Monthly Archives: May 2017

Around 4,500 years ago, a mysterious craze for bell-shaped pottery swept across prehistoric Europe. Archaeologists have debated the significance of the potsartefacts that define the Bell Beaker culturefor more than a century. Some argue that they were the Bronze Ages hottest fashion, shared across different groups of people. But others see them as evidence for an immense migration of Beaker folk across the continent.

Now, one of the biggest ever ancient-genome studies suggests both ideas are true. The study,posted on bioRxivon May 9, analysed the genomes of 170 ancient Europeans and compared them to hundreds of other ancient and modern genomes. In Iberia and central Europe, skeletons found near Bell Beaker artefacts share few genetic tiessuggesting that they were not one migrating population. But in Britain, individuals connected to Beaker pots seem to be a distinct, genetically related groupthat almost wholly replaced the islands earlier inhabitants.

If true, this suggests that Britains Neolithic farmers (who left behind massive rock relics, including Stonehenge) were elbowed out by Beaker invaders. To me, thats definitely surprising, says Pontus Skoglund, a population geneticist at Harvard Medical School in Boston, Massachusetts, who was not involved in the research. The people who built Stonehenge probably didnt contribute any ancestry to later people, or if they did, it was very little.

Some archaeologists say that the study does not prove the scale of the British Beaker invasion, but agree that it is a major work that typifies how huge ancient-DNA studies are disrupting archaeology. Its groundbreaking, says Benjamin Roberts, an archaeologist at Durham University, UK.

The variety of Beaker artefacts makes it hard to define them as emerging from one distinctive culture: many researchers prefer to call their spread the Bell Beaker phenomenon, says Marc Vander Linden, an archaeologist at University College London. The distinctive pots, possibly used as drinking vessels, are nearly ubiquitous; flint arrowheads, copper daggers and stone wrist guards are common, too. But there are regional differences in ceramics and burial style. And the immense, yet discontinuous, geographical range of Beaker sitesfrom Scandinavia to Morocco, and Ireland to Hungaryhas sown more confusion. After a few hundred years, the pots vanish from the record.

A 2004 analysis of strontium isotopes, which vary according to regional geochemistry, suggested that some Beaker-associated individuals did migrate in their lifetimes. Past ancient-DNA studies have also hinted at a huge migration, linking Beaker-associated individuals in central Europeto an influx of Steppe peoples from what is now Russia and Ukraine.

The latest work, led by geneticists Iigo Olalde and David Reich at Harvard Medical School, involved 103 researchers at dozens of institutions, including Bronze Age archaeologists. Reichs team analysed more than 1million DNA variants across the genomes of individuals who lived in Europe between 4700 and 1200BC. The team declined to comment because the paper has not yet been published in a peer-reviewed journal.

The analysis seems to dispel the idea of one Beaker people arising from a specific source. Individuals in Iberia (which has been proposed as the wellspring for the culture) shared little ancestry with those in central Europe. Even Beaker-associated people in the same region came from different genetic stock. That pattern contrasts withearlier upheavals in Europe driven by mass migrations, says Skoglund. Bell Beaker is the best example of something that is pots and not people that are spreading, he says.

But in Britain, the arrival of Bell Beaker pots coincided with a shift in the islands genetics. Reichs team analysed the genomes of 19 Beaker individuals across Britain and found that they shared little similarity with those of 35 Neolithic farmers there. The pot-makers were more closely related to 14individuals from the Netherlands, and had lighter-coloured skin and eyes than the people they replaced. By 2000BC, signals of Neolithic ancestry disappear from ancient genomes in Britain, Reichs team findlargely replaced by Beaker-associated DNA. Such turnover is pretty striking, says Garrett Hellenthal, a statistical geneticist at University College Londonwho has studied the peopling of the island through the genomes of living Brits. More data could reveal surprises, but the team makes a good case that Beaker folk replaced the regions early farmers, he says.

Reichs team calculates that Britain saw a greater than 90% shift in its genetic make-up. But Roberts says he doesnt see evidence for such a huge shift in the archaeological record. The rise of cremation in Bronze Age Britain could have biased the finding, he cautions, because it might have eliminated bones that could have been sampled for DNA. Although archaeologists are excited to seeancient DNA yield breakthroughs in problems that have vexed their field for decades, says Linden, he expects some push back against the latest studys conclusions. Its not at all the end of the story.

