the core, is distinctly different from - Conflict of effort - bias in research - conflict of conscience

Today 8:40-9:30 An overview of the metabolic syndrome in humans:

Owen McGuinness PhD Break 9:45-10:50 What is normal animal behavior? Fiona Harrison

PhD 11:10-12:00 How to measure animal behavior and perform a

neurological screen: Examples of therapeutics which alter behavior Fiona Harrison PhD

12:00-1:00 Lunch: 1:00 Tour animal facility (MMPC and then walk over to

Neurobehavioral core) 1:30-4:30 Lab I: Working with mice: Murine Neurobehavioral

Laboratory

Documents

AN ORGAN SYSTEMS APPROACH TO EXPERIMENTAL TARGETING … · AN ORGAN SYSTEMS APPROACH TO EXPERIMENTAL TARGETING OF THE METABOLIC SYNDROME Funded by the National Institutes of Health