Balancing research prestige, human decency, and educational outcomes.


Or why do academic institutions shield predators?  Many working scientists, particularly those early in their careers or those oblivious to practical realities, maintain an idealistic view of the scientific enterprise. They see science as driven by curious, passionate, and skeptical scholars, working to build an increasingly accurate and all encompassing understanding of the material world and the various phenomena associated with it, ranging from the origins of the universe and the Earth to the development of the brain and the emergence of consciousness and self-consciousness (1).  At the same time, the discipline of science can be difficult to maintain (see PLoS post:  The pernicious effects of disrespecting the constraints of science). Scientific research relies on understanding what people have already discovered and established to be true; all too often, exploring the literature associated with a topic can reveal that one’s brilliant and totally novel “first of its kind” or “first to show” observation or idea is only a confirmation or a modest extension of someone else’s previous discovery. That is the nature of the scientific enterprise, and a major reason why significant new discoveries are rare and why graduate students’ Ph.D. theses can take years to complete.

Acting to oppose a rigorous scholarly approach are the real life pressures faced by working scientists: a competitive landscape in which only novel observations  get rewarded by research grants and various forms of fame or notoriety in one’s field, including a tenure-track or tenured academic position. Such pressures encourage one to distort the significance or novelty of one’s accomplishments; such exaggerations are tacitly encouraged by the editors of high profile journals (e.g. Nature, Science) who seek to publish “high impact” claims, such as the claim for “Arsenic-life” (see link).  As a recent and prosaic example, consider a paper that claims in its title that “Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling” (link), without mentioning (in the title) the rather significant fact that the effect was observed in the nematode C. elegans, whose lifespan is typically between 300 to 500 hours and which displays a trait not found in humans (and other vertebrates), namely the ability to assume a highly specialized “dauer” state that can survive hostile environmental conditions for months. Is the work wrong or insignificant? Certainly not, but it is presented to the unwary (through the Harvard Gazette under the title, “In pursuit of healthy aging: Harvard study shows how intermittent fasting and manipulating mitochondrial networks may increase lifespan,” with the clear implication that people, including Harvard alumni, might want to consider the adequacy of their retirement investments


Such pleas for attention are generally quickly placed in context and their significance evaluated, at least within the scientific community – although many go on to stimulate the economic health of the nutritional supplement industry.  Lower level claims often go unchallenged, just part of the incessant buzz associated with pleas for attention in our excessively distracted society (see link).  Given the reward structure of the modern scientific enterprise, the proliferation of such claims is not surprising.  Even “staid” academics seek attention well beyond the immediate significance of their (tax-payer funded) observations. Unfortunately, the explosively expanding size of the scientific enterprise makes policing such transgressions (generally through peer review or replication) difficult or impossible, at least in the short term.

The hype and exaggeration associated with some scientific claims for attention are not the most distressing aspect of the quest for “reputation.”  Rather, there are growing number of revelations of academic institutions protecting those guilty of abusing their dependent colleagues. These reflect how scientific research teams are organized. Most scientific studies involve groups of people working with one another, generating data, testing ideas, and eventually publishing their observations and conclusions, and speculating on their broader implications.

Research groups can vary greatly in size.  In some areas, they involve isolated individuals, whether thinkers (theorists) or naturalists, in the mode of Darwin and Wallace.  In other cases, these are larger and include senior researchers, post-doctoral  fellows, graduate students, technicians, undergraduates,  and even high school students. Such research groups can range from the small (2 to 3 people) to the significantly larger (~20-50 people); the largest of such groups are associated mega-projects, such as the human genome project and the Large Hadron Collider-based search for the Higgs boson (see: Physics paper sets record with more than 5,000 authors).  A look at this site [link] describing the human genome project reflects two aspects of such mega-science: 1) while many thousands of people were involved [see Initial sequencing and analysis of the human genome], generally only the “big names” are singled out for valorization (e.g., receiving a Nobel Prize). That said, there would be little or no progress without general scientific community that evaluates and extends ideas and observations. In this context, “lead investigators” are charged primarily with securing the funds needed to mobilize such groups, convincing funders that the work is significant; it is members of the group that work out the technical details and enable the project to succeed.

