The lab-grown penis:
approaching a medical
milestone
After more than 20 years of research, a
team of scientists are bioengineering
penises in the lab which may soon be
transplanted safely on to patients. It is an
extraordinary medical endeavour that
has implications for a wide range of
disorders
Dr Anthony Atala: ‘We were completely stuck.
We had no idea how to make this structure, let
alone make it so it would perform like the natural
organ.’
Medical research Stem cells Biology
Sexual health Men's health
Dara Mohammadi
Saturday 4 October 2014 14.00 EDT
G athered around an enclosure at the
Wake Forest Institute for
Regenerative Medicine in North
Carolina in 2008, Anthony Atala and his
colleagues watched anxiously to see if
two rabbits would have sex. The
suspense was short-lived: within a
minute of being put together, the male
mounted the female and successfully
mated.
While it’s not clear what the rabbits
made of the moment, for Atala it was
definitely special. It was proof that a
concept he’d been working on since 1992
– that penises could be grown in a
laboratory and transplanted to humans –
was theoretically possible. The male
rabbit was one of 12 for which he had
bioengineered a penis; all tried to mate;
in eight there was proof of ejaculation;
four went on to produce offspring.
The media’s coverage of Atala’s
announcement a year later was
understandably excited. Not just because
of the novelty of a man growing penises
in a laboratory, but because his work
would fulfil a real need for men who
have lost their penis through genital
defects, traumatic injury, surgery for
aggressive penile cancer, or even jilted
lovers exacting revenge.
At present, the only treatment option for
these men is to have a penis constructed
with skin and muscle from their thigh or
forearm. Sexual function can be restored
with a penile prosthetic placed inside.
The prosthetics can be either malleable
rods, with the penis left in a permanently
semi-rigid state and thus difficult to
conceal, or inflatable rods, which have a
saline pump housed in the scrotum. Both
technologies have been around since the
1970s. The aesthetics are crude and
penetration is awkward.
Another option is a penis transplant from
another individual, but this carries a risk
of immunological rejection. The chance
of organ death can be lessened with anti-
rejection drugs, but these drugs have
serious side-effects. Transplants can also
have a psychological impact, especially
with an organ as intimate as the penis. In
2006, a Chinese man was the first to
receive a donor penis ; two weeks after
the 15-hour operation, surgeons removed
the transplanted organ on the request of
both the patient and his partner.
Atala hopes his technique will mitigate
both immunological and psychological
issues because his penises would be
engineered using a patient’s own cells.
“The phallus is actually much longer than
you think,” he explains. “It goes all the
way behind the pelvis, so no matter the
extent of the damage, there is a high
probability that there are salvageable
cells.”
Peruvian-born Atala, a urological
surgeon and professor of regenerative
medicine, heads a 300-strong team at the
institute. He corrects himself constantly,
always going back to edit his speech,
adding words such as “high probability“
or “in all likelihood” to be sure his
sentences are word-perfect. Soft-spoken
and mild-mannered, Atala is a trailblazer
in the field and you can’t help but think
that his measured speech is an attempt
to provide a sure path for others to
follow.
To some, engineering human organs
sounds like science fiction, but for Atala
it’s an absolute necessity. As we live
longer (and thus our organs fail more)
the shortage of organs for donation will
only get worse. If he can work out how to
generate the organs people need in a
reliable and effective way, the technology
can improve a lot of people’s lives. In
2006, Atala and his team announced the
first successful bioengineered organ
transplant , a bladder, which had been
implanted into seven patients in 1999.
Earlier this year he announced the
successful follow-up of four women
given bioengineered vaginas in
2005-2008. Despite these successes, he
says, the penis is proving trickier.
Organs increase in architectural
complexity as they go from flat structures
such as skin, cylindrical structures such
as the vagina, to hollow non-tubular
organs such as the bladder. As a solid
organ, the penis tops this list in both
density of cells and structural
complexity. It consists of a spongy
erectile tissue unique to it. During an
erection, signals from the nerves trigger
blood vessels to dilate, filling this spongy
tissue with blood and causing the penis
to lengthen and stiffen.
“We were completely stuck,” says Atala
of the first few years of research in the
early 90s. “Even the idea of the field of
regenerative medicine was brand new at
the time. We had no idea how to make
this structure, let alone make it so it
would perform like the natural organ.”
Then, in 1994, he figured he could take a
helping hand from Mother Nature. Using
a technique pioneered for biological skin
dressings, he would take a donor penis
and soak it in a mild detergent of
enzymes for a couple of weeks to wash
away the donor cells.
