Animal program leadership and communication.

Shortly after arriving at UW-Madison I was appointed to the Graduate School Institutional Animal Care and Use Committee (IACUC). After receiving tenure in 2000, I became significantly more involved in the UW-Madison animal care and use program. I was appointed Graduate School IACUC Chair in 2002, All Campus IACUC Chair in 2005, and also in 2005 I was asked to serve as the Director of Research Animal Resources Center (RARC). In this position, I was responsible for oversight and leadership of all animal care and use on the UW-Madison campus.  At the direction of then-Chancellor Wiley, and working with Dr. Janet Welter, the newly appointed Chief Campus Veterinarian, I led the team that built up an excellent campus program. Specific accomplishments:

1. Coordinated evaluation of the UW-Madison animal care and use program by external groups, including 3 cycles of outstanding triennial reviews with long lists of commendations by the Association for the Assessment and Accreditation of Animal Care, International (AAALAC), and an audit by UW System that found our program met all regulatory expectations and posed no regulatory risks to System.
2. Directed the development of an outstanding and nationally recognized programs of animal care and use training and public outreach.
3. Directed development of the Specific Pathogen Free Mouse Breeding Core, filling an important need that existing animal care units on campus could not meet.
4. Directed extension of this core to include provision of research services for animals.
5. Published 3 articles addressing critical issues in animal care and use.Sandgren, E.P. (2005). Defining the Animal Care and Use Program. Lab Anim. (NY) 34(10):41-4.
   McEntee, H.I., Sandgren, E.P. (2007). A tool for semiannual review of the institutional animal care and use program. Lab Anim. (NY) 36(9):36-40.
   Sandgren, E.P. (2014). The whole story on animal research. Lab Anim. (NY) 43(6):187.

Animal Research Communication Leadership:

As I assumed the leadership role for the campus animal care and use program, I had to acknowledge and respond to the intense ethical controversy surrounding research with animals. I began to engage in direct interactions with activists and the public, which included formal and informal debates and other public presentations. I became the UW-Madison spokesperson for animal research. Nationally, only a very few individuals have been willing to take on this role. Finally, I organized, served as the first Chair of, and participated in the UW-Madison Forum on Animal Research Ethics (FARE), which sponsored 11 public lecture/discussions by scientists, ethicists, and/or animal activists with differing perspectives on the use of animals in research. Most FARE presentations can be viewed online. I also published descriptions of our experiences with FARE (Sandgren, E.P. 2014. The whole story on animal research. Lab Anim. (NY) 43:187; and http://www.science.wisc.edu/documents/FARE_in_Review.pdf).

Teaching.

I have trained 9 graduate students and one postdoctoral fellow, 8 of whom remain in academic or industrial research and teaching positions. Three of my trainees who were veterinarians applied for and were awarded Special Emphasis Research Career Awards (SERCA) from the National Center for Research Resources under my mentorship. Twenty additional people, including a high school student, undergraduates, and veterinary students, have completed research projects in my laboratory. I have served as minor professor on 48 student PhD committees.

Since joining the Department of Pathobiological Sciences in 1993, I have taught in veterinary general pathology, and in 1997 became course coordinator. In 2003, I developed and have taught annually a series of five lectures on liver structure and disease and principles of general pathology in a required graduate level general toxicology course. I strive to provide students with an understanding of and appreciation for the ways that the animal body responds to injury of any type, and how quite often the resulting disease is caused more by the response than the insult.

In 2007, I began to lecture on the regulation and ethical conduct of research, teaching, and outreach using animals. Lectures were presented to veterinary students, in several Public Health Service-required Research Ethics and Scientific Conduct courses targeted to graduate students and postdoctoral fellows, and to undergraduate students. These presentations build on and are complimented by my experiences as a biomedical scientist using animals in research, as a member and chair of IACUCs, as Director of RARC, and as the UW-Madison spokesperson on issues related to animal research.

Biomedical Research.

Liver neoplasia. Since I received tenure, my laboratory has continued to develop and employ mouse model systems in which we stably create chimeric livers via hepatocyte transplantation.  In these livers, small (~1 mm in diameter) foci of genetically altered hepatocytes coexist with surrounding normal liver. Published and submitted manuscripts have:

1. Assessed the therapeutic potential of hepatocyte transplantation in liver disease.
2. Demonstrated that adult hepatocytes retain extensive replicative potential, even after being stored frozen for years.
3. Quantified (here and here) the effects of oncogene expression on hepatocyte growth in growth permissive and growth restrictive conditions.
4. Determined that cell cross talk in liver mediates toxicity of toxins with peroxisome proliferator activity.
5. Demonstrated that mutant β-catenin could not induce focal hepatocyte growth by itself, and was only weakly transforming, but dramatically synergized with mutant Hras to cause cancer.
6. Determined that the effects of mutant Kras and mutant Hras are not identical in liver, perhaps explaining the much higher frequency of Hras mutations detected in spontaneous mouse liver neoplasms.
7. Shown that oncogenes do not always cooperate to induce more severe liver cancer, and in some combinations can be antagonistic.
8. Confirmed that neoplasms generated by oncogenes usually though not always demonstrate oncogene addiction, which is a dependence on continued oncogene expression for survival and growth.

Manuscripts in preparation will (1) quantify the effects of specific oncogene combinations on hepatocyte transformation frequency; (2) identify marker genes whose expression can predict the initiating genetic molecular lesion(s) in a neoplasm; and (3) identify genes that may cooperate with oncogene expression during neoplastic progression.

Pancreatic neoplasia.  My laboratory provided the first conclusive evidence that mutant Kras expression targeted to mouse acinar cells could cause development of preneoplastic ductal lesions. Most human pancreatic cancer is ductal adenocarcinoma, and subsequent studies with mice and humans have confirmed the acinar cell as the primary source of the disease. We also have shown that acinar-derived cancer progression can involve the process of acinar-to-ductal metaplasia. A future manuscript will show that loss of tumor suppressor genes in Kras mediated preneoplastic lesions is associated with specific but dissimilar pathways of neoplastic progression for different suppressor gene deficits.

I continue to collaborate with other investigators who use these models to evaluate potential therapies for pancreatic cancer. In this role, I provide expertise in animal modeling and also supply experimental mice.

Resource sharing.  It has been my policy to share my animal models with other scientists throughout the world, including former students. Though my research program has been curtailed since 2005, these animals continue to be of great use, as evidenced by their employment in multiple high-impact publications.