As with many such social groups, there are systems in play that serve to establish the status of the individuals involved – something necessary (apparently) in a system in which individuals compete for jobs, positions, and resources.  Generally, one’s status is established through recommendations from others in the field, often the senior member(s) of one’s research group or the (generally small) group of senior scientists who work in the same or a closely related area. The importance of professional status is particularly critical in academia, where the number of senior (e.g. tenured or tenure-track professorships) is limited. The result is a system that is increasingly susceptible to the formation of clubs, membership in which is often determined by who knows who, rather than who has done what (see Steve McKnight’s “The curse of committees and clubs”). Over time, scientific social status translates into who is considered productive, important, trustworthy, or (using an oft-misused term) brilliant. Achieving status can mean putting up with abusive and unwanted behaviors (particularly sexual). Examples of this behavior have recently been emerging with increasing frequency (which has been extensively described elsewhere: see Confronting Sexual Harassment in Science; More universities must confront sexual harassment; What’s to be done about the numerous reports of faculty misconduct dating back years and even decades?; Academia needs to confront sexism; and The Trouble With Girls’: The Enduring Sexism in Science).

So why is abusive behavior tolerated?  One might argue that this reflects humans’ current and historical obsession with “stars,” pharaohs, kings, and dictators as isolated geniuses who make things work. Perhaps the most visible example of such abused scientists (although there are in fact many others : see History’s Most Overlooked Scientists) is Rosalind Franklin, whose data was essential to solving the structure of double stranded DNA, yet whose contributions were consistently and systematically minimized, a clear example of sexual marginalization. In this light, many is the technician who got an experiment to “work,” leading to their research supervisor’s being awarded the prizes associated with the breakthrough (2).

Amplifying the star effect is the role of research status at the institutional level;  an institution’s academic ranking is often based upon the presence of faculty “stars.” Perhaps surprisingly to those outside of academia, an institution’s research status, as reflected in the number of stars on staff, often trumps its educational effectiveness, particularly with undergraduates, that is the people who pay the bulk of the institution’s running costs. In this light, it is not surprising that research stars who display various abusive behavior (often to women) are shielded by institutions from public censure.

So what is to be done? My own modest proposal (to be described in more detail in a later post) is to increase the emphasis on institution’s (and departments within institutions) effectiveness at undergraduate educational success. This would provide a counter-balancing force that could (might?) place research status in a more realistic context.

a footnote or two:

  1.  on the assumption that there is nothing but a material world.
  2. Although I am no star, I would acknowledge Joe Dent, who worked out the whole-mount immunocytochemical methods that we have used extensively in our work over the years).
  3. Thanks to Becky for editorial comments as well as a dramatic reading!

Humanized mice & porcinized people

mouse and pig

A new and relevant news link: “US FDA declares genetically modified pork ‘safe to eat‘”

A practical benefit, from a scientific and medical perspective, of the evolutionary unity of life (link) are the molecular and cellular similarities between different types of organisms. Even though humans and bacteria diverged more than 2 billion years ago (give or take), the molecular level conservation of key systems makes it possible for human insulin to be synthesized in and secreted by bacteria and pig-derived heart valves to be used to replace defective human heart valves (see link). Similarly, while mice, pigs, and people are clearly different from one another in important ways they have, essentially, all of the same body parts. Such underlying similarities raise interesting experimental and therapeutic possibilities.

A (now) classic way to study the phenotypic effects of human-specific versions of genes is to introduce these changes into a model organism, such as a mouse (for a review of human brain-specific human genes – see link).  A example of such a study involves the gene that encodes the protein foxp2, a protein involved in the regulation of gene expression (a transcription factor). The human foxp2  protein differs from the foxp2 protein in other primates at two positions; foxP2 evolution these two amio acid changes alter the activity of the human protein, that is the ensemble of genes that it regulates. That foxp2 has an important role in humans was revealed through studies of individuals in a family that displayed a severe language disorder linked to a mutation that disrupts the function of the foxp2 protein. Individuals carrying this mutant  foxp2 allele display speech apraxia, a “severe impairment in the selection and sequencing of fine oral and facial movements, the ability to break up words into their constituent phonemes, and the production and comprehension of word inflections and syntax” (cited in Bae et al, 2015).  Male mice that carry this foxp2 mutation display changes in the “song” that they sing to female mice (1), while mice carrying a humanized form of foxp2 display changes in “dopamine levels, dendrite morphology, gene expression and synaptic plasticity” in a subset of CNS neurons (2).  While there are many differences between mice and humans, such studies suggest that changes in foxp2 played a role in human evolution, and human speech in particular.

