Realising the promise of stem cells
25 July 2007by Elizabeth Finkel
A spectacular variety of stem cell advances are taking root, from
success in primate cloning and stem cells without embryo death to
treatments for blindness and diabetes.
In June the International Society for Stem Cell Research held it's
annual meeting in Australia's tropical city of Cairns. It was a
fitting location. Outside, lush vegetation covered sea-hugging
mountains and spilled out onto the streets.
And inside at the conference centre – a thousand flowers were
blooming. There was stem cell research of every description: stem
cells from placentas and amniotic fluid; stem cells from cloned
monkey embryos or single parent embryos or stem cells made from
embryo biopsies in a way that left the embryo unharmed. And there was
the promise of clinical success around the corner with dazzling
reports of stem cells that corrected mouse diabetes, blindness and
blood vessel disease.
These diverse blooms had sprung up all over the place; fertilised by
different soils: the soil of necessity, serendipity, medical need,
and sometimes just the result of a brilliant pair of green thumbs. So
let me take you on a conference tour.
Blooms grown on the soil of necessity
Kevin Eggan from Harvard University in Cambridge, U.S., looks like a
college kid but he's already a star performer in stem cell science.
For several years now he's been on a quest for the holy grail: namely
to find the alchemy that will transform a patient's skin cell into a
never-ending supply of tissue-matched stem cells; the seemingly
magical cells able to fix whichever of a patient's organs is in need
of an overhaul.
A couple of years ago, he partly succeeded. He fused skin cells with
embryonic stem cells. But these hybrid stem cells were pretty
abnormal. So Eggan turned to another technique which promises to
deliver stem cells from skin cells, that is: therapeutic cloning. To
carry out this controversial technique, he teamed up with his
colleague George Daley, a haematologist at the Children's Hospital in
Boston.
Human therapeutic cloning is an alchemy that transforms a regular
skin cell into an embryo (and potentially an entire cloned human).
And it is from that embryo, that human embryonic stem cells are
derived. But the first step is the crucial one. It requires an
unfertilised woman's egg to act as the alchemist's vessel. The egg's
own chromosomes are sucked out, so removing its genetic instructions.
They are replaced by the genetic instructions of a skin cell, carried
by the skin cell nucleus. Inside the egg vessel, the skin nucleus
starts developing into a clone embryo. After several days the embryo
is destroyed to derive embryonic stem cells that match the skin cell
donor.
The long wait
Eggan and Daley spent a couple of years just to get their
University's permission to carry out the controversial technique.
Then they waited for women to donate their eggs. As Eggan explained
in his talk, it was a long wait. In fact not a single woman ever
showed up. But it gave him lots of time to think. He realised that
unfertilised eggs were very precious: a woman had no idea how many
she would really need in order to conceive. On the other hand,
fertilised eggs were often thrown away because they were faulty. So
couldn't he use these readily available fertilised eggs instead?
Past evidence suggested not. Researchers had originally tried using
fertilized eggs as cloning vessels, but only unfertilised eggs had
ever worked in mice. But as Eggan sat there thinking, he realized
what the problem must be. In cloning you have to start by removing
the egg's own chromosomes. But the chromosomes of fertilised and
unfertilised eggs differ in a very significant way. In unfertilised
eggs the chromosomes float freely in the cellular soup like fish in
an aquarium. And just as you can net fish from an aquarium while
leaving the aquarium fluid intact; you can scoop chromosomes from the
egg yet leave most of the egg goodies intact.
On the other hand in the fertilised egg, the chromosomes get bagged
up in a sac called the nucleus. When you remove the sac, you not only
remove the chromosomes you remove lots of other goodies as well. And
some of those goodies must be essential for cloning. At least that
was what Eggan guessed. If his hunch was right, there was still a way
to use fertilised eggs for cloning. Because a few hours after
fertilisation, just before the egg split in two, the sac around the
chromosomes broke. In theory that should allow someone to fish out
the chromosomes only and leave the other goodies in the egg. Eggan
tested his theory on fertilised eggs whose nuclear sacs had just
broken and it worked: these eggs turned out to be good cloning
vessels.
Accepting the rejects
If fertilised human eggs can be used the same way, Eggan (a most
fitting name) and lots of other researchers will be back in business.
That's because fertility clinics in the U.S. throw away up to 50,000
fertilised eggs each year – because they're faulty; they carry more
than one sperm. But reject eggs like this work fine for cloning.
Eggan has stopped waiting for altruistic women and now plans to apply
to the clinics to use these reject eggs.
Necessity has also been the mother of invention for Robert Lanza, a
scientist at the company Advanced Cell Technology in Massachusetts.
In 2001, U.S. president George Bush decreed that American researchers
cannot use federal funds if their research destroys human embryos;
even if they are surplus embryos from fertility clinics and destined
to be thrown away. So Lanza thought of a way to make embryonic stem
cells without destroying embryos.
It's known that at the eight-cell stage, an embryo can tolerate
losing one or two of its cells, and go on to develop normally. That
is the routine technique behind embryo biopsy—where the single cell
is tested for genetic defects before the embryo is implanted. Last
August Lanza announced in the journal Nature that he had managed to
take one of these biopsy cells and turned it into an everlasting
embryonic stem cell.
