In the embryonic human, an organiser starts its work


Long-sought mechanism for cell development has at last been found. Paul Biegler reports.


Long before this stage, the organiser has been hard at work.
Long before this stage, the organiser has been hard at work.
Elizabeth Livermore/Getty Images

We have had personal organisers for years, from the Filofax and PalmPilot to the calendar on the modern smartphone. To those you can now add a “person” organiser that takes managing stuff to a decidedly higher plane. We’re talking organising cells to become distinct bits of human.

Researchers, led by Ali Brivanlou from the Rockefeller University, New York, US, have found the signal that causes cells in the developing human embryo, which start off “pluripotent” – able to become any type of cell – to choose a future career, in this case getting to work in the nervous system.

The early embryo is already known for amazing feats, not least of which is divvying up cells into three groups or “germ layers”. Cells from the “endoderm” become, among other things, stomach and lung; the “mesoderm” forms muscle and bone; and the “ectoderm” morphs into skin, teeth, and the all-important nervous system. It’s called “gastrulation”.

But studying all this in real human embryos crosses an ethical line.

To stay on the right side of that line the researchers had previously created a “gastruloid”. This is a cluster of human embryonic stem cells, a millimetre or so across, that is basically a working model of an embryo in a Petri dish.

Under the action of a protein called Bone Morphogenetic Protein 4 (BMP4) the team coaxed those generic cells, breathtakingly, into becoming the three germ layers.

But there was always a missing piece to the puzzle.

Back in the 1920s Hilde Mangold and Hans Spemann at the University of Freiberg in Germany identified a bunch of cells in salamanders that marshalled growth of the central nervous system. They called it the “organiser”, and their research bagged Spemann the 1935 Nobel Prize for medicine.

Such an organiser in humans has been something of an elusive chalice. Until now.

Brivanlou’s team has shown that small colonies of cells in the gastruloid produce proteins that signal the germ layers to form tissues that eventually become brain and spinal cord.

They have, in short, found evidence of a human organiser. But the bars in science are high, and for irrefutable proof the researchers set themselves an even harder task.

Using fluorescent markers to track the human cells, they grafted them into chicken embryos to see just how adept the embryonic organiser was at running things. What happened next left Brivanlou stunned.

“To my amazement, the graft not only survived, but actually gave rise to these beautifully organised structures,” he said.

Those structures were the beginnings of the chick’s nervous system, a phenomenon that, the researchers say, shows the organiser to be something that has persisted across aeons of evolution.

“Once you transplant the human organiser into a chicken embryo, the language it uses to instruct the bird cells to establish the brain and nervous system is exactly the same as the one used by amphibians and fish,” says Brivanlou.

The research is published in the prestigious journal Nature, not renowned for hyperbole. So, when the abstract states the “discovery represents a milestone in human embryology”, it very likely does.

Unlocking this cellular key could lead to breakthroughs in regenerative medicine, a nascent field whose goals including growing artificial organs for transplant, and using stem cells to repair tissues in the fight against diseases such as Alzheimer’s, Crohn’s and leukaemia.

While the science is complex, Brivanlou’s philosophy is very much back-to-basics.

“If you want to understand something, you must first understand its origins," he says.

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Paul Biegler is a philosopher, physician and Adjunct Research Fellow in Bioethics at Monash University. He received the 2012 Australasian Association of Philosophy Media Prize and his book The Ethical Treatment of Depression (MIT Press 2011) won the Australian Museum Eureka Prize for Research in Ethics.
  1. https://embryo.asu.edu/pages/spemann-mangold-organizer
  2. https://www.nobelprize.org/nobel_prizes/medicine/laureates/1935/
  3. https://www.nature.com/articles/s41586-018-0150-y
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