Father's Age Influences Rate of Evolution

Chimpanzee.

Father's Age Influences Rate of Evolution

Friday, 13 June 2014

The offspring of chimpanzees inherit 90% of new mutations from their father, and just 10% from their mother, a finding which demonstrates how mutation differs between humans and our closest living relatives, and emphasises the importance of father's age on evolution.

Published today in Science, researchers from the Wellcome Trust Centre for Human Genetics and the Biomedical Primate research Centre in the Netherlands looked at whether, in chimpanzees, there was a heightened risk of fathers passing on mutations to their children compared to humans.

In humans, each individual inherits, on average, about 70 new mutations from their parents. However, this number is influenced by paternal age such that older fathers tend to result in more mutations – in humans each extra year of age results in two extra mutations.

Mutation risk is linked to father's age because the sperm lineage in males keeps dividing, while females have all the eggs they are ever going to produce present at birth. Paternal age is an established risk factor in a number of disorders including schizophrenia and autism.

The study found that the number of new mutations inherited by chimpanzees from their parents is, on average, very similar to that in humans, but that the effect of the father's age is much stronger – each additional year of father's age results in three extra mutations.

The results suggest that sexual selection can influence the rate of evolution through its effect on the male mutation rate.

Professor Gil McVean, from the Wellcome Trust Centre for Human Genetics at the University of Oxford said:

"In humans, a father's age is known to affect how many new mutations he passes on to his children, and is also an established risk factor in a number of mental health disorders.”

"This study finds that in chimpanzees the father's age has a much stronger effect on mutation rate – about one and a half times that in humans. As a consequence, a greater fraction of new mutations enter the population through males, around 90 per cent, compared to humans, where fathers account for 75 per cent of new mutations."

In the study, Wellcome Trust-funded researchers sequenced the genomes of nine western chimpanzees from a three generation family living at the biomedical primate research centre in the Netherlands.

To establish the number of new mutations a child inherits researchers sequence children and their parents and compare the genetic sequence – any change in the sequence that doesn't exist in either parent genome is a new mutation. To find out which parent the mutation comes from you need to sequence members of the next generation of the family.

One explanation for this difference is that chimpanzees, as a result of their mating system, have evolved to produce many more sperm than humans – their testes are over three times the relative size of a human. This means there are likely to be more cycles of sperm production, increasing the opportunity for new mutations to emerge.

The authors suggest that more work needs to be done across other species to investigate the impact of mating behaviour on mutation rates and male mutation bias.

Source: Wellcome Trust 

Contact: Clare Ryan

Reference:

Strong male bias drives germ line mutation in chimpanzees

Oliver Venn, Isaac Turner, Iain Mathieson, Natasja de Groot, Ronald Bontrop, Gil McVean

Science 13 June 2014, Vol. 344 no. 6189 pp. 1272-1275, DOI: 10.1126/science.344.6189.1272

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How Stem Cells Produce Different Kinds of Cells

How Stem Cells Produce Different Kinds of Cells

Sunday, 05 May 2013

The human body contains trillions of cells, all derived from a single cell, or zygote, made by the fusion of an egg and a sperm. That single cell contains all the genetic information needed to develop into a human, and passes identical copies of that information to each new cell as it divides into the many diverse types of cells that make up a complex organism like a human being.

If each cell is genetically identical, however, how does it grow to be a skin, blood, nerve, bone or other type of cell? How do stem cells read the same genetic code but divide into very different types?

The apical tip of fruit fly testis containing germ line 

stem cells and differentiating germ cells. Copies of 

Y chromosome are marked with either red or blue. 

Using this method, the authors discovered that 

germ line stem cells inherit specific copies of Y (and 

X) chromosomes. Credit: Yukiko Yamashita. 

Researchers at the University of Michigan have found the first direct evidence that cells can distinguish between seemingly identical copies of chromosomes during stem cell division, pointing to the possibility that distinct information on the chromosome copies might underlie the diversification of cell types.

Scientists in the lab of Life Sciences Institute researcher Yukiko Yamashita explained how stem cells can distinguish between two identical copies of chromosomes and distribute them to the daughter cells in a process called non-random chromosome segregation. They also described the genes responsible. Their work is scheduled to be published online May 5 in Nature.

"If we can figure out how and why cells are dividing this way, we might be able to get a glimpse of how we develop into a complete human, starting from a single cell," Yamashita said.

"It is very basic science, but understanding fundamental biological processes always has wide-ranging implications that could be exploited in therapeutics and drug discovery."

During the cell division cycle, the mother cell duplicates its chromosomes, generating two identical sets. When the cell divides to become two cells, each cell inherits one set of chromosome copies. In many divisions, the daughter cells are identical to the mother — one skin cell becomes two, for instance.

But in a process called asymmetric division, a cell divides into two daughters that are not identical — a skin stem cell divides into another skin stem cell and a regular skin cell, for example. In that case, the genetic information within the chromosome copies remains the same, but the type of cell, or "cell fate," is different.

The Yamashita lab used stem cells from the testes of the fruit fly Drosophila to study the process of cell division.

"The Drosophila germ line stem cell can be identified at a single-cell resolution, so they are an ideal model," Yamashita said.

The stem cells cluster and are easy to identify; they divide to produce another germ line stem cell and a differentiating cell called a gonialblast, which goes on to eventually become a sperm cell.

The researchers marked the copies of each chromosome in the Drosophila stem cells as they divided. Using this method, they tracked the tendency of the X and the Y chromosome copies to move to the daughter germ line stem cell or to the gonialblast. They were able to demonstrate that copies of X and Y chromosomes (but not other chromosomes) are distinguished and delivered to the daughter cells with a striking bias.

This is the first direct evidence that cells indeed have an ability to distinguish identical copies of chromosomes and separate them in a regulated manner. This ability has been suspected and hypothesized, but never proven.

"We do not know yet why copies of X and Y chromosomes segregate non-randomly," Yamashita said.

"We think maybe specific epigenetic information is transmitted to the germ line stem cell and to the gonialblast."

The findings suggest that the information on the X and Y chromosomes that makes this division possible is primed during gametogenesis — the process of creating ovum or sperm cells — in the parents.

Many other cells throughout the body are able to divide into two different types, especially during embryonic development. Yamashita's next steps are to explore whether the non-random chromosome segregation seen in Drosophila is a widespread phenomenon that is shared by mammals, including humans.

