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

Genome testing services are available to the public and have both potential for and limitations in providing clinically useful information. Virtual Mentor is a monthly bioethics journal published by the American Medical Association.

The threat of bioterrorism has prompted the U.S. to undertake a vast biodefense initiative, including funding biodefense-related scientific research at unprecedented levels. Unfortunately, the many ethical, economic, environmental, legal, and social implications (E(3)LSI) of biodefense research and activities are not yet receiving the attention they warrant. Previously, in laudable demonstrations of foresight and responsibility, the federal government has funded research into the E(3)LSI of other recent scientific endeavors--namely, the Human Genome Project and the nanotechnology research program--through directed appropriations from their respective research budgets. This article advocates and proposes a model for a portion of biodefense funding to be similarly set aside for an E(3)LSI research program to complement biodefense research, to ensure that bioterror preparedness does not give rise to harmful or otherwise undesirable unintended consequences.

* 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 >$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

Multicellular resistance, a subtype of therapeutic resistance manifested in cancer cells grown as three-dimensional multicellular masses, such as spheroids in vitro and solid tumors in vivo, occurs with respect to a variety of anticancer treatment strategies including chemotherapy, ionizing radiation, and even host-mediated antibody-dependent cellular cytotoxicity. Previous studies from our laboratory have shown that multicellular resistance to chemotherapy demonstrated by aggregates of EMT-6 murine mammary carcinoma cells can be overcome by using hyaluronidase to disrupt intercellular adhesive interactions and associated patterns of protein expression. In this proof of principle study, we explored the concept of antiadhesive chemosensitization in the context of human cancer cells by using a monoclonal antibody to disrupt E-cadherin-mediated cell-cell interactions in multicellular spheroids of HT29 human colorectal adenocarcinoma. In so doing, we found that disruption of E-cadherin-mediated adhesion sensitizes multicellular spheroids of HT29 in vitro to treatment with 5-fluorouracil, paclitaxel, vinblastine, and etoposide but not cisplatin. Furthermore, we have found that antibody-mediated blockage of E-cadherin function leads to decreased expression and activity of protein kinase C α and β1, both of which have previously been implicated in chemoresistance exhibited by HT29 cells; however, we have found that the chemosensitization effects of the anti-E-cadherin antibody are independent of its influence on protein kinase C β1.

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

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.

The best defense against a public health emergency is a healthy population with easily accessible health care. Virtual Mentor is a monthly bioethics journal published by the American Medical Association.

Presymptomatic genetic testing for neurodegenerative diseases can help patients make effective treatment decisions, but the medical profession needs to ensure that the increasing use of the tests is done responsibly. Virtual Mentor is a monthly bioethics journal published by the American Medical Association.

Hypothesis 7 the Liberals have just inherited, I wonder whether the Liberals will commit to their promise of shutting down these private MRI clinics. There is no question that Ontarians should have equal access to state-of-the art diagnostic services. However, I question the rationale of selling-off such public services to private hands as inevitability, for a crisis that was born out of chronic under-funding.

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 medicine's public trust and professional identity.

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.

A centralized registry to provide information to consumers regarding the effectiveness of clinical trials is needed to help patients make informed decisions about treatment. Virtual Mentor is a monthly bioethics journal published by the American Medical Association.

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.

A new AMA policy provide guidance for physician-scientists on dual-use research issues and reinforces the message that ethical conduct in scientific research ultimately rests with the individual researcher. Virtual Mentor is a monthly bioethics journal published by the American Medical Association.

Physicians need to take an active role in improving the genetic literacy of the general population and also push for public health policies that make new genetic tools available to everyone. Virtual Mentor is a monthly bioethics journal published by the American Medical Association.

Resistance to antibody-based anticancer approaches has become of considerable interest because of the rapidly growing clinical use of several different monoclonal antibodies as therapeutic agents, coupled with the recent finding that their efficacy may be attributable in part to their participation in host antibody-dependent cellular cytotoxicity. In this proof-of-concept study, we demonstrate the novel ability of an antiadhesive antibody (SHE78-7), targeted at the potent homophilic cell adhesion molecule E-cadherin, to play a dual role as participant in, and sensitizing agent for, host immune-mediated antitumor activity. SHE78-7 disrupted preformed multicellular aggregates (spheroids) of HT29 colon carcinoma cells both in vitro and in vivo in an ascites tumor xenograft model, but had no direct antitumor effect in vitro. In vivo, however, i.p. injection of SHE78-7 significantly prolonged the survival of nude mice carrying established i.p. HT29 xenografts, most notably when injections were given biweekly. This antitumor effect was dependent on the antiadhesive effect of SHE78-7 and could be effectively recapitulated via treatment with a combination of nondisruptive anti-hMHC-I antibodies, capable of recruiting an F(c)-mediated immune response but ineffective as a monotherapy and antiadhesive F(ab')(2) fragments of SHE78-7. Furthermore, additional therapy experiments using such F(ab')(2) fragments, or mice lacking activating F(c)gammaRIII receptors or inhibitory F(c)gammaRIIB, unequivocally indicated a role for host antibody-dependent cellular cytotoxicity, mediated by F(c)gammaRIII and negatively regulated by F(c)gammaRIIB. Taken together, the results suggest a possible means of improving antibody-based therapies of cancer, namely targeting antigens, selectively expressed or up-regulated by target cancer cells, which mediate cell-cell adhesive functions.

One of the greatest barriers to the treatment of cancer with chemotherapeutic drugs is acquisition of drug resistance. This includes multidrug resistance mediated by P-glycoprotein (Pgp) to multiple lipophilic natural compounds such as taxanes, doxorubicin (Adriamycin), and vinblastine. The considerable efforts made thus far to reverse this and other types of drug resistance have had very limited success. We report here that a variety of orthotopic human breast cancer xenografts selected for high levels of Pgp and multidrug resistance respond in a significant and durable manner to different continuous low-dose (e.g., one-tenth the maximum tolerated dose of chemotherapy) chemotherapy regimens, when used in combination with an antivascular endothelial cell growth factor (anti-VEGF) receptor-2 (flk-1)-neutralizing antibody (DC101). The Pgp substrates paclitaxel (Taxol), Adriamycin, and vinblastine were all effective using this type of combination treatment, although the chemotherapy protocols showed little or no effect as monotherapies. Similar results were also obtained using cisplatinum (a non-Pgp substrate drug) against cisplatinum-resistant tumors. Evidence of significant tumor cell death by the combination treatment was detected within 3 weeks of initiation of therapy by histopathological analysis, in the absence of shrinkage of tumor mass. There were, however, marked differences in the cumulative toxicity of long-term regimens of Adriamycin and cisplatinum, where toxicity was observed, when compared with the tubulin inhibitors, vinblastine and Taxol, where it was not. We conclude that vascular-targeting protocols involving frequent administration of very low doses of certain chemotherapeutic drugs can provide a stable and safe way to circumvent multidrug resistance in established orthotopically growing tumors, as long as these are used in combination with a second antiangiogenic drug, in this case, anti-VEGFR-2 blocking antibodies.

Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate vaccines targeting neglected diseases in low- and middle-income countries are now progressing to large-scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public health value of the research; and the research is responsive to local health needs. The four situations are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g. based on epidemiologic or demographic factors), and (4) determining the local burden of disease.