Organoids: a minefield on a chip?

In a special edition of the journal Science, leading researchers have catalogued stunning breakthroughs in the development of organoids – miniature human organs that are used to mimic disease and test treatments, and might one day provide replacement parts for the sick and elderly.

Perhaps nowhere are those advances more pressing than in cancer research.

David Tuveson, from the Cold Spring Harbor Laboratory in New York, US, and Hans Clevers, from the Oncode and Hubrecht Institutes in Utrecht, Netherlands, set out a series of discoveries that is rapidly changing how that disease is managed.

A major goal in cancer is for treatments that target a patient’s specific tumour type. It’s called “precision medicine” and, until recently, has often meant taking slices of a person’s tumour, trying to grow it in a dish, and adding drugs to see if they kill it. Another way is to transplant the tumour cells into mice and give them the drug.

Each method, however, has serious drawbacks.

First off, tumours don’t grow so well in dishes. And waiting for cancer to develop in mice, then watching to see if a drug is effective, can take months. Patients, tragically, often don’t have that long.

Enter the organoid.

Grown from stem cells sourced from the patient’s cancer, these mini-cancers grow quickly in a dish. Hundreds can be created, and so hundreds of potential cancer-beating drugs tested. When the ideal drug is found, the organoid can be transplanted into mice to check the drug works in vivo.

Results in humans have been promising.

“Tumour organoids can faithfully report the drug response of the corresponding patient,” the authors write.

Researchers are also introducing their own tweaks. The gene-splicing technology CRISPR has been put to work making normal cells turn into cancer. At the basic science level, this has helped show how healthy bowel cells turn cancerous.

But the cues that cause cancer also come from the gooey stuff that sits outside a tumour.

Scientists are using organoids to study this tumour “micro-environment”. It usually contains T-cells, immune cells that crowd in to try and fight off the cancer.

The research has led to advances in a field that’s creating a major buzz in the cancer world: immunotherapy, which co-opts the body’s very own immune system to target cancers such as lung, kidney and melanoma.

And as all this data flows in, it is being added to vast “living biobanks” that will be used to guide treatment for other patients.

The ultimate aim, the authors write, is to have a “bacteriology” test – akin to culturing a bacterium and seeing what antibiotics will kill it – for cancer.

“The promise is for the future that… we can test existing drugs or maybe even develop new drugs based on cancer cells from individual patients,” says Clevers in a related video.

Organs do not exist in isolation, however, and one new technique is being used to see how human organs “chat” to each other.

A review led by Dongeun Huh from the Department of Bioengineering at the University of Pennsylvania in Philadelphia, US, explains how “organoids-on-a-chip” can link body parts right there on the bench.

Take the lung’s alveolar cells: tiny air pockets that keep us alive but also get damaged by emphysema, infection and air pollutants. Each alveolus has a blood vessel running next to it, which is also affected by the disease process.

The authors explain how the two tissues can be grown on a chip, from stem cells, to copy the lung’s anatomy. The chip has a membrane with alveolar cells and air on one side, and blood vessels and culture medium on the other.

The virtual reality doesn’t end there.

To mimic the effect of breathing, a vacuum is applied intermittently to the alveolar side. This mini-lung on a bench is being used to screen for the causes and potential cures of lung disease.

But the chip technology could also solve a major challenge of trying to raise a crop of organoids.

To grow, the mini-organs rely on oxygen and nutrients diffusing in directly from the culture medium. The upshot is that when organoids reach a certain size – about the size of a lentil – the nutrients can’t penetrate and they rot from the inside out. {%recommended 7221%}

The bioengineers have been hard at work on that one.

Huh and colleagues detail how chips have been used as a trellis upon which to fashion blood vessels from stem cells. In one case, the vessels grew into and sustained a breast tumour organoid. The artificial blood network was then used to give the cancer drug paclitaxel. Dramatically, it slowed tumour growth.

As if that weren’t enough, the technology is also scaleable.

Step up to the “body-on-a-chip” and you have multiple mini-organs, grown in their own plastic compartments, meeting and greeting via micro channels that relay fluids with chemical messengers. One such creation features stomach, liver and intestinal organoids. The intestine produces hormones that allow “cross talk” with the liver, which then dials down its production of a bile acid enzyme.

And the technology is taking off. Literally.

In a related video, Huh says they recently launched a body-on-a-chip in a rocket to the international space station to study how astronauts become more prone to infection in space.

The idea, it seems, is that “body-on-a-chip” could become the ultimate proxy for experiments on people.

“We could actually use these model systems to test things that are not testable on humans,” says Huh.

There is one field of medicine, however, where the ability to scale up organoids could literally mean the difference between life and death.

The hope of regenerative medicine is that organoids might one day be grown as replacement parts for organs that are diseased or worn out.

But to become like the livers, hearts and other squelchy bits we carry around, organoids are going to have to get a whole lot bigger and more complex.

In a third review, Takanori Takebe and James Wells from the Centre for Stem Cell and Organoid Medicine at the Cincinnati Children’s Hospital Medical Centre in Ohio, US, take us through how you might do that.

In two words, it’s something called “narrative engineering”. The idea is that you look at how organs develop from the embryo onwards, then do things likely to induce the same. It means going right back to the formation of the three “germ” layers, the endoderm, mesoderm and ectoderm, then tracing the narrative arc of each organ’s journey from there on in.

To recreate that odyssey, the authors write, you need a range of interventions, such as limiting the space in which cells grow, subjecting them to mechanical forces such as stretch, giving electrical stimulation to mimic brain cell firing, and adding various growth factors to culture media.

The authors describe this as a “more holistic approach” that “may prove essential for… better organ modelling and eventual transplantation-based therapies”.

There is, however, a final leap the organoid might take that could perhaps trump all others.

A review lead-authored by Marta Shahbazi from the Mammalian Embryo and Stem Cell Group at the University of Cambridge, UK, notes that combining embryonic and trophoblast (early placenta) stem cells “leads to the generation of preimplantation embryo-like structures markedly similar to blastocysts”.

In baby-making, blastocysts are the product of fertilisation that, when implanted in the wall of the uterus, become embryo and placenta. Shahbazi and colleagues draw on that embryology to pose something of a monumental question: “Will stem cell models ever pass the ultimate test of function, which is development following implantation?”

In other words, could you create an embryo organoid that, when put in a womb, will grow into a fully-fledged foetus?

The authors review current knowledge on how controlling of a range of factors, including geometry, the physical environment and chemical signalling, might coax stem cells into becoming an embryo.

They also pose a moral question that many of us may not have even thought of yet.

“It is important to consider when stem cell models of embryos acquire the protections attached to human embryos,” the researchers write.

It is a question that could launch a thousand philosophy PhDs – dissertations that may also be helped along by a concluding insight from those authors.

“Building embryos from stem cells … is the test of whether we can understand the whole from the parts.”

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