Stem cells have the unique property of developing into any cell of the body under the right conditions. For this reason, there is a growing interest in using them to treat disorders such as hemophilia, diabetes and even neurodegenerative disorders such asParkinsons.

Apart from their therapeutic potential, researchers have shown that stem cells can be coaxed to spontaneously develop intominiature organ like structures called "organoids".Organoids recapitulate the intricate physical and biological features of organs and hence are important new tools in understanding human tissue development as well as for finding new drugs to treat disorders.

In this podcast, we discuss the biology of organoids, the hope and hype in medical research as well as potential ethical issuessurrounding their use.

This podcast is written and produced by IndSciComm, a collective of Indian scientists working on increasing public science awareness.

Shruti Muralidhar is a postdoc at the Picower Institute for Learning and Memory at MIT studying how memory is encoded in the brain.

Navneet Vasistha is a postdoctoral researcher at the University of Copenhagen trying to understand the cellular basis of mental health disorders.

Abhishek Chari is a science writer at the Picower Institute for Learning and Memory at MIT with an interest in microbiology and evolution.

(Scroll down past the references to read a transcript of the podcast.)

References and further reading

Skin transplants:

Serial Cultivation of Strains of Human Epidermal Keratinocytes

Grafting of Burns with Cultured Epithelium Prepared from Autologous Epidermal Cells

Cerebral organoids:

Cerebral organoids model human brain development and microcephaly

Pituitary organoids and functional restoration:

Self-formation of functional adenohypophysis in three-dimensional culture

Proto-tooth organoids:

The development of a bioengineered organ germ method

Fully functional bioengineered tooth replacement as an organ replacement therapy

Energy and entropy in living systems:

Energy and entropy flows in living systems

The Science of Self-Organization and Adaptivity

The Ilya Prigogine Nobel Prize

Self-organization in different scientific fields:

The science of self-organization and adaptivity

Self-organization in economics:

From simplistic to complex systems in economics

Self-organization in social sciences:

Self-organization and social science

Protein folding as self-organization:

Self-organization in protein folding and the hydrophobic interaction

Self-organization of cytoskeleton:

Directed cytoskeleton self-organization

Biofilm self-organization:

Self-Organization, Layered Structure, and Aggregation Enhance Persistence of a Synthetic Biofilm Consortium

Antibiotic resistance in biofilms:

Mechanisms of antibiotic resistance in bacterial biofilms

Biofilm formation evades immune system:

Biofilm Formation Avoids Complement Immunity and Phagocytosis of Streptococcus pneumoniae

Biofilms on teeth:

Oral Biofilm Architecture on Natural Teeth

Biofilms in catheter-associated UTIs:

Role of biofilm in catheter-associated urinary tract infection

Model system limitations / Self-organization in embryos and ethical issues:

Self-Organization of Stem Cell Colonies and of Early Mammalian Embryos

Comparisons between tissue cultures and embryo development:

In vitro organogenesis in three dimensions: self-organising stem cells

Categories of self-organization:

Cytosystems dynamics in self-organization of tissue architecture

Importance of apoptosis in embryo development:

Cell death in development: shaping the embryo

Optic cup organoid:

Self-formation of optic cups and storable stratified neural retina from human ESCs

Intestinal organoids:

Establishment of Human Colon Culture System

Intestinal OrganoidsCurrent and Future Applications

14-day rule:

Embryology policy: Revisit the 14-day rule

Early embryos in a dish (commentary):

What if stem cells turn into embryos in a dish?

Early embryos in a dish (research articles):

A method to recapitulate early embryonic spatial patterning in human embryonic stem cells

Ethical issues in human organoid and gastruloid research

The Ethics of Organoids: Scientists Weigh in on New Mini-Organs

Organoids are more like fetal or neonatal organs, not adult organs:

Human cerebral organoids recapitulate gene expression programs of fetal neocortex development

hPSC-derived lung and intestinal organoids as models of human fetal tissue

Organoids and the Zika virus:

The High Schooler Behind the Mini-Brain Generator

Cold Spring Harbor grant for 3D cancer organoids:

CSHL to lead international team developing next-generation organoid cancer research models

Conclusion:

Cutting-edge stem cell therapy proves safe, but will it ever be effective?

Transcript of the podcast

Navneet: A long time ago, in a galaxy far, far... Wait, is that how were starting this podcast? No, actually in 1975, at the Massachusetts Institute of Technology, scientists James Rheinwald and Howard Green developed a method by which they could indefinitely grow human skin in the lab!

