Sunday, April 10, 2016

How extinct humans left their mark on us





Most people in the world share 2-4% of DNA with Neanderthals while a few inherited genes from Denisovans, a study confirms.
Denisovan DNA lives on only in Pacific island dwellers, while Neanderthal genes are more widespread, researchers report in the journal Science.
Meanwhile, some parts of our genetic code show little trace of our extinct cousins.
They include hundreds of genes involved in brain development and language.
"These are big, truly interesting regions," said co-researcher Dr Joshua Akey, an expert on human evolutionary genetics from the University of Washington Medicine, US.
"It will be a long, hard slog to fully understand the genetic differences between humans, Denisovans and Neanderthals in these regions and the traits they influence."

Siberia cave

Studies of nuclear DNA (the instructions to build a human) are particularly useful in the case of Denisovans, which are largely missing from the fossil record.
The prehistoric species was discovered less than a decade ago through genetic analysis of a finger bone unearthed in a cave in northern Siberia.

Image copyright BENCE VIOLA
Image caption The Neanderthal remains were found in a cave in Siberia
Substantial amounts of Denisovan DNA have been detected in the genomes of only a handful of modern-day human populations so far.
DNA of girl from Denisova cave gives up genetic secrets - BBC
"The genes that we found of Denisovans are only in this one part of the world [Oceania] that's very far away from that Siberian cave," Dr Akey told BBC News.
Where the ancestors of modern humans might have had physical contact with Denisovans is a matter of debate, he added.
Denisovans may have encountered early humans somewhere in South East Asia and, eventually, some of their descendants arrived on the islands north of Australia.
Meanwhile, humans repeatedly ran into Neanderthals as they spread across Eurasia.
"We still carry a little bit of their DNA today," said Dr Akey. "Even though these groups are extinct their DNA lives on in modern humans."

Genetic ancestry

The research was carried out by several scientists, including Svante Paabo of the Department of Evolutionary Genetics at the Max-Planck-Institute for Evolutionary Anthropology.
They found that all non-African populations inherited about 1.5-4% of their genomes from Neanderthals.
However, Melanesians were the only population that also had significant Denisovan genetic ancestry, representing between 1.9% and 3.4% of their genome.
"I think that people (and Neanderthals and Denisovans) liked to wander," said Benjamin Vernot of the University of Washington, who led the project.
"And yes, studies like this can help us track where they wandered."

Caveman's best friends? Preserved Ice Age puppies awe scientists

AFP
Moscow (AFP) - The hunters searching for mammoth tusks were drawn to the steep riverbank by a deposit of ancient bones. To their astonishment, they discovered an Ice Age puppy's snout peeking out from the permafrost.
Five years later, a pair of puppies perfectly preserved in Russia's far northeast region of Yakutia and dating back 12,460 years has mobilised scientists across the world.
"To find a carnivorous mammal intact with skin, fur and internal organs -- this has never happened before in history," said Sergei Fyodorov, head of exhibitions at the Mammoth Museum of the North-Eastern Federal University in the regional capital of Yakutsk.
And the discovery could contribute to the lively scientific debate over the origin of domesticated dogs.
When the hunters stumbled on the first frozen pup in 2011, they alerted Fyodorov who immediately flew out to the remote Arctic tundra, about 4,700 kilometres (2,900 miles) from Moscow and only 130 kilometres from the Laptev Sea, which borders the Arctic Ocean.
Last year he returned for a more thorough look and found the second puppy close to the same spot, farther down the slope. Both had died when they were about three months old.
They most likely come from the same litter, said Fyodorov.
Last week he oversaw the removal of the second puppy's remarkably well-preserved brain -- "the first in the world", he said.
"Puppies are very rare, because they have thin bones and delicate skulls," he said.
The duo have been named the Tumat Dog, after the nearest village to the site.
Fyodorov said a preliminary look at the mammoth remains also found at the dig suggested some had been butchered and burned, hinting at the presence of humans. It remains to be seen, however, whether the puppies were domesticated or wild.
The answer can only be determined by reconstructing their genomes, which would take at least a year.
- Grass-eating dogs? -

"Thus far, the lineages of wolves that likely gave rise to dogs have not yet been discovered and it's possible that these puppies could be on that lineage, which would be very exciting," said evolutionary biologist Greger Larson of University of Oxford, one of the scientists behind a collaborative project aimed at finding out when and where dogs became the first domesticated animals.
What makes the dog particularly intriguing is that it managed to become "man's best friend" even before humans became settled farmers.
It is still unclear whether dogs were domesticated in one place or in several places independently, and whether the process started when humans took in cubs or whether wolves themselves gradually drifted to human sites in search of food.
Whatever their precise lineage, the Tumat pups will keep Fyodorov and other scientists busy for some time.
The second puppy's preserved brain will be compared with that of modern dogs and wolves. Parasites found on its body will be analysed, as will the contents of its stomach, which Fyodorov is particularly excited about.
"When we opened it, we were very surprised. The second puppy's stomach is mostly full of twigs and grass," he said, wondering if perhaps the animals were not exclusively carnivorous or whether they


"This material is really exceptional and unique," said Mietje Germonpre, a palaeontologist from the Royal Belgian Institute who partnered up with Fyodorov on the project and came to Yakutsk to oversee the autopsy of the second puppy earlier this month.
"The fact that soft tissue is preserved will give much more information compared to information that can be obtained from 'normal' fossils," she said, meaning bones and teeth.
- Permafrost secrets -
Fyodorov lamented the long time it takes to get ancient biological material to suitable labs due to financial constraints, the rugged terrain and red tape which sometimes means that samples reach laboratories only six months later.
"Everyone understands that the tissue of mammoth fauna loses its structure with every passing second, even in the freezer," he said.
Yakutia's melting permafrost is likely to yield up even more treasures in the coming years, he added, saying the number of reported prehistoric finds has grown "severalfold" in the last decade.
Warm and wet weather and flash floods have been a big contributor to the thaw, he said.
"Right now it's 0 degrees (Celsius) here. That should not be the case in March."
As better transport and technology becomes affordable, he said, locals are embarking on expeditions to more and more remote corners of Siberia to look for the precious and lucrative mammoth tusks, which can sell for tens of thousands of dollars and are increasingly prized by Chinese carvers given trade bans on elephant ivory.
In Russia, indigenous tribes are allowed to hunt for ancient remains on their ancestral lands.
"Our land is locked in by permafrost, but little by little it is revealing its secrets," Fyodorov said.

