A human iPSC cerebral organoid in which pigmented retinal epithelial cells can be seen (from the work of McClure-Begley, Mike Klymkowsky, and William Old.)
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 are extensively folded (they are known as gyrencephalic) while the brain of a mouse is smooth as a babys bottom (and referred to as lissencephalic). In humans, the failure of the brain cortex to fold is known as lissencephaly, a disorder associated with several 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.
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)(more on that in a future post). 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.
The 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 reprogramkidney epithelial cells recovered from urine, a non-invasive approach (9,10). Subsequently, Madeline Lancaster, Jurgen Knblich, and colleagues devised an approach by which such cells could be induced to form what they termed cerebral organoids; they used thismethod 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 Downs syndrome (14); investigatorshave begun to exploit these methodsto study a range of human diseases.
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 embryos 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 brains dynamic neural system. 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 newborns 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 organoids 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 consciousnessmanifest 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, builtduring embryonic and subsequent development, and influenced bysocial 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 anddisciplinarysupport.
The rest is here:
Is it time to start worrying about conscious human mini-brains? - PLoS Blogs (blog)
- Pluripotent stem cells for improved reprogrammed Human ... - February 3rd, 2019
- Induced Pluripotent Stem Cell Market Is Expected to Reach US ... - February 3rd, 2019
- Pluripotent Stem Cell Flow Kit (FMC001): R&D Systems - February 3rd, 2019
- induced pluripotent stem cell | The Science of Parkinson's - February 3rd, 2019
- What Are Induced Pluripotent Stem Cells? | Intro to the ... - January 26th, 2019
- Pluripotent Stem Cells - Stemcell Technologies - December 30th, 2018
- ATCC-HYR0103 Human Induced Pluripotent Stem (IPS) Cells ATCC ... - December 30th, 2018
- Induced Pluripotent Stem Cells Market Report Research ... - December 30th, 2018
- Methods of Producing Thymic Emigrants from Induced ... - December 24th, 2018
- Global Induced Pluripotent Stem Cells Market Analysis (2018 ... - December 24th, 2018
- Human being induced pluripotent stem cells (hiPSCs) display ... - December 24th, 2018
- Induced Pluripotent Stem Cell Overview - genengnews.com - December 8th, 2018
- Induced Pluripotent Stem Cell Market to Reach US$ 2,299.5 ... - September 29th, 2018
- Use Of Induced Pluripotent Stem Cell Models To Elucidate ... - September 29th, 2018
- What Are Induced Pluripotent Cells? - Stem Cell Centers ... - August 23rd, 2018
- Induced Pluripotent Stem Cells (iPSCs) - August 19th, 2018
- Human Induced Pluripotent Stem Cells - Cell Applications - August 19th, 2018
- Induced Pluripotent Stem Cell FAQs | Sigma-Aldrich - July 4th, 2018
- Induced pluripotent stem cell | biology | Britannica.com - July 4th, 2018
- Induced Pluripotent Stem Cell India - StemCellCareIndia - July 2nd, 2018
- Cell potency - Wikipedia - June 27th, 2018
- Induced Pluripotent Stem Cells for Cardiovascular Diagnostics - October 14th, 2017
- Induced Pluripotent Stem Cells | The Progeria Research Foundation - October 14th, 2017
- Disease-Specific & Patient-Specific Induced Pluripotent Stem ... - September 27th, 2017
- INDUCED PLURIPOTENT STEM CELLS - Regents of the University of ... - September 27th, 2017
- British Mitochondria Study Could Provide New Approaches to Treating ALS - ALS News Today - August 30th, 2017
- Can Sirolimus Help Patients with Fibrodysplasia Ossificans Progressiva? - Rare Disease Report - August 22nd, 2017
- Reprogramming 'Fixes' Trisomic Sperm - Asian Scientist Magazine - August 22nd, 2017
- Scientists give star treatment to lesser-known cells crucial for brain development - Seacoastonline.com - August 20th, 2017
- Breakthrough in Gene Editing Comes as Scientists Correct Disease-Causing Mutation in Human Embryo - TrendinTech - August 20th, 2017
- Fertile offspring produced from sterile mice using iPS cells - Kyodo News Plus - August 20th, 2017
