Physicists confirm (what biologists have already konwn for years) there's a second layer of information hidden in our DNA

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Theoretical physicists have confirmed that it's not just the information coded into our DNA that shapes who we are - it's also the way DNA folds itself that controls which genes are expressed inside our bodies.

That's something biologists have known for years, and they've even been able to figure out some of the proteins responsible for folding up DNA. But now a group of physicists have been able to demonstrate for the first time through simulations how this hidden information controls our evolution.

Let's back up for a second here, because although it's not necessarily news to many scientists, this second level of DNA information might not be something you're familiar with.

As you probably learnt in high school, Watson and Crick discovered in 1953 that the DNA code that determines who we are is made up of a sequence of the letters G, A, C, and T. 

The order of these letters determines which proteins are made in our cells. So, if you have brown eyes, it's because your DNA contains a particular series of letters that encodes for a protein that makes the dark pigment inside your iris.

But that's not the whole story, because all the cells in your body start out with the exact same DNA code, but every organ has a very different function - your stomach cells don't need to produce the brown eye protein, but they do need to produce digestive enzymes. So how does that work?

Since the '80s, scientists have found that the way DNA is folded up inside our cells actually controls this process. Environmental factors can play a big role in this process too, with things like stress known to turn certain genes on and off through something known as epigenetics.

But the mechanics of the DNA folding is the original control mechanism. That's because every single cell in our body contains around 2 metres of DNA, so to fit inside us, it has to be tightly wrapped up into a bundle called a nucleosome - like a thread around a spool.

And the way the DNA is wrapped up controls which genes are 'read' by the rest of the cell - genes that are all wrapped on the inside won't be expressed as proteins, but those on the outside will. This explains why different cells have the same DNA but different functions.

In recent years, biologists have even started to isolate the mechanical cues that determine the way DNA is folded, by 'grabbing onto' certain parts of the genetic code or changing the shape of the 'spool' the DNA is wrapped around. 

So far, so good, but what do theoretical physicists have to do with all this?

A team from Leiden University in the Netherlands has now been able to step back and look at the process on a whole-genome scale, and confirm through computer simulations that these mechanical cues are actually coded into our DNA. 

The physicists, led by Helmut Schiessel, did this by simulating the genomes of both baker's yeast and fission yeast, and then randomly assigning them a second level of DNA information, complete with mechanical cues.

They were able to show that these cues affected how the DNA was folded and which proteins are expressed - further evidence that the mechanics of DNA are written into our DNA, and they're just as important in our evolution as the code itself.

This means the researchers have shown that there's more than one way that DNA mutations can affect us: by changing the letters in our DNA, or simply by changing the mechanical cues that arrange the way a strand is folded.

"The mechanics of the DNA structure can change, resulting in different packaging and levels of DNA accessibility," they explain, "and therefore differing frequency of production of that protein."

Again, this is confirming what many biologists already knew, but what's really exciting is the fact that the computer simulations open up the possibility for scientists manipulate the mechanical cues that shape DNA - which means they might one day be able to fold DNA to hide unwanted genes, like the ones that trigger disease.

We're a long way off doing that, but the more scientists understand about how our DNA is controlled and folded, the closer we get to being able to improve upon it. The research has been published in PLOS ONE. 

"Multiplexing Genetic and Nucleosome Positioning Codes: A Computational Approach". 

Behrouz Eslami-Mossallam Raoul D. Schram Marco Tompitak John van Noort Helmut Schiessel

Abstract

Eukaryotic DNA is strongly bent inside fundamental packaging units: the nucleosomes. It is known that their positions are strongly influenced by the mechanical properties of the underlying DNA sequence. Here we discuss the possibility that these mechanical properties and the concomitant nucleosome positions are not just a side product of the given DNA sequence, e.g. that of the genes, but that a mechanical evolution of DNA molecules might have taken place. We first demonstrate the possibility of multiplexing classical and mechanical genetic information using a computational nucleosome model. In a second step we give evidence for genome-wide multiplexing in Saccharomyces cerevisiae and Schizosacharomyces pombe. This suggests that the exact positions of nucleosomes play crucial roles in chromatin function.

