Wednesday, February 1, 2012

Create Pluripotent Human Stem Cells

An article from the economist.

A PARTICULAR sheep has haunted stem-cell researchers for years. In 1996 Ian Wilmut, of the Roslyn Institute, in Edinburgh, removed the nucleus of an ovine egg cell and replaced it with that of an adult cell. The resulting hybrid was grown into a tiny embryo known as a blastocyst, implanted into the womb of a surrogate mother, and went on to become Dolly, the world’s most famous ewe.
This trick—cloning an adult mammal by nuclear transplantation—has never, as far as anyone knows, been repeated on humans. Apart from the technical difficulties, the ethical objections have dissuaded most serious researchers from even trying. But those researchers would like to get to the blastocyst stage, because that would allow them to make what are known as pluripotent stem cells, which are cells that can go on to turn into a wide variety of other cell types. In the immediate future, such cells might be used (because they are genetically identical to known individuals) to screen drugs for gene-specific side effects. In the longer term they might yield transplantable organs with the same genotype as the recipient, thus eliminating the problem of rejection.

This week Scott Noggle of the New York Stem Cell Foundation, a charitable research institute, and his colleagues report a step towards that goal. In a paper in Nature they describe a way of creating pluripotent human stem cells (albeit imperfectly, since the cells in question end up with two sets of chromosomes) by nuclear transplantation. Intriguingly, they seem, at the same time, to have dealt with one of the ethical objections to this sort of work. This is: how do you get your hands on enough human eggs to do it in the first place?
Doing well by doing good
In America, fertile women sometimes sell eggs to sterile members of their sex for reproductive purposes. Such sales are not frowned on if no coercion is involved. Bioethicists have, however, been reluctant to sanction egg sales for research. Indeed, California and Massachusetts, two important centres of stem-cell science, forbid the practice. Dieter Egli, one of Dr Noggle’s co-authors, once tried to get round this restriction by asking women in Massachusetts to donate eggs to a project he was undertaking in that state. He and his colleagues advertised extensively and received many calls. But when the inquirers learned what was involved, most of them shied away. The main deterrent, it turned out, was the lack of payment.
In 2006 the International Society for Stem Cell Research (ISSCR) suggested a possible solution. Scientists might pay for eggs, they opined, so long as a suitable committee monitored the exchange. The money, the ISSCR suggested, should not be enough to provide “undue inducement” for women to sell their eggs.
In the study they have just published, Dr Noggle and Dr Egli tested this idea out. They worked in New York state, which has, since 2009, allowed the use of public funds to buy eggs for research. And, to be sure there was no undue inducement, they approached only women who had already decided (in order to help another woman’s fertility) to sell an egg. They offered these women the same price, $8,000, to sell their eggs for research instead.
It worked. And, armed with 270 eggs, the researchers got down to business. They swapped some of the eggs’ nuclei with those of adult male skin cells—basically, the same procedure Sir Ian used to create Dolly. Using a pulse of calcium ions as a stimulant, they persuaded the cells to start dividing. However, the process of division stopped abruptly when between six and ten daughter cells had been created.
That, Dr Noggle and Dr Egli reasoned, might be caused by problems linked either to the adult cell nucleus, or to the process by which the egg’s nucleus was extracted. To test this, they took some of the remaining eggs and did a different experiment. Instead of enucleating them, they kept them intact and inserted the adult cell’s nucleus alongside the original one. In this case, development proceeded apace, resulting in a blastocyst. Dr Noggle and Dr Egli were then able to create pluripotent stem cells from their tiny embryo—but these had chromosomes both from the egg and the skin cell, making them useless for therapy.
Despite that wrinkle, this piece of research marks a turning point. The next step is to try to create stem cells without the leftover chromosomes from the egg. If that can be done, the new method may take over from the existing lash-up by which pluripotent stem cells with the genomes of particular individuals are made using transcription factors. A transcription factor is a molecule that regulates gene activity, and a particular combination of four of them has been found to turn ordinary body cells into something that looks remarkably like a pluripotent stem cell. “Remarkably like”, however, is not the same as “identical”. The route Dr Noggle and Dr Egli are taking may deal with that distinction.
Which is not to say that there will be no further controversy—at least, in the United States. The laws in California and Massachusetts, for example, have not been changed, so in those states eggs will continue to be in short supply. Moreover, America’s National Institutes of Health will not pay for research on stem cells, such as these, that are derived from embryos created for research. Other countries may not be so squeamish. China, for one, is particularly interested in stem-cell research. No doubt its scientists are reading Dr Noggle’s paper with interest.

Hype Over Hope

An article from the economist on hype over hope.

THE unrelenting pace of scientific accomplishment often outstrips the progress of moral thought, leaving people struggling to make sense, initially at least, of whether heart transplants are ethical or test-tube babies desirable. Over the past three decades scientists have begun to investigate a branch of medicine that offers astonishing promise—the ability to repair the human body and even grow new organs—but which destroys early-stage embryos to do so. In “The Stem Cell Hope” Alice Park, a science writer at Time magazine, chronicles the scientific, political, ethical and personal struggles of those involved in the work.
Embryonic stem cells are pluripotent: they have the ability to change into any one of the 200-odd types of cell that compose the human body; but they can do so only at a very early stage. Once the bundle has reached more than about 150 cells, they start to specialise. Research into repairing severed spinal cords or growing new hearts has thus needed a supply of stem cells that come from entities that, given a more favourable environment, could instead grow into a baby.