Another way to study the role of human genes using mouse as a model system is to generate what are known as chimeras, named after the creature in Greek mythology composed of parts of multiple organisms.  A couple of years ago, Goldman and colleagues (3) reported that human glial progenitor cells could, when introduced into immune-compromised mice (to circumvent tissue rejection), displaced the mouse’s own glia, replacing them with human glia cells.iPSC transplant Glial cells are the major non-neuronal component of the central nervous system. Once thought of as passive “support” cells, it is now clear that the two major types of glia, known as astrocytes and oligodendrocytes, play a number of important roles in neural functioning [back track post].  In their early studies, they found that the neurological defects associated with the shaker mutation, a mutation that disrupts the normal behavior of oligodendrocytes, could be rescued by the implantation of normal human glial progenitor cells (hGPCs)(4).  Such studies confirmed what was already known, that the shaker mutation disrupts the normal function of myelin, the insulating structure around axons that dramatically speeds the rate at which neuronal signals (action potentials) move down the axons and activate the links between neurons (synapses). In the central nervous system, myelin is produced by oligodendrocytes as they ensheath neuronal axons.  Human oligodendrocytes derived from hGPCs displaced the mouse’s mutation carrying oligodendrocytes and rescued the shaker mouse’s mutation-associated neurological defect.

golgi staining- diagramSubsequently, Goldman and associates used a variant of this approach to introduce hGPCs (derived from human embryonic stem cells) carrying either a normal or mutant version of the  Huntingtin protein, a protein associated with the severe neural disease Huntington’s chorea (OMIM: 143100)(5).  Their studies strongly support a model that locates defects associated with human Huntington’s disease to defects in glia.  This same research group has generated hGPCs from patient-derived, induced pluripotent stem cells (patient-derived HiPSCs). In this case, the patients had been diagnosed with childhood-onset schizophrenia (SCZ) [link](6).  Skin biopsies were taken from both normal and children diagnosed with SCZ; fibroblasts were isolated, and reprogrammed to form human iPSCs. These iPSCs were treated so that they formed hGPCs that were then injected into mice to generate chimeric (human glial/mouse neuronal) animals. The authors reported systematic differences in the effects of control and SCZ-derived hGPCs; “SCZ glial mice showed reduced prepulse inhibition and abnormal behavior, including excessive anxiety, antisocial traits, and disturbed sleep”, a result that suggests that defects in glial behavior underlie some aspects of the human SCZ phenotype.

The use of human glia chimeric mice provides a powerful research tool for examining the molecular and cellular bases for a subset of human neurological disorders.  Does it raise a question of making mice more human?  Not for me, but perhaps I do not appreciate the more subtle philosophical and ethical issues involved. The mice are still clearly mice, most of their nervous systems are composed of mouse cells, and the overall morphology, size, composition, and organization of their central nervous systems are mouse-derived and mouse-like. The situation becomes rather more complex and potentially therapeutically useful when one talks about generating different types of chimeric animals or of using newly developed genetic engineering tools (the CRISPR CAS9 system found in prokaryotes), that greatly simplify and improve the specificity of the targeted manipulation of specific genes (link).  In these studies the animal of choice is not mice, but pigs – which because of their larger size produce organs for transplantion that are similar in size to the organs of people (see link).  While similar in size, there are two issues that complicate pig to human organ transplantation: first there is the human immune system mediated rejection of foreign  tissue and second there is the possibility that transplantation of porcine organs will lead to the infection of the human recipient with porcine retroviruses.

The issue of rejection (pig into human), always a serious problem, is further exacerbated by the presence in pigs of a gene encoding the enzyme α-1,3 galactosyl transferase (GGTA1). GGTA1 catalyzes the addition of the gal-epitope to a number of cell surface proteins. The gal-epitope is “expressed on the tissues of all mammals except humans and subhuman primates, which have antibodies against the epitope” (7). The result is that pig organs provoke an extremely strong immune (rejection) response in humans.  The obvious technical fix to this (and related problems) is to remove the gal-epitope from pig cells by deleting the GGTA1 enzyme (see 8). It is worth noting that “organs from genetically engineered animals have enjoyed markedly improved survivals in non-human primates” (see Sachs & Gall, 2009).

