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Three methods for gene-expression profiling have now been combined to produce spatially defined single-cell maps of developing human organs from limited sample material, overcoming a major hurdle in studying human development. A framework for spatially resolved single-cell maps of human organs.

Single-cell analysis is a valuable tool for dissecting cellular heterogeneity in complex systems1. However, a comprehensive single-cell atlas has not been achieved for humans. Here we use single-cell mRNA sequencing to determine the cell-type composition of all major human organs and construct a scheme for the human cell landscape (HCL). We have uncovered a single-cell hierarchy for many tissues that have not been well characterized. We established a 'single-cell HCL analysis' pipeline that helps to define human cell identity. Finally, we performed a single-cell comparative analysis of landscapes from human and mouse to identify conserved genetic networks. We found that stem and progenitor cells exhibit strong transcriptomic stochasticity, whereas differentiated cells are more distinct. Our results provide a useful resource for the study of human biology.

An ingenious technique allows the monitoring of brain-wide patterns of neuronal activity in a vertebrate at the cellular level, while the animal interacts with a virtual environment. See Article p.471 Improvements in technology have allowed neuroscientists to dissect the relationship between behaviour and activity in specific neural circuits. However, in a model system such as the zebrafish, it is potentially possible to track neural activity in circuits on a much broader scale. Using a virtual-reality-based imaging system, Florian Engert and colleagues track the dynamics of adaptive locomotion at single-neuron resolution in navigating fish to derive candidates for functional elements that drive motor learning.

How did organismal complexity evolve at a cellular level, and how does a genome encode it? The answer might lie in differences, not in the number of genes an organism has, but rather in the regulation of gene expression.

Since the discipline of space biology was launched over 40 years ago there have been many developments, some of which were reviewed and discussed at a workshop last month. The workshop was unusual in that it focused on the effects of microgravity above the cellular level -- in contrast to much of contemporary biology, which is concerned more with molecules.

Bezrukov and Vodyanoy reply — The possibility that the mechanism of stochastic resonance might account for the sensitivity of organisms to industrial low-frequency magnetic and/or electric fields has inspired much discussion1,2,10. In a recent Letter6 we formulated a physical model of stochastic resonance that permits quantitative analysis of the phenomenon in a variety of systems. Astumian and co-workers apply our results to the intriguing but difficult question of the role of stochastic resonance in signal detection at the level of a single cell. For a ‘typical cell’ of 100 μm radius, they come to a conclusion that stochastic resonance increases cell sensitivity to small signals,but that this increase is not significant enough to account for the effects reported by others2. Although we agree with their treatment of our theory, we show that for smaller cells stochastic resonance can improve signal detection considerably.

NEURONES which respond preferentially to slits of light of a given orientation have been found at the ganglion cell level of the retina1, as well as at higher centres of the visual system2–4. Present knowledge about the morphology of such cells and the organisation of the inputs to these cells does not account for the origins of their specialised receptive field properties. We report here that the horizontal cells impaled in the visual streak of the turtle retina (a specialised linear area centralis5 analogous to the fovea of higher vertebrates) respond preferentially to slits of light oriented parallel to the streak and thus parallel to the horizontal meridian of the animal's visual field5. Anatomical studies demonstrate that these horizontal cells are all elongated and oriented in the direction of the streak. Thus, our findings show that a class of neurones exists in the retina whose morphologies may form the basis for their specialised receptive field properties.

THE occurrence of pleural and peritoneal mesotheliomata is linked with the inhalation of asbestos fibres1,2. Experimentally, mesotheliomata have been induced by the intrapleural inoculation of asbestos fibres into rats3. These findings suggest that the incorporation of the fibres disturbs processes at the cellular level. The possibility that they induce chromosome abnormalities was indicated by V. Timbrell (personal communication) and we have investigated it further using cultured Chinese hamster cells.