This article is reproduced with permission and wasfirst publishedon May 17, 2017.

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Bronze-Age "Beaker Culture" Invaded Britain, Ancient-Genome ... - Scientific American

The Scientist

First In Vivo Human Genome Editing Tested in New Clinical Trial The Scientist DEResearchers have edited the human genome before, but always in cells outside the body. Now, biotech company Sangamo Therapeutics is recruiting participants for clinical trials in which patients with hemophilia B, Hurler syndrome, or Hunter syndrome ... and more »

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First In Vivo Human Genome Editing Tested in New Clinical Trial - The Scientist

The discovery of genome-editing enzymes such as CRISPR-Cas9 has resulted in numerous efforts to develop new therapeutics to address genetic disease. Thats because the ability to make modifications to a patients genome holds tremendous potential. Unfortunately, potential might be all it has right now.

There are a few barriers right now to this technology really hitting the mainstream, said Ross Wilson, project scientist and principal investigator at the University of California Berkeley, California Institute for Quantitive Biosciences. One of the main concerns is around safety, and a lot of work and testing is being done when these enzymes modify a genome to make sure they are not making unwanted modifications at the same time. The good news is these enzymes are making precise edits without unwanted effects. Another nice thing is scientists are developing new versions of these enzymes that are even better and even less likely to make unwanted changes to genomes.

[Also:Intermountain makes strides in precision medicine, advanced imaging]

Another barrier to bringing CRISPR to the mainstream is related to the delivery of the therapeutic enzymes, which is the field Wilsons lab is focusing on.

Its pretty easy to take human cells in a petri dish and modify them using these enzymes, because we can use a little electric shock to trick the cells into taking the enzymes inside, Wilson said. But this is the sort of thing that cant really be done in a living patient. Cells are very savvy when it comes to what they let inside because they have to defend against viruses, for example. These genome editing enzymes look like a threat.

Indeed, a major challenge is getting around the cells defenses and carrying out genome editing for efficient modification of cells within a patient. However, one type of therapy moving forward quickly is called autologous transplantation, essentially a patient making a donation to themselves.

Learn more at thePrecision Medicine Summitin Boston, June 12-13, 2017. Register here.

The way this works is you take out some blood cells from a patient and in the laboratory make a modification to those cells and then return these cells to the patient, Wilson said. One gene-based disease that could be cured this way is sickle cell disease. If you take a patients stem cells out, edit the genome in those cells, and transplant them back into the patient, you can cure the gene that is responsible for sickle cell.

Therapies based on autologous transplantation will be the first to really take root, Wilson said.

But this is a narrow window of therapies, Wilson said. If you wanted to reach the broadest number of patients you would need a way to edit the genome inside a living patient. Thats the second big barrier.

[Also:Direct-to-consumer genetic tests: Great for patients, tough on doctors]

Another barrier to this kind of genetic work is the level of understanding of the genetic foundation of different disease states.

There are a lot of things people suffer from, like heart disease, for example, where a lot of genes may be working together to cause a poor outcome in a patient, he said. As medical research advances, we will have a better picture of what sort of things need to be edited to give people better outcomes. Our understanding of the interplay between our genes and our health is one of the things that will give us the most opportunity in putting gene editing therapy to use.

Wilson will discuss precision medicine issues at the HIMSS and Healthcare IT News Precision Medicine Summit, June 12-13, 2017, in Boston, during a session entitled How genome editing might reshape the medical landscape.

Twitter:@SiwickiHealthIT Email the writer: bill.siwicki@himssmedia.com

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Genome editing has a long way to go before widespread buy-in ... - Healthcare IT News

Meaningful public debate seems almost impossible in an era of political bubbles isolating us one from another and facts becoming a matter of opinion. Unfortunately, our political culture is crumbling just as rapid scientific breakthroughs confront us with some of the most serious moral, ethical and policy questions of our age.