When Neanderthals and Modern Humans Meet

Chinese researchers have genetically modified human embryos—yet again

http://qz.com

Less than a year ago, when a group of leading researchers was calling for a moratorium on the use of a revolutionary technology, Chinese researchers shocked the world by using it to genetically modify human embryos. The worry was that unfettered access to the technology might enable such embryos to become fully grown humans, who will then pass on mutations to all their offspring. The risk of unintended consequences seemed too great.
Now a different group of Chinese researchers have again wielded the technology to genetically modify human embryos. This time, however, the reaction from some scientists is just an annoyed shrug. Clearly a lot happened in the last year for perceptions to change so drastically.
The technology in question is called CRISPR, and it allows researchers to make genetic modifications with greater precision than ever before. In 2015, Chinese researchers used CRISPR to target genes responsible for a blood disorder called β-thalassaemia. They were only able to replace the defective gene in 28 out 71 embryos. Worse still, it left a slew of unintended changes in other parts of the genome.
In the latest attempt, researchers at Guangzhou Medical University have gone a step ahead. Instead of trying to correct mutations that could cause disease, they used CRISPR technology to insert a genetic mutation which might offer resistance against HIV.
The mutation was targeted in the CCR5 gene, which is responsible for producing a protein that HIV uses to latch on, enter, and infect a human immune cell. If the CCR5 gene were mutated, the logic goes, the HIV virus would not be able to infect—and thus the mutation would confer resistance to the disease.
The researchers report in the Journal of Assisted Reproduction and Genetics that they were successfully inserted the mutated gene in four out of 26 embryos. And, even in the successful cases, not all copies of the CCR5 gene were modified. In other cases mutations were caused that weren’t intended.
The experiment had been approved by a local ethics committee, which ensured that the study followed Chinese government guidelines. All the experimental human embryos were “non-viable,” which means they would have been unable to become fully grown humans. Such abnormal embryos are an inevitable part of in-vitro fertilization therapy, where sometimes two sperms insert their DNA into a single egg.
“The results are both comforting and disturbing,” says Peter Donovan of the University of California at Irvine. “The good news is that the technique worked for this group in the same way that it did for the first group… an important part of the scientific process showing it wasn’t a fluke the first time. The salutary lesson is that there is still much to be learned about gene editing in human embryos before it is ready for prime time.”
The rate of failure has made some bioethicists and scientists question the motives of Chinese researchers who continue to test CRISPR in human embryos. They argue that, while CRISPR offers greater precision, it still isn’t ready for testing in human embryos. Others, like Donovan, maintain that it will be studies using donated human embryos that will give us the most understanding.
Despite the divided opinion, there is definitely a change in perception. The first study reporting the genetic modification of human embryos resulted in a summit held in November between the science academies of China, the US and the UK. After days of deliberation, the world’s leading geneticists agreed that, while no CRISPR-modified embryos should become full human beings, research using human embryos can continue.
The Chinese group that did the latest work insists that their “proof-of-concept” may provide solutions to improving human health. They write, “Despite the significant scientific and ethical issues involved, however, we believe that it is necessary to keep developing and improving the technologies for precise genetic modifications in humans.

http://qz.com/

2015 was the year it became OK to genetically engineer babies


December 22, 2015
In April of this year, researchers in China published the results of an experiment in modifying the DNA of human embryos. Though the embryos they worked on were damaged ones that could not have grown into living babies, it sent a tremor through the scientific establishment.
Just a month earlier, a group of leading geneticists had called for a moratorium on gene-editing in embryos. Since any genetic changes would get passed on to future generations, they argued, the risk of unintended consequences was too great. And in November, at a summit in Washington DC, scientists from across the world agreed that, while research should continue, it’s still too risky to allow any altered embryos to grow into full human beings.
And, yet, when historians of science look back decades from now, they may well mark 2015 as the year genetically engineering humans became acceptable. That’s because, while the world was paying attention to the gene-editing summit, a more momentous decision had been made just a month earlier in the UK. There, a governmental body got ready to hand out licenses for creating a particular kind of genetically engineered human—using a technique the US tried and then banned 13 years ago.
This technique won’t create the fabled “designer babies” just yet. But the changes made to an embryo will be hereditary, and thus alter the genetic makeup of all the offspring to follow. The story of how we got here, and what will come next, is why 2015 will be remembered as a turning-point.


Just getting better

Our ability to do some form of genetic engineering goes back 40,000 years. Selective breeding created a tamer and more likable version of a wolf, the common ancestor of all today’s dogs.
Our desire to design better humans is also old. In Plato’s Republic, Socrates calls for a state-run program to get the best citizens to mate so that the population could be improved.
By the 19th century, the ideology of eugenics—a word not invented by Plato, but coined much later from the Greek for “good breeding”—had taken such a hold that countries were passing laws for such programs. Before World War II, 30 states in the US had passed some form of eugenics laws that mandated sexual sterilization of those deemed unfit (typically the mentally ill).
Only after the horror of Hitler’s genocide did the world recoil from eugenics. Most geneticists never returned to the idea that biological intervention would build a better society than social intervention. As Nathaniel Comfort, a professor of history of medicine, writes in Aeon, eugenics survived only in the form of “preventive medicine for genetic diseases”—such as screening people for them and, occasionally, treating them with gene therapy.
Not everyone stopped trying. Taking inspiration from Aldous Huxley’s Brave New World, eugenicist Robert Graham created the Repository for Germinal Choice, a sperm bank for the super-intelligent. The bank existed from 1980 to 1999 and had some 19 high-IQ donors, including at least one Nobel laureate (William Shockley).
The resulting “Genius Babies ”—some 200 of them—are no different from normal people. One of those conceived through Graham’s sperm bank told CNN, “There’s only so much you can control when it comes to genetics. It all has to do with what you give to your family.”


