Neanderthal Genome III: Entire Neanderthal Genome Decoded

Researchers Publish the First High-Quality Neanderthal Genome

Wednesday, 20 March 2013

The Max Planck Institute for Evolutionary Anthropology, in Leipzig, Germany, has completed the genome sequence of a Neanderthal and makes the entire sequence available to the scientific community today.

Svante Pääbo holding the skull of a 

Neanderthal. Credit: Frank Vinken.

In 2010, Dr. Svante Pääbo and his colleagues presented the first draft version of the Neanderthal genome from data collected from three bones found in a cave in Croatia. They have now used a toe bone excavated in 2010 in Denisova Cave in southern Siberia to generate a high-quality genome from a single Neanderthal individual.

The Leipzig team has used sensitive techniques they have developed over the past two years to sequence every position in the genome about 50 times over, using DNA extracted from 0.038 grams of the toe bone. The analysis of the genome together with partial genome sequences from other Neanderthals, and the genome from a small finger bone discovered in the same cave, shows that the individual is closely related to other Neanderthals in Europe and western Russia. Remarkably, Neanderthals and their relatives, Denisovans, were both present in this unique cave in the Altai Mountains on the border between Russia, China, Mongolia and Kazakhstan.

The figure shows a tree relating this genome

to the genomes of Neanderthals from Croatia,

from Germany and from the Caucasus as well

as the Denisovan genome recovered from a

finger bone excavated at Denisova Cave. It

shows that this individual is closely related to

these other Neanderthals. Thus, both Neanderthals

and Denisovans have inhabited this cave in

southern Siberia, presumably at different times.

Credit: Max Planck Institute for Evolutionary

Anthropology. 

In the 2010 draft version of the Neanderthal genome, each position was determined, on average, once. In the now-completed version of the genome every position was determined on average 50 times over. This allows even the small differences between the copies of genes that this Neanderthal individual inherited from its mother and father to be distinguished. Today, the Leipzig group makes the entire Neanderthal genome sequence available for the scientific community over the internet.

“The genome is of very high quality”, says Dr. Kay Prüfer, who coordinates the analyses of the genome in Leipzig.

“It matches the quality of the Denisovan genome, presented last year, and is as good as or even better than the multiple present-day human genomes available to date.”

“We are in the process of comparing this Neanderthal genome to the Denisovan genome as well as to the draft genomes of other Neanderthals. We will gain insights into many aspects of the history of both Neanderthals and Denisovans and refine our knowledge about the genetic changes that occurred in the genomes of modern humans after they parted ways with the ancestors of Neanderthals and Denisovans” says Dr. Svante Pääbo.

The group will present a paper describing the genome later this year.

“But we make the genome sequence freely available now to allow other scientists to profit from it even before it is published” says Pääbo.

The project is made possible by financing from the Max Planck Society and is part of efforts since almost 30 years by Dr. Pääbo’s group to study ancient DNA. The toe bone was discovered by Professor Anatoly Derevianko and Professor Michael Shunkov from the Russian Academy of Sciences in 2010 during their excavations at Denisova Cave, a unique archaeological site which contains cultural layers indicating that human occupation at the site started up to 280,000 years ago.

Source: Max Planck Institute for Evolutionary Anthropology

Contact: Sandra Jacob

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Stem Cell Research Could Expand Clinical Use of Regenerative Human Cells

Stem Cell Research Could Expand Clinical Use of Regenerative Human Cells

Tuesday, 19 March 2013

Research led by a biology professor in the School of Science at Indiana University-Purdue University Indianapolis (IUPUI) has uncovered a method to produce retinal cells from regenerative human stem cells without the use of animal products, proteins or other foreign substances, which historically have limited the application of stem cells to treat disease and other human developmental disorders.

The study of human induced pluripotent stem cells (hiPSCs) has been pursued vigorously since they were first discovered in 2007 due to their ability to be manipulated into specific cell types. Scientists believe these cells hold considerable potential for cell replacement, disease modelling and pharmacological testing. However, clinical applications have been hindered by the fact that, to date, the cells have required animal products and proteins to grow and differentiate.