Source: University of Michigan 

Contact: Laura J. Williams

Reference:

Chromosome-specific nonrandom sister chromatid segregation during stem-cell division

Swathi Yadlapalli &  Yukiko M. Yamashita

Nature (2013), doi:10.1038/nature12106

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The Viruses Within and What Keeps Them There

Biologists wake dormant viruses and uncover mechanism for survival Wednesday, 13 January 2010 It is known that viral "squatters" comprise nearly half of our genetic code. These genomic invaders inserted their DNA into our own millions of years ago when they infected our ancestors. But just how we keep them quiet and prevent them from attack was more of a mystery until EPFL researchers revived them. The reason we survive the presence of these endogenous retroviruses — viruses that attack and are passed on through germ cells, the cells that give rise to eggs and sperm — is because something keeps the killers silent. Now, publishing in the journal Nature, Didier Trono and his team from EPFL, in Switzerland, describe the mechanism. Their results provide insights into evolution and suggest potential new therapies in fighting another retrovirus — HIV. By analysing embryonic stem cells in mice within the first few days of life, Trono and team discovered that mouse DNA codes for an army of auxiliary proteins that recognize the numerous viral sequences littering the genome. The researchers also demonstrated that a master regulatory protein called KAP1 appears to orchestrate these inhibitory proteins in silencing would-be viruses. When KAP1 is removed, for example, the viral DNA "wakes up," multiplies, induces innumerable mutations, and the embryo soon dies. Because retroviruses tend to mutate their host's DNA, they have an immense power and potential to alter genes. And during ancient pandemics, some individuals managed to silence the retrovirus involved and therefore survived to pass on the ability. Trono explains that the great waves of endogenous retrovirus appearance coincide with times when evolution seemed to leap ahead. "In our genome we find traces of the last two major waves. The first took place 100 million years ago, at the time when mammals started to develop, and the second about fifty million years ago, just before the first anthropoid primates," he says. The discovery of the KAP1 mechanism could be of interest in the search for new therapeutic approaches to combat AIDS. The virus that causes AIDS can lie dormant in the red blood cells it infects, keeping it hidden from potential treatments. Waking the virus up could expose it to attack. To view a YouTube video related to this release, please visit The Viruses Within - Interview with Didier Trono, EPFL. Reference: KAP1 controls endogenous retroviruses in embryonic stem cells Helen M. Rowe, Johan Jakobsson, Daniel Mesnard, Jacques Rougemont, Séverine Reynard, Tugce Aktas, Pierre V. Maillard, Hillary Layard-Liesching, Sonia Verp, Julien Marquis, François Spitz, Daniel B. Constam & Didier Trono Nature 463, 237-240 (14 January 2010), doi:10.1038/nature08674 ......... ZenMaster

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Sea Lamprey Discard One-fifth of Their Genome

Growing lamprey embryo’s discard millions of units of their DNA Tuesday, 21 July 2009 Researchers have discovered that the sea lamprey, which emerged from jawless fish first appearing 500 million years ago, dramatically remodels its genome. Shortly after a fertilized lamprey egg divides into several cells, the growing embryo discards millions of units of its DNA. The findings were published this month in the Proceedings of the National Academy of Sciences. The lead author is Jeramiah Smith, a postdoctoral fellow in genome sciences at the University of Washington (UW) working in the Benaroya Research Institute laboratory of Chris Amemiya, who is also a UW affiliate professor of biology. Theirs is believed to be the first recorded observation of a vertebrate – an animal with a spinal column – extensively reorganizing its genome as a normal part of development. A few invertebrate species, like some roundworms, have been shown to undergo extensive genome remodelling. However, stability was thought to be vital in vertebrates' genomes to assure their highly precise, normal functioning. Only slight modifications to allow for immune response were believed to occur in the vertebrate genome, not broad-scale rearrangements. Smith, Amemiya and their research team inadvertently discovered the dynamic transformations in the sea lamprey genome while studying the genetic origins of its immune system. The researchers were trying to deduce how the sea lamprey employs a copy-and-paste mechanism to generate diverse receptors for detecting a variety of pathogens. The researchers were surprised to notice a difference between the genome structure in the germline – the cells that become eggs and the sperm that fertilize them – and the genome structure in the resulting embryonic cells. The DNA in the early embryonic cells had myriad breaks that resembled those in dying cells, but the cells were not dying. The embryonic cells had considerably fewer repeat DNA sequences than did the sperm cells and their precursors. "The remodelling begins at the point when the embryo turns on its own genes and no longer relies on its mom's store of mRNA," said Smith. The restructuring does not occur all at once, but continues for a long while during embryonic development. It took at lot of work for the scientists to see what was lost and when. They learned, among other findings, that the remodelled genome had fewer repeats and specific gene-encoding sequences. Deletions along the strands of DNA are also thought to move certain regulatory switches in the genome closer to previously distant segments. The scientists do not know how this happens, or why. Smith said that his favourite hypothesis, yet unproven, is that the extra genetic material might play a role in the proliferation of precursor cells for sperm and eggs, and in early embryonic development. The genetic material might then be discarded either when it is no longer needed or to prevent abnormal growth. The alteration of the sea lamprey genome and of invertebrates that restructure their genome appears to be tightly regulated, according to Smith, yet the resulting structural changes seem almost like the DNA errors that give rise to cancers or other genomic disorders in higher animals. Learning how sea lamprey DNA rearrangements are regulated during development might provide information on what stabilizes or changes the genome, he said, as well the role of restructuring in helping form different types of body cells, like fin, muscle, or liver cells. If 20 percent of their genome disappears, how do sea lampreys pass along the full complement of their genes to their offspring? "The germline – those precursor cells for sperm and eggs – is a continuous lineage through time," Smith explained. "The precursor cells for sperm and egg are set apart early in lamprey development. The genome in that cell population should never change." Genetic material is assumed to be lost only in the early embryonic cells destined to become body parts and not in cells that give rise to the next generation. The researchers have been looking for the primordial stem cells for sperm and eggs hidden away in the lamprey, but they are difficult to find. Researchers do not yet know how the sea lamprey's genome guides the morphing it undergoes during its life. Sea lampreys have a long juvenile life as larvae in fresh water, where they eat on their own. Their short adult lives are normally spent in the sea as blood-sucking parasites. Their round, jawless mouths stick like suction cups to other fish. Several circular rows of teeth rasp through the skin of their unlucky hosts. Their appetite is voracious. Later, as they return to streams and rivers along the northern Atlantic seaboard, sea lampreys atrophy until they are little more than vehicles for reproduction. After mating, they perish. Populations of sea lamprey were landlocked in the Great Lakes and other nearby large lakes after canals and dams were built in the early 1900's. They thrive by parasitizing (and killing) commercially important fish species and are considered a nuisance in the Great Lakes region. Biologists are interested in the sea lamprey partly because of its alternating lifestyles, but largely because it represents a living fossil from around the time vertebrates originated. Close relatives of sea lampreys were on earth before the dinosaurs. It's possible that the sea lamprey's dynamic genome biology might someday be traced back in evolutionary history to a point near, and perhaps including, a common ancestor of all vertebrates living today, the authors of the study noted. "Sea lampreys have a half billion years of evolutionary history," Smith said. "Evolutionary biologists and geneticists can compare their genomes to other vertebrates and humans to see what parts of the lamprey genome might have been present in our primitive ancestors. We might begin to understand how changes in the sea lamprey genome led to their distinct body structure and how fishes evolved from jawless to jawed." Amemiya added: "We don't really know where this discovery about the sea lamprey's remodelling of its genome will take us. It is common in science for the implications of a finding not to be realized for several decades. It's less about connecting the dots to a specific application, and more about obtaining a broad understanding of how living things are put together." ......... ZenMaster

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Reprogramming Adult Testis Cells to Pluripotency

