Scientists have corrected the genetic fault that causes Down's syndrome– albeit in isolated cells – raising the prospect of a radical therapy for the disorder.

In an elegant series of experiments, US researchers took cells from people with DS and silenced the extra chromosome that causes the condition. A treatment based on the work remains a distant hope, but scientists in the field said the feat was the first major step towards a "chromosome therapy" for Down's syndrome.

"This is a real technical breakthrough. It opens up whole new avenues of research," said Elizabeth Fisher, professor of neurogenetics at UCL, who was not involved in the study. "This is really the first sniff we've had of anything to do with gene therapy for Down's syndrome."

Around 750 babies are born with DS in Britain each year while globally between one in a 1000 and one in 1100 births are DS babies. Most experience learning difficulties.

Despite advances in medical care that allow most to live well into middle age, those who have the disorder are at risk of heart defects, bowel and blood disorders, and thyroid problems.

Though a full treatment is still many years off, the work will drive the search for therapies that improve common symptoms of DS, from immune and gastrointestinal problems, to childhood leukaemia and early-onset dementia.

"This will accelerate our understanding of the cellular defects in Down's syndrome and whether they can be treated with certain drugs," said Jeanne Lawrence, who led the team at the University of Massachusetts.

"The long-range possibility – and it's an uncertain possibility – is a chromosome therapy for Down's syndrome. But that is 10 years or more away. I don't want to get people's hopes up."

In a healthy person, almost every cell in the body carries 23 pairs of chromosomes, which hold nearly all of the genes needed for human life. But glitches in the early embryo can sometimes leave babies with too many chromosomes. Down's syndrome arises when cells have an extra copy of chromosome 21.

Lawrence's team used "genome editing", a procedure that allows DNA to be cut and pasted, to drop a gene called XIST into the extra chromosome in cells taken from people with Down's syndrome.

Once in place, the gene caused a buildup of a version of a molecule called RNA, which coated the extra chromosome and ultimately shut it down.

Previous studies found that the XIST gene is crucial for normal human development. Sex is determined by the combination of X and Y chromosomes a person inherits: men are XY, and women are XX. TheXIST gene sits on the X chromosome, but is only active in women. When it switches on, it silences the second X chromosome.

Lawrence's work shows that the gene can shut down other chromosomes too, a finding that paves the way for treating a range of other "trisomy" disorders, such as Edward syndrome and Patau syndrome, caused by extra copies of chromosomes 18 and 13 respectively.

Writing in the journal Nature, the team describes how cells corrected for an extra chromosome 21 grew better, and developed more swiftly into early-stage brain cells. The work, the researchers write, "surmounts the major first step towards potential development of chromosome therapy".

The work is already helping scientists to tease apart how an extra chromosome 21 causes a raft of problems that strike people with Down's syndrome at various ages. "By the time people with Down's syndrome are in their 60s, about 60% will succumb to dementia. One question is, if we could turn off the extra chromosome in adults, would that stop or ameliorate their dementia?" said Fisher. Another approach would cut the risk of leukaemia by silencing the extra chromosome in bone marrow cells.

The US team has already begun work that aims to prevent Down's syndrome in mice, by silencing the extra chromosome 21 in early-stage embryos. "That would correct the whole mouse, but it's not really practical in humans," said Lawrence.

A chromosome therapy for humans would be fraught with practical and ethical difficulties. To prevent Down's syndrome, the genome editing would have to be performed on an embryo or foetus in the womb, and correct most, if not all, of the future child's cells. That is far beyond what is possible, or allowed, today.

Center for Cancer in Britain hired a game studio to produce for them a computer game in which players will take on the role of doctors. It allows the audience to analyze in real time the actual and current scientific data and named Cell Slider.
 
From the center said that for the first three months' mobile researchers "analyzed data for scientific teams would take over 3 years.

The development of technology allowed the scientific world to identify many new causes of cancer - carcinogens and mutations. But the colossal amounts of data that are piling up faster than they can be analyzed, often significantly delayed the work of scientists. Problem with the data is that most computers have to be specifically programmed for each study, which creates a likelihood of mistakes and too slow for their needs. Because data can be analyzed by eye, they decided to turn it into a game.

