New stem cell method makes functioning liver cells

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By Kate Kelland

LONDON | Wed Oct 12, 2011 3:57pm EDT

LONDON (Reuters) - British scientists have developed a new stem cell technique for growing working liver cells which could eventually avoid the need for costly and risky liver transplants.

A team of researchers led by the Sanger Institute and the University of Cambridge used cutting-edge methods to correct a genetic mutation in stem cells derived from a patient's skin biopsy, and then grew them into fresh liver cells.

By putting the new liver cells into mice, they showed they were fully functioning.

"We have developed new systems to target genes and ... correct ... defects in patient cells," said Allan Bradley, director of the Sanger Institute.

At a briefing about the work, Bradley said the technique -- the first success of its kind -- leaves behind no trace of the genetic manipulation, except for the gene correction.

"These are early steps, but if this technology can be taken into treatment, it will offer great possible benefits for patients," he added.

Stem cells are the body's master cells, the source for all other cells. Scientists say they could transform medicine, providing treatments for blindness, spinal cord and other severe injuries, and new cells for damaged organs.

Research is focused on two main forms -- embryonic stem cells, which are harvested from embryos, and reprogrammed cells, also known as induced pluripotent stem cells or iPS cells, which are reprogrammed from ordinary skin or blood cells.

When they were first discovered in 2006, iPS cells looked like a perfect solution to the ethical debate over the use of embryonic stem cells because they are made in a lab from ordinary skin or blood cells. Embryonic stem cells are usually harvested from leftover embryos at fertility clinics and their use is opposed by many religious groups.

But in recent years, concerns have been raised that iPS cells may not be as "clean" or as capable as embryonic cells.

Last year, a group led by Robert Lanza, of the U.S. firm Advanced Cell Technology, compared batches of iPS cells with embryonic stem cells and noticed the iPS cells died more quickly and were much less able to grow and expand.

CORRECTING MUTATION

In Wednesday's study, published in the journal Nature, the British team took skin cells from a patient with a mutation in a gene called alpha1-antitrypsin, which is responsible for making a protein that protects against inflammation.

People with mutant alpha1-antitrypsin are not able to release the protein properly from the liver, so it becomes trapped there and eventually leads to liver cirrhosis and lung emphysema. This is one of the most common inherited liver and lung disorders and affects about one in 2,000 people of North European origin, the researchers said.

Having harvested the skin cells, the scientists reprogrammed them back into stem cells and then used a type of "molecular scissor" technique known as a zinc finger nuclease to snip the cells' genome at precisely the right place and insert a correct version of the gene using a DNA transporter called piggyBac.

The leftover piggyBac sequences were then removed from the cells, cleaning them up and allowing them to be converted into liver cells without any trace of residual DNA damage at the site of the genetic correction.

"We then turned those cells into human liver cells and put them in a mouse and showed that they were viable," David Lomas, a Cambridge professor of respiratory biology who also worked on the team, told reporters at the briefing.

Ludovic Vallier, also from Cambridge University, said the results were a first step toward personalized cell therapy for genetic liver disorders. "We still have major challenges to overcome...but we now have the tools necessary," he said.

The researchers said it could be another five to 10 years before full clinical trials of the technique could be run using patients with liver disease. But if they succeed, liver transplants -- costly and complicated procedures where patients need a lifetime of drugs to ensure the new organ is not rejected -- could become a thing of the past.

"If we can use a patient's own skins cells to produce liver cells that we can put back into the patient, we may prevent the future need for transplantation," said Lomas.

(Additional reporting by Simon Roach; Editing by Tim Pearce)

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Human 'cloning' makes stem cells

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5 October 2011 Last updated at 18:04 GMT By James Gallagher Health reporter, BBC News Lead scientist Dr Dieter Egli: "Research gives hope for making cells to cure human disease in the future"

A form of cloning has been used to create personalised embryonic stem cells in humans, say researchers.

Genetic material was taken from an adult skin cell and transferred into a human egg. This was grown to produce an early embryo.

Stem cells have huge potential in medicine as they can transform into any other cell type in the body.