Immediately after the announcement of the birth of Dolly the sheep—the clone of an adult ewe whose mammary cells Ian Wilmut had tricked into behaving like a developing embryo—American scientists were hauled before the nation’s politicians who were uneasy at the implication that people might also be cloned. Concern at the speed of scientific progress had previously stalled publicly funded research into contentious topics, for example, into in vitro fertilisation. But it did not stop the work from taking place: instead the IVF industry blossomed in the private sector, funded by couples desperate for a baby and investors who had spotted a lucrative new market.
That is also what happened with human stem cells. After a protracted struggle over whether to ban research outright—which pitted Nancy Reagan, whose husband suffered from Alzheimer’s disease, against a father who asked George Bush’s advisers, “Which one of my children would you kill?”—Mr Bush blocked the use of government money to fund research on any new human embryonic stem-cell cultures. But research did not halt completely: Geron, a biopharmaceuticals company based in Menlo Park, California, had started “to mop up this orphaned innovation”, as Ms Park puts it, by recruiting researchers whose work brought them into conflict with the funding restrictions.
Meanwhile, in South Korea a maverick scientist claimed not only to have cloned human embryos but also to have created patient-specific cultures that could, in theory, be used to patch up brain damage or grow a kidney. Alas, he was wrong. But a Japanese scientist did manage to persuade adult skin cells to act like stem cells. If it proves possible to scale up his techniques, that would remove the source of the controversy over stem-cell research.
Three months after he took office, Barack Obama lifted restrictions on federal funding for research on new stem-cell cultures, saying that he thought sound science and moral values were consistent with one another. But progress has been slow: the first human trials in America, involving two people with spinal-cord injuries who have been injected with stem cells developed by Geron, are only just under way. The sick children who first inspired scientists to conduct research into stem cells in order to develop treatments that might help them are now young adults. As Ms Park notes, the fight over stem-cell research is not over, and those who might benefit from stem-cell medicine remain in need.

Stem Cell Research

An article from the economist which I am to be very interesting.

FOURTEEN years ago James Thomson of the University of Wisconsin isolated stem cells from human embryos. It was an exciting moment. The ability of such cells to morph into any other sort of cell suggested that worn-out or damaged tissues might be repaired, and diseases thus treated—a technique that has come to be known as regenerative medicine. Since then progress has been erratic and (because of the cells’ origins) controversial. But, as two new papers prove, progress there has indeed been.
This week’s Lancet published results from a clinical trial that used embryonic stem cells in people. It follows much disappointment. In November, for example, a company in California cancelled what had been the first trial of human embryonic stem cells, in those with spinal injuries. Steven Schwartz of the University of California, Los Angeles, however, claims some success in treating a different problem: blindness. His research, sponsored by Advanced Cell Technology, a company based in Massachusetts, involved two patients. One has age-related macular degeneration, the main cause of blindness in rich countries. The other suffers from Stargardt’s macular dystrophy, its main cause in children. Dr Schwartz and his team coaxed embryonic stem cells to become retinal pigment epithelium—tissue which supports the rod and cone cells that actually respond to light—then injected 50,000 of them into one eye of each patient, with the hope that they would bolster the natural supply of these cells.
The result was a qualified success. First and foremost, neither patient had an adverse reaction to the transplant—always a risk when foreign tissue is put into someone’s body. Second, though neither had vision restored to any huge degree, each was able, four months after the transplant, to distinguish more letters of the alphabet than they could beforehand.

Whether Dr Schwartz’s technique will prove truly useful remains to be seen. Experimental treatments fail far more often than they succeed. But the second paper, published in Nature by Lawrence Goldstein of the University of California, San Diego, and his colleagues, shows how stem cells can be of use even if they do not lead directly to treatment.
Since 2006 researchers have been able to reprogram adult cells into an embryonic state, using proteins called transcription factors. Though these reprogrammed cells, known as induced pluripotent stem (iPS) cells, might one day be used for treatment, their immediate value is that they are also an excellent way to understand illness. Using them, it is possible to make pure cultures of types of cells that have gone wrong in a body. Crucially, the cultured cells are genetically identical to the diseased ones in the patient.
Dr Goldstein is therefore using iPS cells to try to understand Alzheimer’s disease. The brains of those with advanced Alzheimer’s are characterised by deposits, known as plaques, of a protein-fragment called beta-amyloid, and by tangles of a second protein, called tau. But how these plaques and tangles are related remains unclear. To learn more, Dr Goldstein took tissue from six people: two with familial Alzheimer’s, a rare form caused by a known genetic mutation; two with sporadic Alzheimer’s, whose direct cause is unknown; and two unaffected individuals who acted as controls. He reprogrammed the cells collected into iPS cells, then nudged them to become nerve cells.
In three of the four Alzheimer’s patients these lab-made nerve cells did, indeed, show higher levels of beta-amyloid and tau—and also of another characteristic of the disease, an enzyme called active GSK3-beta. Since he now had the cells in culture, Dr Goldstein could investigate the relationship between the three.
To do so he treated the cultured cells with drugs. He found that a drug which attacked beta-amyloid directly did not lead to lower levels of tau or active GSK3-beta; but a drug which attacked one of beta-amyloid’s precursor molecules did have that effect. That is useful information, for it suggests where a pharmacological assault on the disease might best be directed.
In the short term, at least, iPS-based studies of this sort are likely to yield more scientific value than clinical experiments of the type conducted by Dr Schwartz, even though they are not treatments in themselves. That will, though, require many more pluripotent cells. And at least one firm is selling a way to make billions of iPS cells for just that purpose. Its founder, appropriately, is Dr Thomson.