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Israeli Scientists Develop First Haploid Human Stem Cells – NoCamels – Israeli Innovation News (press release) (blog)

Israeli scientists have developed the first haploid human stem cells, a discovery that will change our understanding of human genetics and medical research.

Already being used to predict whether people are resistant to chemotherapy drugs, the finding earned Igo Sagi, a PhD student at the Hebrew University of Jerusalem, the 2017 Kaye Innovation Award.

The long-sought haploid

Most of the cells in our body are diploid, which means they carry two sets of chromosomes (the structure in which DNA is contained) one chromosome from each parent. Haploid cells, in contrast, contain only a single set of chromosomes.

Scientists have long been trying to develop haploid stem cells. It is an important area of research, as embryonic stem cells are able to grow into any cell in the human body; this makes them extremely useful for treatment of diseases.

Haploid cells in particular are a powerful discovery, as they allow for a much better understanding of the human genetic makeup. For example, in diploid cells, it is difficult to identify the effects of mutations in one chromosome because the other copy is normal and provides a backup. Haploid cells dont have this limitation.

SEE ALSO: Five Israeli Biotech Companies Using Stem Cells To Change The Face Of Medicine

Up until now, scientists have only succeeded in creating haploid embryonic stem cells in animals such as mice, rats, and monkeys. The research conducted by Igo Sagi was the first time anyone was able to successfully isolate and maintain human haploid embryonic stem cells. These haploid stem cells were able to turn into many other cell types, such as brain, heart, and pancreas, while still retaining a single set of chromosomes.

The benefits are immense. Professor Nissim Benvenisty, who worked with Sagi on the research, explained: It will aid our understanding of human development for example, why we reproduce sexually instead of from a single parent. It will make genetic screening easier and more precise, by allowing the examination of single sets of chromosomes. And it is already enabling the study of resistance to chemotherapy drugs, with implications for cancer therapy.

SEE ALSO: Biological Breakthrough: Researchers Succeed In Creating Human Egg and Sperm Cells In Lab

Haploid Human Embryonic Stem Cells

Diagnosis of Chemotherapy Resistance

Based on this research, Yissum, the Technology Transfer arm of the Hebrew University, launched the company NewStem. The company is currently developing a diagnostic kit that can predict resistance to chemotherapy drugs. The large library of human haploid stem cells they are amassing will allow them to provide therapeutic and reproductive products, as well as personalized medication.

The haploid stem cells were developing have the potential to change the face of medical research as they hold a pivotal role in regenerative medicine, disease therapy and cancer research, revealed CEO of NewStem, Ayelet Dilion-Mashiah.

The research was conducted by Igo Sagi, a doctoral student at the Hebrew University of Jerusalem, along with Professor Nissim Benvenisty, Director of the Azrieli Center for Stem Cells and Genetic Research at the Hebrew University. The Kaye Innovation Awards at the Hebrew University of Jerusalem have been awarded annually since 1994 with the goal of encouraging academics to develop innovative methods and inventions with good commercial potential.

Photo:Azrieli Center for Stem Cells and Genetic Research at Hebrew University

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Israeli Scientists Develop First Haploid Human Stem Cells – NoCamels – Israeli Innovation News (press release) (blog)

Shrinking Bat Genomes Spark a New Model of Evolution – WIRED

Take an onion. Slice it very thin. Thinner than paper thin: single-cell thin. Then dip a slice in a succession of chemical baths cooked up to stain DNA. The dyed strands should appear in radiant magentathe fingerprints of lifes instructions as vivid as rose petals on a marital bed. Now you can count how much DNA there is in each cell. Its simply a matter of volume and density. A computer can flash the answer in seconds: 17 picograms. Thats about 16 billion base pairsthe molecular links of a DNA chain.

Original story reprinted with permission from Quanta Magazine, an editorially independent publication of the Simons Foundation whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences.

Maybe that number doesnt mean much to you. Or maybe youre scratching your head, recalling that your own hereditary blueprint weighs in at only 3 billion base pairs. Huh? joked Ilia Leitch, an evolutionary biologist at the Royal Botanic Gardens, Kew, in England. Her reaction mimicked the befuddlement of countless anthropocentric minds who have puzzled over this discrepancy since scientists began comparing species genomes more than 70 years ago. Why would an onion have five times more DNA than we have? Are they five times more clever?

Of course, it wasnt just the onion that upended assumptions about a link between an organisms complexity and the heft of its genetic code. In the first broad survey of animal genome sizes, published in 1951, Arthur Mirsky and Hans Rispioneers in molecular biology and electron microscopy, respectivelyreported with disbelief that the snakelike salamander Amphiuma contains 70 times as much DNA as a chicken, a far more highly developed animal. The decades that followed brought more surprises: flying birds with smaller genomes than grasshoppers; primitive lungfish with bigger genomes than mammals; flowering plants with 50 times less DNA than humans, and flowering plants with 50 times more; single-celled protozoans with some of the largest known genomes of all.

Lucy Reading-Ikkanda/Quanta Magazine; Source: Animal Genome Size Database

Even setting aside the genetic miniatures of viruses, cellular genome sizes measured to date vary more than a millionfold. Think pebbles versus Mount Everest. Its just crazy, Leitch said. Why would that be?

By the 1980s, biologists had a partial answer: Most DNA does not consist of genesthose functional lines of code that translate into the molecules carrying out the business of a cell. Large genomes have vast amounts of noncoding DNA, Leitch said. Thats whats driving the difference.

But although this explanation solved the paradox of the clever onion, it wasnt particularly satisfying. It just opened up more cans of worms, said Ryan Gregory, a biologist at the University of Guelph who runs the online Animal Genome Size Database. Why, for instance, do some genomes contain very little noncoding DNAalso, controversially, often called junk DNAwhile others hoard it? Does all this clutteror lack of itserve a purpose?

This past February, a tantalizing clue arose from research led by Aurlie Kapusta while she was a postdoctoral fellow working with Cedric Feschotte, a geneticist then at the University of Utah, along with Alexander Suh, an evolutionary biologist at Uppsala University in Sweden. The study, one of the first of its kind, compared genome sequences across diverse lineages of mammals and birds. It showed that as species evolved, they gained and shed astonishing amounts of DNA, although the average size of their genomes stayed relatively constant. We see the genome is very dynamic, very elastic, said Feschotte, who is now at Cornell University.

To explain this tremendous DNA turnover, Feschotte proposes an accordion model of evolution, whereby genomes expand and contract, forever gathering up new base pairs and dumping old ones. These molecular gymnastics represent more than a curiosity. They hint at hidden forces shaping the genomeand the organisms that genomes beget.

The first signs that inheritance involves the transmission of more than just genes emerged around the time that Mirsky and Ris were marveling at the enormousness of the salamander genome. In the 1940s, a Swedish geneticist named Gunnar stergren became fascinated with odd hereditary structures found in some plants. stergren wrote that the structures, known as B chromosomes, appeared to have no useful function at all to the species carrying them. He concluded that these extraneous sequences were genetic parasiteshijackers of the host genomes reproductive machinery. Three decades later, the evolutionary biologist Richard Dawkins solidified this idea in his popular 1976 book The Selfish Gene ; the theory was quickly adapted to explain genome size.