According to the center's director - Dr. Joanna Reynolds, the accuracy with which the human brain is able to analyze the information in no way inferior to the analytical power of the computer, but while introducing faster software, a brain is more effective than a single processor .
 
Since it became available for free access on the Internet, Cell Slider scored over 350 000 players from around the world who have committed over 1,600,000 accurate analysis of the information forwarded in the form of game information.

And the principle of action is inspired by the program SETI @ home: a multinational enterprise to search for extraterrestrial life, receiving huge amounts of data from satellites and satellites of the planet and the Internet and sends them into small pieces and parcels of volunteers. These volunteers run the program on your computer, it automatically analyzes the data and a few minutes sent them back to ready the backup type.

The process researchers use to generate induced pluripotent stem cells (iPSCs) -- a special type of stem cell that can be made in the lab from any type of adult cell -- is time consuming and inefficient. To speed things up, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) turned to kinase inhibitors. These chemical compounds block the activity of kinases, enzymes responsible for many aspects of cellular communication, survival, and growth.

As they outline in a paper published September 25 in Nature Communications, the team found several kinase inhibitors that, when added to starter cells, help generate many more iPSCs than the standard method. This new capability will likely speed up research in many fields, better enabling scientists around the world to study human disease and develop new treatments.

"Generating iPSCs depends on the regulation of communication networks within cells," explained Tariq Rana, Ph.D., program director in Sanford-Burnham's Sanford Children's Health Research Center and senior author of the study. "So, when you start manipulating which genes are turned on or off in cells to create pluripotent stem cells, you are probably activating a large number of kinases. Since many of these active kinases are likely inhibiting the conversion to iPSCs, it made sense to us that adding inhibitors might lower the barrier."

According to Tony Hunter, Ph.D., professor in the Molecular and Cell Biology Laboratory at the Salk Institute for Biological Studies and director of the Salk Institute Cancer Center, "The identification of small molecules that improve the efficiency of generating iPSCs is an important step forward in being able to use these cells therapeutically. Tariq Rana's exciting new work has uncovered a class of protein kinase inhibitors that override the normal barriers to efficient iPSC formation, and these inhibitors should prove useful in generating iPSCs from new sources for experimental and ultimately therapeutic purposes." Hunter, a kinase expert, was not involved in this study.

The promise of iPSCs

At the moment, the only treatment option available to many heart failure patients is a heart transplant. Looking for a better alternative, many researchers are coaxing stem cells into new heart muscle. In Alzheimer's disease, researchers are also interested in stem cells, using them to reproduce a person's own malfunctioning brain cells in a dish, where they can be used to test therapeutic drugs. But where do these stem cells come from? Since the advent of iPSC technology, the answer in many cases is the lab. Like their embryonic cousins, iPSCs can be used to generate just about any cell type -- heart, brain, or muscle, to name a few -- that can be used to test new therapies or potentially to replace diseased or damaged tissue.

It sounds simple enough: you start with any type of differentiated cell, such as skin cells, add four molecules that reprogram the cells' genomes, and then try to catch those that successfully revert to unspecialized iPSCs. But the process takes a long time and isn't very efficient -- you can start with thousands of skin cells and end up with just a few iPSCs.

Inhibiting kinases to make more iPSCs

Zhonghan Li, a graduate student in Rana's laboratory, took on the task of finding kinase inhibitors that might speed up the iPSC-generating process. Scientists in the Conrad Prebys Center for Chemical Genomics, Sanford-Burnham's drug discovery facility, provided Li with a collection of more than 240 chemical compounds that inhibit kinases. Li painstakingly added them one-by-one to his cells and waited to see what happened. Several kinase inhibitors produced many more iPSCs than the untreated cells -- in some cases too many iPSCs for the tiny dish housing them. The most potent inhibitors targeted three kinases in particular: AurkA, P38, and IP3K.

Working with the staff in Sanford-Burnham's genomics, bioinformatics, animal modeling, and histology core facilities -- valuable resources and expertise available to all Sanford-Burnham scientists and the scientific community at large -- Rana and Li further confirmed the specificity of their findings and even nailed down the mechanism behind one inhibitor's beneficial actions.