And there is a real urgency. Scientific breakthroughs surrounding human gene editing, for instance, have moved medical treatments that seemed science fiction just a few years ago within scientists reach. Today, tools like CRISPR/Cas9 allow making modifications to the human genome in ways that are more efficient and safer than ever before. And the science emerges rapidly, constantly offering new venues for treating what used to be incurable diseases.

The idea of editing the human genome raises questions that science alone cannot answer. What are the ethical and moral boundaries of the human race editing its own genome? Who will have access to many of the potentially expensive medical treatments resulting from this new area of research? And where is the line between treating serious disease and enhancing humans beyond what society considers normal?

None of these questions have simple or obvious answers. What is needed are broad societal discussions, not just about the scientific risks and benefits, but also about the moral, political, and societal complexities surrounding human genome editing.

Even though the scientific community cannot provide definitive answers to some of these moral or political questions, meaningful public debate is impossible if it is not based on the best available science and accurate facts. We in the scientific community therefore have a special obligation to fully engage with a broader publicboth about the science of human gene editing and on the societal concerns that may arise from its applications.

As members of the National Academy of Science and National Academy of Medicine study committee that recently released its final report on human genome editing, we were tasked to offer opinions about the future direction and medical promise of breakthroughs in biology. We looked intensely through public hearings here and abroadas well through a literature reviewfor diverse voices on the moral, regulatory and ethical issues associated with multiple uses of these technologies. Our conclusions point to the hopes and perils these breakthroughs offer.

We all recognized that none of us could or should speak for the larger public. A central theme throughout our report was the need for the key decision makers in scienceboth private and governmentto commit to a robust, systemic, substantive and ongoing public dialog. The Genome Editing report was a step along that road, but it is not the final destination.

Some mechanisms for engagement are already in place, especially including when it comes to the approval of clinical trials within existing regulatory frameworks. But the need for broad public debate will likely emerge from questions that fall outside of the regulatory realm and deal with areas where science raises value-based or moral concerns.

For the scientific community, this will sometimes mean going beyond their comfort zone and engaging with a wide variety of audiences on questions of faith, morality, and values. It also means that the reason for the scientific community to engage in these debates is not to convince people of particular viewpoints or to promote this new technology. Instead, what all public engagement efforts should have in common is a commitment to listening to and respecting the voices of others, including ones from audiences less versed in the details or facts of the subject matter. And listening can start long before the engagement itself, using public opinion surveys, focus groups, and a host of other tools.

The broader scientific community also has a responsibility to engage as educators to offer facts to help inform the debate, particularly if faced with groups who intentionally misrepresent or ignore the best available science and facts that underline it. Scientists need to understand that a majority of citizens who may express concerns about human gene editing or its applications are neither ignorant nor wrong.

Policy choices for most citizens involve weighing different societal, political, moral, and scientific risks and benefits. It is very likely that some will agree with scientists that a technology like human gene editing is safe and still oppose it on moral or religious grounds. The relative weight we as citizens put on any risk or benefit depends on social contexts, including class or economic status, on media portrayals, and on personal value systems, to name just a few. All of those factors shape how we each recalculate our mental algorithms as new information about risks or benefits emerges.

Public engagement on human gene editing is not a box that we need to check before proceeding with potentially controversial applications. It is an ongoing process that will help science and society understand and navigate the societal, political and moral complexities that will emerge as CRISPR and other scientific breakthroughs continue to innovate medicine and many other areas of our lives.

In sum, the time for science policy setting being done exclusively by scientists is over, and when ethical and moral issues (like genome editing) arise the era of full public engagement has begun.

See more here:
Human Genome Editing: Who Gets to Decide? - Scientific American (blog)

May 17, 2017 Credit: CC0 Public Domain

Harvard Medical School researchers have mapped the interaction partners for proteins encoded by more than 5,800 genes, representing over a quarter of the human genome, according to a new study published online in Nature on May 17.

The network, dubbed BioPlex 2.0, identifies more than 56,000 unique protein-to-protein interactions87 percent of them previously unknownthe largest such network to date.

BioPlex reveals protein communities associated with fundamental cellular processes and diseases such as hypertension and cancer, and highlights new opportunities for efforts to understand human biology and disease.

The work was done in collaboration with Biogen, which also provided partial funding for the study.

