Meeting summary of Paris human gene editing workshop

Editors note: This is a guest post from Caroline Simons who is attending the two Paris meetings on human gene editing. For more background on those meetings see here.

By Caroline Simons

There were just over a hundred participants at the workshop organized by the Federation of European Academies of Medicine, the UK Academy of Medical Sciences and the Académie Nationale de Médicine France. That number included experts in the fields of science, medicine, law and bioethics. They came from Europe, the US and China (and, I think I may have heard, one French politician).Caroline Simons

Some were engaged in active research, others represented national academies, policy making bodies, patients, research funders and industry. I noted one participant from the US represented DARPA, a reminder that gene-editing technologies may have harmful as well as therapeutic applications. There were about a dozen journalists, of whom two may cover this event in English – Anna McKie of Research Fortnight and Oliver Moody of The Times.

Académie Nationale de Médicine

Académie Nationale de Médicine, Credit Caroline Simons

The aim of the workshop was to consider current scientific activities in the European Union (EU) regarding genome editing and the regulatory landscape across the EU member states for this research and its clinical application in humans. The stated intention was to foster discussion between experts, provide information to the public and stakeholders and to consider whether an EU regulatory framework to govern the safe and acceptable use of human genome editing is desirable, and how it could be achieved. There were no agreed conclusions or recommendations from this workshop, but many interesting presentations and observations. A paper which will draw on the workshop discussions is to be published.

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Fantastic organoid voyage: views from inside a mini-organ

Fantastic VoyageDid you ever see the classic sci-fi movie, Fantastic Voyage?

In it, the heroes travel inside of the human body in a craft, observing all kinds of awesome biology in an up close and personal kind of way on route into the brain with the goal to do microsurgery of a sorts.

Even though this movie came out a year before I was born, I saw it later as a kid and found it captivating.

“What if we could travel inside the body or even inside organs?” I thought back then. It seemed like we could learn amazing things first hand.

A new technology called organoids or mini-organs kind of makes this possible today.

In fact, organoids are extra exciting because this technology allows us to make miniature version of organs and then do science on them. The organoids can be differentiated and grown, depending on the type you want to make, from pluripotent or adult stem cells or other sources of tissue.

Even though we cannot literally climb inside to take a look, we can do the next best thing using histology and advanced microscopy even on “living” organoids. In a great piece of science writing, Cassandra Willyard, talks us through all the various new kinds of human organoids: liver, kidney, brain, pancreas, stomach, lung, breast, and the list goes on including “guts” as per the quote from Hans Clevers at right from Willyard’s article. I love this quote.Hans Clevers

If we could shrink ourselves down and literally climb inside a human organoid, what would we see? What amazing things might we report on from this voyage?

In mini-brains we’d see neurons, synapses, glia, oligodendrocytes, and fiber tracts. We even might be witness to electrical activity in this mini-brain that represents actual rudimentary thought of a kind. Imagine seeing that “in person” from the inside.

Cerebral organoidsIn a mini-kidney or liver organoid, we might see all different kinds of cellular and tissue activities. If we dropped the equivalent of a micro bottle of vodka or tiny firecracker inside as a model of injury, we might see the organs kick into action to repair themselves.

In a breast organoid we might see milk production from the inside or the first signs of breast cancer formation. In a mini-lung, we could possibly see lung cancer germinate too or hike around inside airways such as bronchi, bronchioles, and alveoli. A bio-spelunker.

Exploring inside a heart organoid you could feel what it is like to be inside of something very similar to a beating heart. Would you like the rhythm and beat or feel like there’s a constant earthquake?

Inside the organoids in the lab you don’t have to worry about some nasty immune cell trying to knock you off either.

Some of the labs focusing on organoid research have discovered important things about normal human development and disease from this work. The Madeline_Lancasterresearchers include teams from the labs of Drs. Hans Clevers, Jürgen Knoblich, Melissa Little, Takanori Takebe, and a growing number of others. The late Yoshiki Sasai did pioneering work in this area as well.

The postdocs and other trainees in these labs have done work that has changed our visions of what is possible in stem and developmental biology in a dish. For instance, Dr. Madeline Lancaster’s work on mini-brains has opened a lot of minds to all that is possible in brain neuroscience in a dish (see images above of a mini-brain and of Dr. Lancaster at right).

An organoid is not just a model system either, but also might have therapeutic potential. Tissues grown in 3-D that take on the form and function of real human organs even if in miniature form could form the basis of innovative therapies in the future as well.