"We found that manipulating the activity of these kinases can substantially increase cellular reprogramming efficiency," Rana said. "But what's more, we've also provided new insights into the molecular mechanism of reprogramming and revealed new functions for these kinases. We hope these findings will encourage further efforts to screen for small molecules that might prove useful in iPSC-based therapies."

Two recent studies by CRG researchers delve into the role of chromatin modifying enzymes and transcription factors in tumour cells.

In one, published on September 9 in Genes & Development, it was found that the PARP1 enzyme activated by kinase CDK2 is necessary to induce the genes responsible for the proliferation of breast cancer cells in response to progesterone. In addition, extensive work has been undertaken to identify those genes activated by the administration of progesterone in breast cancer, the sequences that can be recognised and how these genes are induced. This work will be published on November 21 in the journal Molecular Cell.

Cancer is a complex set of diseases and only thanks to advances in genomic techniques have researchers begun to understand, at a cellular and molecular level, the mechanisms which are disrupted in cancer cells, a prerequisite for developing effective strategies to treat these diseases.

One clear example of this is breast cancer. It has long been known that hormones such as estrogen and progesterone encourage the proliferation of cancer cells. Because of this, one of the most common treatments is the administration of hormone receptor blockers. The block, however, affects all the cells of the body not only the cancer cells, and causes a number of side effects in patients. Additionally, most cancers develop resistance after a time and continue to grow despite anti-hormone therapy. To treat these patients it is necessary to understand the mechanisms that trigger the proliferation, which will allow their direct inhibition.

The scientists from the Cromatin and Gene Expression lab at the CRG, led by Miguel Beato, are dedicated to understanding how hormones activate cell division in breast cancer, focusing on regulating the expression of the genes that control the cell cycle.

Hormone receptors are transcription factors that bind to DNA sequences in the vicinity of the genes they regulate. But the DNA of the genes is packed into a dense structure known as "chromatin," which is considered a barrier preventing the access of transcription factors to genes. Therefore the chromatin must be decompacted for the transcription factors to activate the target genes expressed in RNA and subsequently translate them into proteins that stimulate cell proliferation. This is where the progesterone, via its receptor, activates various enzymes initiating chromatin opening.

In the study published on September 1 in the journal Genes & Development, the researchers looked at the role of an enzyme, PARP-1, which is primarily responsible for the repair of cuts in DNA. "It was not known how PARP-1 is activated and we found that it happens via the activation of another enzyme, CDK2, which phosphorylates and activates PARP-1, which in turn modifies the histone H1 and the chromatin displacement. And if PARP1 does not do this, many of the progesterone's target genes are not regulated," explains Roni Wright, first author of the study. Wright is a postdoctoral researcher in Beato's lab. She believes that much remains to be discovered in this area of research. "This experiment was conducted on cell lines, but now we have to do it on real, patient cells to see if their behaviour is the same," adds the researcher.

How do we know how the proliferation of cancer cells is controlled?

Gene regulation (how genes activate and deactivate) is the key to the overall understanding of how our genome works and when this function is altered. "It is important to discover the mechanism by which genes are activated around chromatin," explains Miguel Beato, head of the Chromatin and Gene Expression group. The chromatin packs the DNA at several levels, the first being the "nucleosomes," which help stabilise the DNA chain. "It was thought that the chromatin structure was not relevant to explaining how genes turn on and off, but we have discovered that it is crucial," adds Beato.

The second study, published online on November 21, 2012 in the journal Molecular Cell, addresses this issue. Firstly, all the genes that progesterone activates or represses in breast cancer cells were identified. Then the researchers identified which DNA sequences recognise the progesterone receptor in the genome. They found that these represented only a small proportion of the possibilities, making them think that interaction with DNA was not sufficient. It was necessary for the sequences which bind to the receptor to be incorporated into nucleosomes, which also provide interaction sites. "It seems that chromatin has a lot to do with determining which genes are activated and which are not," says Cecilia Ballaré, first author of this second paper.

The researchers believe that the only way to create increasingly specific and effective cancer treatments is by studying the role of all the elements that regulate gene expression and cell proliferation in response to hormones. "Knowing the exact way progesterone affects the proliferation of cancer cells may help develop more specific treatments that fight only cancer cells and thus produces fewer side effects," adds Ballaré.