Beyond our control

That comment defines the limits of science today. In the 1970s, we finally understood how to tweak the genes of microbes, plants and animals to achieve certain traits. But in humans, with the exception of a few things such as color blindness or tasting certain foods, “designer baby” traits, such as greater intelligence, taller stature, stronger muscles, or better memory, are controlled by hundreds of genes, each of which also perform many other critical functions. Tools that can deal with such complexity are still a long way off.
For now, then, the only foreseeable use for gene-editing is to prevent disease. And the goal is to make genetic tools good enough to do that without any unintended consequences.
Since 1989, thousands of people have received experimental gene therapies. Typically these involve the use of a “vector”—a biological vehicle, such as a virus, that can deliver the correct copy of a faulty gene to the specific cells in the body affected by the genetic disorder, such as cancer cells or faulty cells in the eye.
While most of these treatments have been safe, only a few have been effective. China approved the world’s first gene therapy in 2003 to treat certain kinds of cancers. Europe got its first in 2012 that treats a rare inherited disorder (pdf) affecting the pancreas. The US is likely to get its first gene therapy approved in 2016 to treat a form of blindness.
None of these therapies, however, have used the latest advance in gene-editing: CRISPR-Cas9, a highly precise copy-and-paste tool that allows for the removal and replacement of individual genes. Since its development in 2012, it has become an instant favorite among scientists.
CRISPR-Cas9’s immediate potential lies in curing single-gene disorders in embryos. Changes made at that stage would affect every cell in the body and could cure many diseases. We know some 4,000 such disorders, and, though each is rare, put together they could change the lives of millions in the next generation, and keep many more free from those diseases for all the generations to follow.
However, the Chinese study earlier this year showed that we might need something even more precise than CRISPR-Cas9 currently is. Only in one-third of the 86 embryos was the faulty gene erased as predicted, and even in those cases, CRISPR-Cas9 had also modified things it wasn’t meant to—the unintended consequences scientists worry about.
There is, however, another form of genetic engineering of human embryos. This is the one that the US tried and then banned, and that the British government recently opened licensing applications for. And what’s probably more important for the future of the debate is how Britain decided the technology works and is safe.


Three-parent child

Alana Saarinen was born in the US with three biological parents. Two of them contribute more than 99% of her genetic material and the third provides the rest. She is one of only 30 or so people in the world who grew from a genetically engineered embryo into a healthy adult.
Sharon and Paul Saarinen had attempted in-vitro fertilization (IVF) four times, but without success. A likely reason was that Sharon’s egg cells had faulty mitochondria. These are like biological batteries within a cell—they play an essential role in converting your food into the energy that powers your body. Uniquely, they also have their own DNA (though it’s only some 37 of the 20,000 or so genes that make up the human genome).
During reproduction, when an egg cell fuses with a sperm cell, creating the first cell of an embryo, it’s only the DNA in its nucleus that is a mix of both parents’ DNA. Mitochondria and their DNA are passed on directly from mother to offspring. Because Sharon Saarinen’s mitochondria were faulty, she basically needed a mitochondria transplant in order to conceive.
That was where the third parent came in. A donor provided an egg cell, whose nucleus was removed and healthy mitochondria along with other bits of the cell were transferred to Sharon’s egg. The egg cell was then mixed with Paul’s sperm cells in a normal IVF procedure, and the resulting embryo would become Alana Saarinen.
This technique won’t only help women like Sharon conceive. In a lot of cases with faulty mitochondria, pregnancies proceed normally, but the child then turns out to have one of several mitochondrial diseases, which can lead to all sorts of problems, from poor growth to autism to diabetes. One in every 5,000 children suffers from one of them.
Mitochondrial replacement therapy like the Saarinens had is currently the only known way of preventing mitochondrial diseases. But since they conceived Alana in 2000, only some 30 or so children have been born using the technique. In 2002, the US Food and Drug Administration (FDA) banned its use. Apart from ethical concerns about scientists “playing God,” there was a scientific worry too. We had never attempted to edit the “germ line”—the DNA that is transferred from one generation to another—and the risks were unknown. (About 10% of the pregnancies that resulted from this treatment had complications, but it wasn’t clear whether the procedure was to blame.)

Selfish genes

The FDA ban meant that US women with faulty mitochondria were left with difficult choices (pdf). They could choose not to have children, or undergo IVF and pick the fertilized embryo with the fewest defective mitochondria—taking a gamble on whether their child would develop mitochondrial disease.
But nearly a decade later the UK government’s Human Fertilization and Embryology Agency (HFEA) took up the case. In 2012, after taking a detailed look at the results of studies on animals and humans, it deemed that mitochondrial replacement therapy was “not unsafe”—meaning that the benefits of curing mitochondrial disease would outweigh the risks of the procedure.
The interesting thing was what the HFEA did next. In Sept. 2012, it launched a public consultation, creating a website that explained both the risks and benefits, and holding public events to do the same. Then it conducted a survey and asked people to send in their comments online. After the public had shown broad support for the therapy—and despite stiff opposition from scholarly groups and religious groups alike—the HFEA spent two years taking the necessary steps to get the regulations discussed in parliament. In February, MPs agreed to allow the use of the therapy under strict guidelines. In October, the process for handing out licenses began.
We already use genetic engineering to create climate-resistant crops and drug-producing bacteria. Now one of the world’s most scientifically advanced countries—and, fittingly, the birthplace of IVF—has agreed that genetically modified humans, too, are sometimes not just OK, but desirable. This is what makes 2015 an historic year.
Based on past progress, it is likely that genetic enhancements to humans will become a reality step by step. Just like mitochondrial replacement therapy, they will first appear for a very narrow purpose, such as curing single-gene disorders, and then, likely over many decades, we might reach the stage of creating those fabled designer babies.
That gives us enough time to deliberate the implications of each step. When our decisions will affect generations of humans to come, it is important we use that time well. The process that HFEA designed to win public and political support is a model worth emulating. If each step were to get the same scrutiny that mitochondrial replacement therapy got, genetically modified humans could become as normal as genetically modified crops and bacteria are today—and, barring the occasional controversy, as widely accepted.
Corrected Dec. 23: An earlier version of this post incorrectly said that Sharon Saarinen’s nucleus was implanted in a donor’s egg. It also said that HFEA began handing out licenses in October, but in fact it then began the process of handing them out.

