Embryo Project Encyclopedia

Mechanism of Notch Signaling: The image depicts a type of cell signaling, in which two animal cells interact and transmit a molecular signal from one to the other. The process results in the production of proteins, which influence the cells as they differentiate, move, and contribute to embryological development. In the membrane of the signaling cell, there is a ligand (represented by a green oval). The ligand functions to activate a change in a receptor molecule. In the receiving cell, there are receptors; in this case, Notch proteins (represented by orange forks). The Notch proteins are embedded in the receiving cell membrane, and they have at least two parts: an intracellular domain (inside the cell) and the receptor (outside the cell). Once the ligand and receptor bind to each other, a protease (represented by the dark red triangle) can sever the intracellular domain from the rest of the Notch receptor. Inside the nucleus of the receiving cell (represented by the gray area) are the cellês DNA (represented by the multi-colored helices) and its transcription factors (blue rectangles). Transcription factors are proteins that bind to DNA to regulate transcription, the first step in gene expression, which eventually yields proteins or other products. Initially, repressor proteins (represented by a red irregular hexagon) prevent transcription factors from allowing transcription. When the severed Notch receptor intracellular domain reaches the nucleus, it displaces the repressor. The transcription factor can then signal for transcription to occur. 1) There is a Notch receptor protein in the membrane of a receiving cell, and a ligand for this receptor (for example, Delta) in the membrane of the signaling cell. When the ligand binds to the receptor, the intracellular domain of the receptor changes shape. 2) Inside the receiving cell, there are proteases. Once the intracellular domain of the receptor changes shape, the protease can bind to it and shear the intracellular domain away from the rest of the receptor molecule. 3) The severed intracellular domain is shuttled to the receiving cell nucleus. Here, the intracellular domain displaces a repressor protein. This allows a transcription factor to initiate DNA transcription. During transcription, DNA is used as a template to create RNA. Following transcription, the process of translation occurs, which uses RNA as a template to create proteins. These proteins influence the behavior, fate, and differentiation of cells, which contribute to normal embryonic development

The United States Food and Drug Administration, or FDA, published 'General Considerations for the Clinical Evaluation of Drugs,' in September 1977. The document defined acceptable practices for investigators who studied new drugs. Specifically, the document outlined the common clinical trial methods. Clinical trials are studies to test whether a new drug is safe before doctors can prescribe it to patients. Prior to 1977, the Protection of Human Subjects Rule primarily regulated clinical drug trials, but it did not specify who could and could not be included in clinical trials. In the document, the FDA recommended that anyone who could become pregnant be excluded from early-phase clinical trials to minimize risks to a potential fetus. After the FDA published the document, investigators excluded women from clinical trials. The document ultimately prevented women of reproductive capacity from participating in early phase clinical trials, which affected women’s health research.

Charles Knowlton was a physician and author who advocated for increased access to information about reproduction in the nineteenth century in the US. Throughout his early medical education, Knowlton was particularly interested in anatomy and on several instances robbed graves for bodies to dissect. In 1832, Knowlton authored The Fruits of Philosophy, a pamphlet that contained detailed descriptions of the reproductive organs and information on conception and methods to control reproduction. Knowlton circulated his work among his patients until it was republished in Boston, Massachusetts, in 1832. For publishing a book on sex and methods of birth control, Knowlton was convicted of breaking obscenity laws, which prevented the transmission of obscene materials. After his death, social activists Charles Bradlaugh and Annie Besant republished his work in London, England. Knowlton’s writing about sex and birth control allowed individuals to understand and take control of their reproduction and initiated a public discussion about obscenity laws.

In 1993, the NIH published the Revitalization Act that established guidelines for minorities’ and women’s participation in clinical research. Before the 1990s, investigators largely excluded women from their research based on the 1979 guidance from the US Food and Drug Administration, or FDA. The FDA urged investigators to exclude any woman who was or could become, pregnant to protect the woman and any developing fetuses from harm. Between 1979 and 1993, several other US governmental agencies urged investigators to increase the number of women in their clinical research to improve the state of women’s healthcare. After Congress passed the National Institutes of Health Revitalization Act, hereafter Revitalization Act of 1993, investigators who used NIH funds for clinical research were required to include both women and minorities in their clinical research. The Revitalization Act established the Office of Research on Women’s Health headquartered in Washington, DC and required investigators to include women in their clinical research, thus improving the quality of women’s health research.

