Discovery and rediscoveries of Golgi cells.

When Camillo Golgi invented the black reaction in 1873 and first described the fine anatomical structure of the nervous system, he described a 'big nerve cell' that later took his name, the Golgi cell of cerebellum ('Golgi'schen Zellen', Gustaf Retzius, 1892). The Golgi cell was then proposed as the prototype of type-II interneurons, which form complex connections and exert their actions exclusively within the local network. Santiago Ramón y Cajal (who received the Nobel Prize with Golgi in 1906) proceeded to a detailed description of Golgi cell morphological characteristics, but functional insight remained very limited for many years. The first rediscovery happened in the 1960s, when neurophysiological analysis in vivo revealed that Golgi cells are inhibitory interneurons. This finding promoted the development of two major cerebellar theories, the 'beam theory' of John Eccles and the 'motor learning theory' of David Marr, in which the Golgi cells regulate the spatial organisation and the gain of input signals to be processed and learned by the cerebellar circuit. However, the matter was not set and a series of pioneering observations using single unit recordings and electronmicroscopy raised new issues that could not be fully explored until the 1990s. Then, the advent of new electrophysiological and imaging techniques in vitro and in vivo demonstrated the cellular and network activities of these neurons. Now we know that Golgi cells, through complex systems of chemical and electrical synapses, effectively control the spatio-temporal organisation of cerebellar responses. The Golgi cells regulate the timing and number of spikes emitted by granule cells and coordinate their coherent activity. Moreover, the Golgi cells regulate the induction of long-term synaptic plasticity along the mossy fibre pathway. Eventually, the Golgi cells transform the granular layer of cerebellum into an adaptable spatio-temporal filter capable of performing several kinds of logical operation. After more than a century, Golgi's intuition that the Golgi cell had to generate under a new perspective complex ensemble effects at the network level has finally been demonstrated.

Q & A with Daniel L. Hartl, Recipient of the 2019 Thomas Hunt Morgan Medal.

The Genetics Society of America's Thomas Hunt Morgan Medal honors researchers for lifetime achievement in genetics. The recipient of the 2019 Morgan Medal is Daniel Hartl of Harvard University, who is recognized for his influential and diverse contributions to genetics research. The unifying theme of Hartl's broad impacts on transmission, population, evolutionary, and medical genetics has been the combination of theoretical insights with cutting-edge experimental techniques. Some of his contributions include revealing the genetics of segregation distortion, developing statistical frameworks for estimating the effects of selection, application of these frameworks to natural and experimental populations, discovery of the mariner transposon and its influence on genome evolution, insights into the evolution of gene expression differences, and modeling the evolution of malaria parasite populations. Hartl is also known as a supportive mentor who has trained many prominent geneticists that continue to shape the field.

Ion Channels: History, Diversity, and Impact.

From patch-clamp techniques to recombinant DNA technologies, three-dimensional protein modeling, and optogenetics, diverse and sophisticated methods have been used to study ion channels and how they determine the electrical properties of cells.

Organoids: A historical perspective of thinking in three dimensions.

In the last ten years, there has been a dramatic surge in the number of publications where single or groups of cells are grown in substrata that have elements of basement membrane leading to the formation of tissue-like structures referred to as organoids. However, this field of research began many decades ago, when the pioneers of cell culture began to ask questions we still ask today: How does organogenesis occur? How do signals integrate to make such vastly different tissues and organs given that the sequence of the genome in our trillions of cells is identical? Here, we summarize how work over the past century generated the conceptual framework that has allowed us to make progress in the understanding of tissue-specific morphogenetic programs. The development of cell culture systems that provide accurate and physiologically relevant models are proving to be key in establishing appropriate platforms for the development of new therapeutic strategies.

Implementation and Challenges of Direct Acoustic Dosing into Cell-Based Assays.

Since the adoption of Labcyte Echo Acoustic Droplet Ejection (ADE) technology by AstraZeneca in 2005, ADE has become the preferred method for compound dosing into both biochemical and cell-based assays across AstraZeneca research and development globally. The initial implementation of Echos and the direct dosing workflow provided AstraZeneca with a unique set of challenges. In this article, we outline how direct Echo dosing has evolved over the past decade in AstraZeneca. We describe the practical challenges of applying ADE technology to 96-well, 384-well, and 1536-well assays and how AstraZeneca developed and applied software and robotic solutions to generate fully automated and effective cell-based assay workflows.

Isolation and growth of adult human epidermal keratinocytes in cell culture. 1978.

Human epidermal keratinocytes may be isolated in high yield from 0.1 mm keratotome sections of adult skin by short-term trypsin release. When plated on a collagen-coated plastic surface or on a collagen gel, keratinocytes attach with high efficiencies (greater than 70%) and form confluent, stratified cultures. Cell populations of predominantly basal cells produce proliferative primary cell cultures while populations of basal cells and malpighian cells result in nonproliferative primary cultures. Both nonproliferative and proliferative primary cultures may be subcultured on collagen gels following dispersion by trypsin and EDTA. Methotrexate strongly inhibits proliferative keratinocytes at low concentrations (0.1 microgram/ml) but has no cytotoxic effect on non-proliferative cells. L-serine and dexamethasone increase the multiplication rate of both primary and subcultured human keratinocytes.

Biological stereology: history, present state, future directions.

The development of a quantitative structural platform for experimental biology--extending across a hierarchy of sizes ranging from molecules to organisms--has been punctuated by a series of major achievements over the last 30 years. Stereology, a form of quantitative morphology, has contributed handsomely to this success. A personal view is presented highlighting key events in the development of biological stereology. We also examine stereology with a view toward future developments in biology and speculate how stereology might contribute to the new biological infrastructure currently being built with computers.

[Circulating cancer cells in the peripheral blood].

Occasional observations on this subject were seen until 1995 when Engell reported the large study on circulating cancer cells in the peripheral blood. Engell's report generated great enthusiasm in our country also. But, these cytologic method have a low sensitivity. Consequently, studies on the circulating tumor cells have been abandoned. However, since 1987, RT-PCR and other molecular biologic method were introduced for the identification of circulating cancer cells and micrometastases in bone marrow as well as in lymphnode. Serial analysis of a large number of patients by well-qualified laboratories have been performed. Several authors have shown a significant correlation between detection of cancer cells and relapse in some forms of malignancies. These research may be beneficial in the staging of cancer, in monitoring the effectiveness of cancer treatment, etc. Detection of cancer cells in the peripheral blood likely to have a profound impact on the practice of clinical oncology.