 http://qz.com/

The pros and cons of genetically engineering your children



December 03, 2015
From time to time, science troubles philosophers with difficult ethical questions. But none has been as difficult as considering permanently altering the genetic code of future generations. At a meeting that began on Dec. 1 in Washington DC, the world’s leading gene-editing experts met with ethicists, lawyers, and interested members of the public to decide whether it should be done.
Gene-editing tools have existed since 1975, when a meeting of a similar kind was held to discuss the future of genetic technology. But recent developments have made the technology safe enough to consider turning science fiction into reality. In fact, in April, Chinese researchers announced that they had conducted experiments to remove genes of an inheritable disease in human embryos (embryos that were alive but damaged, so they could not have become babies).
So the stakes are high. By eliminating “bad” genes from sperm and egg cells—called the “germline”—these tools have the potential to permanently wipe out diseases caused by single mutations in genes, such as cystic fibrosis, Huntington’s disease, or Tay-Sachs.
At the same time, there is huge uncertainty about what could go wrong if seemingly troubling genes are eliminated.
One of the key researchers in the field is Jennifer Doudna at the University of California, Berkeley. She has been touted for a Nobel Prize for the development of CRISPR-Cas9, a highly precise copy-paste genetic tool. In the build-up to the meeting, Doudna made her concerns clear in Nature:
“Human-germline editing for the purposes of creating genome-modified humans should not proceed at this time, partly because of the unknown social consequences, but also because the technology and our knowledge of the human genome are simply not ready to do so safely.”
Her sentiments were echoed in a report released before the meeting by the Center for Genetics and Society. They believe that research in genetic tools must advance, but only through therapy for adults (where genetic modifications are targeted at some cells in the body but not passed on to kids, such as in curing a form of inherited blindness). The report continues:
“But using the same techniques to modify embryos in order to make permanent, irreversible changes to future generations and to our common genetic heritage—the human germline, as it is known—is far more problematic.”
Consider sickle-cell anemia, an occasionally fatal genetic disorder. Its genes, though clearly harmful, have persisted and spread because, while having two copies of the sickle-cell gene causes anemia, having just one copy happens to provide protection against malaria, one of the most deadly diseases in human history. Had we not known about their benefits, eliminating sickle-cell genes would have proved to be a bad idea.
More importantly, there is a worry that once you allow for designer babies you go down a slippery slope. Emily Smith Beitiks, disability researcher at the University of California, San Francisco, said recently:
“These proposed applications raise social justice questions and put us at risk of reviving eugenics—controlled breeding to increase the occurrence of ‘desirable’ heritable characteristics. Who gets to decide what diversity looks like and who is valued?”
But the history of science shows that it is hard to keep such a cat in the bag. Once developed, technologies have a way of finding their way into the hands of those who desire to use them. That worries George Church, a geneticist at Harvard Medical School, who has been a strong voice in this debate since the beginning. In Nature, he writes:
“Banning human-germlined editing could put a damper on the best medical research and instead drive the practice underground to black markets and uncontrolled medical tourism, which are fraught with much greater risk and misapplication.”
And many believe that the risks of gene-editing are not that high anyway. Nathaniel Comfort, a historian of medicine at Johns Hopkins University in Baltimore, writes in Aeon:
“The dishes do not come à la carte. If you believe that made-to-order babies are possible, you oversimplify how genes work.”
That is because abilities, such as intelligence, height, or personality traits, involve thousands of genes. So there may be some things that you cannot genetically enhance much, and certainly not safely. And even knowingly changing the human genome is not as big a deal as some make it out to be, Church notes:
“Offspring do not consent to their parents’ intentional exposure to mutagenic sources that alter the germ line, including chemotherapy, high altitude, and alcohol—nor to decisions that reduce the prospects for future generations, such as misdirected economic investment and environmental mismanagement.”
The meeting ended on Dec. 3, and the committee of organizers—10 scientists and two bioethicists—came to a conclusion on the debate. They believe that the promises of germline editing are too great to scupper future developments. They endorse that research should continue in non-human embryos and “if, in the process of research, early human embryos … undergo gene editing, the modified cells should not be used to establish a pregnancy.” That is because the committee believes that we neither know enough about safety issues to allow any clinical application, nor enough about how society will respond to the use of this technology in humans.
And, yet, perhaps the the last word on the debate should go to a woman in the audience at the meeting. Her child died only six days old after torturous seizures caused by a genetic ailment. She implored the research community, “If you have the skills and the knowledge to eliminate these diseases, then freakin’ do it!”