However, the stem cells formed contained chromosomes from both the adult and the egg cells.

The technique used - somatic cell nuclear transfer - shot to fame in 1997 when Dolly the sheep, the first mammal to be cloned from an adult cell, was unveiled to the world.

A South Korean scientist, Hwang Woo-suk, had claimed to have created stem cells from cloned human embryos, but was found to have faked the evidence.

The lead researcher at the New York Stem Cell Foundation Laboratory, Dr Dieter Egli, said there was "a great question mark" about whether the cloning technique could be reliably used in humans.

Dolly the sheep

He said other "groups had tried before, but failed".

Writing in the journal Nature, he said his group had also failed using traditional techniques.

When they removed the genetic material from the egg and replaced it with the chromosomes from a skin cell, the egg divided but failed to go past the 6-12 cell stage.

However, when they left the egg's own genetic material in place and added the skin chromosomes, the egg developed. It reached the blastocyst stage, which can contain up to 100 cells and is the usual source of embryonic stem cells.

Eggs and sperm both have one set of chromosomes, which combined means adults have two copies of each chromosome.

In this technique the two adult copies are added to the single copy in the egg meaning a total of three, which can be problematic.

Continue reading the main story

Many diseases are impossible to treat. As the researchers put it they "cannot be cured, they can only be cared for".

Stem cells are one of the great hopes of medicine because they can turn into any other type of cell - nerve, heart, bone, skin, liver etc.

Create heart cells and it might be possible to repair the damage from a heart attack. Insulin-producing cells are destroyed in patients with type 1 diabetes, but stem cells could one day be used to grow more.

There are already clinical trials taking place. The first embryonic stem cell trial in Europe, testing a treatment for progressive sight loss, has started in London.

However this does not use the patient's own cells. Immunosuppressant drugs are likely to be needed to prevent rejection. This is why making stem cells from the body's own cells is seen as such a gold standard of medicine.

Often embryos without the correct number of chromosomes do not develop at all. Down's syndrome is caused by three copies of just one chromosome.

Researchers will need to produce embryonic cells which have only donor DNA, however, once the egg starts to divide the chromosomes are combined in the nucleus and would be near impossible to separate.

Dr Egli told the BBC: "The cells we have made are not yet for therapeutic use. There is clearly more work to be done, this is early days.

"We see this as a step on that road, so now we do know that a human egg can turn an adult specialised cell, such as a skin cell, into a stem cell."

Prof Mary Herbert, from the Institute for Ageing and Health at Newcastle University, said: "This study shows that the conventional approach to somatic cell nuclear transfer is inefficient in humans.

"However, the authors were able to increase the efficiency by leaving the host oocyte [egg] genome in place.

"While this approach does not in itself provide a solution, it takes us a step closer to understanding where the problems lie."

No embryos required

Recently a different route to stem cells has been used. Instead of using an egg, a chemical bath "reprogrammes" an adult cell into a stem cell.

While this is seen as more ethical, there are concerns about whether such cells could be used therapeutically. There are differences between embryonic and "induced" stem cells, with the latter being more prone to expressing cancer causing genes.

Prof Robin Lovell-Badge, from the UK National Institute for Medical Research, said: "This paper will be seen as significant both by those who are trying to use somatic cell nuclear transfer to produce human patient-specific embryonic stem cell lines and by those who oppose human 'cloning' experiments."

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HEALTH MANAGEMENT. Adult stem cells used to grow cervical vertebrae