Fig 1. Nucleosomal DNA model with bp step dependent mechanical properties.
(A) The rigid base-pair model is forced, using 28 constraints (indicated by red spheres), into a lefthanded superhelical path that mimics the DNA conformation in the nucleosome crystal structure [4].
(B) Fraction of dinucleotides GC and AA/TT/TA at each position along the nucleosome model found in 10 million high affinity sequences produced by MMC at 100 K. The solid and dashed lines indicate minor and major groove bending sites; the nucleosome dyad is at 0 bp. The model recovers the basic nucleosome positioning rules [1, 3].
(C) Same as (B), but on top of 1200 coding sequences (produced by sMMC). The same periodic signals are found albeit with a smaller amplitude.

Fig 2. Mechanical energy landscape along a 500 bp stretch of the YAL002W gene of S. cerevisiae.
(A) Elastic energy of the nucleosome model as a function of position obtained from a Monte Carlo simulation at 50 K.
(B) Effective energy including excluded volume between nucleosomes. In both, (A) and (B), the vertical lines indicate experimentally determined nucleosome positions from the unique nucleosome map [25].
(C) The top graph shows a fraction of the original landscape from (A), the five landscapes below are produced via sMMC with the nucleosome positioned at the corresponding dashed vertical line. The minima can be shifted freely on top of genes, proving that multiplexing is possible. 

Fig 3. Mechanisms underlying multiplexing.
(A) Energy landscape (black dashed curve) of a sequence with highly optimized nucleosome affinity at −5 bp, produced by MMC at very low temperature (15 K). The colored curves are landscapes for three synonymous mutants (three different codon frames) that are optimized via sMMC for high affinity at position 0. The maximum cannot be turned into a minimum in this case, signaling that multiplexing would not be possible on genomes if they were selected for highest nucleosome affinity. 

(B) Distribution of AA, TT and TA dinucleotides around minor groove bending site −25 bp for the shifted nucleosome from Fig 2C bottom. Dashed blue curves: natural preferences (attained through MMC), red curves: distribution obtained from sMMC on that particular stretch of the YAL002W gene; both simulations are performed at 100 K. Though not optimal, sMMC brings in AA at a position close to its preferred position (amplitude almost 1) indicating the plasticity of the mechanical code.

Fig 4. Multiplexing in two eukaryotic genomes.
(A) Normalized Fourier amplitudes for the distribution of the synonymous codons for threonine along nucleosomes on top of genes (purple curve) and for the distribution of the corresponding trinucleotides along nucleosomes outside genes (green curve) [25]. The peaks at 10 bp (indicated by an arrow) are due to nucleosome positioning that appears weaker on top of genes but might signal multiplexing instead.
(B) Same as (A), but for S. pombe [26].
(C) The normalized 10 bp amplitude inside vs. outside genes of all 20 amino acids for the two yeast species. The arrows indicate threonine. All points below the line have smaller amplitudes inside genes, a hallmark of multiplexing.

ORIGINAL: Science Alert
FIONA MACDONALD
9 JUN 2016

From Living Computers to Nano-Robots: How We’re Taking DNA Beyond Genetics

DNA is one of the most amazing molecules in nature, providing a way to carry the instructions needed to create almost any life form on Earth in a microscopic package. Now scientists are finding ways to push DNA even further, using it not just to store information but to create physical components in a range of biological machines.

Deoxyribonucleic acid or “DNA” carries the genetic information that we, and all living organisms, use to function. It typically comes in the form of the famous double-helix shape, made up of two single-stranded DNA molecules folded into a spiral. Each of these is made up of a series of four different types of molecular component: adenine (A), guanine (G), thymine (T), and cytosine (C).

Genes are made up from different sequences of these building block components, and the order in which they appear in a strand of DNA is what encodes genetic information. But by precisely designing different A, G, T and C sequences, scientists have recently been able to develop new ways of folding DNA into different origami shapes, beyond the conventional double helix.

This approach has opened up new possibilities of using DNA beyond its genetic and biological purpose, turning it into a Lego-like material for building objects that are just a few billionths of a meter in diameter (nanoscale). DNA-based materials are now being used for a variety of applications, ranging from templates for electronic nano-devices, to ways of precisely carrying drugs to diseased cells.

DNA-based nanothermometers

Designing electronic devices that are just nanometers in size opens up all sorts of possible applications but makes it harder to spot defects. As a way of dealing with this, researchers at the University of Montreal have used DNA to create ultrasensitive nanoscale thermometers that could help find minuscule hotspots in nanodevices (which would indicate a defect). They could also be used to monitor the temperature inside living cells.