By then, scientists had learned that B chromosomes are only a tiny fraction of the molecular parasites making genomes fat. The most prolific freeloaders are mobile strings of DNA called transposons, identified in 1944 by Barbara McClintock, the groundbreaking cytogeneticist who was honored with a Nobel Prize for that discovery. Transposons are popularly known as jumping genes, although they are rarely in fact true genes. They can get passed down from one generation to the next or transmitted between species, like viruses, and they come in several flavors. Some encode enzymes that snip a transposon out of its place in a genome and paste it elsewhere. Others copy themselves by manufacturing RNA templates or stealing enzymes from other transposons. (You can get parasites within parasites, Gregory said.)

Lucy Reading-Ikkanda/Quanta Magazine

Its not hard to see how these copies could quickly multiply, eventually taking over large portions of a genome. (More than 100 can pop up in a single generation of flies; they make up 85 percent of the maize genome and almost half of our own.) Proponents of the selfish DNA theory saw this pileup as the driving force of genome evolution: Within the ecosystem of a cells nucleus, natural selection would favor fast-multiplying transposons. But only up to a point. Once a genome reached a certain size, its bulk would start to interfere with an organisms well-beingfor example, by slowing the division of cells and thus the rate of the organisms growth. Selection would kick in again, preventing further expansion. The limit would depend on the organisms biology.

New evidence soon complicated this picture. In the late 1990s, Dmitri Petrov, then a doctoral student at Harvard University, began tracking small mutations in insectsrandom genetic changes of up to a few hundred base pairs that resulted from DNA damage, copying mistakes and poor strand repair. He started with flies. Analyzing defunct transposons, he showed that old code was being scrapped more quickly than new lines were being written (because random mutations are more likely to delete existing base pairs than to insert new ones). He wondered if this deletion bias might explain the flys relatively compact genome. He repeated the experiment in crickets and grasshoppers, whose genomes are, respectively, 10 and 100 times as large as the flys. This time, the deletion rates, although still dominant, were indeed considerably slower. Were some genomes bulkier than others simply because they werent as quick to clear out debris?

Based on these and similar observations, Petrov laid out a new model of genome size. Transposons, he argued, would always accumulate, sometimes very quickly. (Maize, for example, has doubled its genome in only 3 million years.) But over eons, small excisions would slowly chip away at a genomes bulk. Eventually, the pace of expunction would match the pace of creation, and the genome would settle into equilibrium. Any number of forces in the chaotic nucleus might setor resetthis balance.

Not everyone was convinced. Gregory, for one, maintained that spontaneous change happened too slowly to account for the dramatic morphing of genome size in many lineages. But no one could deny that loss was a powerful transformative force. As Gregory wrote in The Evolution of the Genome , there are more complex interactions between [transposons] and their hosts than strict parasitism. The tricky part was finding them.

For Feschotte, the tip-off came from a bat. By the early 2000s, following advances in DNA sequencing, labs had begun decoding whole genomes and sharing the data online. At the time, Feschottes group was not particularly interested in the evolutionary dynamics of genome size, but they were extremely curious about what transposons could reveal about the history of life. So when the genome of the common little brown bat ( Myotis lucifugus ), the first genome sequence from a bat, appeared in 2006, Feschotte was thrilled. Bats have strikingly small genomes for a mammaltheyre more like those of birdsand it seemed likely they would hold surprises.

The tiny red viscacha rat has the largest known genome of any mammal.

MICHAEL A. MARES; STEVE BOURNE

Southern bent-wing bats have some of the smallest mammalian genomes, despite resembling the viscacha rat in size and complexity.

STEVE BOURNE

Parsing the creatures 2 billion base pairs, Feschotte and his colleagues did stumble on something strange. We found some very weird transposons, he said. Because these oddball parasite sequences didnt appear in other mammals, they were likely to have invaded after bats diverged from other lineages, perhaps picked up from an insect snack some 30 to 40 million years ago. Whats more, they were incredibly active. Probably 20 percent or more of the bats genome is derived from this fairly recent wave of transposons, Feschotte said. It raised a paradox because when we see an explosion of transposon activity, wed predict an increase in size. Instead, the bat genome had shrunk. So we were puzzled.

There was only one likely explanation: Bats must have jettisoned a lot of DNA. When Kapusta joined Feschottes lab in 2011, her first project was to find out how much. By comparing transposons in bats and nine other mammals, she could see which pieces many lineages shared. These, she determined, must have come from a common ancestor. Its really like looking at fossils, she said. Researchers had previously assembled a rough reconstruction of the ancient mammalian genome as it might have existed 100 million years ago. At 2.8 billion base pairs, it was nearly human-size.

Next, Kapusta calculated how much ancestral DNA each lineage had lost and how much new material it had gained. As she and Feschotte suspected, the bat lineages had churned through base pairs, dumping more than 1 billion while accruing only another few hundred million. Yet it was the other mammals that made their jaws drop.

Mammals are not especially diverse when it comes to genome size. In many animal groups, such as insects and amphibians, genomes vary more than a hundredfold. By contrast, the largest genome in mammals (in the red viscacha rat) is only five times as big as the smallest (in the bent-wing bat). Many researchers took this to mean that mammalian genomes just dont have much going on. As Susumu Ohno, the noted geneticist and expert in molecular evolution, put it in 1969: In this respect, evolution of mammals is not very interesting.

Aurlie Kapusta, a research associate in human genetics at the University of Utah and the USTAR Center for Genetic Discovery.

Mary-Anne Karren

But Kapustas data revealed that mammalian genomes are far from monotonous, having reaped and purged vast quantities of DNA. Take the mouse. Its genome is roughly the same size it was 100 million years ago. And yet very little of the original remains. This was a big surprise: In the end, only one-third of the mouse genome is the same, said Kapusta, who is now a research associate in human genetics at the University of Utah and at the USTAR Center for Genetic Discovery. Applying the same analysis to 24 bird species, whose genomes are even less varied than those of mammals, she showed that they too have a lively genetic history.

No one predicted this, said J. Spencer Johnston, a professor of entomology at Texas A&M University. Even those genomes that didnt change size over a huge period of timethey didnt just sit there. Somehow they decided what size they wanted to be, and despite mobile elements trying to bloat them, they didnt bloat. So then the next obvious question is: Why the heck not?

Feschottes best guess points at transposons themselves. They provide a very natural mechanism by which gain provides the template to facilitate loss, he said. Heres how: As transposons multiply, they create long strings of nearly identical code. Parts of the genome become like a book that repeats the same few words. If you rip out a page, you might glue it back in the wrong place because everything looks pretty much the same. You might even decide the book reads just fine as is and toss the page in the trash. This happens with DNA too. When its broken and rejoined, as routinely happens when DNA is damaged but also during the recombination of genes in sexual reproduction, large numbers of transposons make it easy for strands to misalign, and that slippage can result in deletions. The whole array can collapse at once, Feschotte said.

Cedric Feschotte, a professor of molecular biology and genetics at Cornell University, recently of the University of Utah.

University of Utah Health

This hypothesis hasnt been tested in animals, but there is evidence from other organisms. Its not so different from what were seeing in plants with small genomes, Leitch said. DNA in these species is often dominated by just one or two types of transposons that amplify and then get eliminated. The turnover is very dynamic: in 3 to 5 million years, half of any new repeats will be gone.