pig to humanThe second obstacle to pig → human transplantation is the presence of retroviruses within the pig genome.  All vertebrate genomes, including those of humans, contain many inserted retroviruses; almost 50% of the human genome is retrovirus-derived sequence (an example of unintelligent design if ever there was one). Most of these endogenous retroviruses are “under control” and are normally benign (see 9). The concern, however, is that the retroviruses present in pig cells could be activated when introduced into humans. To remove (or minimize) this possibility, Niu et al set out to use the CRISPR CAS9 system to delete these porcine endogenous retroviral sequences (PERVs) from the pig genome; they appear to have succeeded, generating a number of genetically modified pigs without PERVs (see 10).  The hope is that organs generated from PERV-minus pigs from which antigen-generating genes, such as α-1,3 galactosyl transferase, have also been removed or inactivated together with more sophisticated inhibitors of tissue rejection, will lead to an essentially unlimited supply of pig organs that can be used for heart and other organ transplantation (see 11), and so alleviate the delays in transplantation, and so avoid deaths in sick people and the often brutal and criminal harvesting of organs carried out in some countries.

The final strategy being explored is to use genetically modified hosts and patient derived iPSCs  to generate fully patient compatible human organs. To date, pilot studies have been carried out, apparently successfully, using rat embryos with mouse stem cells (see 12 and 13), with much more preliminary studies using pig embryos and human iPSCs (see 14).  The approach involves what is known as chimeric  embryos.  In this case, host animals are genetically modified so that they cannot generate the organ of choice. Typically this is done by mutating a key gene that encodes a transcription factor directly involved in formation of the organ; embryos missing pancreas, kidney, heart, human pig embryo chimeraor eyes can be generated.  In an embryo that cannot make these organs, which can be a lethal defect, the introduction of stem cells from an animal that can form these organs can lead to the formation of an organ composed primarily of cells derived from the transplanted (human) cells.

At this point the strategy appears to work reasonably well for mouse-rat chimeras, which are much more closely related, evolutionarily, than are humans and pigs. Early studies on pig-human chimeras appear to be dramatically less efficient. At this point, Jun Wu has been reported as saying of human-pig chimeras that “we estimate [each had] about one in 100,000 human cells” (see 15), with the rest being pig cells.  The bottom line appears to be that there are many technical hurdles to over-come before this method of developing patient-compatible human organs becomes feasible.  Closer to reality are PERV-free/gal-antigen free pig-derived, human compatible organs. The reception of such life-saving organs by the general public, not to mention religious and philosophical groups that reject the consumption of animals in general, or pigs in particular, remains to be seen.

figures reinserted & minor edits 23 October 2020 – new link 17 December 2020.
references cited

  1. A Foxp2 Mutation Implicated in Human Speech Deficits Alters Sequencing of Ultrasonic Vocalizations in Adult Male Mice.
  2. A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice
  3. Modeling cognition and disease using human glial chimeric mice.
  4. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination.
  5. Human glia can both induce and rescue aspects of disease phenotype in Huntington disease
  6. Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia.
  7.  The potential advantages of transplanting organs from pig to man: A transplant Surgeon’s view
  8. see Sachs and Gall. 2009. Genetic manipulation in pigs. and Fisher et al., 2016. Efficient production of multi-modified pigs for xenotransplantation by ‘combineering’, gene stacking and gene editing
  9. Hurst & Magiokins. 2017. Epigenetic Control of Human Endogenous Retrovirus Expression: Focus on Regulation of Long-Terminal Repeats (LTRs)
  10. Nui et al., 2017. Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9
  11. Zhang  2017. Genetically Engineering Pigs to Grow Organs for People
  12. Kobayashi et al., 2010. Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells.
  13. Kobayashi et al., 2015. Targeted organ generation using Mixl1-inducible mouse pluripotent stem cells in blastocyst complementation.
  14. Wu et al., 2017. Interspecies Chimerism with Mammalian Pluripotent Stem Cells
  15. Human-Pig Hybrid Created in the Lab—Here Are the Facts

Is it time to start worrying about conscious human “mini-brains”?

A human iPSC cerebral organoid in which pigmented retinal epithelial cells can be seen (from the work of McClure-Begley et al.).   Also see “Can lab-grown brains become conscious?” by Sara Readon Nature 2020.