- Brain Spheroids Hatch Mature Astrocytes | ALZFORUM - Alzforum - August 20th, 2017
- How Do We Get Pluripotent Stem Cells? | Boston Children's ... - August 15th, 2017
- induced pluripotent stem cell (iPS cell) | biology ... - August 15th, 2017
- Induced Pluripotent Stem Cells: Global Markets Report 2017-2021 - August 15th, 2017
- MESO-BRAIN initiative receives 3.3million to replicate brain's neural networks through 3D nanoprinting - Cordis News - August 15th, 2017
- Global Induced Pluripotent Stem Cells Market: HTF Market - August 15th, 2017
- Induced Pluripotent Stem Cells in Global Effort to ... - August 15th, 2017
- Artificial Blood Vessels Mimic Rare Accelerated Aging Disease - Duke Today - August 15th, 2017
- Induced Pluripotent Stem Cells Market Demands, Trends, Growth ... - MilTech - August 15th, 2017
- Dopaminergic neurons derived from iPSCs in non-human primate model - Phys.Org - August 12th, 2017
- How Food Preservatives May Disrupt Human Hormones - Laboratory Equipment - August 10th, 2017
- ASU grad students' lab skills help earn funding for cutting-edge biomedical research - Arizona State University - August 10th, 2017
- CRISPR Corrects Disease Mutation in Human Embryos - Genetic Engineering & Biotechnology News (blog) - August 3rd, 2017
- World's 1st trial of drug developed from iPS cells to begin - Japan ... - Japan Today - August 3rd, 2017
- Stem Cell Glossary - Closer Look at Stem Cells - August 2nd, 2017
- What are induced pluripotent stem cells or iPS cells? - Stem ... - August 2nd, 2017
- A New Epigenetic Barrier to Induced Pluripotent Stem Cells - WhatIsEpigenetics.com - August 2nd, 2017
- SBP Scientist Receives Prestigious WM Keck Foundation Grant - Newswise (press release) - July 11th, 2017
- Grnenthal Group: Launch of the Project - Modelling Neuron-glia Networks Into a Drug Discovery Platform for Pain ... - PR Newswire (press release) - July 8th, 2017
- The Global Market for Induced Pluripotent Stem Cells (iPSCs) should reach $3.6 Billion in 2021, Increasing at a CAGR ... - Business Wire (press... - July 8th, 2017
- This Study Could Help Extend the Human Lifespan - Futurism - July 8th, 2017
- Embryonic stem cells to be available for medical use in Japan by next March - The Japan Times - July 5th, 2017
- Treating Asthma with Stem Cells | Technology Networks - Technology Networks - July 1st, 2017
- When C9ORF72 Silences U2, Spliceosomes Can't Find What They ... - Alzforum - July 1st, 2017
- The Stem Cell Revolution - Seeking Alpha - July 1st, 2017
- Evotec in neurology iPSC drug discovery collaboration with stem-cell specialist Censo - FierceBiotech - July 1st, 2017
- induced pluripotent stem cells - eurostemcell.org - January 27th, 2017
- Induced Pluripotent Stem Cell Repository | California's ... - January 23rd, 2017
- Embryonic stem (ES) cells and induced pluripotent stem ... - January 17th, 2017
- Induced pluripotent stem cell Wikipedia StemCell Therapy - December 17th, 2016
- Induced stem cells - Wikiversity - December 17th, 2016
- Stem Cell Glossary - stemcells.nih.gov - December 5th, 2016
- Clinical potential of human-induced pluripotent stem cells ... - December 5th, 2016
- Why Induced Pluripotent Stem Cells Are Vital for Glaucoma ... - December 3rd, 2016
- Live Cell Imaging of Induced Pluripotent Stem Cell ... - November 23rd, 2016
- Induced Pluripotent Stem Cells - cellapplications.com - November 23rd, 2016
- Induced pluripotent stem cell models from X-linked ... - November 23rd, 2016
- Generation of germline-competent induced pluripotent stem ... - November 22nd, 2016
- Induced pluripotent stem-cell therapy - Wikipedia - November 18th, 2016
- Generation of Neural Crest-Like Cells From Human ... - November 14th, 2016
- Generation of Induced Pluripotent Stem Cells with ... - November 3rd, 2016
- Induced pluripotent stem cells and Parkinson's disease ... - October 27th, 2016
- Induced Pluripotent Stem Cells: A New Frontier for Stem ... - October 27th, 2016
- Induced Pluripotent Stem Cells (iPS) - UCLA Broad Stem Cell - October 21st, 2016
- Induced stem cells - Wikipedia - October 18th, 2016
- Stem Cell Basics VI. | stemcells.nih.gov - October 12th, 2016
- Induced Pluripotent Stem Cell Initiative | California's ... - October 7th, 2016
- Induced Pluripotent Stem Cells: 10 Years After the ... - September 28th, 2016
- The Promise of Induced Pluripotent Stem Cells (iPSCs ... - September 23rd, 2016