Scientists have synthesized a 'minimal genome' with only genes necessary for life

A pioneering accomplishment in the field of genetic research could help scientists gain new insights into the very definition of life. The new research, published Thursday in the journal Science, describes the synthetic creation of a “minimal genome” — a cell containing only the genes absolutely required to keep itself alive.
With just 473 genes, it’s the smallest genome of any living, dividing cell found in nature and may provide important insights into the fundamental genetic requirements for life.
The idea of designing and studying a “minimal genome” is a concept that’s fascinated scientists for decades. In fact, unlocking the secrets of the genome has been a preoccupation of genetic researchers since the first genome sequencing was performed on a bacterium in 1995 — the event that ultimately led to this week’s breakthrough, according to the new study’s authors.
Researchers have designed and synthesized a minimal bacterial
genome, containing only the genes necessary for life.
Image: C. Bickel/Science
“This is a study that had its origins a little over 20 years ago in 1995, when this institute sequenced the very first genome in history, Haemophilus influenzae,” said the new paper’s senior author J. Craig Venter, founder of the J. Craig Venter Institute, which specializes in genomic research, during a Wednesday teleconference.
Later that same year, the institute also sequenced the genome of a second type of bacteria, Mycoplasma genitalium. These breakthroughs allowed for the first genomic comparisons between two different species, Venter said.
Venter is most famous for his role as a leader of the team that first sequenced the human genome in 2000.
“[My colleagues] and myself were discussing the philosophy of these differences in the genomes and decided the only way to answer basic questions about life would be to get to a minimal genome, and probably the only way to do that would be by trying to synthesize a genome,” Venter said.

Image: Giphy
“And that started our 20-year quest to do this.”
The reason that researchers must synthesize, or essentially design their own, minimal genome is because just about every living organism we know of contains more genes than are actually necessary for its basic survival. Even the simplest bacteria contain extra, nonessential genes that are related to its growth, development and ability to react to its environment, but that aren’t technically required to keep the cell alive.
So in order to get down to a truly minimal genome, scientists must take an existing genetic sequence and pare it down themselves, cutting away all the nonessential genes until they end up with only the ones that are absolutely essential

They do this by creating synthetic genomes — genomes that are designed and chemically built from the ground up using our existing knowledge of an organism’s genetic information.
Along the way, scientists can add or delete genetic information as they see fit. It’s the same basic principle that’s used in genetic engineering research. But in the case of a minimal genome, the goal is to slice off as much unnecessary genetic information as possible without changing or adding anything else to the organism’s genome.
And that’s just what Venter and his colleagues set out to do.

DNA minimalism

They started with the genome of a type of bacteria known as Mycoplasma mycoides, a parasite normally found in cows and goats. In 2010, the group succeeded in building the complete M. mycoides genome from scratch and transplanting it into another cell.
J. Craig Venter receives the National Medal of Science on
October 7, 2009 in Washington, DC.
Image: Getty Images
This time around, they used a variety of methods to whittle the genome down before transplanting it.
To start, the researchers divided the bacterium’s genome into eight different segments that could be individually altered and tested — just to make the experiments a little more manageable. They then applied a handful of techniques to peel away the nonessential genes.
They call this their “design-build-test” approach.
First, they applied their basic knowledge of genetics and biochemistry to infer which genes might be safe to remove — but this technique did not produce viable cells.
The researchers then conducted a series of experiments in which they inserted bits of foreign genetic information — called transposons — into the genome in order to disrupt the functions of certain genes and figure out which ones the cell could do without. This process helped them whittle down the genome until no more genes could be removed.
Along the way, the researchers were able to divide the bacterium’s genes into three major categories: essential, nonessential and quasi-essential, meaning they weren’t absolutely required for life but were necessary to help the cell grow at a healthy pace.
It allowed them to discover how much we don’t know, even about the core sections of the genome
Venter and his colleagues also discovered that the genome contained a number of redundant genes — pairs of genes that performed the same function in the cell. These genes made the whittling process a little confusing at first — if one of the redundant genes was removed (but not the other), the cell would continue functioning, tricking the researchers into believing it was a nonessential gene.
A great deal of trial and error was required in order for the researchers to classify all the genes.
Finally, though, they reached a point where no more genes could be removed without killing the cell.
The result is the smallest genome ever recorded in a self-replicating — that means alive and able to divide — cell. It contains just 473 genes, all of which are either directly required to keep the cell alive or to enable it to grow and divide fast enough to be practical for the researchers’ experiments.
J. Craig Venter poses before a gene map of a flu-causing
bacterium in his Rockville, Md., office, March 12, 1997.
Image: Ruth Fremson/AP
Interestingly, about a third of the resulting genome consists of genes with unknown biological functions. Most of the known essential genes perform functions related to expressing genes, passing down genetic information from one generation to the next, or performing essential functions in the cell’s membrane and cytosol, so the scientists predict that the unknown genes will have similar jobs — we just don’t know what yet.
“One of the great findings but also the great caveats of this work is that it allowed them to discover how much we don’t know, even about the core sections of the genome,” said Adam Arkin, director of the Synthetic Biology Institute at the University of California Berkeley, in a statement.
That said, Venter also noted that the concept of a minimal cell is context-dependent.
The specific genes that an organism requires to survive — even an organism as simple as a bacterial cell — depend on what kind of environment the cell is living in and what kinds of nutrients are available to it.
And, of course, one species’ minimal genome would likely differ significantly from that of another species.
With that in mind, exploring different forms of minimal genomes could have important industrial applications, said Daniel Gibson, another of the study’s authors and another scientist at the J. Craig Venter Institute, during the same teleconference.
Because these cells are so simple, devote all their energy to essential functions and are subject to very few genetic mutations, they are “straightforward to engineer” and could provide helpful insights into more complex types of biosynthesis in the future, he said.
Still, there’s plenty of work left to be done before the study of minimal genomes may yield practical applications.
“The major limitation is that this is the beginning of a very long road,” said Sriram Kosuri, an assistant professor of biochemistry at UCLA, in a statement.
“It's not as if this new minimal genome will automatically lead to either fundamental insights or industrial applications immediately. That said, they've created a self-replicating biological organism that might be a better starting point for such scientific and engineering goals than continuing to study natural systems."
 
 

Scientists May Have Found the Key to Curing Autism, Cancer and HIV

Gene editing tool CRISPR-Cas9 has made it possible to isolate RNA in living cells for the first time.