CYCLIC AMP evokes or mediates a multitude of responses in animals and microorganisms1,2. Whereas the occurrence and regulatory role of cyclic AMP in these organisms is well established, little is known about its role in plants. Cyclic AMP has been reported to mimic certain effects of gibberellins, indoleacetic acid (IAA) and phytochrome in higher plants but in no case has its endogenous presence been unequivocally demonstrated3,4. We describe here a new response of cyclic AMP at the cellular level in the moss protonema; the results show that it is involved in the differentiation of chloronema cells. The intracellular level of cyclic AMP in these cells is four- to sevenfold higher as compared with that in caulonema cells. In a leaky chloronema-repressed mutant isolated by us, cyclic AMP is shown to enhance the differentiation of chloronema filaments.

THE structural complexity of nervous tissues and the presence of non-neuronal elements have hindered investigations into the actions of morphine at the cellular level in the vertebrate central nervous system, and contribute to the difficulty of determining whether morphine acts pre- or postsynaptically. Although presynaptic effects of morphine are documented, to our knowledge there has been no demonstration of an effect of morphine on postsynaptic neurotransmitter receptors using intracellular recording techniques.

ACCORDING to the classical work of Harrison and his followers1–6, the anteroposterior polarity of amphibian limbs consists of a ‘molecular polarisation’ of the cells which has been acquired by the late gastrula stage of development. I here present evidence that the polarity of the anteroposterior pattern is caused at a later stage of development by a signal emitted from a region posterior to the limb rudiment. In so far as this signal can travel in both directions it is not necessary to postulate any polarity at the cellular level.

INJURY1,2, nerves3 and hormones4 have been identified as essential for limb regeneration in amphibia. There seem to be differences in the “current of injury” between regenerating and non-regenerating types of amphibians5; partial limb regeneration can be induced in the latter type by simulating the “current of injury” of the regenerating form6. The cellular process of fracture healing in the amphibian is directly related to the electrical phenomena produced by the fractured bone7 and maximally effective ranges for current density can be determined at the cellular level. This led to the concept of a control system the key element of which was the induction of blastema formation in response to appropriate electrical factors8. The absence of regeneration in the mammal may therefore be due to the absence of adequate electrical factors. We report here the consequences of restoring factors which seem to be of practical as well as theoretical interest.

IT would be convenient to be able to measure the antibody response to alloantigens of the major histocompatibility complex (MHC) at a cellular level. As MHC alloantigens are expressed on erythrocyte membranes in mice one might suppose that a conventional Jerne plaque assay with enumeration of haemolytic plaque-forming cells (allo-PFC) against a lawn of suitable allogeneic erythrocytes would be straightforward. In fact such assays have proved difficult, with very few plaques being detected1,2. We have found the same problem in detecting allo-PFC in the spleens of alloimmunised rats. Although alloantisera raised in appropriate strain combinations have a high titre in a direct complement dependent haemolytic assay (Fig. 1) emphasising the potential value of this convenient assay for alloantibody in the rat3,4, very few allo-PFC were found in spleen cell suspensions from hyperimmunised donors. We show here that the discrepancy may be due to the homogeneity of the antibody product of a single PFC compared with the heterogeneity of serum antibody.

WE report that the mouse fibroblasts known as L-929 cells have androgen and oestrogen receptors (R-A and R-E), as well as the glucocorticosteroid receptors (R-G) reported earlier1,2. This observation may lead to an increased interest in L cells as they provide a convenient system for studies of the biology and pharmacology of hormones at the cellular level.

MYOID conduction has been suspected in the Cnidaria for some sixty years1, but has only recently been demonstrated2,3. There are no recordings available of activity at the cellular level; until now potentials from cnidarian muscles have been recorded with large extracellular electrodes covering a number of active units.

IN publications describing a series of experiments a group of Dutch investigators1 recently gave quantitative results on the radioprotective power of different chemical agents at the cellular level in an in vitro system. Assayed by the degree to which radiation damage, as measured by the loss of reproductive integrity of human kidney cells, was prevented, it was shown that the protective activity of cysteamine depends on the concentration of the compound used for treatment.