Thats not the case for larger genomes. What we see in big plant genomesand also in salamanders and lungfishis a much more heterogeneous set of repeats, none of which are present in [large numbers], Leitch said. She thinks these genomes must have replaced the ability to knock out transposons with a novel and effective way of silencing them. What they do is, they stick labels onto the DNA that signal to it to become very tightly condensedsort of squishedso it cant be read easily. That alteration stops the repeats from copying themselves, but it also breaks the mechanism for eliminating them. So over time, Leitch explained, any new repeats get stuck and then slowly diverge through normal mutation to produce a genome full of ancient degenerative repeats.

Meanwhile, other forces may be at play. Large genomes, for instance, can be costly. Theyre energetically expensive, like running a big house, Leitch said. They also take up more space, which requires a bigger nucleus, which requires a bigger cell, which can slow processes like metabolism and growth. Its possible that in some populations, under some conditions, natural selection may constrain genome size. For example, female bow-winged grasshoppers, for mysterious reasons, prefer the songs of males with small genomes. Maize plants growing at higher latitudes likewise self-select for smaller genomes, seemingly so they can generate seed before winter sets in.

Some experts speculate that a similar process is going on in birds and bats, which may need small genomes to maintain the high metabolisms needed for flight. But proof is lacking. Did small genomes really give birds an advantage in taking to the skies? Or had the genomes of birds flightless dinosaur ancestors already begun to contract for some other reason, and did the physiological demands of flight then shrink the genomes of modern birds even more? We cant say whats cause and effect, Suh said.

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Its also possible that genome size is largely a result of chance. My feeling is theres one underlying mechanism that drives all this variability, said Mike Lynch, a biologist at Indiana University. And thats random genetic drift. Its a principle of population genetics that driftwhereby a genetic variant becomes more or less common just by sheer luckis stronger in small groups, where theres less variation. So when populations decline, such as when new species diverge, the odds increase that lineages will drift toward larger genomes, even if organisms become slightly less fit. As populations grow, selection is more likely to quash this trait, causing genomes to slim.

None of these models, however, fully explain the great diversity of genome forms. The way I think of it, youve got a bunch of different forces on different levels pushing in different directions, Gregory said. Untangling them will require new kinds of experiments, which may soon be within reach. Were just at the cusp of being able to write genomes, said Chris Organ, an evolutionary biologist at Montana State University. Well be able to actually manipulate genome size in the lab and study its effects. Those results may help to disentangle the features of genomes that are purely products of chance from those with functional significance.

Many experts would also like to see more analyses like Kapustas. (Lets do the same thing in insects! Johnston said.) As more genomes come online, researchers can begin to compare larger numbers of lineages. Four to five years from now, every mammal will be sequenced, Lynch said, and well be able to see whats happening on a finer scale. Do genomes undergo rapid expansion followed by prolonged contraction as populations spread, as Lynch suspects? Or do changes happen smoothly, untouched by population dynamics, as Petrovs and Feschottes models predict and recent work in flies supports?

Or perhaps genomes are unpredictable in the same way life is unpredictablewith exceptions to every rule. Biological systems are like Rube Goldberg machines, said Jeff Bennetzen, a plant geneticist at the University of Georgia. If something works, it will be done, but it can be done in the most absurd, complicated, multistep way. This creates novelty. It also creates the potential for that novelty to change in a million different ways.

Original story reprinted with permission from Quanta Magazine , an editorially independent publication of the Simons Foundation whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences.

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Shrinking Bat Genomes Spark a New Model of Evolution – WIRED

Scientists use gene editing to correct mutations in humans – DeathRattleSports.com

Each year, millions of people around the world are affected by diseases caused by mutations that occur in the very early stages of development.

But many of those diseases could soon cease to exist, thanks to a gene editing technique that uses the controversial CRISPR-Cas9 system.

In a world first, scientists have used the technique to correct a mutation for a heart condition in embryos, so that the defect would not be passed on to future generations.

The findings could pave the way for improved IVF outcomes, as well as eventual cures for some of the thousands of diseases caused by mutations in single genes.

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The work is a collaboration between the Salk Institute, Oregon Health and Science University (OHSU) and Koreas Institute for Basic Science.

Professor Juan Carlos Izpisua Belmonte, an author of the study, said: Thanks to advances in stem cell technologies and gene editing, we are finally starting to address disease-causing mutations that impact potentially millions of people.

Gene editing is still in its infancy so even though this preliminary effort was found to be safe and effective, it is crucial that we continue to proceed with the utmost caution, paying the highest attention to ethical considerations.

In the study, the researchers were able to correct a mutation that causes an inherited heart disease, called hypertrophic cardiomyopathy (HCM).

HCM is an inherited disease of your heart muscle, where the muscle wall of your heart becomes thickened.

A: An incredibly powerful gene-editing tool that is transforming the way DNA is manipulated and modified. First demonstrated in 2013, it is based on a system bacteria use to defend themselves against invading viruses.

A: In its most basic form, the gene editing tool kit consists of a small piece of RNA a genetic molecule closely related to DNA and an enzyme protein called Cas9.

The RNA component is programmed to latch onto a specific DNA sequence. Then Cas9 slices through the strands of DNA, like a pair of molecular scissors.

A: By cutting away precisely targeted elements of DNA, active genes can be switched off. Defective parts of a gene can also be removed, allowing the fault to be repaired.

A: Here, nature comes into play. Once a piece of DNA has been snipped out in a cell, natural repair systems kick in to try to repair the damage.

More advanced gene editing systems include additional template DNA the cell can use to mend the break, making it possible to re-write the genetic code.

This was what the scientists conducting the new research planned to do. In the event, the embryos went their own way.

Instead of adopting the researchers template, their cells exploited the fact that only one copy of the gene carried by sperm was defective.

They based their repairs on the other, functioning, copy of the gene inherited from the women who donated their eggs for the research.

A: A lot more research has to be done before the technique is shown to be safe and effective enough to be used in the clinic.

Also, altering nuclear DNA in a developing embryo is currently illegal.

A change in the law would be needed before such treatments can be considered, and this would involve addressing some profound ethical questions.

If in future gene editing of embryos is given the green light, it could potentially prevent thousands of diseases being passed onto future generations.

It is caused by a mutation in the MYBPC3 gene, and those affected have a 50 per cent chance of passing the disease on to their own children.

Using a skin biopsy from a man with HCM, the researchers generated stem cells to use in their study.

The researchers used a technique based on CRISPR-Cas9 a genetic tool that can cut and paste small sections of DNA, deleting or repairing flawed genes to correct the HCM mutation in the cells.

CRISPR-Cas9 works as a pair of genetic scissors designed to cut the DNA near the position of the mutation.

The cut is then spontaneously repaired by the cell with different mechanisms: one repairs the DNA without leaving any trace, while the other introduces some unwanted insertions or deletions of a few base pairs near the cutting site.

While previous studies have injected CRISPR-Cas9 after IVF, they faced problems due to mosaicism in which embryos have some repaired cells, and others that carry the mutation.

To overcome this issue, the researchers injected the CRISPR-Cas9 and the sperm into the egg at the same time.

Using this technique, they found that the mosaicism did not occur.

During testing, CRISPR-Cas9 cut the DNA at the correct position in all tested embryos.

Forty-two out of the 58 embryos tested did not carry the HCM mutation.