Playing it safe without the use of genes, viruses or reprogramming proteins Wednesday, 08 July 2009 Kinarm Ko and Hans Schöler's team at the Max Planck Institute for Molecular Biomedicine in Münster have succeeded for the first time in culturing a clearly defined cell type from the testis of adult mice and converting these cells into pluripotent stem cells without introduced genes, viruses or reprogramming proteins. These stem cells have the capacity to generate all types of body tissue. The culture conditions alone were the crucial factor behind the success of the reprogramming process. (Cell Stem Cell, July 2, 2009) The testis is a sensitive organ and an astonishing one at that. Even at the age of 70, 80 or 85, men have cells that constantly produce new sperm. Therefore, they can conceive embryos and become fathers at almost any age - assuming they can find a sufficiently young female partner. Based on this, researchers have long assumed that cells from the testis have a similar potential as in embryonic stem cells: that is, a pluripotency that enables them to form over 200 of the body's cell types. In fact, a number of researchers have recently stumbled on the multiple talents in the male gonads of humans and mice. It all began with the work of Takashi Shinohara's team in 2004. The Japanese scientists discovered that, like embryonic stem cells, certain cells in the testis of newborn mice are able to develop into different kinds of tissue. In 2006, scientists working with Gerd Hasenfuß and Wolfgang Engel in Gottingen reported that such adaptable cells can also be found in adult male mice. Additionally, Thomas Skutella and his colleagues at the University of Tübingen recently made headlines when they cultured comparable cells from human testis tissue. A bewildering variety of cells "At first glance, it would appear that it has long been established that pluripotent cells exist in the testis of adult humans and mice," says Schöler. "However, it is often unclear as to exactly which cells are being referred to in the literature and what these cells can actually do." (See Background article) This is not only due to the fact that the testis contains a multitude of different cells. Scientists who dismantle tissue in the laboratory must carefully separate and analyse the cells to establish which cell type they have under the microscope. The question of potency is a controversial one among stem cell researchers, as binding benchmarks have yet to be defined. What some scientists would define as "pluripotent" is just about deemed "multi-potent", that is, as having a limited capacity for differentiation, by others. Greater certainty can be provided by carrying out the relevant tests. These include, among other things, a test to establish whether, after injection into early embryos, the cells are able to contribute to the development of the new organism and gamete formation, and to pass on their genes to further generations. However, not every team carries out all of these tests and important questions are left unanswered, even in articles published in renowned journals. Stable original cell line With their work, Ko and his colleagues wanted to establish clarity from the outset. To this end, they started by culturing a precisely defined type of cell, so-called germline stem cells (GSCs), from the testis of adult mice. In their natural environment, these cells can only do one thing: constantly generate new sperm. Moreover, their own reproduction is an extremely rare occurrence. Only two or three of them will be found among the 10,000 cells in the testis tissue of a mouse. However, they can be isolated individually and reproduced as cell lines with stable characteristics. Under the usual cell culturing conditions, they retain their unipotency for weeks and years. Consequently, all they can do is reproduce or form sperm. What nobody had guessed until now, however, was that a simple trick is enough to incite these cells to reprogram. If the cells are distributed on new Petri dishes, some of them revert to an embryonic state once they are given sufficient space and time. "Each time we filled around 8000 cells into the individual wells of the cell culture plates, some of the cells reprogrammed themselves after two weeks," reports Ko. And when the switch in these germline-derived pluripotent stem cells (gPS) has been reversed, they start to reproduce rapidly. The researchers have proven that the "reignition" of the cells has actually taken place with the aid of numerous tests. Not only can the reprogrammed cells be used to generate heart, nerve or endothelial cells, as is the case with embryonic stem cells, the scientists can also use them to produce mice with mixed genotypes, known as chimeras, from the new gPs, and thus demonstrate that cells obtained from the testis can pass their genes on to the next generation. Whether this process can also be applied to humans remains an open question. There is much to suggest, however, that gPS cells exceed all previously artificially reprogrammed cells in terms of the simplicity of their production and their safety. Reference: Induction of pluripotency in adult unipotent germline stem cells Kinarm Ko, Natalia Tapia, Guangming Wu, Jeong Beom Kim, Marcos J Araúzo-Bravo, Philipp Sasse, Tamara Glaser, David Ruau, Dong Wook Han, Boris Greber, Kirsten Hausdörfer, Vittorio Sebastiano, Martin Stehling, Bernd K. Fleischmann, Oliver Brüstle, Martin Zenke and Hans R. Schöler Cell Stem Cell, July 2, 2009, doi:10.1016/j.stem.2009.05.025 Background article: The germ of pluripotency Mito Kanatsu-Shinohara und Takashi Shinohara Nature Biotechnology 24(6), June 2006, doi: 10.1038/nbt0606-663 ......... ZenMaster

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Testes Stem Cell Can Change Into Other Body Tissues

Testes Stem Cell Can Change Into Other Body Tissues Monday, 05 January 2009 Scientists at the Stanford University School of Medicine and at UC-San Francisco have succeeded in isolating stem cells from human testes. The cells bear a striking resemblance to embryonic stem cells — they can differentiate into each of the three main types of tissues of the body — but the researchers caution against viewing them as one and the same. According to the study, the testes stem cells have different patterns of gene expression and regulation and they do not proliferate and differentiate as aggressively as human embryonic stem cells. The findings, published in the January issue of the journal Stem Cells, are in contrast to those reported in a recent Nature paper, which concluded that the cells were, in fact, as pluripotent as embryonic stem cells. Pluripotent cells can become any cell in the body and form tumours called teratomas when transplanted into mice. "It's time to reinterpret the data," said Renee Reijo-Pera, PhD, professor of obstetrics & gynaecology at Stanford, "and to accept that we're beginning to discover many different types of stem cells. Although they are all related to each other, they also all have unique therapeutic applications in which they surpass other family members." Reijo-Pera, who is the director of Stanford's Center for Human Embryonic Stem Cell Research and Education, collaborated with male infertility specialist Paul Turek, MD, a professor of urology at UCSF and the director of The Turek Clinic in San Francisco, to conduct the research. Reijo-Pera and Turek are co-senior authors of the study. The stem cells from the testes seem to hover in a gray area between true pluripotency and the more limited, tissue-specific multipotency exhibited by many types of adult stem cells. They termed the cells "multipotent germline stem cells." Germ cells are those cells in the body that differentiate to make sperm and eggs. Playing to these cells' strengths — in this case, their likely ability to differentiate into cells involved in male reproduction — may be a wiser choice than trying to pigeonhole them as embryonic-stem-cell-wannabes, said Reijo-Pera. "These cells could potentially treat infertility or other diseases in men," Turek said. But the lure of pluripotency is strong. An easily accessible source of unmodified, pluripotent human cells would allow physicians and researchers to create cell lines and tissues identical to others in the donor's body. Theoretically, such cells could be used as a perfectly matched therapy for that particular donor — perhaps to generate new cartilage to repair a knee injury or new neurons to treat nerve damage. Alternatively, the technique could be used to derive cell lines carrying specific disease-causing mutations — from a man with Parkinson's, for example — on which to conduct research. Coaxing specialized, or differentiated, adult cells to regress back into a more malleable, embryonic-stem-cell-like state (a process called "induced pluripotency") would also allow scientists to realize the therapeutic benefits of embryonic cells without the thorny ethical problems that plague cells derived from embryos. Until recently, however, the reprogramming of differentiated cells required the use of viruses to introduce specific genes into the cells, which may limit their therapeutic usefulness. The researchers used cells obtained via biopsies conducted to diagnose male infertility in 19 of the clinic's patients. Each patient's cells were cultured in a manner similar to human embryonic stem cells; two of the 19 samples yielded cell lines with many characteristics of the pluripotent cells. One of the two patients from whom the cell lines were derived withdrew from the study and his samples were discarded. Further study on the remaining cell line indicated that it expressed many, but not all, genes associated with pluripotency. The cells could also be induced to differentiate into decidedly non-testicular neural cell precursors and they expressed the telomerase enzyme essential to keep pluripotent cells young and unspecialized. However, when the researchers examined the cells' patterns of methylation — a modification to DNA that affects gene expression — they found that the newly derived cell line was less-thoroughly methylated as compared to human embryonic stem cells in one region and more heavily methylated than human embryonic stem cells in another region. Finally, when the researchers injected the human stem cells into mice with compromised immune systems, they showed only a limited ability to form a teratoma — a kind of tumour formed of many cell types. Teratoma formation resulting from the aggressive proliferation and differentiation of transplanted stem cells is a hallmark of true pluripotency. Together, the results suggest that the stem cells isolated from male testes have some, but not all the characteristics of true pluripotent cells. "It's not yet possible to completely re-create human embryonic stem cells from germline cells," said Reijo-Pera, "These cells differ in gene expression, methylation and in their ability to form teratomas. But it's the fact that they are different that makes them so interesting. Suggesting otherwise would do a disservice to the research community by overlooking the fact that these cells are a unique cell type that could be really useful in the study of human germ cell formation." Reference: Isolation and Characterization of Pluripotent Human Spermatogonial Stem Cell-Derived Cells Nina Kossack, Juanito Meneses, Shai Shefi, Ha Nam Nguyen, Shawn Chavez, Cory Nicholas, Joerg Gromoll, Paul J Turek, Renee A Reijo-Pera Stem Cells, 2008; doi:10.1634/stemcells.2008-0439 ......... ZenMaster