STEADY-STATE algal suspensions have been a favourite subject in studies of inhibitory effects of light on photosynthesis1–5. Light intensities several times higher than the intensity of full sunlight were often employed. The unfavourable effects of strong light were seen in the decreased photosynthetic rates1–4 and/or in the destruction of the photosynthetic pigments5. A recovery process has been observed after transferring the organism into dark or to lower light intensities2,4,5. An emphasis on the dependence of the photo-inhibition on a very strong light has obscured the much wider nature of the phenomenon. The general employment of steady-state suspensions precluded an insight into the complexity of the situation on the cellular level.

RECENTLY, Neumann and Silverberg1 presented results of experiments which were very similar to those which we had briefly reported earlier2,3. They concluded that amino-acids facilitate the transport of copper at the cellular level and presented conclusive evidence to support this. They further concluded that the facilitation of copper transport by amino-acids fulfils the criteria of an “active transport system”, as it is dependent on temperature, concentration and oxygen, and operates against a chemical concentration gradient.

IN cell biochemistry, it is desirable to have criteria for identifying abnormal changes resulting from experimental manipulation, especially during the induction of synchrony. For this purpose, use has been made of the concept of unbalanced growth, first introduced by Cohen and Barner1, to explain the death of a thymine-requiring mutant of Escherichia coli as a result of continued cytoplasmic synthesis in the absence of proportional DNA synthesis. Most people who use this concept are doubtless aware that its foundation must be in the biochemical processes within individual cells and that the fundamental definition of “balance” should be at the cellular level. There are, however, examples in the literature in which it is concluded, on the basis of changes in the gross composition of mammalian cell cultures in which the age distribution of cells is changing, that growth is “unbalanced” without proper consideration of the possibility that the changes might result merely from redistribution of individual cells in the several phases of the life cycle, rather than from significant changes in their composition.

Although it has been established that swimming in scyphozoans is under control of rhopalial pacemakers and an associated subumbrellar nerve-net1–3, little is known about this control at the cellular level. There is some doubt whether scyphozoan neurones have all-or-none action potentials3–6. Here we show that subumbrellar neurones of the sea wasp Carybdea rastonii Haacke (Class Scyphozoa, Order Cubomedusae) propagate such action potentials, and that activity in these neurones originates in the rhopalial pacemakers and produces a contraction of the swimming musculature. The neurophysiology of swimming has not previously been studied in this order.

CERTAIN amine oxides exert a protective effect against radiation injury1,2. Reserpine has also been shown to have this action3. This suggested a comparison between reserpine and its N-oxide. Groups of 20 CF–1 mice were administered various doses of the two compounds 24 hr. before X-irradiation with 600 r. (Table 1). Radiation conditions were the same as described previously1. Both compounds produced typical reserpine effects, sedation and ptosis, but the N-oxide was less active per dose. All three doses of reserpine N-oxide significantly increased the ST50 day, whereas only one dose of reserpine had this effect (Table 1). On the basis of total survival it requires twice as much reserpine as its N-oxide to decrease mortality by 25 per cent, and neither compound is as effective as quinoxaline di-N-oxide1 or anhydroerythromycin N-oxide2. Mechanisms of action are probably different, since the reserpine compounds exert no antibiotic effects. However, they have the proper chemical structures postulated for removing oxidizing radicals2. Protection might be partially the result of the release of known protective compounds, adrenaline and 5-hydroxytryptamine5. The release of catecholamines and 5-hydroxytryptamine is essentially complete 16 hr. after reserpine administration, and the binding sites, as well as the plasma content, do not begin to contain appreciable amounts of these amines for at least 4 days6–9. Metabolism and excretion are also going on at this time, and in all probability the amount of such amines available for exerting a protective effect is below that necessary for such an action. On the other hand, reserpine has been found in body tissues for at least 48 hr. following a single dose10. Most of the reserpine was found in the tissue cells where, in the present radiation experiment, it could act as a protecting compound. The fact that reserpine and its N-oxide exert only a slight protective effect against lethal X-irradiation points out the need for continuing the search for compounds having low toxicity and greater protective effects at the cellular level.