In other words, this technique increased the probability of inheriting the healthy gene from 50 per cent to 72.4 per cent.

The highly controversial technique is still at an early experimental stage.

There is no question of any attempt being made to create babies with the genetic modification, which would be illegal both in the US and the UK.

But a leading member of the team has hinted that first steps towards bringing the treatment to patients could take place in the UK under the direction of the fertility regulator the Human Fertilisation and Embryology Authority (HFEA).

Dr Shoukhrat Mitalipov, from Oregon Health and Science University (OHSU) in Portland, said in a telephone briefing with journalists: Maybe .. (the) HFEA might take a lead on this, but Im quite sure before these clinical trials can go on they have to go through, I believe, Parliament to change a law.

So there is still a long road ahead, particularly if you want to do it in a regulatory way.

US regulatory barriers to such research are so high they could be insurmountable.

In the US, taxpayer funds cannot pay for research that destroys human embryos.

And Congress has banned the US Food and Drug Administration (FDA) from even considering the possibility of human clinical trials involving embryos with edited inherited genes.

More liberal Britain has already blazed a trail by becoming the first country officially to sanction mitochondrial replacement therapy (MRT), seen by some as opening the door to designer babies.

The researchers also found that human embryos have an alternative DNA repair system, where the Cas9-induced cuts in the DNA coming from the sperm are repaired using the healthy eggs DNA as a template.

This explained why the remaining 27.6 per cent embryos still had the HCM mutations.

Additionally, the researchers found that there were no off-target changes made during the testing.

Some people are voicing their opposition to the gene-editing technology.

Dr David King, director of Human Genetics Alert, said: If irresponsible scientists are not stopped, the world may soon be presented with a fait accompli of the first GM baby.

We call on governments and international organisations to wake up and pass an immediate global ban on creating cloned or GM babies, before it is too late.

There is absolutely no medical need to use this technology to avoid the birth of children with genetic diseases, since genetic selection techniques can prevent their birth, where that is appropriate.

So scientists racing to develop this technology must be driven by something else: irresponsible technological enthusiasm, the desire for fame, or the financial gain of being the first to market designer babies.

Dr Jun Wu, one of the papers first authors, said: Our technology successfully repairs the disease-causing gene mutation by taking advantage of a DNA repair response unique to early embryos.

During testing, none of the embryos were allowed to develop beyond five days after conception.

But had they produced offspring, those with the repair would no longer be at risk of developing HCM, or passing the defective gene onto their own children.

Dr Shoukhrat Mitalipov, who also worked on the study, said: Every generation on would carry this repair because weve removed the disease-causing gene variant from that familys lineage.

By using this technique, its possible to reduce the burden of this heritable disease on the family and eventually the human population.

While the results are extremely promising, the researchers warn that they are very preliminary, and that further studies will be needed to make sure there are no unwanted side effects.

Professor Belmonte said: Our results demonstrate the great potential of embryonic gene editing, but we must continue to realistically assess the risks as well as the benefits.

Dr Daniel Dorsa, senior vice president for research at OHSU added: The ethical considerations of moving this technology to clinical trials are complex and deserve significant public engagement before we can answer the broader question of whether its in humanitys interest to alter human genes for future generations.

But not everyone is happy about the study, and claim that it is the first step in the development of designer babies.

Dr David King, director of Human Genetics Alert, said: If irresponsible scientists are not stopped, the world may soon be presented with a fait accompli of the first GM baby.

We call on governments and international organisations to wake up and pass an immediate global ban on creating cloned or GM babies, before it is too late.

There is absolutely no medical need to use this technology to avoid the birth of children with genetic diseases, since genetic selection techniques can prevent their birth, where that is appropriate.

So scientists racing to develop this technology must be driven by something else: irresponsible technological enthusiasm, the desire for fame, or the financial gain of being the first to market designer babies.

James Clapper, US director of national intelligence was right to call the creation of GM babies a weapon of mass social destruction.

Charlie Gard would not have been saved by gene editing his embryo in the way described by Dr Shoukhrat Mitalipov and his fellow scientists.

The technique worked for the heart failure condition hypertrophic cadiomyopathy because the disorder is due to a fault in a single gene inherited from one parent.

Charlies illness, infantile onset encephalomyopathy mitochondrial DNA depletion syndrome (MDDS) is an autosomal recessive disorder, which only manifests itself if the gene fault is inherited from both parents.

The disease leads to a loss of mitochondrial DNA, housed in cellular power plants that supply energy to vital organs.

Because of the gene defect Charlie was unable to transfer energy to his muscles, kidneys and brain.

Although it affects mitochondrial DNA, the rare condition is triggered by a fault in the cell nucleus passed down by both a childs mother and father.

The American researchers admitted that fixing such a recessive genetic error caused by two mutated copies of a gene would be far more challenging.

This is because the repair they carried out depended on having one good copy of the gene.

The scientists used a molecular scissors technique called Crispr-Cas9 to snip away precisely targeted elements of defective DNA carried by fertilising sperm.

Once the dysfunctional DNA was removed, Mother Nature took over as the embryos own repair systems fixed the damage using the good gene copy inherited from the egg donor mothers as a template.

Without the mothers functioning genes, it is unlikely the fix would have succeeded.

Although the scientists introduced their own healthy gene template, at the end of the day this played no part in the repair.

Charlie died on July 28, aged 11 months, after being at the centre of a painful legal battle between his parents and Londons Great Ormond Street Hospital.

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Scientists use gene editing to correct mutations in humans – DeathRattleSports.com

Israeli team finds biological basis for rare neurological kids’ disease – The Jerusalem Post

The secret to healing what ails you lies within your own DNA. (photo credit:DREAMSTIME)

The biological basis of a severe and mysterious neurological disorder in children that is caused by a single error in one gene has been described for the first time by a multinational team led by researchers from Jerusalem.

Just published in the American Journal of Human Genetics, the study was headed by Prof. Orly Elpeleg of the pediatrics department at the Hebrew University of Jerusalems Faculty of Medicine and director of the genetics department at Hadassah- University Medical Center.

Elpeleg credits the discovery to deep sequencing technology that Hadassah and Hebrew U. were among the first to introduce into clinical practice in Israel and in the world.

The team found that affected childrens cells are flooded with ribosomal RNA and are poisoned by it. It was the first time an excess of ribosomal RNA has been linked to a disease in human regression and neurodegeneration.

The disease does not yet have a name.

At first, affected children lead normal lives and seem identical to their age-matched peers.

However, beginning at age three to six, they show neurological deterioration gradually losing motor, cognitive and speech functions. Although the condition progresses slowly, most patients are completely dependent sometime between 15 to 20 years of age.

Working with colleagues from the Pennsylvania State University College of Medicine and a multinational research team, the Israeli-led team have now identified and studied seven children from Canada, France, Israel, Russia and the US who suffer from the disorder.

The researchers found in all patients the same spontaneously occurring, non-inherited genetic change in a gene, named UBTF, responsible for ribosomal RNA formation.

It is because of this small change that patients cells are flooded with ribosomal RNA.

Ribosomes are responsible for the translation and production of cell proteins. They are made up of ribosomal proteins and of ribosomal RNA in a precise ratio.

The researchers found an identical error in the same gene in all the patients tested, representing a difference of one letter among the roughly three billion that make up human DNA.