The nanothermometers are made using loops of DNA that act as switches, folding or unfolding in response to temperature changes. This movement can be detected by attaching optical probes to the DNA. The researchers now want to build these nanothermometers into larger DNA devices that can work inside the human body.

Biological nanorobots

Researchers at Harvard Medical School have used DNA to design and build a nanosized robot that acts as a drug delivery vehicle to target specific cells. The nanorobot comes in the form of an open barrel made of DNA, whose two halves are connected by a hinge held shut by special DNA handles. These handles can recognize combinations of specific proteins present on the surface of cells, including ones associated with diseases.

When the robot comes into contact with the right cells, it opens the container and delivers its cargo. When applied to a mixture of healthy and cancerous human blood cells, these robots showed the ability to target and kill half of the cancer cells, while the healthy cells were left unharmed.

DNA barrel. Image credit: Campbell Strong, Shawn Douglas, and Gaël McGill.

Bio-computers in living animals

Because DNA structures can act as switches, moving from one position to another and back again, they can be used to perform the logical operations that make computer calculations possible. Researchers at Harvard and Bar-Ilan University in Israel have used this principle to build different nanoscale robots that can interact with each other, using their DNA switches to react to and produce different signals.

What’s more, the scientists implanted the robots into a living animal, in this instance a cockroach. This allowed them to develop a novel type of biological computer that can control the delivery of therapeutic molecules inside the cockroach by switching elements of their structure “on” or “off”. A trial of these DNA nanorobots is now scheduled to take place in humans.

Light-harvesting antennas

As well as creating minuscule machines, DNA can provide a way for us to copy natural processes at the nanoscale. For example, nature can capture energy from the sun using photosynthesis to convert light into chemical energy, which acts as fuel for plants and other organisms (and the animals that eat them). Researchers at Arizona State University and the University of British Columbia have now built a three-arm DNA structure that can capture and transfer light that mimics this process.

Photosynthesis occurs in living organisms thanks to tiny antennas made up of a large number of pigment molecules at specific orientations and distances from each other, which are able to absorb visible light. The artificial DNA-based structures act as similar antennas, controlling the position of specific dye molecules that absorb the light energy and channel it to a reaction centre where it is converted into chemical energy. This work could pave the way for devices capable of more efficiently using the most abundant source of energy we have at our disposal: sunlight.

So what’s next for DNA nanotechnology? It is hard to know but, with DNA, nature has given us a very versatile tool. It is now up to us to make the best use of it.

ORIGINAL: Singularity Hub

By MATTEO PALMA

ON JUN 07, 2016

Just a SmidgION: Oxford Nanopore announce iPhone-powered sequencing

CTO Clive Brown announces new Oxford Nanopore sequencing and library prep devices during his keynote address to the company’s user group conference

Stop the presses! Not something we call on a regular bases at FLG towers because, well, our work is largely digital. But when the latest news from Oxford Nanopore landed on our desks this afternoon, this old print journalism adage felt rather apt.

Clive Brown, CTO of Oxford Nanopore, talks at the London Calling Conference, via Oxford Nanopore

Yesterday, in his keynote address to the company’s user group conference in London, CTO Clive Brown announced the development of a new smartphone-powered nanopore sequencer, whimsically (and very Britishly) named ‘SmidgION’.

“Even I can’t believe they let me get away with that name,” chuckled Clive during his presentation.

Tiny SmidgION is currently in early-stage development

With 256 channels per flow cell, SmidgION will be smaller than the company’s existing MinION device, and is expected to come to market in 2017. 

MinION has established itself as a versatile field device, and is set to make history later this year as the first device used to sequence DNA in space. With SmidgION Oxford Nanopore are continuing to appeal to the field researcher, with potential applications in monitoring disease outbreaks, and real-time species identification in the fight against wildlife crime. 

Brown also revealed Project Zumbador, also in early development, a combined sample and library prep device that would deliver DNA captured on beads directly into the flow cell. Event attendee and one of our favourite genomics bloggers Keith Robison (Omics! Omics!) shared some images of the early prototype during his twitter coverage.

Zumbador prototype in hand #nanoporeconf pic.twitter.com/oOfzx97lGZ

— Keith Robison (@OmicsOmicsBlog) May 26, 2016

Note – Keith has now written his own coverage of the Oxford Nanopore announcements, including a photo diary in which he takes his personalised MinION device on a bike ride around London.