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Genetically Modified Human Embryo Stirs Controversy

Scientists create first GM human embryo 
Tuesday, 13 May 2008 

Researchers at Cornell University in New York have made a breakthrough in genetics by creating the first genetically modified (GM) human embryo. The GM embryo was produced to study how early cells in the embryo develop, but the scientists destroyed it just after five days. Led by Nikica Zaninovic, researchers at Cornell University used a virus to add a gene, a green fluorescent protein, to an embryo left over from assisted reproduction. It is believed to be the first documented genetic modification of a human embryo. 

Zaninovic's achievement was announced at the American Society for Reproductive Medicine annual meeting in 2007, but was only publicized recently when the United Kingdom's reproductive technology regulators reviewed the research. One of the authors of the study said to AP that the work was focused on stem cells. He noted that the researchers used an abnormal embryo that could never have developed into a baby anyway. 

"None of us wants to make designer babies," said Dr. Zev Rosenwaks, director of the Center for Reproductive Medicine and Infertility at New York-Presbyterian/Weill Cornell Medical Center. Dr. Rosenwaks said the research had been approved by a review board at his medical center and been privately financed, so it did not violate federal restrictions on research involving human embryos. 

 Doctors already put foreign genes into people as part of gene therapy to treat diseases. But those genetic changes generally cannot be passed on to future generations because they are made to only certain types of cells in the body, like blood cells or muscle cells. Genetic changes made to an embryo would theoretically be heritable if the embryo became a baby. So far, this has been a no-go area for scientists and medical professionals. 

 The breakthrough has brought with it major concerns. The British regulator, the Human Fertilisation and Embryology Authority (HFEA), has even cautioned that such controversial experiments may lead to "large ethical and public interest issues". However, the HFEA has said that it is preparing for scientists to apply for licences to create GM embryos. 

A paper, published by the authority, states: “The bill has taken away all inhibitions on genetically altering human embryos for research. The Science and Clinical Advances Group [of the HFEA] thought there were large ethical and public interest issues and that these should be referred for debate.” 

 The House of Commons in Britain is about to consider legislation permitting this and other controversial reproductive technologies, such as the creation of chimeras – human-animal hybrid embryos. The first voting on this Bill took place yesterday in the British Parliament. There the MPs voted to allow, with a great majority, the plan to update the human embryology laws to continue to their next Parliamentary stage. The research raises a number of difficult ethical questions. 

Though adding a fluorescent protein was merely a proof-of-principle step, modified embryos could be used to research human diseases. Scientists say embryos wouldn't be allowed to develop for more than a few weeks, much less implanted in a woman and brought to term. If the embryos were allowed to develop, genetic modifications – which would be permanent and passed to future generations – might prevent disease. 

Modifications might also be used for other reasons – physical appearance, intellectual prowess and personality changes – though the necessary science remains hypothetical at this point. Developing such techniques would necessarily involve at this stage trial-and-error and risk-taking with human life.

Let's have that debate:
What do you think CellNEWS readers? 

• Should genetically modified human embryos be used in research, or reproduction? Both? Neither? 
• What would be the advantages or disadvantages? 
• Would it OK to produce ‘designer babies’ in the future, when the technique is perfected? 

Reference: 

Genetic Modification Of Preimplantation Embryos and Embryonic Stem Cells (ESC) by Recombinant Lentiviral Vectors: Efficient and Stable Method for Creating Transgenic Embryos and ESC 

N. Zaninovic, J. Hao, J. Pareja, D. James, S. Rafii, Z. Rosenwaks. 

ASRM 2007 Annual Meeting, Poster session. 

Other Online Resources: 

HFEA 

Center for Genetics and Society 

Human Genetics Alert 

Genetics and Public Policy Center 

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ZenMaster

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at http://cellnews-blog.blogspot.com/