By finding the identical change in children with the identical clinical disease, the researchers determined the altered gene was indeed the cause of the disease.

Elpeleg initially encountered the disease in a young girl who came to Hadassah.

Five years ago, I saw a patient who was healthy until the age of three and then experienced a disturbance in her walking and motor function, speech and cognition. Around that time, we had introduced the deep-sequencing technology for clinical use at Hadassah, which enabled us to read all the coding genetic material of a person within a couple of days, in order to identify genetic defects.

Since 2010, Hadassah has assembled the largest genetic mapping database in Israel with around 2,400 patients.

Searching for similar genetic defects in this database, we found a nine-year-old boy who had been treated at Hadassah and now lives in Russia. The boy had been healthy until the age of five and then displayed neurological deterioration just like the girl I had diagnosed, said Elpeleg.

Dr. Simon Edvardson, a pediatric neurologist at Hadassah, flew to Russia, examined the boy, took genetic samples from him and his parents and confirmed that his illness was identical to that of the Israeli girl. We then knew we had identified a new disease that was not recognized in the medical literature, said Elpeleg.

Comparing their data in a program called Gene Matcher, the researchers found several more children around the world who shared an identical genetic defect and the same course of disease.

To understand the mechanism of the newly identified disease, the researchers collaborated with Dr. George-Lucian Moldovan at Pennsylvania State University College of Medicine who confirmed the disease mechanism in the childrens cells, there is an excess RNA of the ribosome, which probably causes brain cells to be flooded and poisoned.

While there is currently no cure for genetic diseases of this kind, the identification of the exact mutation may allow for the planning of therapies designed to silence the mutant gene.

Science may not be able to repair the gene, but now that our findings are published, it may be possible to make early identification of the disease and in the future find ways to prevent such a serious deterioration, Elpeleg said.

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Israeli team finds biological basis for rare neurological kids’ disease – The Jerusalem Post

Scientists Remove Disease-Causing Mutations from Human Embryos – Mental Floss

Researchers have successfully edited the genes of viable human embryos to repair mutations that cause a dangerous heart condition. The team published their controversial research in the journal Nature.

The versatile gene-editing technique known as CRISPR-Cas9 is no stranger to headlines. Scientists have already used it to breed tiny pigs, detect disease, and even embed GIFs in bacteria. As our understanding of the process grows more advanced and sophisticated, many researchers have wondered how it could be applied to human beings.

For the new study, an international team of researchers fertilized healthy human eggs with sperm from men with a disease called hypertrophic cardiomyopathy, a condition that can lead to sudden death in young people. The mutation responsible for the disease affects a gene called MYBPC3. Its a dominant mutation, which means that an embryo only needs one bad copy of the gene to develop the disease.

Or, considered another way, this means that scientists could theoretically remove the disease by fixing that one bad copy.

Eighteen hours after fertilizing the eggs, the researchers went back in and used CRISPR-Cas9 to snip out mutated MYBPC3 genes in some of the embryos and replace them with healthy copies. Three days later, they checked back in to see how their subjectswhich were, at this point, still microscopic balls of cellshad fared.

The treatment seemed successful. Compared to subjects in the control group, a significant number of edited embryos appeared mutation- and disease-free. The researchers also found no evidence that their intervention had led to any unwanted new mutations, although it is possible that the mutations were there and overlooked.

Our ability to edit human genes is improving by the day. But, many ethicists argue, just because we can do it doesnt mean that we should. The United States currently prohibits germline editing of human embryos by government-funded researchers. But theres no law against such experimentation in privately funded projects like this one.

The same day the new study was published, an international committee of genetics experts issued a consensus statement advising against editing any embryo intended for implantation (pregnancy and birth).

“While germline genome editing could theoretically be used to prevent a child being born with a genetic disease, its potential use also raises a multitude of scientific, ethical, and policy questions, Derek T. Scholes of the American Society of Human Genetics said in a statement. These questions cannot all be answered by scientists alone, but also need to be debated by society.”

Ethicists and sociologists are concerned by the slippery slope of trying to build a better human. Many people with chronic illness and disability live happy, complete lives and report that theyre limited more by discrimination than by any medical issues.

Disability studies expert Lennard Davis of the University of Illinois says we cant separate scientific decisions from our societys history of violence against, and oppression of, disabled and sick people.

A lot of this terrific science and technology has to take into account that the assumption of what life is like for people who are different is based on prejudice against disability, he told Nature in 2016.

Rosemary Garland-Thomson is co-director of the Disability Studies Initiative at Emory University. Speaking to Nature, she said we are at a cultural and ethical precipice: At our peril, we are right now trying to decide what ways of being in the world ought to be eliminated.

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Scientists Remove Disease-Causing Mutations from Human Embryos – Mental Floss

Scientists find genetic ‘trail’ to mysterious Biblical civilization – New York Post

DNA research is shining new light on the Biblical Canaanite civilization, which existed thousands of years ago in the Middle East.

The ancient civilization, which created the first alphabet and is mentioned frequently in the Bible, has long fascinated historians. LiveScience reports that, because the Canaanites kept their records on papyrus, rather than clay, relatively little is known about them.

Now, however, scientists have found a genetic trail back to the Canaanites ancient world.

By sequencing the genomes of five Canaanites that lived 4,000 years ago with genomes from 99 people living in modern day Lebanon, researchers identified a strong genetic link to the mysterious civilization.

The results surprised the scientists, whose work was supported by UK biomedical research charity The Wellcome Trust.

In light of the enormously complex history of this region in the last few millennia, it was quite surprising that over 90 percent of the genetic ancestry of present-day Lebanese was derived from the Canaanites, said Chris Tyler-Smith, senior group leader at The Wellcome Trust Sanger Institute, in a statement.

In addition to the ancient Canaanite DNA, the analysis of genomes from the modern day Lebanese people also showed a small proportion of Eurasian ancestry that may have come from conquests by Assyrians, Persians or Macedonians, according to the experts.

The researchers also discovered that the ancient Canaanites were a mixture of local people, who settled in farming villages during the Neolithic period, and eastern migrants who arrived about 5,000 years ago. Using ancient DNA we show for the first time who were (genetically) the ancient Canaanites, how they were related to other ancient populations and what was their fate, explained Marc Haber, a genetic data expert at The Wellcome Trust Sanger Institute, in an email to Fox News. Our work shows the power of genetics in filling gaps in human history when the historical records are absent or scarce.

Haber added that the results complement Biblical accounts of the Canaanites. While the Israelites are commanded to utterly destroy the Canaanites in Deuteronomy 20:16-18, Judges 1 describes the survival of a number of Canaanite communities.

Canaanites once lived in what we now recognize as Israel, the Palestinian territories, Lebanon, Syria and Jordan. The remains of the five ancient Canaanites studied as part of the DNA research were recovered in the modern-day Lebanese city of Sidon.

The research was published in the American Journal of Human Genetics on July 27.

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Scientists find genetic ‘trail’ to mysterious Biblical civilization – New York Post

Impact of gene editing breakthrough will be muted – Irish Times

Medical genetic disorders affect about one person in 25. Genetic engineering and DNA sequencing invented in the 1970s led to a revolution in genetics. Photograph: AP

The work on the repair of a gene in human eggs, reported in the journal Nature, is an important scientific achievement. It made use of Crispr (clustered regularly interspaced short palindromic repeats) technology to make a single specific change in the three billion units of the human genome. The work is indeed a stunning application of Crispr, with some elegant and surprising results and the publicity is good for my science but it is not likely to change the way reproductive medical genetics is practised and it raises no new ethical problems.