Annie Wood Besant was a social activist who advocated for women’s access to birth control as well as marriage reform, labor reform, and Indian Nationalism in the nineteenth century in England and India. In her early career, Besant was involved in various social and political advocacy organizations including the National Secular Society, the Malthusian League, and the Fabian Society. Besant gave many public lectures and authored various articles in support of secularism, workers’ rights and unionization, and women’s rights. In 1877, Besant and her colleague Charles Bradlaugh republished the pamphlet The Fruits of Philosophy, by Charles Knowlton, on reproduction and contraception. Besant and Bradlaugh were tried for violating the obscenity law that prohibited the publication of obscene material, including sex and contraception. Later in her life, she converted to theosophy and moved to India where she joined the Theosophical Society. In India, Besant campaigned for Indian self-rule and became the president of the Indian National Congress. Besant, through republication of The Fruits of Philosophy and many public lectures and writings on women’s rights, expanded public knowledge of birth control.

Charles Bradlaugh was as a political and social activist in the seventeenth century in England. He held leadership positions in various organizations focused on social and political activism including the Reform League, the London Secular Society, the newspaper National Reformer, and the National Secular Society. Throughout his career, Bradlaugh advocated for better conditions for the working poor, and for the separation of government and religion. The British government prosecuted him numerous times for violating laws prohibiting the publication, sale, and transmission of antireligious, antigovernment, and obscene materials. In 1877, Bradlaugh and another secularist, Annie Besant, republished The Fruits of Philosophy, a pamphlet about contraceptive techniques originally whose author was physician Charles Knowlton. In the nineteenth century, individuals did not have access to information on sex, reproduction, and contraception, as much of society argued such information encouraged immoral behavior. Bradlaugh and Besant were tried for publishing information on sexual anatomy, conception, and methods to control reproduction. Bradlaugh expanded public knowledge of reproduction and contraception, and initiated the process of dismantling the obscenity laws.

'On the Permanent Life of Tissues outside of the Organism' reports Alexis Carrel's 1912 experiments on the maintenance of tissue in culture media. At the time, Carrel was a French surgeon and biologist working at the Rockefeller Institute in New York City. In his paper, Carrel reported that he had successfully maintained tissue cultures, which derived from connective tissues of developing chicks and other tissue sources, by serially culturing them. Among all the tissue cultures Carrel reported, one was maintained for more than two months, whereas previous efforts had only been able to keep tissues in vitro for three to fifteen days. Carrel’s experiments contributed to the development of long-term tissue culture techniques, which were useful in the study of embryology and eventually became instrumental in stem cell research. Despite later evidence to the contrary, Carrel believed that as long as the tissue culture method was accurately applied, tissues kept outside of the organisms should be able to divide indefinitely and have permanent life.

In 2014, the United States Food and Drug Administration published the Pregnancy and Lactation Labeling Rule to amend previous guidelines for the prescription of drugs for pregnant and lactating women. The 2014 Pregnancy and Lactation Labeling Rule was intended to increase the safety and efficacy of prescription drugs by making drug labels easier for physicians to understand and utilize. The Pregnancy and Lactation Labeling Rule restructured drug labels and required that they include narratives describing drug-associated risks to women and fetuses, rather than using complicated letter categories. The Pregnancy and Lactation Labeling Rule changed the framework for drug labeling, making it easier for doctors to prescribe safe and effective drugs to pregnant women, lactating women, and people of reproductive capacity.

In 1832, Charles Knowlton published The Fruits of Philosophy, a pamphlet advocating for controlling reproduction and detailing methods for preventing pregnancy. Originally published anonymously in Massachusetts, The Fruits of Philosophy was an illegal book because United States law prohibited the publishing of immoral and obscene material, which included information about contraception. In The Fruits of Philosophy, Knowlton detailed recipes for contraceptives and advocated for controlling reproduction. In 1877 in Europe, social activists Charles Bradlaugh and Annie Besant republished the pamphlet in London, England. At that time, many governments, including the United Kingdom, still considered the book illegal material due to its discussion of contraception. The Fruits of Philosophy was one of the first publications detailing contraceptive methods for controlling reproduction and activists used it in some of the first attempts at repealing obscenity laws in the United States and Great Britain. Through their efforts, Knowlton and those who later republished the pamphlet increased knowledge of reproduction and awareness of methods of contraception. By challenging anti-obscenity laws, the author and activists also helped with the eventual weakening and dissolution of such law.

In 2006, the United States Food and Drug Administration, or FDA, published the “Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products,” also called the Physician Labeling Rule, to improve the safety and efficacy of prescription drugs and drug products. Within the Physician Labeling Rule, the FDA includes a section titled “Use in Specific Populations” or Section 8, which refers to drugs used by pregnant women, lactating women, and people of reproductive capacity. The FDA stated that the purpose of the Physician Labeling Rule was to make drug labels easier for physicians to understand and use when prescribing drugs to pregnant women. With the Physician Labeling Rule, the FDA improved patient-physician communication and the safety of drug use during pregnancy.