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Ethics of Lab Made Gametes

The Hinxton Group on Science, Ethics and Policy Challenges of Pluripotent Stem Cell-Derived Gametes Tuesday, 15 April 2008 The Hinxton Consortium, which was formed in 2004 to investigate the ethics and legality of stem cells, yesterday issued its recommendations for how research aimed at creating artificial gametes – sperm and eggs – should proceed. They warn politicians not to block scientific inquiry into subjects such as stem cells and embryo research just because there is a difference of opinion on the ethics or morality of the work. They also said that moral disagreements in society should never be used on their own to stop scientific investigation. "Societies have the authority to regulate science, and scientists have a responsibility to obey the law. However, policy-makers should refrain from interfering with scientific inquiry unless there is a substantial justification for doing so that reaches beyond disagreements based solely on divergent moral conviction. Any interference with scientific inquiry should be derived from reasonable concerns about demonstrable risks of harm to persons, societal institutions, or society as a whole," the consortium said. Scientists are working on a number of ways of making stem cells derived from embryos, or ordinary tissue such as skin, and turning them in the laboratory into mature sperm and eggs that could then be used in IVF clinics for fertility treatment. In Britain, the Human Tissues and Embryo Bill, that is currently making its way through Parliament, would allow research into human artificial gametes but further changes to the law would be needed to allow doctors to use such sperm and eggs on patients. Professor John Harris, a bioethicist at Manchester University who is part of the consortium, said that while the development of artificial sperm or eggs to treat infertile couples was still a long way off, it is important the work is not blocked from the start. "At this stage the real ethical issue is to ensure that the science can continue... Is society ready for it? We don't know that, and of course if it isn't, then it won't happen, but there is probably some considerable time in which this could be discussed," Professor Harris said. "Any tool can have applications that people can object to, from kitchen knives to anything else." The research has also prompted speculation that sperm could be produced from a woman or eggs from a man, allowing lesbian or gay couples to have children to whom both partners make an equal genetic contribution. One possible way of making sperm and eggs would be to engineer them from skin cells. Researchers, however, dismissed the prospect of male eggs and female sperm as science fiction in the new Hinxton group report. Professor Robin Lovell-Badge, of the National Institute for Medical Research in London, and a member of the group’s steering committee, said there may be insuperable barriers to the possibility of one sex making both types of gametes. “It would be very difficult to get eggs from XY cells, and even more difficult to get sperm from XX cells – my own view, indeed, is that the latter is impossible.” Human sex is determined by the inheritance patterns of the X and Y chromosomes: women have two copies of the X, while men have one X and one Y. As several genes that are critical to sperm production are carried on the Y chromosome, this will make it “difficult or even impossible” to turn female cells with two X chromosomes into sperm under any circumstances currently known to science. The production of eggs from male cells is a little less problematic, but even this is likely to be “very difficult”, the report said. Reference: Consensus Statement: Science, Ethics and Policy Challenges of Pluripotent Stem Cell-Derived Gametes The Hinxton Group ......... ZenMaster

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ACT Make hESC Lines Without Destroying Embryos

ACT Make hESC Lines Without Destroying Embryos 
Thursday, 10 January 2008

Advanced Cell Technology, Inc. together with colleagues announced today the development of five human embryonic stem cell (hESC) lines without the destruction of embryos. These new results have the potential to end the ethical debate surrounding the use of embryos to derive stem cells. In fact, the NIH report to the President refers to this technology as one of the viable alternatives to the destruction of embryos. The new method will be published today in the journal Cell Stem Cells, published by Cell Press. 

The peer-reviewed technique was initially carried out by ACT scientists under the direction of Robert Lanza, M.D., and then independently replicated by scientists on the West Coast. Single cells were removed from the embryos using a technique similar to preimplantation genetic diagnosis (PGD). The biopsied embryos continued to develop normally and were then frozen. The cells that were removed were cultured utilizing a proprietary methodology that recreates the optimal developmental environment, which substantially improved the efficiency of deriving stem cells to rates comparable to using the traditional approach of deriving stem cells from the inner cell mass of a whole blastocyst stage embryo. The stem cells were genetically normal and differentiated into cell types of all three germ layers of the body, including blood cells, neurons, heart cells, cartilage, and other cell types of potentially therapeutic significance. 

“This is a working technology that exists here and now,” said Robert Lanza, M.D., Chief Scientific Officer at Advanced Cell Technology and senior author of the paper. 

“It could be used to increase the number of stem cell lines available to federal researchers immediately. We could send these cells out to researchers tomorrow. If the White House approves this new methodology, researchers could effectively double or triple the number of stem cell lines available within a few months. Too many needless deaths continue to occur while this research is being held up. I hope the President will act now and approve these stem cell lines quickly.” 

 The paper published today also addresses several other important issues. First, the stem cells were derived without culturing multiple cells from each embryo together, and at efficiency levels similar to that reported for conventional stem cell derivation techniques using blastocysts. Second, it addresses ethical objections that the derivation system required co-culture with hESCs from other embryos that were destroyed. The current study demonstrates that hESC co-culture is not an essential part of the derivation procedure. The stem cell lines generated in the present study appear to have the same characteristics as other hESC lines, including expression of the same markers of pluripotency, self-renewing capacity, genetic stability, and ability to differentiate into derivatives of all three germ layers of the body. 

“We are excited that our new method for generating human embryonic stem cell lines without the destruction of embryos has been accepted for inclusion by such a prestigious publication,” said William M. Caldwell IV, Chairman and CEO of Advanced Cell Technology. 

“This new approach addresses the President Bush’s ethical concerns. We are hopeful that the NIH will consider this new approach for federal funding. We believe that such consideration reflects the desire of the American people to bring therapies derived from stem cell research to patients with few or no alternatives.” 

Reference: 
Human Embryonic Stem Cell Lines Generated without Embryo Destruction 
Other contributors to the study and publication include Young Chung and Irina Klimanskaya, Sandy Becker, Tong Li, Marc Maserati, and Shi-Jiang Lu of Advanced Cell Technology; Tamara Zdravkovic, Olga Genbacev, and Susan Fisher of the University of California, San Francisco; and Dusko Ilic and Ana Krtolica of StemLifeLine. 
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ZenMaster

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Yamanaka Turns Human Fibroblasts to ESC-like Cells