The claims made for the work, amplified by the media, will raise expectations in families carrying genes with severe medical effects and has already excited the critics who fear that geneticists are busy undermining our society. So let us first look at what has been achieved in the science, and then tease out some of the implications.

Medical genetic disorders cause a great deal of suffering and affect about one person in 25. Genetic engineering and DNA sequencing invented in the 1970s led to a revolution in genetics. Mutant genes causing many genetic disorders have been identified. Advances in human embryology led to in-vitro fertilisation (IVF) in 1978, leading to the birth of more than five million children and untold happiness in their families. The question arose whether IVF could be useful in dealing with medical genetic cases.

By the early 1990s geneticists could detect mutant genes in single cells taken from IVF embryos without harming the embryos. This led to the gradual introduction of preimplantation genetic diagnosis (PGD). Today parents who are concerned that they may conceive a child with a significant genetic disorder can produce embryos by IVF, these may be tested for the genetic defect and one or more unaffected embryos can then be implanted.

PGD requires a specific probe for each genetic mutation. Some mutations are common, such as F508 in cystic fibrosis, but for many families the mutations have to be analysed and specific probes prepared and tested. As many people know, IVF is itself complex PGD adds another level of complexity, meaning that the number of successful clinical cases dealt with worldwide to date is still only a few thousand. PGD is in its infancy.

So what will be the clinical impact of the new method on PGD? In their experiments, biologist Shoukhrat Mitalipov and his fellow researchers treated 58 embryos in which about 50 per cent carried the normal and half the mutant gene. After treatment they found that 42 (or 72 per cent) carried two normal genes. The mutant gene had been repaired in an estimated 13 out of 29 embryos. Crucially, not all embryos were repaired, nor was it possible to say that Crispr did not cause other unintended, off-target damage to other genes. The embryos were not implanted.

The authors suggest that repair by Crispr will increase the efficiency of PGD. In fact it will have almost no practical effect on PGD services, for two reasons. First, not all of the defective genes are repaired, so after Crispr the embryos still have to be screened by standard PGD to avoid implanting mutant genes. Second, repairing is much more complicated than the current method, which is already complicated. Two Swedish commentators who work in the field note dryly: Embryo genetic testing [PGD] during IVF remains the standard way to prevent the transmission of inherited diseases in human embryos.

In contrast to its use in reproductive medical genetics, use of Crispr in repairing genes in body tissues is a really promising approach to treating genetic disorders after birth, but that is another story.

What do we really need to do in developing PGD? The technical priority is to make IVF itself more efficient. Then we need to refine the current methods of PGD and apply them routinely to a much wider range of genetic mutations. The social priority is to provide PGD on national health services to all couples faced with a high chance of conceiving a child with a major genetic disorder.

Now what about the ethics? Since PGD, which is a medical procedure, is well accepted in international medicine there is nothing new on that front. If in the past, like the Catholic Church, you opposed IVF (and PGD), or the wishes of parents to avoid having children with genetic disorders, this work will not change opinions, and should not increase your concerns.

It is possible that the Crispr techniques of changing genes will be used for non-medical purposes in reproduction, for example to alter genetic qualities which have nothing to do with health. In the UK, such use is regulated by the Human Fertilisation and Embryology Authority, and might be made illegal (as for example is the non-medical use of PGD for sex selection). But it may be more difficult to make all applications illegal for example, parents might wish to have a child with blue instead of brown eyes, and if so is foolishness something we should make illegal?

One thing is clear. It is long past time that we put into effect the recommendations of the Irish Commission on Assisted Human Reproduction of 2005 dealing with these issues, which are not new, and are well known to the Government. IVF is not regulated in Ireland, nor is PGD, making it difficult for pioneers in the field such as Dr John Waterstone of Cork Fertility to provide a service that is badly needed in Ireland.

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Impact of gene editing breakthrough will be muted – Irish Times

Here’s where experts say we should draw the line on gene-editing experiments on human embryos – Los Angeles Times

A day after a blockbuster report that researchers had edited harmful genetic mutations out of human embryos in an Oregon lab, an international group of genetics experts urged scientists against taking the next step.

A panel of the American Society of Human Genetics, joined by representatives from 10 organizations scattered across the globe, recommended against genome editing that culminates in human pregnancy. Their views were published Thursday in the American Journal of Human Genetics.

In the United States, the Food & Drug Administration forbids any medical use of gene editing that would affect future generations, and the agency strictly regulates experimental use of the technology in labs. But around the world, scientists sometimes circumvent restrictions like these by conducting clinical work in countries that have no such strictures.

People who want to gain access to these techniques can find people willing to perform them in venues where they are able to do so, said Jeffrey Kahn, director of the Berman Center for Bioethics at Johns Hopkins University. That underscores the importance of international discussion of what norms we will follow.

Indeed, some of the groups signing on to the new consensus statement acknowledged that they inhabit parts of the world in which medical and scientific regulatory bodies scarcely exist, or are not robust.

The panel said it supports publicly funded research of the sort performed at Oregon Health & Science University and reported Wednesday in the journal Nature. Such work could facilitate research on the possible future applications of gene editing, according to its position statement.

In the Nature study, researchers created human embryos with a mutation in the MYBPC3 gene that causes an often fatal condition called inherited hypertrophic cardiomyopathy. Then they edited the DNA of those embryos during the first five days of their development. At that point, the embryos were extensively analyzed and used to create stem cell lines that can be maintained indefinitely and used for further research.

But advancing to the next step allowing pregnancies to proceed with altered embryos will require further debate, the genetics specialists asserted.

They cited persistent uncertainties regarding the safety of gene-editing techniques. They also said the ethical implications of so-called germ-line editing, which would alter a patients genetic code in ways that would affect his or her offspring, remain insufficiently considered.

Panel members raised questions about who would have access to therapies made possible by manipulating the genome, and how existing inequities could be exacerbated. And they expressed concerns that the availability of germ-line editing could encourage experiments in eugenics the creation of people engineered for qualities such as intelligence, beauty or strength that would set them apart as superior.

Perhaps the most deeply felt concern is conceptual: the sense that in identifying some individuals and their traits as unfit, we experience a collective loss of our humanity, the group wrote.

The position statement comes on the heels of the Nature study reporting the first successful use in human embryos of a relatively new and increasingly popular gene-editing technique known as CRISPR-Cas9. That study offered some reassurance that unforeseen or off target effects of such therapies can be avoided with certain practices.

Study leader Shoukhrat Mitalipov, a biologist at the Oregon university, said that while there is a long road ahead, he hoped to employ these techniques in human clinical trials in the coming years.

The genetics groups consensus statement lays out some of the scientific and ethical debates that should come before any trial would attempt the incubation and birth of children whose faulty genes had been repaired while they were still embryos.

The group also voiced concerns about the potential impact of germ-line editing on families and societies in which they might become widely used.