Interestingly, Brown also announced that Oxford Nanopore are no longer selling devices that contain the R7 nanopore. R7 has given way to R9, the company’s name for a membrane protein derived from Escherichia coli. This development may help the company to side-step a recent legal challenge from Illumina, which claimed that the R7 pore infringed a patent license. Oxford Nanopore licensed the new pore from VIB in Belgium and University College London in March 2016.

ORIGINAL: Front Line Genomics

Liz Harley

27 MAY 16

After a secret meeting, scientists announce they are making synthetic human genomes

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It's happening.

An international group of scientists has just announced their plan to create a synthetic human genome within 10 years - which means they're going to try to write a brand new DNA code for human life from scratch.

The ambitious undertaking, called Human Genome Project-write, could be the key to understanding human disease better than ever before, and it could also greatly reduce the cost of genetic sequencing. It's an incredibly exciting project for science, but what's worrying some is the fact that the project has been launched without the public having been properly consulted on any ethical concerns.

Rumours about the new project started last month, when 150 scientists met in a closed-door meeting at Harvard Medical School to talk about building an entirely synthetic human genome.

The fact that journalists weren't allowed to be at the meeting was met with criticism, and now 25 of the researchers have outlined their proposal in Science- although it hasn't done much to relieve concerns. 

Posed as an unofficial follow-up to the hugely important Human Genome Project (HGP) - which ended in 2004 and resulted in the complete mapping of our genetic code - the goal of HGP-write is to take things one step further and not just read our genomes, but create them.

The expectation is that this research, if nothing else, will drop the price of genetic engineering and testing 1,000-fold over the next decade - which would be pretty incredible, seeing as we're already able to sequence an entire genome for under US$1,000 today.

"[T]he goal of HGP-write is to reduce the costs of engineering and testing large genomes, including a human genome, in cell lines, more than 1,000-fold within 10 years, while developing new technologies and an ethical framework for genome-scale engineering as well as transformative medical applications," the researchers wrote in a draft of a press release obtained by

The Washington Post (no official press release has been put out as yet).

To pull this off, the scientists say they'll attempt to raise US$100 million of private and public funding over the next decade, and collaborate with international groups in order to get it done.

And as cool as that would be, they've definitely got their work cut out for them. Although scientists have managed to create synthetic genomes for bacteria the past, writing a complete human DNA code is going to be A LOT harder.

As Bec Crew reported for us back in May, creating a synthetic human genome "means figuring out which chemicals are needed to create the 3 billion bases of DNA that sit inside the 23 pairs of chromosomes found inside every cell nucleus in our body".

Oh, and then they're going to have to work out where all those chemicals go, put them together in lab in the right order, and then arrange them so that they can direct a cell to stay alive.

The good news is that this crazily ambitious project could teach us a whole lot about our biology and disease. But, as someone on Facebook is bound to point out to you today, it could also help scientists get one step closer to creating 'designer babies'.

The concern is that this kind of research could teach us more about how to engineer humans that are resistant to disease, or are exceptionally strong or intelligent. While it's actually not as simple as programming whatever traits we want, it's definitely something we'd be closer to after this project. 

To be very clear, that isn't anywhere near the intention of this project. The researchers state outright that their project will end in the petri dish, and they have no intention of keeping any of the human genome cell lines alive.

But critics are saying that the problem is that the proposal laid out in Science still really doesn't deal with the ethical concerns that it brings up.

The team does write that they "will enable broad public discourse on HGP-write; having such conversations well in advance of project implementation will guide emerging capabilities in science and contribute to societal decision-making", though they don't really outline exactly what questions those discussions will involve. 

There are existing stem cell research guidelines that will apply to their research, but because this is such a new undertaking, the researchers will have the responsibility of creating many new rules as they go.

"Before launching into such a momentous project, questions need to be asked," including whether it should even occur, Stanford University bioengineer Drew Endy told MIT Technology Review. "The authors fail to pose these essential questions. In fact, in their proposal, they fail to pose any questions."

But for all those ethical concerns, the undeniable truth is that this project is probably going to benefit all of us, and our children, in ways we can't even imagine.

"This is as bold an aim as the original human genome project and the authors of this Science paper acknowledge that their new aim will be met with similar controversy as the original HGP had to contend with," synthetic biologist John Ward, from University College London, told the Genetic Expert News Service via email.

"But its now well accepted that the original HGP opened up the possibility and increasingly, the reality, for new medical treatments in human genetic diseases and cancer and we will be reaping the benefits of this for decades to come," he added.