This is the first report of scientists being able to grow an organ in the lab. Their litmus test came five years later, when they were asked to treat two patients admitted to the Brigham Hospital with significant burns. Not only were Green and his colleagues able to graft skin sheets grown from the patients own cells, but in six months time, these grafts could no longer be distinguished from the surrounding unburnt skin.

Attempts at growing other organs have not met with a similar degree of success, for a variety of reasons.

However, with recent advances in stem-cell biology, researchers have found that by growing stem cells in just the right way, they can produce tiny blobs of tissue that look and function like organs.

Depending on what molecular cues are added, scientists have been able to grow what can lazily be called mini-brains, mini-pancreas, mini-retinal tissues, etc. The collective term given to these lab-grown tissues is organoids. My name is Navneet.

Abhishek: Im Abhishek.

Shruti: This is Shruti.

All: And we are IndSciComm. In this podcast, were going to be talking about what these organoids are and what they are not, how close are they are to actual organs, what their future potential is and a whole host of other interesting things.

***

Navneet: So, lets begin with the basics. What are organoids and why are they interesting?

a. An organoid is a three-dimensional mass of cells that superficially resembles an organ or a gland. Researchers have generated several kinds of organoids using what they know about the development of different organs. Some examples are cerebral or brain organoids, intestinal organoids, pituitary organoids and so on.

b. Essentially, what makes them interesting is that cells grown in a dish with the right nutrient and cell growth factors can form something like mini-organs.

c. Some organoids have been transplanted into mice to restore functions or structures that they are lacking. For example, transplanted pituitary organoids have helped to restore the function of dysfunctional pituitary glands in mice. In fact, scientists have even transplanted a proto tooth organoid into the mouth of an adult mouse and watched it develop into a fully grown tooth!

***

Abhishek: So, cells can form structures of higher complexity like organoids. In essence, simple things (cells) come together to form more complex things (organs). This phenomenon is called self-organization. But how is this possible? Doesnt the second law of thermodynamics say that entropy has to increase over time?

How can order be created out of chaos, if entropy can only be increased? Entropy, by the way, is just the technical term for randomness. The solution is to rearrange the system using energy. Any decrease in entropy in one part of the system can be compensated by a proportionally larger increase in entropy in another part of the system.

As a simple analogy, consider the problem of cleaning your room. One way is to throw everything thats lying around into a cupboard. The room definitely looks more ordered but that doesnt detract from the mess inside the cupboard. Therefore, you havent reduced the net entropy of the systemyou have merely re-distributed it.

This isnt just some quirky, obscure thermodynamics loophole. A Nobel Prize in Chemistry was given for understanding how order can be generated from disorder, to Ilya Prigogine in 1977.

So, there is a theoretical basis to explain the origin of complexity in our universe. Self-organization as a phenomenon has been studied in physics, chemistry, biology and many other disciplines, including economics and sociology.

Now, getting back to the point. The three of us, we are all biologists by training. And just to remind our listeners, we still want to talk about organoids. So, lets work our way up to organoids by showing you how self-organization is necessaryright from the level of molecules to the level of the organism.

At the simplest level, we have molecules that can self-organize into more complex configurations. This happens with proteins, that are formed as a long, disorganized chain of amino acids. But, they fold themselves into complex nanomachines. Some of these can juggle atoms between other molecules, acting as catalysts for important biological reactions.

Next, molecules can self-organize into mega-structures that form important components in cells. Polymerization of small molecules helps to form the protein-based skeleton inside cells and the protein coats of some viruses.

Moving up from molecules, even apparently simple organisms like bacteria can self-organize themselves into marvels of biological architecture called biofilms. In this combined state, bacteria in biofilms can resist antibiotics, fight off the immune system and demonstrate feats of resilience that single cells are incapable of. You can blame biofilms for everything from the gunk on your teeth after a good nights sleep, to entrenched catheter infections and many other things in between.

All organisms are dependant, to varying degrees, on self-organization to make them what they are. Every multicellular organism, all the way from slime molds to plants and animals, starts off life as a single cell that has to replicate itself to make an embryo.

***

Shruti: The early embryo is a mass of stem cells without the defining features of a multicellular organismlike a head, tail, limbs and so on. Provided they get the right cues or signals, these stem cells are capable of forming a complete organism. Researchers study these cues and other steps in embryo development using animal models like mice.

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