Arguably, the ability to easily request interventions intended to reduce medical risks and costs could make parents less tolerant of perceived imperfections or differences within their families, panel members wrote. Clinical use of germline gene editing might not be in the best interest of the affected individual if it erodes parental instinct for unconditional acceptance.

melissa.healy@latimes.com

@LATMelissaHealy

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Here’s where experts say we should draw the line on gene-editing experiments on human embryos – Los Angeles Times

Genetics expert discusses creating ground rules for human germline editing – Medical Xpress

August 4, 2017

A Stanford professor of genetics discusses the thinking behind a formal policy statement endorsing the idea that researchers continue editing genes in human germ cells.

A team of genetics experts has issued a policy statement recommending that research on editing human genes in eggs, sperm and early embryos continue, provided the work does not result in a human pregnancy.

Kelly Ormond, MS, professor of genetics at the Stanford School of Medicine, is one of three lead authors of the statement, which provides a framework for regulating the editing of human germ cells. Germ cells, a tiny subset of all the cells in the body, give rise to eggs and sperm. Edits to the genes of germ cells are passed on to offspring.

The statement, published today in the American Journal of Human Genetics, was jointly prepared by the American Society for Human Genetics and four other human genetics organizations, including the National Society of Genetic Counselors, and endorsed by another six, including societies in the United Kingdom, Canada, Australia, Africa and Asia.

Germline gene editing raises a host of technical and ethical questions that, for now, remain largely unanswered. The ASHG policy statement proposes that federal funding for germline genome editing research not be prohibited; that germline editing not be done in any human embryo that would develop inside a woman; and that future clinical germline genome editing in humans not proceed without a compelling medical rationale, evidence supporting clinical use, ethical justification, and a process incorporating input from the public, patients and their families, and other stakeholders.

Ormond recently discussed the issues that prompted the statement’s creation with writer Jennie Dusheck.

Q: Why did you think it was important to issue a statement now?

Ormond: Much of the interest arose a couple of years ago when a group of researchers in China did a proof of principle study demonstrating that they could edit the genes of human embryos.

The embryos weren’t viable [meaning they could not lead to a baby], but I think that paper worried people. Gene editing in human germ cells is not technically easy, and it’s not likely to be a top choice for correcting genetic mutations. Still, it worried us that somebody was starting to do it.

We’ve been able to alter genes for many years now, but the new techniques, such as CRISPR/Cas9, that have come out in the past five years have made it a lot easier, and things are moving fast. It’s now quite realistic to do human germline gene editing, and some people have been calling for a moratorium on such work.

Our organization, the American Society of Human Genetics, decided that it would be important to investigate the ethical issues and put out a statement regarding germline genome editing, and what we thought should happen in the near term moving forward.

As we got into the process, we realized that this had global impact because much of the work was happening outside of the United States. And we realized that if someone, anywhere in the world, were moving forward on germline genome editing, that it was going to influence things more broadly. So we reached out to many other countries and organizations to see if we could get global buy-in to the ideas we were thinking about.

Q: Are there regulations now in place that prevent researchers from editing human embryos that could result in a pregnancy and birth?

Ormond: Regulations vary from country to country, so research that is illegal in one country could be legal in another. That’s part of the challenge and why we thought it was so important to have multiple countries involved in this statement.

Also, since 1995 the United States has had regulations against federal funding for research that creates or destroys human embryos. We worry that restricting federal funding on things like germline editing will drive the research underground so there’s less regulation and less transparency. We felt it was really important to say that we support federal funding for this kind of research.

Q: Is germline editing in humans useful and valuable?

Ormond: Germline editing doesn’t have many immediate uses. A lot of people argue that if you’re trying to prevent genetic disease (as opposed to treating it), there are many other ways to do that. We have options like prenatal testing or IVF and pre-implantation genetic testing and then selecting only those embryos that aren’t affected. For the vast majority of situations, those are feasible options for parents concerned about a genetic disease.

The number of situations where you couldn’t use pre-implantation genetic diagnosis to avoid having an affected child are so few and far between. For example, if a parent was what we call a homozygote for a dominant condition such as BRCA1 or Huntington’s disease, or if both members of the couple were affected with the same recessive condition, like cystic fibrosis or sickle cell anemia, it wouldn’t be possible to have a biologically related child that didn’t carry that gene, not unless germline editing were used.

Q: What makes germline editing controversial?

Ormond: There are families out there who see germline editing as a solution to some genetic conditions. For example, during a National Academy of Sciences meeting in December of 2015, a parent stood up and said, “I have a child who has a genetic condition. Please let this move forward; this is something that could help.”

But I also work in disability studies, as it relates to genetic testing, and there are many individuals who feel strongly that genetic testing or changing genes in any way makes a negative statement about them and their worth. So this topic really edges into concerns about eugenics and about what can happen once we have the ability to change our genes.

Germline gene editing impacts not just the individual whose genes are edited, but their future offspring and future generations. We need to listen to all of those voices and try to set a path that takes all of them into account.

That’s a huge debate right now. A lot of people say, “Let’s not mess around with the germline. Let’s only edit genes after a person is born with a medical condition.” Treating an existing medical condition is different from changing someone’s genes from the start, in the germline, when you don’t know what else you’re going to influence.

Q: There was a paper recently about gene editing that caused mutations in excessive numbers of nontargeted genes, so called “off-target effects.” Did that result surprise you or change anything about what you were thinking?

Ormond: I think part of the problem is that this research is moving very fast. One of our biggest challenges was that you can’t do a good ethical assessment of the risks and benefits of a treatment or technology if you don’t know what those risks are, and they remain unclear.

We keep learning about potential risks, including off-target mutations and other unintended consequences. Before anyone ever tries to do germline gene editing in humans, it is very important that we do animal studies where the animals are followed through multiple generations, so that we can see what happens in the long term. There’s just a lot that we don’t know.

There are so many unknowns that we don’t even know what guidelines to set. For example, what’s an appropriate new mutation level in some of these technologies? What is the risk we’re willing to take as we move forward into human studies? And I think those guidelines need to be set as we move forward into clinical trials, both in somatic cells [cells of the body, such as skin cells, neurons, blood cells] and in germline cells.

It’s really hard because, of course, we’re talking about, for the most part, bad diseases that significantly impact quality of life. So if you’re talking about a really serious disease, maybe you’re willing to take more risk there, and these new mutations aren’t likely to be as bad as the genetic condition you already have. But we don’t know, right?

We haven’t had any public dialogue about any of this, and that’s what we need to have. We need to find a way to educate the public and scientists about all of these issues so people can have informed discussions and really come together as this moves forward, so that were not in that reactive place when it potentially becomes a real choice.

And that goes back to your first question, which is why did we feel like we needed to have a statement now? We wanted to get those conversations going.

Explore further: 11 organizations urge cautious but proactive approach to gene editing

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Genetics expert discusses creating ground rules for human germline editing – Medical Xpress

Ancient DNA solves mystery of fate of Bible’s Canaanites – The Columbian

A A

In the Bronze Age, between 4,000 and 3,000 years ago, a diverse group of people called the Canaanites lived in the Middle East. Despite their culture and influence one of the only golden calf idols discovered was found in the Canaan seaport of Ashqelon they left behind little information about themselves. Other civilizations made records of them, such as the Greeks, Egyptians and the authors of the Hebrew Bible. But, without Canaanite texts to cite, scholars view the ancient people as a bit of an enigma.

We havent found any of their writings, said Chris Tyler-Smith, a geneticist who studies human evolution at the Sanger Institute in Britain. Perhaps they wrote on papyrus but not longer-lasting clay. We dont have direct information from them, he said. In that sense, they are a mystery.