Jason Meyer, Ph.D., assistant professor of

biology, has produced retinal cells from human

induced pluripotent stem cells without the use

of any animal products or foreign substances.

The chemical method could help expand clinical

 use of stem cell regeneration. Credit: School

of Science at IUPUI. 

A research team led by Jason S. Meyer, Ph.D., assistant professor of biology, successfully differentiated hiPSCs in a lab environment — completely through chemical methods — to form neural retinal cell types (including photoreceptors and retinal ganglion cells). Tests have shown the cells function and grow just as efficiently as those cells produced through traditional methods.

"Not only were we able to develop these (hiPSC) cells into retinal cells, but we were able to do so in a system devoid of any animal cells and proteins," Meyer said.

"Since these kinds of stem cells can be generated from a patient's own cells, there will be nothing the body will recognize as foreign."

In addition, this research should allow scientists to better reproduce these cells because they know exactly what components were included to spur growth and minimize or eliminate any variations, Meyer said. Furthermore, the cells function in a very similar fashion to human embryonic stem cells, but without controversial or immune rejection issues because they are derived from individual patients.

Retinal pigment epithelial (RPE) cells derived

from human induced pluripotent stem cells

possess numerous characteristics of native

RPE cells when examined by immunocyto-

chemistry. Credit: Jason Meyer. 

"This method could have a considerable impact on the treatment of retinal diseases such as age-related macular degeneration and forms of blindness with hereditary factors," Meyer said.

"We hope this will help us understand what goes wrong when diseases arise and that we can use this method as platform for the development of new treatments or drug therapies."

"We're talking about bringing stem cells a significant step closer to clinical use," Meyer added.

Meyer, along with two graduate students, have worked for two years on this research with the help of an Indiana University Collaborative Research Grant and funding from the School of Science at IUPUI and the American Health Assistance Foundation.

The research will be published in the April edition of Stem Cells Translational Medicine. Co-authors include Akshayalakshmi Sridhar and Melissa M. Steward.

Meyer began researching hiPSCs while he was a post-doctoral research associate at the University of Wisconsin in Madison, where James Thomson, Ph.D., was one of two investigators to develop hiPSCs from adult cells in 2007. The other, Shinya Yamanaka, Ph.D, from Japan's Kyoto University, was awarded the Nobel Prize for Physiology or Medicine in 2012 for discovering the ability of mature cells to be reprogrammed into stem cells.

Source: Indiana University-Purdue University Indianapolis School of Science 

Contact: David Hosick

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Transplanted Brain Cells in Monkeys Light Up Personalized Therapy

UW study is key step toward treating disease with stem cells

Thursday, 14 March 2013

For the first time, scientists have transplanted neural cells derived from a monkey's skin into its brain and watched the cells develop into several types of mature brain cells, according to the authors of a new study in Cell Reports. After six months, the cells looked entirely normal, and were only detectable because they initially were tagged with a fluorescent protein.

Because the cells were derived from adult cells in each monkey's skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual.

And since the skin cells were not "foreign" tissue, there were no signs of immune rejection — potentially a major problem with cell transplants.

Standing at centre, Su-Chun Zhang, professor of 

neuroscience in the School of Medicine and Public 

Health, talks with his staff as they prepare stem-cell 

cultures in the Zhang's research lab at the Waisman 

Center at the University of Wisconsin–Madison on 

March 8, 2013. Pictured at right are postdoctoral 

students Yan Liu, background, and Lin Yao, 

foreground. Credit: Photo by Jeff Miller.

"When you look at the brain, you cannot tell that it is a graft," says senior author Su-Chun Zhang, a professor of neuroscience at the University of Wisconsin-Madison.

"Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope."