A FUNCTIONAL adaptation to hypoxia has been described in cardiac tissue from rats acclimatized to altitude1, but little information is available to explain why hibernating rodents are more tolerant to hypoxia than non-hibernating rodents, even at body temperatures near 37° C (ref. 2). Adaptations which enable hibernators to maintain physiological integrity at body temperatures of 3°–5° C could contribute to survival of severe hypoxia3; this interpretation, however, remains open to question. After exposure to hypoxia, no greater oxygen carrying capacity was found in the blood of a typical hibernator (Citellus lateralis) than in that of the rat4. Thus the ability of the hibernator to survive hypoxia could be associated with a functional adaptation to lowered pO2 at the tissue and/or cellular level.

SALICYLATE is a powerful metabolic stimulant. It increases oxygen consumption by man, both in health1 and disease1,2 and also by laboratory animals3–5. This stimulant action was located at cellular level when the drug was found to increase the oxygen uptake of liver and brain slices6. In these respects salicylate resembles 2 : 4-dinitrophenol and the resemblance becomes all the more remarkable with the recent demonstration that salicylate also inhibits oxidative phosphorylation by mitochondrial preparations7. This is the essential biochemical action of 2 : 4-dinitrophenol8,9, and the fact that salicylate possesses similar properties may explain their common effects. Further exploration of this possibility has been carried out in another field by comparing simultaneously the effect of salicylate and 2 : 4-dinitrophenol on wheat coleoptile growth; it has already been established that 2 : 4-dinitrophenol in low concentrations inhibits growth of corn coleoptiles10.

A DEMONSTRATION of utilization of carbon dioxide by propionic acid bacteria1 drastically changed the long-entertained idea that carbon dioxide played only an indirect part in heterotrophic growth, by utilization of organic substances produced in autotrophic assimilation. After later evidence indicated that growth of many bacterial cultures stopped below a minimum concentration of carbon dioxide, the opinion gained support that heterotrophs, and indeed all living cells, can utilize, and possibly even require, carbon dioxide for growth and reproduction2. Reproduction on a cellular level means cell multiplication. The requirement for carbon dioxide in cell multiplication could not be proved or disproved until a technique was developed enabling separation of growth from cell division3,4.

σ VIRUS multiplies in Drosophila and confers to it a characteristic sensitivity to carbon dioxide1. Although many data have been collected about this virus, so far all virological and genetic investigations have been concerned with the complex system formed by the virus and the host organism. To understand better the relationships between σ virus and its host at the cellular level, we have been developing techniques to cultivate Drosophila cells in vitro and infect them with σ virus.

THE accurate localization of an enzyme at the cellular level by a cytochemical technique requires a full investigation of artefacts due to diffusion of enzyme, reagents and reaction products. The classical superimposed-section technique does not have a sufficient resolving power to evaluate diffusion artefacts over the small distances inside a cell. A technique has been developed which enables the enzyme in small areas inside a cell in a tissue section to be inactivated. In this way diffusion during a cytochemical reaction can be investigated. The method makes use of the enzyme-inactivating action of the long wave-length ultra-violet light obtained from a glass-jacketed 250-watt B.T.H. mercury lamp. This is focused on the section mounted in water between two coverslips by an 8-mm. apochromatic objective. A mask in front of the lamp acts as the light source, and in this way slits or patterns of small holes can be focused on the section.

MORPHOGENETIC changes induced by red light (660 nm) and mediated by the pigment-protein phytochrome are well documented1,2. Less is known, however, about phytochrome-mediated effects of red light at the cellular level. We show here that red light induces the development of etiolated apices of pea stems and that one consequence of this development is the net synthesis of a plastid-localized protein, namely fraction I protein, and an increase in its associated enzyme activity, ribulose-1,5-bisphosphate (RuDP) carboxylase3. Two other enzymes of the Calvin cycle show similar increases in activity. The magnitude of these increases and their reversibility by irradiation with far-red light (730 nm) implicates phytochrome rather than protochlorophyllide as the primary photoregulator of the synthesis of these enzymes.