The fact that experiments on people are severely constrained is a major obstacle in understanding human development and disease.  Some of these constraints are moral and ethical and clearly appropriate and necessary given the depressing history of medical atrocities.  Others are technical, associated with the slow pace of human development. The combination of moral and technical factors has driven experimental biologists to explore the behavior of a wide range of “model systems” from bacteria, yeasts, fruit flies, and worms to fish, frogs, birds, rodents, and primates.  Justified by the deep evolutionary continuity between these organisms (after all, all organisms appear to be descended from a single common ancestor and share many molecular features), experimental evolution-based studies of model systems have led to many therapeutically valuable insights in humans – something that I suspect a devotee of intelligent design creationism would be hard pressed to predict or explain (post link).

While humans are closely related to other mammals, it is immediately obvious that there are important differences – after all people are instantly recognizable from members of other closely related species and certainly look and behave differently from mice. For example, the surface layer of our brains is extensively folded (they are known as gyrencephalic) while the brain of a mouse is smooth as a baby’s bottom (and referred to as lissencephalic). In humans, the failure of the brain cortex to fold is known as lissencephaly, a disorder associated with severe neurological defects. With the advent of more and more genomic sequence data, we can identify human specific molecular (genomic) differences. Many of these sequence differences occur in regions of our DNA that regulate when and where specific genes are expressed.  Sholtis & Noonan (1) provide an example: the HACNS1 locus is a 81 basepair region that is highly conserved in various vertebrates from birds to chimpanzees; there are 13 human specific changes in this sequence that appear to alter its activity, leading to human-specific changes in the expression of nearby genes (↓). At this point ~1000 genetic elements that are different in humans compared to other vertebrates have been identified and more are likely to emerge (2).  Such human-specific changes can make modeling human-specific behaviors, at the cellular, tissue, organ, and organism level, in non-human model systems difficult and problematic (3, 4).   It is for this reason that scientists have attempted to generate better human specific systems.

human sequence divergence

One particularly promising approach is based on what are known as embryonic stem cells (ESCs) or pluripotent stem cells (PSCs). Human embryonic stem cells are generated from the inner cell mass of a human embryo and so involve the destruction of that embryo – which raises a number of ethical and religious concerns as to when “life begins” (5).  Human pluripotent stem cells are isolated from adult tissues but in most cases require invasive harvesting methods that limit their usefulness.  Both ESCs and PSCs can be grown in the laboratory and can be induced to differentiate into what are known as gastruloids.  Such gastruloids can develop anterior-posterior (head-tail), dorsal-ventral (back-belly), and left-right axes analogous to those found in embryos (6) and adults (top panel ↓). In the case of PSCs, the gastruloid (bottom panel ↓) is essentially a twin of the organism from which the PSCs were derived, a situation that raises difficult questions: is it a distinct individual, is it the property of the donor or the creation of a technician.  The situation will be further complicated if (or rather, when) it becomes possible to generate viable embryos from such gastruloids.

Axes

gastruloid-embryo-comparisonThe Nobel prize winning work of Kazutoshi Takahashi and Shinya Yamanaka (7), who devised methods to take differentiated (somatic) human cells and reprogram them into ESC/PSC-like cells, cells known as induced pluripotent stem cells (iPSCs)(8), represented a technical breakthrough that jump-started this field. While the original methods derived sample cells from tissue biopsies, it is possible to reprogram kidney epithelial cells recovered from urine, a non-invasive approach (910).  Subsequently, Madeline Lancaster, Jurgen Knōblich, and colleagues devised an approach by which such cells could be induced to form what they termed “cerebral organoids” (although Yoshiki Sasai and colleagues were the first to generate neuronal organoids); they used this method to examine the developmental defects associated with microencephaly (11).  The value of the approach was rapidly recognized and a number of studies on human conditions, including  lissencephaly (12), Zika-virus infection-induced microencephaly (13), and Down’s syndrome (14);  investigators have begun to exploit these methods to study a range of human diseases – and rapid technological progress is being made.

