2020-03-01_Cosmos_Magazine

I

DID NOT BECOMEa scientist to cure cancer.

I was one of those types who are curiosity-driven;

give me the blue-sky mystery and I’ll leap into it.

So when in June 2019 Megan Donnell told me she

was using research I’d participated in 30 years ago to

find a cure for her two sick children, it hit me with

the force of revelation: blue sky research reallydoes

pay off.

It may be an article of faith inked into your grant

proposals, but when you spend your days with fruit

flies, as I did in the mid-1980s at the University of

California San Francisco, it can be a little hard to

believe.

Though I had no medical problem in mind, I was

trying to answer a rather profound question: how does

the mush of an embryo sculpt itself into a body? At my

lab and others around the world, we found the answer

lay with a set of so-called ‘pattern-forming’ genes. In

the same way that a tailor draws a pattern on a sheet of

fabric to guide the cutting and sewing of the garment,

these genes lay down a pattern on the newly-laid fly

egg to instruct the construction of its body. My gene

of interest went by the name engrailed. A few hours

after a fruit fly egg is fertilised, engrailed lays down

a pattern of 15 stripes along the developing embryo,

which provide the pattern to start constructing the

15 segments of the fly grub.

What was so thrilling was that these pattern-

forming genes weren’t just involved in the

construction of fruit flies; other researchers found

the same pattern-forming genes at work instructing

the embryos of frogs, mice and humans. While later

researchers delved deeper and deeper to unravel the

details of just how pattern-forming genes guide the

development of embryos, one stream of this research

took a turn that was quite beyond my imagination.

From the early 2000s, researchers began using

pattern-forming genes to instruct human embryonic

cells to make tissues for patients. Today, advanced

clinical trials are offering patients made-to-order

grafts for skin, pancreas and retina. Even more

startling, the pattern-forming genes are being put to

work to make small replicas of human brains in a dish,

dubbed brain organoids.

It was Megan who made me realise that this science

fiction technology had well and truly arrived. We first

met at a conference in September 2018, discussing

genetic testing for prospective parents. Members of

inbred communities, including Ashkenazi Jews (like

myself ), have long availed themselves of genetic tests

to ensure they are not carriers of afflictions such as

Tay-Sachs – a fatal neurodegenerative disease from

which infants typically die by the age of four. But

members of the wider community are not immune;

any couple can wake to the living nightmare of

discovering they have passed on a fatal genetic disease

to their offspring.

That was Megan’s cautionary tale. A tall,

attractive, dynamic woman, her children Isla and

Jude appeared normal at birth. But by the time Isla

was two, there were concerns. Unlike most toddlers

she was not putting words into sentences. Jude was

born soon after, and he too had drawn the genetic

short straw.

The Donnells were unaffected – and unknowing

• carriers of the Sanfilippo gene. Its function is
  to clear away heparan sulfate, a sugar that holds
  proteins together in the matrix between cells. Absent
  a functioning copy of the gene, the sugar levels build
  up and start poisoning the brain.
  Megan and her husband Allan each carried one
  gene that functioned and one that didn’t. There

Soon after fertilisation, the
gene called engrailed quickly
lays down the fruit fly grub’s
pattern of 15 body segments.
Organoids developed utilising
similar pattern-forming
techniques may offer a
solution for Sanfillipo sufferers
such as Megan Donnell’s
children Isla and Jude
(opposite).

RESEARCH PIC / NICO BLUE

Engrailed Embryonic Fruit fly

Drosophila melanogaster

78 – COSMOS Issue 86

BRAIN ORGANOID