160323_dna


Mutations in RNA are linked to autism, cancer, and fragile X syndrome.
By + More

The cures for some of the world's most perplexing diseases might be closer than we think.
According to a study published in Cell, researchers have determined how to isolate and edit messenger RNA that carries genetic instructions from the cell's nucleus to make new proteins for the first time using gene-editing tool Clustered Regularly Interspaced Short Palindromic Repeats, also known as CRISPR-Cas9.

They have previously used this tool to remove HIV from human immune cells and shut down HIV replication permanently, according to a study published in Nature in March.
“It opens up a new area of thinking about manipulating genes and disease,” Gene Yeo, associate professor of molecular medicine at UCSD and a senior author of the study, told Discovery. “In many diseases you cannot edit the genome, you can break the genome into pieces. But here we are doing transcription engineering or editing. That’s quite exciting.”
The gene-editing technique could lead to treatments for diseases that are linked to defective RNA and have previously been untreatable. These include certain cancers, fragile X syndrome and autism.
[READ: FDA Orders Warning Labels on Prescription Narcotic Painkillers]
CRISPR-Cas9 can also potentially be used to edit genes that determine our physical features and maybe even our personality, leading to ethical questions about how to responsibly use the technology.
Discovery reports that the National Academy of Sciences is working on a set of ethical rules for this burgeoning field.

Monday, March 14, 2016

How Gut Bacteria Are Shaking Up Cancer Research



 http://www.bloomberg.com/


  • Roche says it plans to study role of microbiome in cancer
  • Vedanta expects more drug companies to enter the field
Top scientists at Roche Holding AG and AstraZeneca Plc are sizing up potential allies in the fight against cancer: the trillions of bacteria that live in the human body.
"Five years ago, if you had asked me about bacteria in your gut playing an important role in your systemic immune response, I probably would have laughed it off," Daniel Chen, head of cancer immunotherapy research at Roche’s Genentech division, said in a phone interview. "Most of us immunologists now believe that there really is an important interaction there."
Two recent studies published in the journal Science have intrigued Chen and others who are developing medicines called immunotherapies that stimulate the body’s ability to fight tumors.
In November, University of Chicago researchers wrote that giving mice Bifidobacterium, which normally resides in the gastrointestinal tract, was as effective as an immunotherapy in controlling the growth of skin cancer. Combining the two practically eliminated tumor growth. In the second study, scientists in France found that some bacterial species activated a response to immunotherapy, which didn’t occur without the microbes.

Human Microbiome

That’s increased drugmakers’ interest in the human microbiome -- the universe of roughly 100 trillion good and bad bacteria, fungi and viruses that live on and inside the body. Roche is already undertaking basic research in the field and plans to investigate the microbiome’s potential for cancer treatment, Chen said.
"Certainly, we are already scanning the space for interesting opportunities as the science continues to emerge," he said. "We are very interested in testing these in a controlled setting."
Some experienced investors are skeptical and see the possibility of an approved product for cancer to be at least five years away.
"To therapeutically influence the microbiome long-term in humans is a big hurdle," said Sander van Deventer, managing partner at venture-capital firm Forbion Capital Partners. "The microbiome is very stubborn. Everything we’ve done so far has only had a temporary effect."

Nestle’s Investment

Earlier in his career, van Deventer chaired the department of gastroenterology and hepatology at the Academic Medical Center in Amsterdam, the first clinic in the world to perform fecal transplants to fight hospital infection Clostridium difficile with good bacteria. Forbion hasn’t yet invested in any microbiome biotechs, "but we’re looking at all of them all the time," he said.
Efforts are under way to turn bacteria into regulated pharmaceutical products to treat illnesses of the gut, where the microbes reside.
Nestle SA last January invested $65 million in ambridge, Massachusetts-based Seres Therapeutics Inc., which is developing a treatment for Clostridium difficile, which affects the digestive system. That follows early efforts to harness the microbiome’s benefits, which spawned probiotic foods and supplements as well as transplants of healthy bacteria.
The promise in cancer will draw more large drugmakers into exploring the human microbiome, said Bernat Olle, chief executive officer of Vedanta Biosciences, a Boston-based startup.

Treatment Potential

"That’s the sense we get based on how we’re being approached by new pharma groups and how serious they seem to be about wanting to enter the field,” Olle said in a phone interview. Vedanta last year announced a license agreement with Johnson & Johnson on its experimental microbiome drug for inflammatory bowel disease.
Another startup, 4D Pharma Plc, in November said it had discovered a bacterium that produces a response comparable to that of an immunotherapy in animal tests for breast and lung cancers. The London-listed company plans to start trials in patients by the end of this year. To support research in autoimmune and neurological diseases, in addition to cancer, the company has raised over 100 million pounds ($140 million) from investors over the last two years, CEO Duncan Peyton said in a phone interview.
French biotech Enterome is taking a different approach: developing treatments based on bacterial secretions. Enterome plans to close a private financing round of about 15 million euros this month, according to CEO Pierre Belichard. More news may be on the way.

‘Active Discussions’

"We are in active discussions with the usual suspects in the immunotherapy space," Belichard said in an interview in London.
Those active in the field include a wide range of pharma companies including AstraZeneca, Roche, Bristol-Myers Squibb Co., and Merck & Co.
"Personally, I think it’s a fascinating area," Susan Galbraith, head of oncology research at AstraZeneca, said in an interview in London.
Studies have shown that immunotherapies have varying degrees of success even in genetically identical mice, and the Science study from Chicago suggests that the diversity of the microbiome may help explain that variability, Galbraith said. AstraZeneca isn’t conducting its own research in the area and would prefer to wait to see evidence in human trials before getting involved, she said.
The sheer number of bacteria, some of which could actually switch off an immune response, and the question of how much bacteria is needed, make it a complex area of research, Roche’s Chen said. It’s possible that the same bacteria could induce both harmful and helpful responses, depending on the patient, he said.
Still, "it’s one of the most interesting developments we’ve seen in science over the last several years," he said.