Neurosurgery researchers at UC Davis Health System have used a new, leading-edge stem cell therapy to promote the growth of bone tissue following the removal of cervical discs -- the cushions between the bones in the neck -- to relieve chronic, debilitating pain.
The procedure was performed by associate professors of neurosurgery Kee Kim and Rudolph Schrot. It used bone marrow-derived adult stem cells to promote the growth of the bone tissue essential for spinal fusion following surgery, as part of a nationwide, multicenter clinical trial of the therapy.
Removal of the cervical disc relieves pain by eliminating friction between the vertebrae and/or nerve compression. Spinal fusion is used following surgery for degenerative disc disease, where the cushioning cartilage has worn away, leaving bone to rub against bone and herniated discs, where the discs pinch or compress nerves.
"We hope that this investigational procedure eventually will help those who undergo spinal fusion in the back as well as in the neck," said Kim, who also is chief of spinal neurosurgery at UC Davis. "And the knowledge gained about stem cells also will be applied in the near future to treat without surgery those suffering from back pain."
Millions of Americans are affected by spine diseases, with approximately 40 percent of all spinal fusion surgery performed for cervical spinal fusion. Some 230,000 patients are candidates for spinal fusion, with the numbers of potential patients increasing by 2 to 3 percent each year as the nation's population ages.
"This is an exciting clinical trial to test the ability of the bone-forming stem cells from healthy donors to help patients with spinal disease," said Jan Nolta, director of the UC Davis Institute for Regenerative Cures.
"For the past 50 years, bone marrow-derived stem cells have been used to rebuild patients' blood-forming systems. We know that subsets of stem cells from the marrow also can robustly build bone. Their use now to promote vertebral fusion is a new and extremely promising area of clinical study," she said.
The stem cell procedure at UC Davis took place early in August. The patient was a 53-year-old male from the Sacramento region with degenerative disc disease.
In the surgery, called an anterior cervical discectomy, a cervical disc or multiple discs are removed via an incision in the front of the neck. The investigational stem cell therapy then is applied to promote fusion of the vertebrae across the space created by the disc removal.
The stem cells are derived from a healthy single adult donor's bone marrow, and thus are very homogenous, Kim said. They are grown in culture to high concentration with minimal chance for rejection by the recipient, he said.
Adequate spinal fusion fails to occur in 8 to 35 percent or more of patients, and persistent pain occurs in up to 60 percent of patients with fusion failure, which often necessitates additional surgery.
"A lack of effective new bone growth after spine fusion surgery can be a significant problem, especially in surgeries involving multiple spinal segments," said Schrot, co-principal investigator for the study. "This new technology may help patients grow new bone, and it avoids harvesting a bone graft from the patient's own hip or using bone from a deceased donor."
Current methods of promoting spinal fusion include implanting bone tissue from the patient's hip or a cadaver to encourage bone regrowth as well as implanting bone growth-inducing proteins. However, the Food and Drug Administration has not approved the use of bone morphogenetic proteins for cervical spinal fusion. Their use has been associated with life-threatening complications, particularly in the neck.
The leading-edge stem cell procedure is part of a prospective, randomized, single-blinded controlled study to evaluate the safety and preliminary efficacy of an investigational therapy: modified bone marrow-derived stem cells combined with the use of a delivery device as an alternative to promote and maintain spinal fusion.
The study includes 10 investigational centers nationwide. The UC Davis Department of Neurological Surgery anticipates enrolling up to 10 study participants who will be treated with the stem cell therapy and followed for 36 months after their surgeries. A total of 24 participants will be enrolled nationwide.
The study is one of several clinical trials under way in the UC Davis Spine Center and led by Kim. He anticipates launching a clinical trial soon to study the safety of injecting stem cells into disc tissue to repair degenerated discs.
The current study is sponsored by Mesoblast, Ltd., of Melbourne, Australia, which is developing adult universal-donor stem cell products built upon the discovery of adult-derived mesenchymal precursor cells. Kim and Schrot will not be compensated for their participation in the study.

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HEALTH MANAGEMENT. Created set of mammalian cells with single chromosome.