“You’re left with a mostly collagen
scaffold – a skeleton if you like, that
looks and feels just like the organ,”
explains James Yoo, one of Atala’s
collaborators at the institute. “Think of it
like a building. If you remove all the
furniture and the people, you’re still left
with the main structure of the building.
Then you replace the tenants with new
ones. That’s the whole idea. It’s just that
the building is a penis and the tenants
are cells.”
The next step is to reseed the structure
with the patient’s own cells taken in a
biopsy from salvageable tissue and
grown in culture. Smooth muscle cells,
which relax during an erection to allow
the vessels to dilate and the penis to fill
with blood, are first, followed by
endothelial cells which line the interior
surface of blood and lymphatic vessels.
When ready, the bioengineered penis is
ready to be transplanted to the recipient.
So why, six years on from successfully
engineering a penis for rabbits, have they
not yet done the same for humans? Atala
explains that, as is often the case with
these things, scaling up is proving
difficult. “Even though we can make
them in a very small mammal, we have
to tweak the technology, the processes,
the ratio of cells and so on, to get larger
and larger structures. That’s pretty much
what we’ve been doing since the
rabbits.”
They’ve made encouraging progress.
Atala has engineered half a dozen human
penises. Although they are not yet ready
for transplanting, Atala’s team are
assessing the structures for safety and
effectiveness. One machine squashes,
stretches and twists them to make sure
they can stand up to the wear of
everyday life; another pumps fluid into
them to test erections. Sliced segments
are tested at the genetic, cellular and
physiological level.
“It’s a rigorous testing schedule,” says
Atala, wearily. “But we’re trying to get
approval from the US Food and Drug
Administration so we know everything is
perfect before we move to a first in-man
test.”
Neither Atala nor Yoo will be pushed for
a date for the first test in man, saying
only that they’d expect it to occur within
five years. “In the end we’re aiming for
the entire size of the organ,” says Atala.
“But in reality our first target is going to
be partial replacement of the organ.”
In the short term, this would include
growing smaller lengths for partially
damaged penises, but would also include
replacing parts of the penis to help cure
erectile dysfunction. Degradation of the
spongy erectile tissue, says Tom Lue, a
urological surgeon at the University of
California, San Francisco, is the leading
cause of impotence in old age. Disorders
such as high blood pressure or diabetes
can damage the delicate tissue – the
resulting scar tissue is less elastic,
meaning the tissue cannot completely fill
with blood and the penis cannot become
fully erect.
“Show me a hundred 70-year-old men
with erectile dysfunction,” says Lue, “and
I’ll bet you 90% of them have scar
material in their penis.” Traumatic injury
or priapism, a condition that leaves men
with an increasingly painful erection for
hours or even days, can also damage the
tissue and cause erectile dysfunction in
younger men. “If you replace the
damaged spongy tissue you can give
these men a better erection.”
Engineering the spongy tissue for
replacement is one of Atala and Yoo’s
interim goals. Lue is also hoping to
restore erections, but for less severely
damaged penises. For instance, some
men become impotent after surgery for
prostate or rectal cancer because the
nerves that regulate erections, which run
through the rectum and prostate into the
centre of the penis, can get damaged.
Likewise with traumatic injury, if the
vessels are severed then the penis cannot
fill with blood.
Microsurgery to connect the vessels and
nerves in the penis is possible but often
ineffective. Lue is testing whether
injecting stem cells into the base of the
penis can encourage the nerves and cells
to rejoin. His work might also help Atala
and Yoo to stimulate nerve and vessel
regrowth when the day comes for the
first in-man trial of a bioengineered
penis. Twenty-two years into his research
to bioengineer a human penis, Atala is a
man who is both excited and impatient
for that day. And you’d suspect he’s not
the only one.
Bioengineered organs: The story so far…
Bladder
In 1999 the bladder became the first
laboratory-grown organ to be given to a
human. Atala and his colleagues took
cells from a biopsy from seven patients
with bladder disease. The cells were
cultured and then seeded, layer by layer,
on to a biodegradable, bladder-shaped
collagen scaffold. After about eight weeks
they were transplanted to patients,
where the organs developed and
integrated into the body.
Vagina
Another pilot study, this time in four
women with a rare congenital
abnormality that causes the vagina and
uterus to be underdeveloped or absent.
Using a similar technique to the one used
to make bladders, in 2005 they implanted
the first vagina. Up to eight years after
transplant, all four organs have normal
structure and function. This technique
could be used to help women following
injury or cancer.
Penis and beyond
In 2004, they implanted the first
bioengineered urethra into five boys.
This technology will help in their work
towards reconstructing the penis. Atala
and his colleagues are also working on 30
different organs and tissues including a
kidney, which could be made using a 3D
printer, and tissue for the liver, heart and
lung.
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