“This is the first time I saw, in a nonhuman primate, that the transplanted cells were so well integrated, with such a minimal reaction. And after six months, to see no scar, that was the best part," Marina Emborg says, an associate professor of medical physics at UW-Madison and the lead co-author of the study. "

The cells were implanted in the monkeys "using a state-of-the-art surgical procedure" guided by an MRI image, says Emborg. The three rhesus monkeys used in the study at the Wisconsin National Primate Research Center had a lesion in a brain region that causes the movement disorder Parkinson's disease, which afflicts up to 1 million Americans. Parkinson's is caused by the death of a small number of neurons that make dopamine, a signalling chemical used in the brain.

The transplanted cells came from induced pluripotent stem cells (iPS cells), which can, like embryonic stem cells, develop into virtually any cell in the body. iPS cells, however, derive from adult cells rather than embryos.

In the lab, the iPS cells were converted into neural progenitor cells. These intermediate-stage cells can further specialize into the neurons that carry nerve signals, and the glial cells that perform many support and nutritional functions. This final stage of maturation occurred inside the monkey.

Zhang, who was the first in the world to derive neural cells from embryonic stem cells and then iPS cells, says one key to success was precise control over the development process.

"We differentiate the stem cells only into neural cells. It would not work to transplant a cell population contaminated by non-neural cells."

Another positive sign was the absence of any signs of cancer, says Zhang — a worrisome potential outcome of stem cell transplants.

This neuron, created in the Su-Chun Zhang lab at the 

University of Wisconsin–Madison, makes dopamine, 

a neurotransmitter involved in normal movement. The 

cell originated in an induced pluripotent stem cell, which 

derive from adult tissues. Similar neurons survived and 

integrated normally after transplant into monkey brains 

— as a proof of principle that personalized medicine may 

one day treat Parkinson's disease (Date: 2010). Credit: 

courtesy by Yan Liu and Su-Chun Zhang, Waisman 

Center, University of Wisconsin–Madison. 

"Their appearance is normal, and we also used antibodies that mark cells that are dividing rapidly, as cancer cells are, and we do not see that. And when you look at what the cells have become, they become neurons with long axons [conducting fibres], as we'd expect. They also produce oligodendrocytes that are helping build insulating myelin sheaths for neurons, as they should. That means they have matured correctly, and are not cancerous."

The experiment was designed as a proof of principle, says Zhang, who leads a group pioneering the use of iPS cells at the Waisman Center on the UW-Madison campus. The researchers did not transplant enough neurons to replace the dopamine-making cells in the brain, and the animal's behaviour did not improve.

Although promising, the transplant technique is a long way from the clinic, Zhang adds.

"Unfortunately, this technique cannot be used to help patients until a number of questions are answered: Can this transplant improve the symptoms? Is it safe? Six months is not long enough. And what are the side effects? You may improve some symptoms, but if that leads to something else, then you have not solved the problem."

Nonetheless, the new study represents a real step forward that may benefit human patients suffering from several diseases, says Emborg.

"By taking cells from the animal and returning them in a new form to the same animal, this is a first step toward personalized medicine."

The need for treatment is incessant, says Emborg, noting that each year, Parkinson's is diagnosed in 60,000 patients.

"I'm gratified that the Parkinson's Disease Foundation took a risk as the primary funder for this small study. Now we want to move ahead and see if this leads to a real treatment for this awful disease."

"It's really the first-ever transplant of iPS cells from a non-human primate back into the same animal, not just in the brain," says Zhang.

"I have not seen anybody transplanting reprogrammed iPS cells into the blood, the pancreas or anywhere else, into the same primate. This proof-of-principle study in primates presents hopes for personalized regenerative medicine."

Source: University of Wisconsin-Madison 

Contact: Su-Chun Zhang

Reference:

Induced Pluripotent Stem Cell-Derived Neural Cells Survive and Mature in the Nonhuman Primate Brain

Marina E. Emborg, Yan Liu, Jiajie Xi, Xiaoqing Zhang, Yingnan Yin, Jianfeng Lu, Valerie Joers, Christine Swanson, James E. Holden, Su-Chun Zhang

Cell Reports, 14 March 2013, 10.1016/j.celrep.2013.02.016

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