The Economist Asia - 24.02.2018

68 Science and technology The EconomistFebruary 24th 2018

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AKE the fertilised egg of a pig. From

each cell in the resulting embryo cut out

a gene or genes that promote the develop-

ment of the animal’s heart. Inject human

stem cells from a patient who needs a new

heart into the embryo and then place it

into the womb of a sow. Wait nine months.

The result is an adult pig with a heart made

of human cells. The pig can be slaughtered

and the heart transplanted into the patient

who provided the stem cells, for whom the

organ will be a geneticmatch.

That, at least, is the hope of a panel of re-

searchers who presented their work to the

AAASmeeting. For, though this kind of bio-

logical melding may trip the disgust cir-

cuits, the value of such a procedure, were it

possible, is clear.

First, transplantable organs are scarce

and demand for them is increasing. As life

in general, and cars in particular, become

safer, the supply of bodies with healthy or-

gans in them is shrinking. Meanwhile, peo-

ple are living longer. As a result, some

75,000 individuals in America alone are

waiting for organs. Every day around 20 of

them die. Besides increasing the supply of

organs, growing them in animals might

also increase their utility. The genetic

match between organ and patient would

mean those receiving transplanted organs

would no longer need to take immuno-

suppressive drugs to stop rejection.

All this makes growing organs in live-

stock a tantalising alternative to harvesting

them from the dead. Thousands of years of

breeding have yielded beasts which grow

fast, so a patient need not wait long while

his future heart develops inside a young

animal. Sheep, cows and pigs are all

roughly the right size to host human or-

gans. And, since such animals are already

raised for their flesh and skin, their use to

grow more valuable things should meet

with no objection beyond squeamishness.

Creating human organs in this way

would rely on the union of two recent de-

velopments in biotechnology. CRISPR/

Cas9, a genetic-engineering tool discov-

ered in 2012, would snip away portions of

the animal-host’s genome that control the

development of the organ being grown.

This would create a “genetic vacuum”

which could be filled by induced pluripo-

tent stem cells, the second breakthrough,

made in 2006. Human pluripotent stem

cells can grow into many different kinds of

tissues, filling the void left in the develop-

ing animal with an organ made from the

patient’s own cells.

That this combination works in princi-

ple was first shown last year, when a group

at the Salk Institute in California reported

making mice with eyes, pancreases, hearts

and other organs composed of rat cells.

Such mixed-species creatures are known

as chimeras, after a monsterin Greek my-

thology. Many of these mouse-rat chime-

ras lived to adulthood, and one reached its

second birthday which, for a small rodent,

is old age. A second group, led by Hiro-

mitsu Nakauchi of Stanford University

showed that a mouse pancreas grown this

way in a rat, which then had parts of it

transplanted into a mouse genetically

identical to the one that supplied the stem

cells employed, could control diabetes in

that mouse. Dr Nakauchi had thus created

a working, transplantable organ.

The creation of chimeras that include

human organs is more challenging, be-

cause people are less closely related to

sheep and pigs than mice are to rats. Never-

theless, Dr Nakauchi and his group have

followed up their mouse work by growing

human pancreas cells in pig fetuses. An-

other panellist, Pablo Rossof the Universi-

ty of California, Davis, said he had man-

aged a similar feat in sheep. In both cases

the chimeric animals were not brought to

term. Were that to happen, their human

pancreas cells might hypothetically be ex-

tracted and transplanted into people suf-

fering from diabetes, in order to revive a

patient’s ability to produce insulin.

Dr Nakauchi and Dr Ross both per-

formed their tricks by usingCRISPR/Cas9

to snip a gene called Pdx1 from the embry-

os of theirpigs and sheep. This gene en-

codes a protein crucial to pancreatic devel-

opment, thus creating the genetic vacuum

that the human pluripotent stem cells go

on to fill. But Pdx1 is not the only gene that

can be silenced in this way. Daniel Garry of

the University of Minnesota uses the tech-

nique to shut down Etv2 in pigs. Etv2 con-

trols the development of the vascular sys-

Transplants and biotechnology

Mix and match

AUSTIN

Stem cells and gene editing may turn

domestic animals into organ factories

the AAASmeeting, Paul Kenny, of the

Icahn School of Medicine, in New York,

also turned to mice.

The root of Dr Kenny’ssuspicion was

the discovery, post mortem, in the brains

of patients who had been suffering from

these conditions, of elevated levels of three

micro-RNAs, called MiR206, MiR132 and

MiR133b. He and his colleague Molly Heyer

therefore looked at the role of these micro-

RNAs in regulating brain cells called parv-

albumin interneurons, which are thought

to be involved in schizophrenia.

Picking one, MiR206, for closer exami-

nation, the two researchers created a

mouse strain in which the gene for MiR206

was switched off in the parvalbumin inter-

neurons. They then performed experi-

ments to study the behaviour of these

mice, assuming that switching the gene off

might protect them against schizophrenia-

like symptoms. Surprisingly, they found

the opposite.

Their first experiment was to play the

mice a sudden, loud noise. This will startle

any creature, mouse or man. If the noise is

preceded by a softer one, however, both

humans and murines react far less when

the loud noise comes. They are expecting

it. But people with schizophrenia seem

never to learn this expectation. And nei-

ther, to the researchers’ surprise, do mice

with the MiR206 knockout.

The scary moment

For people, these observations are often ex-

plained by the fact that one symptom of

schizophrenia is increased fear. And, in a

second experiment, Dr Kenny and Dr

Heyer showed, again contrary to expecta-

tion, thatMiR206-knockouts were unusu-

ally fearful as well.

The researchers used a box which con-

tained two lights, each positioned above a

lever. First, a light would blink on and go

off. Then, after a delay, both lights would

come on. That was the signal for the mouse

to press a lever. If the lever the mouse

pressed was the one not under the initial

light, the animal received some food. Drs

Kenny and Heyer found that the knocked-

out mice collected less food than did nor-

mal ones. But this was not because they

were making mistakes. If they pressed a le-

ver, they picked the correct one as often as

a normal mouse would. Instead, they were

pressing any lever less often. That was be-

cause they spent most of their time hiding

in the corners of the box opposite the wall

with the lights and levers. Again, they

seemed abnormally afraid.

What all this means for the study of

schizophrenia is unclear. It is possible that

examination of the other two pertinent

micro-RNAs may shed more light on the

matter. More generally, though, both Dr

Kenny’s work and Ms Chan’s are good ex-

amples of the fact that there is more to

genes than was once believed. 7