Talking about such an ambitious program again should be incredibly exciting, but as much as we love to see science advance our understanding of biology to all new heights, projects like this need to come with the appropriate level of ethical discussion - if only for the fact that without upfront, transparent discussion, the public is never going to trust what's going on.

And in a world of misinformation, anti-vaxxers, and climate change denial, the last thing we need is to give people a reason to be wary of science.

Let's do this, but let's do it right.

ORIGINAL: Science Alert
FIONA MACDONALD
3 JUN 2016

Should we synthesise a human genome?

As specialists gather in private to discuss a grand plan for constructing a human genome, Drew Endy and Laurie Zoloth argue that such an enormous moral gesture should not be discussed behind closed doors.

CREDIT: MARIO TAMA/GETTY IMAGES

At Harvard today, an invitation-only group of about 150 scientists, lawyers, and entrepreneurs, met to discuss if and how to construct from scratch an entire human genome – the heritable genetic material that in nature is transferred from parents to children.

The meeting was originally organised to focus on “deliverables and industry involvement” with the primary goal of the project being “to synthesise a complete human genome in a cell line within a period of 10 years”.

Such a synthetic genome could then be tested in a laboratory by replacing the existing genome within a human cell. All this would still be far removed from making a synthetic human.

However, the possibility of making a human cell, whose genome is realised from only digital information and raw materials, should trigger broader considerations. 

For context, total synthesis of a human genome is becoming plausible at an accelerating rate. Thanks to new production techniques developed since 2003 the cost of assembling the genetic material encoding genes, the “building blocks” of life, has decreased from $4.00 to just three cents per individual letter, or “base pair” of deoxyribonucleic acid (DNA). 

As a result, the estimated initial cost of printing the DNA fragments encoding a three billion base pair human genome has dropped from $12 billion to $90 million. 

If cost reductions continue in the way they have been, then this price would approach $100,000 within 20 years. However, such dramatic additional cost reductions might never be realised without an overwhelming demand.

Advocates of synthetising a human genome, therefore argue that some open, collaborative “grand challenge” is needed to drive development of such technologies. 

While we strongly agree that sustained improvements in DNA construction tools are essential for advancing basic biological science and improving public health we are sceptical that synthesising a human genome is an appropriate demand driver.

We recall how controversies associated with many of the earliest genome synthesis projects delivered unintended consequences. 

For example, a project that made polio virus from scratch in 2002 generated such fear that public funding for improving DNA synthesis tools was cancelled, unwittingly harming research across diverse and unrelated fields while policy makers struggled to imagine how such tools could ever be controlled.

We argue that the synthesis of less controversial and more immediately useful genomes along with greatly improved sub-genomic synthesis capacities (for example, the real-time printing of plasmids the casettes that transfer genes between cells) should be pursued instead.

"In a world where human reproduction has already become a competitive marketplace...
it is easy to make up far stranger uses of human genome synthesis."

These are alternatives that would deliver broad and diverse public benefits.

Other topics on today’s agenda included changing the human genome itself. For example, could scientists synthetise a modified human genome that is resistant to all natural viruses? 

They likely could, for purely beneficial purposes, but what if others then sought to synthesise modified viruses that overcame such resistance? Might doing so start a genome-engineering arms race? 

And, what of even greater changes that can be imagined?

In a world where human reproduction has already become a competitive marketplace, with eggs, sperm and embryos carrying a price, it is easy to make up far stranger uses of human genome synthesis capacities. 

Would it be OK, for example, to sequence and then synthesise Einstein’s genome? If so how many Einstein genomes should be made and installed in cells, and who would get to make them? 

Taking a step back, just because something becomes possible, how should we approach determining if it is ethical to pursue?

Given that human genome synthesis is a technology that can completely redefine the core of what now joins all of humanity together as a species, we argue that discussions of making such capacities real, like today’s Harvard conference, should not take place without open and advance consideration of whether it is morally right to proceed.

When the first people at the table mostly have significant and direct material interests in proceeding, everyone, not just those in the room, risk out-of-control competition between public and private interests, ethical conflicts of interest, and temptations to manipulate human subject consent.

Pluralistic, public, and deliberative discussions are instead the best appropriate way to frame paths forward.

We note that the narrative of creation of the human is the central narrative for many religious communities.

To create a human genome from scratch would be an enormous moral gesture whose consequences should not be framed initially on the advice of lawyers and regulators alone.