Simple recipe turns human skin cells into embryonic stem cell-like cells Tuesday, 20 November 2007 A simple recipe — including just four ingredients — can transform adult human skin cells into cells that resemble embryonic stem cells, researchers report in an immediate early publication of the journal Cell, a publication of Cell Press. The converted cells have many of the physical, growth and genetic features typically found in embryonic stem cells and can differentiate to produce other tissue types, including neurons and heart tissue, according to the researchers. They added, however, that a comprehensive screen of the activity of more than 30,000 genes showed that the so — called “induced pluripotent stem (iPS) cells” are similar, not identical, to embryonic stem cells. "Pluripotent" refers to the ability to differentiate into most other cell types. The chemical cocktail used in the new study is identical to one the team showed could produce iPS cells from adult mouse cells in another Cell report last year. That came as a surprise, said Shinya Yamanaka of Kyoto University in Japan, because human embryonic stem cells differ from those in mice. Those differences had led them to suspect "that some other factors might be required to generate human iPS cells,” he said. The findings are an important step forward in the quest for embryonic stem cell — like cells that might sidestep the ethical stumbling blocks of stem cells obtained from human embryos. He emphasized, however, that it would be “premature to conclude that iPS cells can replace embryonic stem cells.” Embryonic stem cells, derived from the inner cell mass of mammalian blastocysts — balls of cells that develop after fertilization and go on to form a developing embryo — have the ability to grow indefinitely while maintaining pluripotency, the researchers explained. Those properties have led to expectations that human embryonic stem cells might have many scientific and clinical applications, most notably the potential to treat patients with various diseases and injuries, such as juvenile diabetes and spinal cord injury. The use of human embryos, however, faces ethical controversies that hinder the applications of human embryonic stem cells, they continued. In addition, it is difficult to generate patient or disease — specific embryonic stem cells, which are required for their effective application. One way to circumvent these issues is to induce pluripotent status in other cells of the body by direct reprogramming, Yamanaka said. Last year, his team found that four factors, known as Oct3/4, Sox2, c-Myc, and Klf4, could lend differentiated fibroblast cells taken from embryonic or adult mice the pluripotency normally reserved for embryonic stem cells. Fibroblasts make up structural fibers found in connective tissue. Those four factors are “transcription factors,” meaning that they control the activity of other genes. They were also known to play a role in early embryos and embryonic stem cell identity. The researchers have now shown that the same four factors can generate iPS cells from fibroblasts taken from human skin. “From about 50,000 transfected human cells, we obtained approximately 10 iPS cell clones,” Yamanaka said. “This efficiency may sound very low, but it means that from one experiment, with a single ten centimetre dish, you can get multiple iPS cell lines.” The iPS cells were indistinguishable from embryonic stem cells in terms of their appearance and behaviour in cell culture, they found. They also express genetic markers that are used by scientists to identify embryonic stem cells. Human embryonic stem cells and iPS cells display similar patterns of global gene activity. They showed that the converted human cells could differentiate to form three “germ layers” in cell culture. Those primary germ layers in embryos eventually give rise to all the body’s tissues and organs. They further showed that the human iPS cells could give rise to neurons using a method earlier demonstrated for human embryonic stem cells. The iPS cells could also be made to produce cardiac muscle cells, they found. Indeed, after 12 days of differentiation, clumps of cells in the laboratory dishes started beating. The human iPS cells injected under the skin of mice produced tumours after nine weeks. Those tumours contained various tissues including gut — like epithelial tissue, striated muscle, cartilage and neural tissue. They finally showed that iPS cells can also be generated in the same way from other human cells. “We should now be able to generate patient — and disease — specific iPS cells, and then make various cells, such as cardiac cells, liver cells and neural cells,” Yamanaka said. “These cells should be extremely useful in understanding disease mechanisms and screening effective and safe drugs. If we can overcome safety issues, we may be able to use human iPS cells in cell transplantation therapies.” Shinya Yamanaka is also a senior investigator at the Gladstone Institute of Cardiovascular Disease (GICD), an independent, non-profit biomedical research organization affiliated with the University of California, San Francisco. “The rapid application of this approach to human cells has dramatically changed the landscape of stem cell science,” said GICD Director Deepak Srivastava, MD. “Dr. Yamanaka’s work is monumental in its importance to the field of stem cell science and its potential impact on our ability to accelerate the benefits of this technology to the bedside. Not only does this discovery enable more research, it offers a new pathway to apply the benefits of stem cells to human disease.” “Dr. Yamanaka and his group have made yet another extremely important contribution to the stem cell field,” said Richard Murphy, interim president of the California Institute for Regenerative Medicine (CIRM). “Their results open the door to generating alternative sources of pluripotent cells from patients, which is a major step forward. However, much work still needs to be done to fully characterize and understand the capacity of these induced pluripotent cells to study and to treat human diseases.” CIRM’s Murphy added, “Dr. Yamanaka’s work, which uses viral vectors to introduce into cells pluripotency-associated genes, further emphasizes the critical need we have to continue working with naturally occurring human embryonic stem cells, which remain the gold standard against which all alternative sources of human pluripotent stem cells must be tested.” Reference: Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors The researchers include Kazutoshi Takahashi, Kyoto University, in Kyoto, Japan; Koji Tanabe, of Kyoto University, in Kyoto, Japan; Mari Ohnuki, of Kyoto University, in Kyoto, Japan; Megumi Narita, of Kyoto University, in Kyoto, Japan, and the Japan Science and Technology Agency, in Kawaguchi, Japan; Tomoko Ichisaka, of Kyoto University, in Kyoto, Japan, and the Japan Science and Technology Agency, in Kawaguchi, Japan; Kiichiro Tomoda, of the Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA; and Shinya Yamanaka, of Kyoto University, in Kyoto, Japan, the Japan Science and Technology Agency, in Kawaguchi, Japan; and the Gladstone Institute of Cardiovascular Disease, in San Francisco, CA, USA See also: UW-Madison scientists also guide human skin cells to embryonic like state Turning Adult Cells Embryonic How to Make Stem Cells Stay Growing ......... ZenMaster

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Promising new source of stem cells

Stem cells derived from adult testes produce wide range of tissue types Wednesday, 19 September 2007 After a decade of research, Howard Hughes Medical Institute scientists have succeeded in reprogramming adult stem cells from the testes of male mice into functional blood vessels and contractile cardiac tissue. The research offers a promising new source of stem cells for use in organ regeneration studies. Some scientists think that organ-specific adult stem cells may offer the same therapeutic potential as embryonic stem cells, without the ethical concerns or the risk of immune rejection that are associated with embryonic stem cell therapies. However, adult stem cells may lack the plasticity and pluripotency of embryonic stem cells’ capacity to generate any cell type. The study of adult stem cells has also been limited by their relative scarcity in various organs and the attendant difficulties in identifying and harvesting them, as well as differentiating them in large quantities into functional vascularised tissues. HHMI investigator Shahin Rafii and his colleagues at Weill Cornell Medical College appear to have solved some of these problems in male mice. Using spermatogonial progenitor cells obtained from the mouse’s testes, the researchers reprogrammed the cells to form multipotent adult spermatogonial-derived stem cells. If the same can be done with human cells, they say, adult stem cells may be a promising source of new therapies for men, for diseases such as vascular diseases, heart disease, Alzheimer’s, Parkinson’s, stroke, diabetes, and even cancer. Scientists have had good success in deriving pluripotent stem cell lines — those with the ability to develop into multiple cell types — from adult testes cells. But only a small subset of cells from the testes has the potential to become pluripotent, and until now, investigators have lacked a means to identify and isolate them. In a paper published online in the September 20, 2007, issue of the journal Nature, Rafii and colleagues at Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center report that they have identified a novel cell surface marker that is expressed on a unique set of cells within adult testes known as the spermatogonial stem and progenitor cells (SPCs). The marker, GPR125, enabled the scientists to identify and harvest a large number of SPCs from adult mouse testes, then propagate and reprogram them in the lab to become stem cells that could differentiate into many cell types. The researchers demonstrated that these multipotent adult spermatogonial-derived stem cells (MASCs) could develop in vivo into working blood vessel (endothelial) cells and tissue, as well as contractile cardiac tissue, brain cells, and a host of other cell types. They also injected MASCs from culture into mouse blastocysts — embryonic cells — that they implanted in mature female mice. When the blastocysts developed into mice, the researchers could see that the MASCs had differentiated into many kinds of tissue. These data suggested that the MASCs are truly multipotent: reprogrammable to differentiate into functional tissues. Ten years ago, Rafii observed that human testicular cancer cells share many characteristics with adult stem cells. As an oncologist, he also noticed that a large number of patients with testicular cancer develop tumours called teratomas, which contain different types of tissue. Based on these observations, he reasoned that spermatogonia, whose sole function is to generate the precursors to sperm, have the potential to readily give rise to pluripotent cells. As such, he thought, they might prove more amenable to reprogramming than other adult stem cells. Using gene screening studies, Rafii and colleagues discovered a potential specific surface marker on SPCs. Comparison of all cells in the adult testis showed that this G-protein coupled receptor, known as GPR125, was expressed on SPCs, but not other mature germ cells. With GPR125 in hand, Rafii could isolate large numbers of SPCs from adult mouse testes. They also established a highly sophisticated culture system in which the progenitor cells rapidly grow and divide, creating a large population of cells that can be converted into MASCs. “It appears that these specialized GPR125-positive spermatogonial cells could be an easily obtained and manipulated source of stem cells with a similar capability to form new tissues that we see in embryonic stem cells,” said Rafii. For male patients, he believes, “It could someday mean a readily available source of stem cells that gets around ethical issues linked to embryonic stem cells. It also avoids issues linked to tissue transplant rejection, since these autologous cells come from the patient’s own body.” Rafii’s team is currently pursuing a similar study of human testes to determine whether stem cells derived from their spermatogonial progenitor cells share the pluripotency of the mouse MASCs. “We believe this to be an easily obtainable goal in the near future,” he said. If they succeed, several steps remain before such stem cells could be applicable to humans. “We still have to learn the exact biochemical and epigenetic ‘switch’ that tells GPR125-positive SPCs to convert into MASCs,” said Marco Seandel, a senior post-doctoral fellow in Rafii’s laboratory who is the first author of the Nature paper. “Discovering that switch will be crucial to our being able to create MASCs on demand.” There is a chance that implanted cells derived from MASCs may trigger cancer in the recipient. This is an area that requires further investigation, Rafii said. However, he noted, “So far, we haven’t seen any cancer or evidence of pro-cancerous activity in adult mice that are implanted with differentiated MASC cell tissue derivatives.” Rafii and his team have worked out the growing conditions that coax spermatogonial progenitor cells to develop into MASC germ lines — genetically stable stem cells that continue reproducing indefinitely. Stem cell studies have been limited to date by the scarcity of germ cell lines. “None of these GPR125-positive germ cell lines was previously readily available for genetic, biochemical, and cellular analysis by other laboratories,” says Rafii. “We intend to share them with other researchers.” Rafii’s lab is now investigating whether GPR125 can be used to isolate cells from other adult tissues that can be converted into multipotent stem cells. His group has also begun pursuing a similar effort in ovaries. “It’s much more difficult,” he said. “However, it is possible that reprogrammable stem cells with similar properties to GPR125-positive SPCs may also exist, although at very low numbers, in adult mouse or human ovaries.” His lab is actively investigating this intriguing possibility, Rafii said. ......... ZenMaster