At first Lanza was lauded: he appeared to have cut the Gordian knot
strangling stem cell research – embryonic stem cells could be made
without destroying the embryo. Then he was vilified, because it
turned out that in fact, the embryos he used to do his experiment had
been destroyed.
But at Cairns, Lanza redeemed the promise of his earlier research. He
described how he had, in fact, created embryonic stem cells from
three embryos, without harming the embryos. After surrendering a
single cell, they had been safely returned to the freezer, where they
should still be fully viable (based on thousands of cases where
healthy babies have been born from such embryos.) Lanza told me he
has since applied to the U.S. National Institutes of Health, to see
whether embryonic stem cells made by his technique would qualify for
federal funding, since no embryo is destroyed in the process.
Blooms from the soil of medical need
The affable George Daley is the newly incumbent president of the
International Society for Stem Cell research. He is also a physician-
researcher dedicated to his child patients who have genetic blood
diseases. Bone marrow transplants are the best bet for these kids,
but this cure has a two to five per cent chance of killing them. The
risk comes from the bone marrow graft itself which, because it is
foreign, will sometimes attack the patient.
That's why Daley has been dreaming about using a patient's own cells
as the source of their cure. He has achieved the dream in mice. In
2002, he took cells from the tail of a mouse, and using "therapeutic
cloning", reprogrammed them to become embryonic stem cells. Then he
fixed the genetic defect in those cells, turned them into bone marrow
cells, and returned them to the mice to cure their disease. The hope
is to repeat the trick in humans: that's why Daley and Eggan spent
two years trying to get permission to carry out therapeutic cloning.
But Daley also has other balls in the air. Human therapeutic cloning
is extremely difficult – nobody has yet succeeded. But there is
another way to create an embryo that matches its donor. That's an
embryo that develops from a single parent – a so-called parthenote.
These embryos, of course, never develop beyond an early stage. They
occur when a woman's egg starts developing without being fertilised.
Or when two sperm fertilise an egg and the female chromosomes are
kicked out.
It turns out to be quite easy to make these single parent embryos,
and even though they don't develop very far, it is quite easy to make
embryonic stem cells from them. It is certainly a hell of lot easier
than therapeutic cloning. For instance in mice, only 1 per cent of
clone embryos yield stem cells, but 70 per cent of parthenote embryos
will deliver.
Woo Suk Hwang, the Korean cloning expert who defrauded his results,
found this out the hard way. He used over two thousand human eggs to
try therapeutic cloning. His only success was an embryonic stem cell
line that came from a parthenote embryo. That was a genuine world
first – but it's not clear whether Hwang realised what he'd got.
Daley is very eager to test grafts derived from single parent embryos
for their therapeutic potential. Because in theory, they should not
be rejected. In mice such cells have been trained to become bone
marrow cells, and they are not rejected when transplanted back into
the animal that donated the sperm or eggs.
Daley is also trying to get therapeutic cloning to work using cow
eggs as cloning vessels. As far as pushing the research envelope for
his patients, Daley is leaving no stone unturned.
Green thumbs
In this conference the exotic blooms kept popping up right till the
end. Hongkui Deng from Peking University in China was one of the very
well-represented Asian contingent: about a third of the conference
attendees came from Asia. And his talk was a show-stopper.
Researchers have been getting closer and closer to converting
embryonic stem cells into insulin-producing beta cells. These are the
cells that die off in children with type-1 diabetes. Grafts of beta
cells from donated pancreases can control the disease and prevent the
side–effects like blindness and kidney failure. But there will never
be enough donated pancreases to go around.
That's why embryonic stem cells, with their capacity to be grown by
the bucket load, provide great hope. Many labs have now made cells
that look and feel like beta cells. The problem is when they graft
the cells into diabetic mice, they don't work. For some reason though
the cells make insulin, they won't release it when blood sugar levels
rise.
Not so for Deng. He used a slightly different method to make his beta
cells, and when he grafted the cells into diabetic mice, they
performed, releasing their insulin in response to rising blood sugar
levels, and normalizing the blood sugar levels of the mouse. It
worked when he used human embryonic stem cells too, and when he
removed the grafts, the mice went back to being diabetic.
Scientists are cautious about research presented at a conference.
Nevertheless, Bernie Tuch who heads the Diabetes Transplant Unit at
Sydney's Prince of Wales Hospital In Australia in had to admit, " he
seems to have progressed further than anyone else."
It turns out Deng has a reputation for having golden hands: Ten years
ago, when he trained at New York University, he isolated a key
receptor for the AIDS virus. Now at his lab at Peking University, he
has a US$1.9-million grant from software tycoon Bill Gates, and uses
stem cells to work both on HIV vaccines and diabetes.
At Cairns, one could at last move on from the politics and religion
that has so distorted stem cell research – trying to wedge it into
adult versus embryonic stem cells. Here all the disciplines were
enjoying the fecund cross-pollination that science thrives upon – to
allow a thousand flowers to bloom.
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Elizabeth Finkel is a Melbourne-based Science writer, a contributing
editor of Cosmos and the author of Stem Cells: Controversy on the
Frontiers of Science. This article was first broadcast on ABC radio's
Ockham's Razor on 22 July 2007.
http://www.cosmosma
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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