"A gene isn't just a sequence of a piece of DNA. A gene is also the protein it encodes, and we will never understand the genome until we understand the proteome," said co-senior author Wade Harper, the Bert and Natalie Vallee Professor of Molecular Pathology and chair of the Department of Cell Biology at Harvard Medical School. "BioPlex provides a framework with the depth and breadth of data needed to address this challenge."

"This project is an atlas of human protein interactions, spanning almost every aspect of biology," said co-senior author Steven Gygi, professor of cell biology and director of the Thermo Fisher Center for Multiplexed Proteomics at Harvard Medical School. "It creates a social network for each protein and allows us to see not only how proteins interact, but also possible functional roles for previously unknown proteins."

Bait and prey

Of the roughly 20,000 protein-coding genes in the human genome, scientists have studied only a fraction in detail. To work toward a description of the entire cast of proteins in a cell and the interactions between themknown as the proteome and interactome, respectivelya team led by Harper and Gygi developed BioPlex, a high-throughput approach for the identification of protein interplay.

BioPlex uses so-called affinity purification, in which a single tagged "bait" protein is expressed in human cells in the laboratory. The bait protein binds with its interaction partners, or "prey" proteins, which are then fished out from the cell and analyzed using mass spectrometry, a technique that identifies and quantifies proteins based on their unique molecular signatures. In 2015, an initial effort (BioPlex 1.0) used approximately 2,600 different bait proteins, drawn from the Human ORFeome database, to identify nearly 24,000 protein interactions.

In the current study, the team expanded the network to include a total of 5,891 bait proteins, which revealed 56,553 interactions involving 10,961 different proteins. An estimated 87 percent of these interactions have not been previously reported.

Guilt by association

y mapping these interactions, BioPlex 2.0 identifies groups of functionally related proteins, which tend to cluster into tightly interconnected communities. Such "guilt-by-association" analyses suggested possible roles for previously unknown proteins, as these communities often commingle proteins with both known and unknown functions.

The team mapped numerous protein clusters associated with basic cellular processes, such as DNA transcription and energy production, and a variety of human diseases. Colorectal cancer, for example, appears to be linked to protein networks that play a role in abnormal cell growth, while hypertension is linked to protein networks for ion channels, transcription factors and metabolic enzymes.

"With the upgraded network, we can make stronger predictions because we have a more complete picture of the interactions within a cell," said first author Edward Huttlin, instructor of cell biology at Harvard Medical School. "We can pick out statistical patterns in the data that might suggest disease susceptibility for certain proteins, or others that might suggest function or localization properties. It makes a significant portion of the human proteome accessible for study."

Launching point

The entire BioPlex network and accompanying data are publicly available, supporting both large-scale studies of protein interaction and targeted studies of the function of specific proteins.

Although the network serves as the largest collection of such data gathered to date, the authors caution it remains an incomplete model. The current pipeline expresses bait proteins in only one cell type (human embryonic kidney cells) grown under one set of conditions, for example, and distinct interactions may occur in different cell types or microenvironments.

As the network increases in size and more human proteins are used as baits, scientists can better judge the accuracy of each individual protein interaction by considering its context in the larger network. Isolating the same protein complex several times, each time using a different member as a bait, can provide multiple independent experimental observations to confirm each protein's membership. Moreover, by using prey proteins as bait, many protein interactions can be observed in the opposite direction as well. Both of these scenarios greatly reduce the likelihood that particular interactions were identified due to chance. The team continues to add to BioPlex, with a target goal of around 10,000 bait proteins, which would cover half of the human genome and would further increase the predictive power of the network.

"We certainly aren't seeing all the interactions, but it's a launching point. We think it's important to continue to build this map, to see how much of it is reproduced in other cell types under different conditions, to see whether the interactions are similar or dynamic," Gygi said. "Because whether you're interested in cancer or neurodegenerative disease, basic development or evolutionary fitnessyou can make new hypotheses and learn something from this network."

Explore further: Facebook for the proteome

More information: Architecture of the human interactome defines protein communities and disease networks, Nature (2017). nature.com/articles/doi:10.1038/nature22366

Journal reference: Nature

Provided by: Harvard Medical School

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New study maps protein interactions for a quarter of the human ... - Phys.Org