The perspectives of others including self-identified theologians, philosophers, and ethicists from a variety of traditions should be sought out from the very beginning.

Critical voices representing civil society, who have long been sceptical of synthetic biology’s claims, should also be included. 

The creation of new human life is one of the last human-associated processes that has not yet been industrialised or fully commodified. It remains an act of faith, joy, and hope. 

Discussions to synthetise, for the first time, a human genome should not occur in closed rooms. 

Drew Endy is Associate Professor of Bioengineering at Stanford University.

Laurie Zoloth is a professor of medical ethics and humanities at Northwestern University, Chicago.

ORIGINAL: Cosmos Magazine

Scientists Seek Ban on Method of Editing the Human Genome

Jennifer A. Doudna, an inventor of a new genome-editing technique, in her office at the University of California, Berkeley. Dr. Doudna is the lead author of an article calling for a worldwide moratorium on the use of the new method, to give scientists, ethicists and the public time to fully understand the issues surrounding the breakthrough. Credit Elizabeth D. Herman for The New York Times

A group of leading biologists on Thursday called for a worldwide moratorium on use of a new genome-editing technique that would alter human DNA in a way that can be inherited.
The biologists fear that the new technique is so effective and easy to use that some physicians may push ahead before its safety can be assessed. They also want the public to understand the ethical issues surrounding the technique, which could be used to cure genetic diseases, but also to enhance qualities like beauty or intelligence. The latter is a path that many ethicists believe should never be taken.

“You could exert control over human heredity with this technique, and that is why we are raising the issue,” said David Baltimore, a former president of the California Institute of Technology and a member of the group whose paper on the topic was published in the journal Science.
Related Coverage


A Powerful New Way to Edit DNA  MARCH 3, 2014


Matter: In Short-Lived Fish, Secrets to Aging FEB. 27, 2015

Ethicists, for decades, have been concerned about the dangers of altering the human germline — meaning to make changes to human sperm, eggs or embryos that will last through the life of the individual and be passed on to future generations. Until now, these worries have been theoretical. But a technique invented in 2012 makes it possible to edit the genome precisely and with much greater ease. The technique has already been used to edit the genomes of mice, rats and monkeys, and few doubt that it would work the same way in people.

The technique holds the power to repair or enhance any human gene. “It raises the most fundamental of issues about how we are going to view our humanity in the future and whether we are going to take the dramatic step of modifying our own germline and in a sense take control of our genetic destiny, which raises enormous peril for humanity,” said George Q. Daley, a stem cell expert at Boston Children’s Hospital and a member of the group.

The biologists writing in Science support continuing laboratory research with the technique, and few if any scientists believe it is ready for clinical use. Any such use is tightly regulated in the United States and Europe. American scientists, for instance, would have to present a plan to treat genetic diseases in the human germline to the Food and Drug Administration.

The paper’s authors, however, are concerned about countries that have less regulation in science. They urge that “scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans” until the full implications “are discussed among scientific and governmental organizations.”

Though such a moratorium would not be legally enforceable and might seem unlikely to exert global influence, there is a precedent. In 1975, scientists worldwide were asked to refrain from using a method for manipulating genes, the recombinant DNA technique, until rules had been established.

“We asked at that time that nobody do certain experiments, and in fact nobody did, to my knowledge,” said Dr. Baltimore, who was a member of the 1975 group. “So there is a moral authority you can assert from the U.S., and that is what we hope to do.”

Recombinant DNA was the first in a series of ever-improving steps for manipulating genetic material. The chief problem has always been one of accuracy, of editing the DNA at precisely the intended site, since any off-target change could be lethal. Two recent methods, known as

• zinc fingers and 
• TAL effectors, 

came close to the goal of accurate genome editing, but both are hard to use. The new genome-editing approach was invented by Jennifer A. Doudna of the University of California, Berkeley, and Emmanuelle Charpentier of Umea University in Sweden.

Their method, known by the acronym Crispr-Cas9, co-opts the natural immune system with which bacteria remember the DNA of the viruses that attack them so they are ready the next time those same invaders appear. Researchers can simply prime the defense system with a guide sequence of their choice and it will then destroy the matching DNA sequence in any genome presented to it. Dr. Doudna is the lead author of the Science article calling for control of the technique and organized the meeting at which the statement was developed.

Though highly efficient, the technique occasionally cuts the genome at unintended sites. The issue of how much mistargeting could be tolerated in a clinical setting is one that Dr. Doudna’s group wants to see thoroughly explored before any human genome is edited.