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Stem cells in adult testes provide alternative to ESCs for organ regeneration

Isolation of specialized subsets of spermatogonial stem cells generate a wide range of cell and tissue types Wednesday, 19 September 2007 Easily accessed and plentiful, adult stem cells found in a male patient's testicles might someday be used to create a wide range of tissue types to help him fight disease — getting around the need for more controversial embryonic stem cells. That's the promise of a breakthrough study in mice led by a team from Weill Cornell Medical College in New York City, who report their findings in the September 20 issue of Nature. Using spermatogonial progenitor stem cells (SPCs) obtained from the mouse's testes, the researchers were able to redirect the cells' development in the lab to form so-called "multi-potent adult spermatogonial-derived stem cells" (MASCs). It was these cells that went on to develop into working blood vessel (endothelial) cells and tissue, as well as cardiac cells, brain cells and a host of other cell types. Prior research conducted elsewhere has used genetic manipulation to reprogram adult cells derived from connective tissue to acquire stem-cell potential, differentiating into various organ-specific tissues. However, this reprogramming method — called "induced pluripotency" — resulted in generation of multi-potent stem cells that carried an increased risk of transforming into malignant cells. "What's really novel about our work is that — unlike induced pluripotency — these mouse SPCs do not require any addition or tweaking of genes to get them to form the multi-potent cells (MASCs) that then go on to produce all of these cell types," notes senior author Dr. Shahin Rafii, Arthur Belfer Professor of Genetic Medicine and director of the Ansary Stem Cell Center for Regenerative Medicine at Weill Cornell Medical College and a noted Howard Hughes Medical Institute investigator. "Some hurdles remain, of course — we have to replicate these findings in humans, and we haven't discovered the exact 'switch' that would allow us to control SPC development on demand," Dr. Rafii says. "Nevertheless, it appears that these unique specialized spermatogonial cells could be an easily obtained and manipulated source of stem cells with exactly the same capability to form new tissues that we see in embryonic stem cells." SPCs lie within a specific area of the testes and their sole function is to generate the precursors to sperm. "Normally, the spermatogonial progenitor cell is committed to only that function, and they're remarkably efficient, keeping men fertile well into advanced age," notes the study's lead author, Dr. Marco Seandel, researcher at the Howard Hughes Medical Institute and researcher/medical oncology fellow at Memorial Sloan-Kettering Cancer Center in New York City. Dr. Seandel provided the first real breakthrough in this research, developing the first efficient means of growing large quantities of SPCs for experimental use in the lab. "That really allowed us to go full steam ahead in examining the potential of these very interesting cells," explains Dr. Rafii. In their experiments, the Weill Cornell team concocted the perfect in vitro biochemical environment for the SPCs. This included particular helper cell types and growth factors aimed at fostering SPCs development away from creating germ cells and towards what scientists called "multipotency" — the ability to develop into many different cell types. Along the way, the team also cleared another hurdle. "One problem with working with SPCs is that they've been extremely difficult to identify. We discovered that, within the testicular environment, only SPCs express a particular marker called GPR125," Dr. Seandel says. "That's a quantum leap forward in terms of being able to harvest and work with these cells." Left to "soak" in their specially designed cell culture conditions, SPCs eventually made the change the team was hoping for. They did not develop into germ cells but instead grew to become multi-potent adult spermatogonial-derived stem cells (MASCs). In both in vitro and mouse-tissue studies, the Weill Cornell group watched as the MASCs differentiated into the full range of cell types. "We took them furthest when it came to endothelial cells," says Dr. Daylon James, a co-author and investigator in Dr. Rafii's laboratory. "In experiments in live mouse tissue, we were able to show that these MASC-derived endothelial cells did more than just form — they also joined up with, and functioned alongside, other blood vessels." MASCs also produced contractile "beating heart" cardiac cells, neurons, and muscle cells in the laboratory, the researchers add. But challenges remain. "We still don't understand the exact biochemical and genetic 'switch' that tells the cells to become MASCs," Dr. Seandel says. "Discovering that switch will be crucial to our being able to create MASCs on a routine basis." "The other hurdle is to repeat this success in human cells, by utilizing the same stem-cell markers, including GPR125 and also another specific marker, Plzf," states Dr. Pier Paolo Pandolfi, a collaborator in the study. Dr. Pandolfi is currently a professor at Harvard Medical School. Drs. Ilaria Falciatori, Sergey Shmelkov and Jiyeon Kim are other researchers in Dr. Rafii's lab, who are using GPR125 to isolate stem cells from other adult tissues with the potential of converting them into multi-potent stem cells with regenerative potential. Still, the findings in Nature are extremely promising. "For male patients, it could someday mean a readily available source of stem cells that gets around ethical issues linked to embryonic stem cells. It also avoids issues linked to tissue transplant rejection, since these 'autologous stem cells' are derived from the patient's own body," Dr. Rafii says. Given the pioneering surgical technology developed by the Department of Urology at Weill Cornell — by Drs. Peter Schlegel, Marc Goldstein and Douglas Scherr — it is expected that routine retrieval of adult human testicular tissue could be performed safely and in a timely fashion. Would such an approach work in the female ovary, which also contains a large population of germ cells? The Weill Cornell team says similar techniques might work there as well, although at this point it's just a theory. "Our achievement using these testes-derived cells has taken us over a decade of painstaking investigation to achieve," says Dr. Rafii. "It points to the potential of this remarkable, but — until now — poorly accessed and understood stem cell." "We hope this seminal paper will set the stage for designing clinical strategies for regenerating failing organs in patients with heart disease, Alzheimer's, Parkinson's, stroke, diabetes, arthritis, macular degeneration and infertility induced by chemotherapy and irradiation," Dr. Rafii adds. "Delivering stem cells derived from MASCs, loaded with toxic factors, to the tumour microenvironment may also provide a novel strategy to target tumour blood vessels and inhibit cancer growth and metastasis." Reference: Generation of functional multipotent adult stem cells from GPR125+ germline progenitors Marco Seandel1, Daylon James, Sergey V. Shmelkov, Ilaria Falciatori, Jiyeon Kim, Sai Chavala, Douglas S. Scherr, Fan Zhang, Richard Torres, Nicholas W. Gale, George D. Yancopoulos, Andrew Murphy, David M. Valenzuela, Robin M. Hobbs, Pier Paolo Pandolfi & Shahin Rafii Nature 449, 346-350 (20 September 2007) doi:10.1038/nature06129 ......... ZenMaster