Researchers have mammalian cells using a single set of chromosomes for the first time in research, created by the Wellcome Trust and EMBO. The technology should enable that scientists better establish the relationship between genes and their function.
Mammal cells contain usually two sets of chromosomes - the mother, an inherited from the father set. The genetic information in this chromosome sets, that helps to determine how our bodies to develop. Changes in the genetic code can cause that or increase the risk of diseases.
To understand how our genes function, scientists manipulate the genes in animal models - how fly, zebrafish and mice - and watch the impact of these changes. As each cell contains two copies of each chromosome, the connection between genetic changes and their physical effects or 'Phenotype' - determination is immense but complex.
Now, in research worship and Martin Leeb of the Wellcome Trust Centre published in the journal nature, DRS Anton for stem cell research at the University of Cambridge report a technique, the stem cells, which can create only a single set of chromosomes from a mouse unfertilized egg. The stem cells can be used to identify mutations in genes, that of cells affect behaviour in culture. In a further step, the cells can be implanted into the mouse for the analysis of a change in organs and tissues may.
The technique was used previously in zebrafish, but this is the first time that it was successfully used to generate such mammalian stem cells.
Dr. pig, Wellcome Trust senior research fellow, explains: "these embryonic stem cells are much simpler than normal mammalian embryonic stem cells." All genetic changes that we introduce to the single set of chromosomes is simply to determine impact. "This will be useful to the explore systematically signalling mechanisms within the cell and as networks of genes regulate development."
The researchers hope that this technique advance mammal genetics and our understanding of gene function relationship in the same way that a similar technique geneticists understand simple zebrafish animal model has helped.
Understand how our genetic makeup functions and how this knowledge can be applied to improve our health by the Wellcome Trust is one of the most important strategic challenges. This new study, Dr. Michael Dunn, Director of the molecular and physiological of Sciences, the Wellcome Trust, says:
"This technology will help scientists some significant obstacles to overcome, so far the functions of genes, to study so hard." "This is often the first step to understand why mutations lead to disease and ultimately to new treatments."

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HEALTH MANAGEMENT. New substances speed up drug transport in cells

Biologists at the Technical University of Darmstadt have discovered that the drastic reduction could allow means to accelerate the transport of the active substances of drugs in living cells, dosages of medications in the future.
Drugs do not have their impact, until they have taken up by the associated cells of the institution concerned and for metabolism it there. While many there, is all types of cells, each cell surrounded by a membrane independently of its kind, that is only permeable of certain substances or particles. Biomedical researchers have selectively sought therefore new opportunities for the introduction of drugs in cells. Prof. Cristina Cardoso and Dr. Henry D. Hercé, by the Technical University of Darmstadt biology Dept. have before recent considerable progress in this direction, that they have found means for significantly the transport of a substance, in particular water soluble substances, accelerated studied through the cell membrane.
Darmstadt biologists work with short protein chains, to drill the their way through the cell membranes for this over several years. Such tiny proteins called "cell penetrating peptides" (CPPs), serve as a type of vehicle for active ingredients of drugs that are simply staple himself on the CPPs and be considered along with the latter in cells.
Cyclic proteins transport drugs faster
In an article, only in the International Journal communication (10.1038/ncomms1459) is published in nature, Darmstadt, biologists have shown that cyclic proteins particularly well are much greater than the linear chain of CPPs vehicles, since both are their transportation costs and speeds to transport. In practice, what means is that in the future doses of the drug and the delays start to drugs that could be drastically reduced to show their effects.
For example, the small protein TAT a flexible linear chain, whose "Rückgrat" has different, attached side branches. The backbone has a fairly large number of degrees of freedom, that is to say, is very flexible, because its lateral branches are. Darmstadt group studies conducted have shown that transport strongly transport through cell membranes by a less flexible, cyclic structure of the vehicle, since it seems improved, that be the deciding factor, that Guanidinium group in offices on the side should on the widest possible basis, that is more likely distances, in which a cyclic structure, where the vehicle backbone is a closed loop and extend Guanidinium group so radially outward from the loop. For example, cyclic TAT drive cell membranes fifteen minutes earlier than the usual, linear chain of TAT, where closure of the chain improves transport efficiency in the TAT and other arginine-rich CPPs.
Plan in future biologists at the TU Darmstadt, the transport of certain, water-soluble, to study active ingredients. To resolve are, how cells cope with cyclical, nano scale transporter, namely, whether the latter by cast out cells, broken down by them, or simply unchanged through them and, finally, whether their trials held carried to cells in artificial conditions, be confirmed by in-vivo studies.

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