The production of cerebral organoids from reprogrammed human somatic cells has also attracted the attention of the media (15).  While “mini-brain” is certainly a catchier name, it is a less accurate description of a cerebral organoid, itself possibly a bit of an overstatement, since it is not clear exactly how “cerebral” such organoids are. For example, the developing brain is patterned by embryonic signals that establish its asymmetries; it forms at the anterior end of the neural tube (the nascent central nervous system and spinal cord) and with distinctive anterior-posterior, dorsal-ventral, and left-right asymmetries, something that simple cerebral organoids do not display.  Moreover, current methods for generating cerebral organoids involve primarily what are known as neuroectodermal cells – our nervous system (and that of other vertebrates) is a specialized form of the embryo’s surface layer that gets internalized during development. In the embryo, the developing neuroectoderm interacts with cells of the circulatory system (capillaries, veins, and arteries), formed by endothelial cells and what are known as pericytes that surround them. These cells, together with interactions with glial cells (astrocytes, a non-neuronal cell type) combine to form the blood brain barrier.  Other glial cells (oligodendrocytes) are also present; in contrast, both types of glia (astrocytes and oligodendrocytes) are rare in the current generation of cerebral organoids. Finally, there are microglial cells,  immune system cells that originate from outside the neuroectoderm; they invade and interact with neurons and glia as part of the brain’s dynamic neural capillary and neuronssystem. The left panel of the figure shows, in highly schematic form how these cells interact (16). The right panel is a drawing of neural tissue stained by the Golgi method (17), which reveals ~3-5% of the neurons present. There are at least as many glial cells present, as well as microglia, none of which are visible in the image. At this point, cerebral organoids typically contain few astrocytes and oligodendrocytes, no vasculature, and no microglia. Moreover, they grow to be about 1 to 3 mm in diameter over the course of 6 to 9 months; that is significantly smaller in volume than a fetal or newborn’s brain. While cerebral organoids can generate structures characteristic of retinal pigment epithelia (top figure) and photo-responsive neurons (18), such as those associated with the retina, an extension of the brain, it is not at all clear that there is any significant sensory input into the neuronal networks that are formed within a cerebral organoid, or any significant outputs, at least compared to the role that the human brain plays in controlling bodily and mental functions.

The reasonable question, then, must be whether a  cerebral organoid, which is a relatively simple system of cells (although itself complex), is conscious. It becomes more reasonable as increasingly complex systems are developed, and such work is proceeding apace. Already researchers are manipulating the developing organoid’s environment to facilitate axis formation, and one can anticipate the introduction of vasculature. Indeed, the generation of microglia-like cells from iPSCs has been reported; such cells can be incorporated into cerebral organoids where they appear to respond to neuronal damage in much the same way as microglia behave in intact neural tissue (19).

We can ask ourselves, what would convince us that a cerebral organoid, living within a laboratory incubator, was conscious? How would such consciousness manifest itself? Through some specific pattern of neural activity, perhaps?  As a biologist, albeit one primarily interested in molecular and cellular systems, I discount the idea, proposed by some physicists and philosophers as well as the more mystical, that consciousness is a universal property of matter (20,21).  I take consciousness to be an emergent property of complex neural systems, generated by evolutionary mechanisms, built during embryonic and subsequent development, and influenced by social interactions (BLOG LINK) using information encoded within the human genome (something similar to this: A New Theory Explains How Consciousness Evolved). While a future concern, in a world full of more immediate and pressing issues, it will be interesting to listen to the academic, social, and political debate on what to do with mini-brains as they grow in complexity and perhaps inevitably, towards consciousness.

Footnotes and references

Thanks to Rebecca Klymkowsky, Esq. and Joshua Sanes, Ph.D. for editing and disciplinary support. Minor updates and the reintroduction of figures 22 Oct. 2020.

  1. Gene regulation and the origins of human biological uniqueness
  2.  See also Human-specific loss of regulatory DNA and the evolution of human-specific traits
  3. The mouse trap
  4. Mice Fall Short as Test Subjects for Some of Humans’ Deadly Ill
  5. The status of the human embryo in various religions
  6. Interactions between Nodal and Wnt signalling Drive Robust Symmetry Breaking and Axial Organisation in Gastruloids (Embryonic Organoids)
  7.  Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors
  8.  How iPS cells changed the world
  9.  Generation of Induced Pluripotent Stem Cells from Urine
  10. Urine-derived induced pluripotent stem cells as a modeling tool to study rare human diseases
  11. Cerebral organoids model human brain development and microcephaly.
  12. Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia
  13. Using brain organoids to understand Zika virus-induced microcephaly
  14. Probing Down Syndrome with Mini Brains
  15. As an example, see The Beauty of “Mini Brains”
  16. Derived from Central nervous system pericytes in health and disease
  17. Golgi’s method .
  18. Cell diversity and network dynamics in photosensitive human brain organoids
  19. Efficient derivation of microglia-like cells from human pluripotent stem cells
  20. The strange link between the human mind and quantum physics – BBC:
  21. Can Quantum Physics Explain Consciousness?