Scientists also say that replacing a defective gene with a normal one may seem entirely harmless but perhaps would not be.

“We worry about people making changes without the knowledge of what those changes mean in terms of the overall genome,” Dr. Baltimore said. “I personally think we are just not smart enough — and won’t be for a very long time — to feel comfortable about the consequences of changing heredity, even in a single individual.”

Many ethicists have accepted the idea of gene therapy, changes that die with the patient, but draw a clear line at altering the germline, since these will extend to future generations. The British Parliament in February approved the transfer of mitochondria, small DNA-containing organelles, to human eggs whose own mitochondria are defective. But that technique is less far-reaching because no genes are edited.

There are two broad schools of thought on modifying the human germline, said R. Alta Charo, a bioethicist at the University of Wisconsin and a member of the Doudna group.
One is pragmatic and seeks to balance benefit and risk.
The other “sets up inherent limits on how much humankind should alter nature,” she said.
Some Christian doctrines oppose the idea of playing God, whereas in Judaism and Islam there is the notion “that humankind is supposed to improve the world.” She described herself as more of a pragmatist, saying, “I would try to regulate such things rather than shut a new technology down at its beginning.”

Other scientists agree with the Doudna group’s message. “It is very clear that people will try to do gene editing in humans,” said Rudolf Jaenisch, a stem cell biologist at the Whitehead Institute in Cambridge, Mass., who was not a member of the Doudna group. “This paper calls for a moratorium on any clinical application, which I believe is the right thing to do.”

Writing in Nature last week, Edward Lanphier and other scientists involved in developing the rival zinc finger technique for genome editing also called for a moratorium on human germline modification, saying that use of current technologies would be “dangerous and ethically unacceptable.”

The International Society for Stem Cell Research said Thursday that it supported the proposed moratorium.

The Doudna group calls for public discussion, but is also working to develop some more formal process, such as an international meeting convened by the National Academy of Sciences, to establish guidelines for human use of the genome-editing technique.

“We need some principled agreement that we want to enhance humans in this way or we don’t,” Dr. Jaenisch said. “You have to have this discussion because people are gearing up to do this.”


ORIGINAL: NYTimes

By NICHOLAS WADE 

MARCH 19, 2015

Scientists Successfully Insert Woolly Mammoth DNA Into Elephant Genome

Photo credit: AuntSpray/ Shutterstock

In true "Jurassic Park" style, scientists at Harvard University have successfully managed to insert genes from the woolly mammoth into the genome of an elephant. While this may represent significant progress in the field, lead researcher George Church has reportedly played down claims that the work brings us closer to recreating these iconic animals.

Woolly mammoths (Mammuthus primignius) may have appeared more than 400,000 years ago during the middle Pleistocene, but they actually didn’t die out all that long ago. Alongside most other large mammal species residing in the Northern Hemisphere, they disappeared from most of their range across mainland Eurasia and North America about 10,000 years ago, but a small population of some 500-1,000 individuals survived on Wrangel Island in the Arctic Ocean for a further 6,000 years.

New Genome Sequences Reveal the Bird Tree of Life

A global, four-year project involving hundreds of scientists shows how avian lineages diverged after the dinosaurs’ extinction.

ERIC JARVIS DESCRIBES HOW THE MASSIVE AVIAN GENOME PROJECT REVEALED KEY RELATIONSHIPS AND EVENTS WITHIN BIRD EVOLUTION. | AAAS/ CARLA SCHAFFER

An international team of researchers has sequenced the genomes of 45 avian species and created the most reliable tree of life for birds to date. Their new avian family tree helps to clarify how modern birds — the most species-rich class of four-limbed vertebrates on the planet — emerged rapidly from a mass extinction event that wiped out the dinosaurs about 66 million years ago.

It also reveals how some of the earliest branches on the bird tree of life diverged, answering many long-standing questions about the common ancestor of birds, crocodilians, and dinosaurs. The findings shed new light on the evolution of avian sex chromosomes, vocal learning in both birds and humans, and the process that led to birds losing their teeth.

The massive comparative genomics project took more than four years to complete and involved hundreds of scientists from about 80 institutions in 20 different countries. The collaboration culminated in multiple studies, eight of which are published in the 12 December issue of Science. Others are published in journals such as Genome Biology and GigaScience.