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One species' entire genome discovered inside another's

Whole-genome transfer raises questions about evolution, sequencing Friday, 31 August 2007 Scientists at the University of Rochester and the J. Craig Venter Institute have discovered a copy of the entire genome of a bacterial parasite residing inside the genome of its host species. The finding, reported in today’s Science, suggests that lateral gene transfer — the movement of genes between unrelated species — may happen much more frequently between bacteria and multicellular organisms than scientists previously believed, posing dramatic implications for evolution. Such large — scale heritable gene transfers may allow species to acquire new genes and functions extremely quickly, says Jack Werren, a principle investigator of the study. The results also have serious repercussions for genome — sequencing projects. Bacterial DNA is routinely discarded when scientists are assembling invertebrate genomes, yet these genes may very well be part of the organism’s genome, and might even be responsible for functioning traits. “This study establishes the widespread occurrence and high frequency of a process that we would have dismissed as science fiction until just a few years ago,” says W. Ford Doolittle, Canada Research Chair in Comparative Microbial Genomics at Dalhousie University, who is not connected to the study. “This is stunning evidence for increased frequency of gene transfer.” “It didn’t seem possible at first,” says Werren, professor of biology at the University of Rochester and a world — leading authority on the parasite, called Wolbachia. “This parasite has implanted itself inside the cells of 70 percent of the world’s invertebrates, coevolving with them. And now, we’ve found at least one species where the parasite’s entire or nearly entire genome has been absorbed and integrated into the host’s. The host’s genes actually hold the coding information for a completely separate species.” Wolbachia may be the most prolific parasite in the world — a “pandemic,” as Werren calls it. The bacterium invades a member of a species, most often an insect, and eventually makes its way into the host’s eggs or sperm. Once there, the Wolbachia is ensured passage to the next generation of its host, and any genetic exchanges between it and the host also are much more likely to be passed on. Since Wolbachia typically live within the reproductive organs of their hosts, Werren reasoned that gene exchanges between the two would frequently pass on to subsequent generations. Based on this and an earlier discovery of a Wolbachia gene in a beetle by the Fukatsu team at the University of Tokyo, Japan, the researchers in Werren’s lab and collaborators at J. Craig Venter Institute (JCVI) decided to systematically screen invertebrates. Julie Dunning-Hotopp at JCVI found evidence that some of the Wolbachia genes seemed to be fused to the genes of the fruit fly, Drosophila ananassae, as if they were part of the same genome. Michael Clark, a research associate at Rochester then brought a colony of ananassae into Werren’s lab to look into the mystery. To isolate the fly’s genome from the parasite’s, Clark fed the flies a simple antibiotic, killing the Wolbachia. To confirm the ananassae flies were indeed cured of the Wolbachia, Clark tested a few samples of DNA for the presence of several Wolbachia genes. To his dismay, he found them. “For several months, I thought I was just failing,” says Clark. “I kept administering antibiotics, but every single Wolbachia gene I tested for was still there. I started thinking maybe the strain had grown antibiotic resistance. After months of this I finally went back and looked at the tissue again, and there was no Wolbachia there at all.” Clark had cured the fly of the parasite, but a copy of the parasite’s genome was still present in the fly’s genome. Clark was able to see that Wolbachia genes were present on the second chromosome of the insect. Clark confirmed that the Wolbachia genes are inherited like “normal” insect genes in the chromosomes, and Dunning-Hotopp showed that some of the genes are “transcribed” in uninfected flies, meaning that copies of the gene sequence are made in cells that could be used to make Wolbachia proteins. Werren doesn’t believe that the Wolbachia “intentionally” insert their genes into the hosts. Rather, it is a consequence of cells routinely repairing their damaged DNA. As cells go about their regular business, they can accidentally absorb bits of DNA into their nuclei, often sewing those foreign genes into their own DNA. But integrating an entire genome was definitely an unexpected find. Werren and Clark are now looking further into the huge insert found in the fruit fly, and whether it is providing a benefit. “The chance that a chunk of DNA of this magnitude is totally neutral, I think, is pretty small, so the implication is that it has imparted of some selective advantage to the host,” says Werren. “The question is, are these foreign genes providing new functions for the host? This is something we need to figure out.” Evolutionary biologists will certainly take note of this discovery, but scientists conducting genome — sequencing projects around the world also may have to readjust their thinking. Before this study, geneticists knew of examples where genes from a parasite had crossed into the host, but such an event was considered a rare anomaly except in very simple organisms. Bacterial DNA is very conspicuous in its structure, so if scientists sequencing a nematode genome, for example, come across bacterial DNA, they would likely discard it, reasonably assuming that it was merely contamination — perhaps a bit of bacteria in the gut of the animal, or on its skin. But those genes may not be contamination. They may very well be in the host’s own genome. This is exactly what happened with the original sequencing of the genome of the ananassae fruit fly — the huge Wolbachia insert was discarded from the final assembly, despite the fact that it is part of the fly’s genome. In the early days of the Human Genome Project, some studies appeared to show bacterial DNA residing in our own genome, but those were shown indeed to be caused by contamination. Wolbachia is not known to infect any vertebrates such as humans. “Such transfers have happened before in the distant past” notes Werren. “In our very own cells and those of nearly all plants and animals are mitochondria, special structures responsible for generating most of our cells’ supply of chemical energy. These were once bacteria that lived inside cells, much like Wolbachia does today. Mitochondria still retain their own, albeit tiny, DNA, and most of the genes moved into the nucleus in the very distant past. Like Wolbachia, they have passively exchanged DNA with their host cells. It’s possible Wolbachia may follow in the path of mitochondria, eventually becoming a necessary and useful part of a cell.” “In a way, Wolbachia could be the next mitochondria,” says Werren. “A hundred million years from now, everyone may have a Wolbachia organelle.” “Well, not us,” he laughs. “We’ll be long gone, but Wolbachia will still be around.” ......... ZenMaster

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