Systems based analysis of human embryos and gene networks involved in cell lineage allocation.

BACKGROUND: Little is understood of the molecular mechanisms involved in the earliest cell fate decision in human development, leading to the establishment of the trophectoderm (TE) and inner cell mass (ICM) stem cell population. Notably, there is a lack of understanding of how transcriptional networks arise during reorganisation of the embryonic genome post-fertilisation. RESULTS: We identified a hierarchical structure of preimplantation gene network modules around the time of embryonic genome activation (EGA). Using network models along with eukaryotic initiation factor (EIF) and epigenetic-associated gene expression we defined two sets of blastomeres that exhibited diverging tendencies towards ICM or TE. Analysis of the developmental networks demonstrated stage specific EIF expression and revealed that histone modifications may be an important epigenetic regulatory mechanism in preimplantation human embryos. Comparison to published RNAseq data confirmed that during EGA the individual 8-cell blastomeres are transcriptionally primed for the first lineage decision in development towards ICM or TE. CONCLUSIONS: Using multiple systems biology approaches to compare developmental stages in the early human embryo with single cell transcript data from blastomeres, we have shown that blastomeres considered to be totipotent are not transcriptionally equivalent. Furthermore we have linked the developmental interactome to individual blastomeres and to later cell lineage. This has clinical implications for understanding the impact of fertility treatments and developmental programming of long term health.

The two fundamental duties of the physician.

The author asserts that physicians have two fundamental duties: they must balance the interests and wishes of the patient with the welfare of the health care system in which they practice. In fact, many physicians actually act in accordance with this dual approach, but they sense an inconsistency between their behaviors and their ideals, which focus on the patient only. The author explains why, as a consequence of this more complex role, medicine must stop viewing the case manager as the unavoidable but unwanted child within the family of medicine and must incorporate case management within the very identity of the physician. Finally, the author explains in detail that when the physician practices according to the dual-stewardship model just described, at least three beneficial consequences will emerge. First, the abysmal quality of end-of-life care in the United States may improve. Second, restraints on funding for last-chance or experimental treatments may, surprisingly, advance patients' interests. Third, an admission that much is not known about many mental illnesses and an acknowledgment that the money spent in treatment often yields limited results may encourage the health system to resist providing unproven treatments. This admission should also lead to more scientific knowledge and more effective approaches to these bewildering problems. In conclusion, the author states that it is not just the physician who must redefine himself in the new world of medicine. Administrators of managed care organizations must face the challenge of redirecting their traditional commitments to stockholders and boards of directors toward the patient-centered values of the physician.

Individual autonomy and the double-blind controlled experiment: the case of desperate volunteers.

This essay explores some concerns about the quality of informed consent in patients whose autonomy is diminished by fatal illness. It argues that patients with diminished autonomy cannot give free and voluntary consent, and that recruitment of such patients as subjects in human experimentation exploits their vulnerability in a morally objectionable way. Two options are given to overcome this objection: (i) recruit only those patients who desire to contribute to medical knowledge, rather than gain access to experimental treatment, or (ii) provide prospective subjects the choice to participate in standard double-blind study or receive the experimental treatment. Either option would guarantee that patients in desperate conditions are given a more meaningful choice and a richer freedom, and thus a higher quality of informed consent, than under standard randomized trials.

The exclusion of theology from public policy: the case of euthanasia.

It is commonly assumed that ethical decisions made on theological grounds belong in the private sphere, but theological arguments have a distinct place in the public's ethical conversation.

The whole truth and nothing but the truth?

KIE: Two commentaries explore the question of how much information should be disclosed to a 16-year-old female patient about the genetic abnormality, testicular feminization (XY genotype), which renders her infertile. She has presented with precancerous testes that require surgical removal and also needs an operation on her vagina in order for her to be able to engage in intercourse. Minoque and Taraszewski argue that full disclosure creates no significant benefit to the patient's freedom to act in accordance with what she considers her own best interest, so that the physician has no obligation to convey the genetic information to the patient or to her parents. Elias and Annas contend that everyone's best interests will be best served only by a full explanation of the syndrome and of the risks and benefits of the suggested surgery for consent to the surgery to be informed.^ieng

Error, malpractice, and the problem of universals.

This article begins with a criticism of McIntyre and Gorovitz's account of medical error. Their theory implies that error, at least sometimes, is a necessary consequence of the inductive character of medical inquiry. The counter intuitive consequences of this account suggest that the issues surrounding induction may not be the most fertile area for developing a coherent interpretation of medical error. Given these shortcomings, I develop a new theory which assumes that the best philosophical soil for constructing a theory of medical error is the problem of universals. I then explain the problem and how the medical universal functions within arguments concerning diagnosis and treatment. A Wittgensteinian solution to the problem is presented which emphasizes the "borderline" character of some, if not many, medical judgments. Next, an argument is offered to establish that questions of medical error are not purely professional questions. This is because the theories used to make such professional judgments permit borderline cases even under the best circumstances. Finally, while there are a number of legitimate responses to this situation, I recommend one which involves legislative action.