The research was led by

• Guojie Zhang from BGI in Shenzhen, China, and the University of Copenhagen in Denmark; 
• Erich Jarvis from the Howard Hughes Medical Institute and Duke University in Durham, North Carolina; and 
• Thomas Gilbert from the Natural History Museum of Denmark and Curtin University in Australia. 

With the expertise of colleagues from around the world, they were able to sequence at least one genome from every major modern bird lineage.

Zhang and his colleagues described their analysis of 48 avian genomes, including the 45 new sequences that they contributed (crow, duck, pigeon, falcon, woodpecker, eagle, ostrich, and many more) along with three genomes that were already available (chicken, turkey, and zebra finch). Their findings help to explain why bird genomes, in general, are about 70% smaller than those of mammals.

BIRD SPECIMENS FROM THE NATIONAL MUSEUM OF NATURAL HISTORY IN WASHINGTON, D.C. ILLUSTRATE SOME OF THE DIVERSE AVIAN SPECIES WHOSE GENOMES WERE SEQUENCED FOR THE PROJECT. | AAAS/ CARLA SCHAFFER

"One major reason that bird genomes are so small is because they don't have much repetitive DNA," explained Zhang during a webcast teleconference. "Another reason is that bird genomes have experienced massive gene loss in their ancestral stages. At least 1,600 genes have been lost in all bird genomes. Many of these genes actually have essential functions in humans, including some related to reproduction, skeleton formation, and lung systems."

"The loss of these key genes may have a significant effect on the evolution of many distinct phenotypes of birds," he continued. "Like their loss of teeth and dysfunction of one of their ovaries."

The analysis also revealed that the earliest common ancestor of land birds, which include parrots and songbirds as well as hawks and eagles, was a predator at the top of its food chain.

In a separate report, Jarvis and colleagues showed that protein-coding genes are not enough to get accurate phylogenetic trees. They suggested that researchers must include non-coding sequences of DNA as well as regions between the genes to provide a more accurate picture.

"In the past, people have been using one, two — up to 10 or 20 genes — to try to infer [bird] species relationships over the last 100 million years or so," said Jarvis. "Our theory has been: If you take the whole genome, you would have a more accurate species tree than just one or two genes [could provide] alone."

Their approach required more than 300 years of CPU time on several supercomputers, but they suggest that it could enable other groups of researchers to reconstruct similar, high-quality species trees for other challenging datasets in the future.

Ed Green from the University of California in Santa Cruz, California, and colleagues described the first sequencing of three crocodilian genomes — the American alligator, the saltwater crocodile, and the Indian gharial — which represent birds' closest living relatives. They revealed that the genomes of such crocodilians are evolving at an exceptionally slow pace.

THE INDIAN GHARIAL IS ONE OF THE CLOSEST LIVING RELATIVES OF BIRDS. | CHRISTOPHER BROCHU

"The molecular evolution of birds is much faster than it is in crocs, turtles, and other reptilian lineages," said Green. "So this avian lineage seems to be faster than other reptiles, but not faster than mammals."

Some of the other Science reports explore long-standing mysteries of bird biology. Qi Zhou from the University of California in Berkeley, California, and colleagues, for example, used the new avian genome sequences to explain how sex chromosomes have evolved in birds. Unlike the human Y chromosome, the avian W chromosome still has many active genes, and sex chromosomes of various bird species are currently at different stages of evolution, they write.

READ MORE ABOUT

THE NEW BIRD FAMILY TREE

SCIENCE AVIAN GENOME

Andreas Pfenning from Duke University with support from the Howard Hughes Medical Institute, along with his colleagues, exploited the sequences to study the molecular specializations between brain circuits that are important for singing in vocal-learning birds and speech in humans. Osceola Whitney, also from Duke University, and his colleagues determined that a whopping 10% of a bird's genome is regulated by singing, with highly diverse patterns across singing brain regions mediated by differences in gene expression.

Robert Meredith from Montclair State University in Montclair, New Jersey, and colleagues suggests that the mutations that eliminated enamel and dentin from the teeth of modern birds, an event which eventually led to toothless beaks-began about 116 million years ago.

Taken together, these reports support the theory of a "big bang" for bird evolution, with many species emerging rapidly during the 10 to 15 million years that followed the dinosaurs' extinction at the Cretaceous-Paleogene Boundary. They're poised to provide a model for other comparative genomics projects for the foreseeable future.

ORIGINAL: AAAS

Brandon Bryn

Natasha D. Pinol

11 December 2014