Oldest ever human genome sequence may rewrite human history



14 March 2016

https://www.newscientist.com/


Cavers

What secrets lurk in the pit of bones?

Javier Trueba, Madrid Scientific Films
The oldest ever human nuclear DNA to be reconstructed and sequenced reveals Neanderthals in the making – and the need for a possible rewrite of our own origins.
The 430,000-year-old DNA comes from mysterious early human fossils found in Spain’s Sima de los Huesos, or “pit of bones”.
The fossils look like they come from ancestors of the Neanderthals, which evolved some 100,000 years later. But a 2013 study found that their mitochondrial DNA is more similar to that of Denisovans (see video, below), who also lived later and thousands of kilometres away, in southern Siberia.
So who were the Sima people – and how are they related to us?
To find out, a team led by Matthias Meyer at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, pieced together parts of the hominin’s nuclear DNA from samples taken from a tooth and a thigh bone.

4_Homo-heidelbergensis_-Sima-de-los-Huesos_Credit-Javier-Trueba-Madrid-Scientific-Films

One of the Sima de los Huesos skeletons

Javier Trueba, Madrid Scientific Films
The results suggest they are more closely related to ancestors of Neanderthals than those of Denisovans – meaning the two groups must have diverged by 430,000 years ago. This is much earlier than the geneticists had expected.
It also alters our own timeline. We know that Denisovans and Neanderthals shared a common ancestor that had split from our modern human lineage. In light of the new nuclear DNA evidence, Meyer’s team suggests this split might have happened as early as 765,000 years ago.
Previous DNA studies had dated this split to just 315,000 to 540,000 years ago, says Katerina Harvati-Papatheodorou at the University of Tubingen in Germany.
But a date of 765,000 years ago actually brings the DNA evidence more in line with some recent fossil interpretations that also suggest an older divergence between modern humans and the ancestor of the Neanderthals and Denisovans.
“I am very happy to see that ideas about the divergence based on ancient DNA and on anatomical studies of the fossil record seem to be converging,” says Aida Gómez-Robles at George Washington University in Washington DC, who was involved in the fossil research.

Tree redrawn?

But if such an ancient split is correct, we might have to redraw parts of our evolutionary tree.
Conventional thinking is that modern humans, Neanderthals and Denisovans all evolved from an ancient hominin called Homo heidelbergensis.
However, H. heidelbergensis didn’t evolve until 700,000 years ago – potentially 65,000 years after the split between modern humans and the Neanderthals and Denisovans.
Instead, another, obscure species called Homo antecessor might now be in the frame as our common ancestor.
This species first appeared more than a million years ago – and its face is very similar to that of modern humans, says Chris Stringer at the Natural History Museum in London.

Further puzzles

“Research must now refocus on fossils from 400,000 to 800,000 years ago to determine which ones might actually lie on the respective ancestral lineages of Neanderthals, Denisovans and modern humans,” he says.
Another puzzle remains. The study confirmed a previous finding that the mitochondrial DNA of the Sima hominin is more similar to Denisovans than to Neanderthals – but no one knows why.
Perhaps there was another unidentified lineage of hominins in Eurasia that interbred with the ancestors of both – but not with the particular group of hominins that evolved into the Neanderthals.
Or, Meyer says, perhaps such mitochondrial DNA was typical of early Neanderthals and Denisovans, and it was only later that Neanderthals acquired different mitochondrial DNA from an African population of “proto-Homo sapiens“.
Journal reference: Nature, DOI: 10.1038/nature17405
Find out more about the oldest human genome dug up in Spain’s pit of bones:

 

Neanderthal diet: Only 20 percent vegetarian

Researchers have long debated the precise diet of early humans, but the latest study is the first to nail down precise percentages.
By Brooks Hays   |   March 14, 2016 at 12:33 PM
Fossil analysis suggests Neanderthals ate a diet of
80 percent meat. Photo by OrdinaryJoe/Shutterstock

TUBINGEN, Germany, March 14 (UPI) -- Neanderthals were apparently too busy hunting and scavenging to pay much attention to Michael Pollan's dietary advice: eat mostly plants.
New isotopic analysis suggests prehistoric humans ate mostly meat. As detailed in a new study published in the journal Quaternary International, the Neanderthal diet consisted of 80 percent meat, 20 percent vegetables.
Researchers in Germany measured isotope concentrations of collagen in Neanderthal fossils and compared them to the isotopic signatures of animal bones found nearby. In doing so, scientists were able to compare and contrast the diets of early humans and their mammalian neighbors, including mammoths, horses, reindeer, bison, hyenas, bears, lions and others.
"Previously, it was assumed that the Neanderthals utilized the same food sources as their animal neighbors," lead researcher Herve Bocherens, a professor at the University of Tubingen's Senckenberg Center for Human Evolution and Palaeoenvironment, said in a news release.
"However, our results show that all predators occupy a very specific niche, preferring smaller prey as a rule, such as reindeer, wild horses or steppe bison, while the Neanderthals primarily specialized on the large plant-eaters such as mammoths and woolly rhinoceroses," Bocherens explained.
All of the Neanderthal and animal bones, dated between 45,000 and 40,000 years old, were collected from two excavation sites in Belgium.
Researchers have long debated the precise diet of early humans, but the latest study is the first to nail down precise percentages.
Bocherens and his colleagues are hopeful their research will shed light on the Neanderthals' extinction some 40,000 years ago.
"We are accumulating more and more evidence that diet was not a decisive factor in why the Neanderthals had to make room for modern humans," he said.