I would say that so far in 2015 organoids are the most exciting development and some have argued they are most important new thing in the stem cell and developmental biology fields.

For past posts on this blog highlighting organoids you can read here.

Heather Main on Carla Kim & Hans Clevers talks on organoids at #ISSCR2015

By Heather Main

Organoids are pretty big in stem cells right now. The last couple of years have attracted a lot of media attention on mini lungs, mini brains, mini kidneys, mini guts and more, giving the impression that scientists know how to specify and organise cells into mini functional organs in the lab. Organoids have become a hot topic in a stem cell environment where our understanding of disease is limited by studying only cell autonomous effects in single cells. If Thursdays ISSCR 2015 plenary is anything to go by, 2 of the 5 talks were on organoids, the first from Carla Kim on lung organoids and the second Hans Clevers on gut and liver organoids.

Carla Kim started with a seemingly irrelevant summary of the fact that just about every cell type in the lung seems to have some sort of stem cell or regenerative capacity but then continued to discuss their work on formation of lung organoids from Sca1+ BASCs (Bronchio Alveolar Stem Cells). Culture of bodies from these sorted stem cells leads to a mixed population of organoids, 20% representing bronchiolar, 60% alveolar and 20% mixed structures. Carla’s research has now shown that Tsp1 increases the proportion of alveolar organoid formation. This is relevant to an increase of Tsp1 seen due to alveolar injury and works towards defining the reactions of lung stem cells to different types of lung damage. I must say however that what caught my attention from a purely human view was Carla’s movie on unidirectional mucin flow in bronchiolar organoids, demonstrating the level of complexity of these structure but also just giving you the school yard giggle of producing snot from pluripotent cells.liver organoid

Hans Clevers talk was such a mass of animation that you found yourself amazed that they have the funding for all of this and a little cheated at the same time that it is the animation that sticks in your mind rather than the data. Hans began with his gut organoids and then moved onto liver organdies (note added from Paul; see image of a liver organoid from one of the Clevers lab papers with the wonderful Meritxell Huch, Hans’ former postdoc as first author, who now has her own lab ).

It was fascinating to see that at least to some extent the gut organoids were capable integrating to gut tissue when transplanted in vivo. The animation showed the organoid splitting to expose its apical surface and then integrating into the tissue through its basal surface. It was unclear to me, but possible I just missed it, if the body was capable of integrating to normal tissue or if some type of damage was required to allow the basal surface to implant in the tissue. Hans also showed forskolin induced swelling of these bodies and rescue of swelling in CRISPR modified Cystic Fibrosis cells. As a progression Hans discussed their developments in liver organoids. These bodies were established from dissociation of liver, which left EPCAM+ bile duct cells that could be programmed to a stem cell state through Wnt and RTK regulation. These liver organoids were used to test responder behaviour of different individuals to drug treatments.

The organoid talks are always beautiful. They always have amazing staining patterns of impressive structural complexities, but what makes them any more interesting than a biopsy in understanding disease? Will they be more powerful for cellular therapies than single cell populations or transplantation of the relevant stem cell of origin? The cost of producing and culturing these organoids needs to be balanced against the benefit of the application over existing and alternative technologies. It was nice to see Hans’ application in responses to chemotherapy, which should be a field that would benefit out of such techniques. The cost to the patient of undergoing a cancer treatment that does nothing to the cancer but ravages their body is huge and will have implications in the number of other treatments that they are able to endure. Chemotherapy treatments themselves have a large financial cost not only for the drugs but the time in hospital, which would further validate the cost of organoid diagnostics.

However, it is not time to throw away autonomous cell studies. The direct effects of genetic diseases on primary affected cell types are essential to understanding the origin of disease. Treating secondary effects will not be as effective, or long-lived, as rescuing the primary effect. Organoids give a second level of understanding which will no doubt lead to increased complexity of autonomous ‘single cell’ cultures towards absolutely defining mechanisms for efficient targeting of therapeutics.

Back to the public, one may imagine that while being a little exciting these ‘mini organ’ studies also seems a little scary to the public and may make them scared of what else we are capable of if we are now growing mini functioning organs. What may need to be a little clearer, at least for the sake of the public, is that while different labs can produce structures with more or less complex hallmarks of structures within particular organs, at this stage we have very little understanding of the processes involved and thus have extremely limited control. It seems that both the starting cell and the culture conditions are important in driving the complexity of tissue formation, but the field is still quite primitive in understanding the complexity of the programs these starting cells undergo. We are also far from the public impression of growing ‘functional’ organs in the lab.