Shane K. Green

Research Ethics Recommendations for Whole-Genome Research: Consensus Statement

Interest in whole-genome research has grown substantially over the past few months. This article explores the challenging ethics issues associated with this work.

Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies

A major obstacle compromising the successful application of many of the new targeted anticancer drugs, including angiogenesis inhibitors, is the empiricism associated with determining an effective biological/therapeutic dose because many of these drugs express optimum therapeutic activity below the maximum tolerated dose, if such a dose can be defined. Hence, surrogate markers are needed to help determine optimal dosing. Here we describe such a molecular marker, increased plasma levels of vascular endothelial growth factor (VEGF), in normal or tumor-bearing mice that received injections of an anti-VEGF receptor (VEGFR)-2 monoclonal antibody, such as DC101. Rapid increases of mouse VEGF (e.g., within 24 hours) up to 1 order of magnitude were observed after single injections of DC101 in non–tumor-bearing severe combined immunodeficient or nude mice; similar increases in human plasma VEGF were detected in human tumor-bearing mice. RAFL-1, another anti-VEGFR-2 antibody, also caused a significant increase in plasma VEGF. In contrast, increases in mouse VEGF levels were not seen when small molecule VEGFR-2 inhibitors were tested in normal mice. Most importantly, the increases in plasma VEGF were induced in a dose-dependent manner, with the maximum values peaking when doses previously determined to be optimally therapeutic were used. Plasma VEGF should be considered as a possible surrogate pharmacodynamic marker for determining the optimal biological dose of antibody drugs that block VEGFR-2 (KDR) activity in a clinical setting.

Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance to alkylating agents.

Similar to other anticancer agents, intrinsic or acquired resistance to DNA-damaging chemotherapeutics is a major obstacle for cancer therapy. Current strategies aimed at overcoming this problem are mostly based on the premise that tumor cells acquire heritable genetic mutations that contribute to drug resistance. Here, we present evidence for an epigenetic, tumor cell adhesion–mediated, and reversible form of drug resistance that is associated with a reduction of DNA mismatch repair proteins PMS2 and/or MLH1 as well as other members of this DNA repair process. Growth of human breast cancer, human melanoma, and murine EMT-6 breast cancer cell lines as multicellular spheroids in vitro, which is associated with increased resistance to many chemotherapeutic drugs, including alkylating agents, is shown to lead to a reproducible down-regulation of PMS2, MLH1, or, in some cases, both as well as MHS6, MSH3, and MSH2. The observed down-regulation is in part reversible by treatment of tumor spheroids with the DNA-demethylating agent, 5-azacytidine. Thus, treatment of EMT-6 mouse mammary carcinoma spheroids with 5-azacytidine resulted in reduced and/or disrupted cell-cell adhesion, which in turn sensitized tumor spheroids to cisplatin-mediated killing in vitro. Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or preventing reduced DNA mismatch repair activity and that the chemosensitization properties of 5-azacytidine may conceivably reflect its role as a potential antiadhesive agent as well as reversal agent for MLH1 gene silencing in human tumors.

Guidelines to Prevent Malevolent Use of Biomedical Research

In February 1975, a group of leading scientists, physicians, and policymakers convened at Asilomar, California, to consider the safety of proceeding with recombinant DNA research. The excitement generated by the promise of this new technology was counterbalanced by concerns regarding dangers that might arise from it, including the potential for accidental release of genetically modified organisms into the environment. Guidelines developed at the conference to direct future research endeavors had several consequences. They permitted research to resume, bringing to an end the voluntary moratorium that the National Academy of Sciences (NAS) had instituted several months earlier. They also served to illustrate that the scientific community was capable of self-governance, thereby securing public trust and persuading Congress not to institute legislative restrictions.1 Finally, they underscored the importance of weighing unforeseen risks inherent in some research against potential benefits that may arise from these same endeavors. In February 2000, a second meeting was held at Asilomar, bringing together members from the same groups, including some of the original attendees.2 This meeting was held in honor of the historic event’s 25th anniversary and in recognition of the scientific community’s increasing attention to the potentially harmful applications of biotechnology in general —for example, to facilitate the use of pathogens as deadly weapons.3 Risk of this latter sort that arises not from research per se but from its intentional misapplication for nefarious purposes constitutes the focus of this report. The possibility that scientific research may generate knowledge with the potential for harmful as well as beneficial applications is not new. In recent years, however, it has become imperative to develop parameters within which to address such research, as heightened concerns have arisen from the threat of biochemical terrorism and warfare.

Addressing Ethical, Social, and Cultural Issues in Global Health Research

Summary The purpose of this paper is to encourage reflection among the global health research community and the research ethics community about how a wide range of ethical, social, and cultural (ESC) influences on the conduct, success, and impact of global health research can best be addressed by consultation services in research ethics (CSRE). We draw on lessons we have learned during our experiences with the ESC Program of the Grand Challenges in Global Health initiative to propose key features of CSRE that may prove useful for those designing or implementing similar programs.

Global Justice and the Proposed Ban on Thimerosal-Containing Vaccines

* Abbreviations: HICs — : high-income countries LMICs — : low- and middle-income countries Thimerosal is an ethyl mercury–containing compound that has been used safely for >60 years as a preservative in multidose vials of vaccines to prevent bacterial and fungal contamination of those vials when they are repeatedly entered to withdraw doses.1,2 In the late 1990s, preservative-free single-dose vials were widely introduced into high-income countries (HICs). This was a precautionary move in response to theoretical concerns, now known to be unfounded, that ethyl mercury in thimerosal could build up in vaccine recipients’ bodies at a rate to similar methylmercury (a known toxin) causing toxicity.3 For low- and middle-income countries (LMICs), where the burdens of vaccine-preventable deaths are most profound, multidose vials of thimerosal-preserved vaccines are a critical part of immunization programs. Extensive additional resources associated with increased manufacturing, shipping, cold-chain storage, administration, and waste-handling infrastructure would be required by a move away from multidose vaccines; for example, a shift to single-dose vials would increase the annual cost of Pan American Health Organization– or UNICEF–supplied vaccines by >

Biodefense: spend, but spend wisely.

300 million.4 In January 2013, governments are set to finalize the products and processes that will be prohibited in a multilateral environmental treaty, backed by the United Nations Environment Programme, which aims to restrict human and environmental exposure to mercury.5 As a mercury derivative, thimerosal could potentially be included within the treaty. Although supportive of the objectives of reducing human and environmental exposure to mercury, the World … Address correspondence to Shane K. Green, PhD, Sandra Rotman Centre, MaRS Building, South Tower, 101 College St, Suite 406, Toronto, ON, Canada, M5G1L7. E-mail: shane.green{at}srcglobal.org

Chapter 6: Physician Professionalism and Preparing for Epidemics: Challenges and Opportunities

*The views expressed in this commentary are those of the authors and do not necessarily represent the views of the American Medical Association.

Antitumor Effects in Mice of Low-dose (Metronomic) Cyclophosphamide Administered Continuously through the Drinking Water

Physicians are instrumental to our national defense against epidemics, whether natural or bioterror-related. Broadly speaking, they are obligated to help rapidly identify threats, prevent the spread of disease, and care for infected patients. Each task presents ethical challenges, including the need to address access to care, balance the medical needs of individuals and communities, and ensure that health professionals continue to treat infectious patients in spite of the risk they present. If physicians can acknowledge these duties and meet these challenges, they have an opportunity to strengthen medicines public trust and professional identity.