Humans Interbred With Hominins on Multiple Occasions, Study Finds

Photo
Skulls of the Neanderthal man. Credit European Pressphoto Agency
The ancestors of modern humans interbred with Neanderthals and another extinct line of humans known as the Denisovans at least four times in the course of prehistory, according to an analysis of global genomes published on Thursday in the journal Science.
The interbreeding may have given modern humans genes that bolstered immunity to pathogens, the authors concluded.
“This is yet another genetic nail in the coffin of our over-simplistic models of human evolution,” said Carles Lalueza-Fox, a research scientist at the Institute of Evolutionary Biology in Barcelona who was not involved in the study.
The new study expands on a series of findings in recent years showing that the ancestors of modern humans once shared the planet with a surprising number of near relatives — lineages like the Neanderthals and Denisovans that became extinct tens of thousands of years ago.
Before disappearing, however, they interbred with our forebears on at least several occasions, and today we carry DNA from these encounters.
The first clues to ancient interbreeding surfaced in 2010, when scientists discovered that some modern humans — mostly Europeans — carry DNA that matches material recovered from Neanderthal fossils.
Later studies showed that the forebears of modern humans first encountered Neanderthals after expanding out of Africa more than 50,000 years ago.
But the Neanderthals were not the only extinct humans that our own ancestors found. A finger bone discovered in a Siberian cave, called Denisova, yielded DNA from yet another group of humans.
Research later indicated that all three groups — modern humans, Neanderthals and Denisovans — shared a common ancestor who lived roughly 600,000 years ago. And, perhaps no surprise, some ancestors of modern humans also interbred with Denisovans.
Some of their DNA has survived in people in Melanesia, a region of the Pacific that includes New Guinea and the islands around it.
Those initial discoveries left major questions unanswered, such as how often our ancestors interbred with Neanderthals and Denisovans. Scientists have developed new ways to study the DNA of living people to tackle these mysteries.
Joshua M. Akey, a geneticist at the University of Washington, and his colleagues analyzed a database of 1,488 genomes from people around the world. The scientists added 35 genomes from people in New Britain and other Melanesian islands in an effort to learn more about Denisovans in particular.
The researchers found that all the non-Africans in their study had Neanderthal DNA, while the Africans had very little or none. That finding supported previous studies.
But when Dr. Akey and his colleagues compared DNA from modern Europeans, East Asians and Melanesians, they found that each population carried its own distinctive mix of Neanderthal genes.
The best explanation for these patterns, the scientists concluded, was that the ancestors of modern humans acquired Neanderthal DNA on three occasions.
The first encounter happened when the common ancestor of all non-Africans interbred with Neanderthals.
The second occurred among the ancestors of East Asians and Europeans, after the ancestors of Melanesians split off. Later, the ancestors of East Asians — but not Europeans — interbred a third time with Neanderthals.
Earlier studies had hinted at the possibility that the forebears of modern humans had multiple encounters with Neanderthals, but until now hard data was lacking.
“A lot of people have been arguing for that, but now they’re really providing the evidence for it,” said Rasmus Nielsen, a geneticist at the University of California, Berkeley, who was not involved in the new study.

Horse-sized dinosaur shows how T. rex became king

AFP
Paleontologist, Hans Sues, of the Smithsonian Museum of Natural History, compares a T-Rex tooth (L) to the tooth of a newly discovered dinosaur during a news conference at the museum, March 14, 2016 in Washington, DC
Paleontologist, Hans Sues, of the Smithsonian Museum of Natural History, compares a T-Rex tooth (L) to the tooth of a newly discovered dinosaur during a news conference at the museum, March 14, 2016 in Washington, DC (AFP Photo/Mark Wilson)
Washington (AFP) - A newly discovered cousin of the T. rex may explain how the legendary dinosaur leapt in size to become undisputed king of the food chain, scientists said Monday.
Until now, researchers have had little evidence of how the iconic predator became one of the largest carnivores to ever roam the Earth before the dinosaurs went extinct 65 million years ago.
The answers could lie in the brain of Timurlengia euotica, a previously unknown relative of the T. rex.
Timurlengia euotica was far smaller than the elephant-sized T. rex, but had already developed the large brain it needed to track and devour prey.
While researchers cautioned that the discovery represents just one animal in a long lineage, its features help illustrate how small tyrannosaurids evolved to grow smarter and larger over time, thanks to keen senses that could help keep their bellies filled.
"The ancestors of T. rex would have looked a whole lot like Timurlengia, a horse-sized hunter with a big brain and keen hearing that would put us to shame," said Steve Brusatte of the University of Edinburgh's School of GeoSciences.
"Only after these ancestral tyrannosaurs evolved their clever brains and sharp senses did they grow into the colossal sizes of T. rex.
"Tyrannosaurs had to get smart before they got big."
The first tyrannosaurs appeared about 170 million years ago and were about the size of a human.
The bones of Timurlengia euotica were uncovered in Uzbekistan, where it lived about 90 million years ago.
By the Late Cretaceous Period, between 66 and 80 million years ago, the T. rex was the don of the big lizards, often weighing more than seven tons.
Not much is known about how the T. rex got so big, "largely because of a frustrating 20-plus-million-year gap in the mid-Cretaceous fossil record, when tyrannosauruses transitioned from small-bodied hunters to gigantic apex predators but from which no diagnostic specimens are known," said the study published in the Proceedings of the National Academy of Sciences.
The new discovery is "the first distinct tyrannosauroid species from this gap."
The specimen was discovered between 1997 and 2006 by a team of palaeontologists, led by researchers at the University of Edinburgh, working in the Kyzylkum Desert in northern Uzbekistan.
"The early evolution of many groups like tyrannosaurs took place in the coastal plains of central Asia in the mid-Cretaceous," said professor Alexander Averianov of Saint Petersburg State University.
Timurlengia's skull was much smaller than that of the T. rex, suggesting it did not grow as big, but its skull shape reveals "that its brain and senses were already highly developed," the report said.
"Timurlengia was a nimble pursuit hunter with slender, blade-like teeth suitable for slicing through meat," said professor Hans Sues, of the National Museum of Natural History in Washington.
"It probably preyed on the various large plant-eaters, especially early duck-billed dinosaurs, which shared its world."