Their final fate, too, was a puzzle. The Hebrew text offers one explanation for the destiny of the Canaanites: annihilation. The Israelites, per Deuteronomy 20:16-18, were commanded to utterly destroy the cities of various tribes including the Canaanites. Those who survived fled or became servants.

But historians are skeptical that either exodus or annihilation occurred. University of North Carolina religious studies professor Bart Ehrman noted in a 2013 blog post that, beyond the Hebrew Bible, there are no references in any other ancient source to a massive destruction of the cities of Canaan.

Now a study of Canaanite DNA, published recently in the American Journal of Human Genetics, rules out the biblical idea that an ancient war wiped out the group. The DNA, when compared to that of modern-day people, shows that the Canaanites managed to leave a long line of descendants. Even if they suffered some defeats, enough people survived that they contributed to the present-day population, Tyler-Smith said.

Tyler-Smith and his colleagues sampled ancient DNA from five Canaanite people who lived 3,750 and 3,650 years ago. Though the skeletal remains were buried in a hot and humid region along the Mediterranean, the scientists were still able to extract genetic material. They mined the petrous bone, a region of skull behind the ear thats also the densest bone in the body.

The geneticists sequenced the Canaanite genome and compared it to genomes of modern people, including Jordanians, Palestinians, Syrians and others from around the world. The comparison revealed that 90 percent of the genetic ancestry of people in Lebanon came from the Canaanites. (The other 10 percent was of a Eurasian steppe population.)

We can say that Lebanese mostly descend from an ancestry that is found in those five individuals, said Marc Haber, a Sanger Institute geneticist and an author of the new study. What we find is that the ancestry has changed, but it has changed very little.

The unbroken genetic heritage was a surprise. From the Bronze Age onward, that coastal Mediterranean region has been the site of repeated conquering and reshuffling of populations. There was more genetic continuity in Lebanon than in a place like England, Tyler-Smith said.

Its an exciting time to be investigating ancient DNA, the geneticists said. The Canaanites were an ideal case study ancient genomes can provide information not available through historical records or archaeology. But the corridor from Egypt to Asia was a path well-worn by many groups moving in and out of Africa.

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Ancient DNA solves mystery of fate of Bible’s Canaanites – The Columbian

Morning Break: Nicotine Fight; Birthday Buzzkill; Another Charlie Gard? – MedPage Today

The CEO of one of the nation’s largest health insurers said Obamacare “cannot be repealed, period, end of sentence.” (CNBC)

Look for Big Tobacco to push back hard against the FDA’s new policy to get nicotine out of cigarettes, Bloomberg reports.

Maybe a secret wish for good health will come true if you don’t blow out the candles on the birthday cake. (USA Today)

Leading genetics organizations said CRISPR-type genome editing should be confined to laboratories for the time being. (American Journal of Human Genetics)

Pig-to-human heart transplantation gets its own research center at the University of Maryland, with $24 million in initial funding.

The world’s biggest manufacturer of generic drugs plans to cut 7,000 jobs and close 15 plants over the next 2 years. (Philadelphia Inquirer)

Experts weighed in on the purported health benefits of coconut water. (CNN)

Is a Charlie Gard-like drama getting ready to play out in the U.S.? (Fox News)

What could possibly go wrong when first-year medical residents work 28-hour shifts? (Houston Chronicle)

An in-depth look at the origin and drivers of the ongoing opioid epidemic. (Vox)

In reversing a malpractice decision involving botched gynecologic surgery, a European appeals court rebuked a Portuguese court for opining that sex isn’t as important to older women. (The Guardian)

If you feel smarter when you’re drinking, maybe it isn’t just the booze talking to you. (Business Insider)

Morning Break is a daily guide to what’s new and interesting on the Web for healthcare professionals, powered by the MedPage Today community. Got a tip? Send it to us: MPT_editorial@everydayhealthinc.com.

2017-08-04T08:45:00-0400

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Morning Break: Nicotine Fight; Birthday Buzzkill; Another Charlie Gard? – MedPage Today

Geisinger experts say gene editing progress, but have concerns – Sunbury Daily Item

Two Geisinger Health System scientists said Wednesdaythe successful editing of human embryos’ DNA to erase an inheritable heart condition shows potential in preventing disease. But both urged caution and said there is more work to be done to ensure the process is safe.

W. Andrew Faucett,Geisinger Genomic Medicine Institute professorand director of policy and education, andF. Daniel Davis,Geisinger chief bioethics officer, were not greatly concerned, however, that the research would lead to genetic manipulation to produce so-called designer babies.

They were commenting on the firstgene editing on human embryos that has been conducted in the United States. The Washington Post reported on Wednesday that researchers said that they consider their work very basic. The embryos were allowed to grow for only a few days and there was never any intention to implant them to create a pregnancy. The ultimate goal, though, is to “correct” disease-causing genes in embryos that will develop into babies.

Details of the experiment using thelaboratory tool known as CRISPR (or Clustered Regularly Interspaced Short Palindromic Repeats), a type of “molecular scissors,”became public Wednesday with a paper in the journal Nature, the Post reported.

“I’m certainly not an expert on that end of it,” said Davis, the bioethics officer. “But this does represent an advance along the evolutionary pathway of a technology. It’s a step forward in ways most people would agree represents progress. There still are legitimate concerns about the more widespread use and clinical applications at this point.”

According to The Post, the researchers used eggs from 12 healthy female donors and sperm from a male volunteer who carries the gene that causes hypertrophic cardiomyopathy, a disease of the heart muscles that can cause no symptoms and remain undetected until it causes sudden cardiac death. The researcherssnipped out the gene that causes the disease and replaced with a copy of the gene.

Faucett said his concerns include whether the technology could lead to other changes in “off-target” genes that would be passed on to future generations.

“We’llfix the heart gene but damage a cancer-causing gene,” he said. “We’ll solve this problem but cause another problem.”

Faucett said it’s impossible to weigh one problem against the other because no one knows what the off-target gene is until it shows itself years later.

“There are 20,000 genes in the human body,” he said. “A lot of genes we don’t understand. Part of what we’re doing at Geisinger is trying to understand the use of genes. Also what do you do with the genes you understand.”

He said, though, Geisinger is not doing gene editing research but studying DNA samples to check for potential for disease in patients and their families.

“We’re not studying embryos,” Faucett said.

Davis said concerns about manipulating DNA to create specific humans are overblown.

“I don’t mean to be a naysayer,” he said. “I just think the real ethical concern is about safety and efficacy.”

He has less concern about designer babies than about people that are going to be harmed by technology. He cited bone marrow transplants and hormonal therapy for women that have been harmful to some patients because the treatments were not adequately investigated.

The Post reported that Shoukhrat Mitalipov, one of the lead authors of the paper and a researcher at Oregon Health & Science University, said he is conscious of the need for a larger ethical and legal discussion about genetic modification of humans, but that his team’s work is justified because it involves “correcting” genes rather than changing them.

Faucett was on the American Society of Human Genetics committee that wrote the society’s position paper on the genome editing. The paper, which comes out today and is endorsed by a number of genetic study groups from around the world, states it is against anything but laboratory testing (without humans).

Email comments to jsylvester@thedanvillenews.com. Follow Sylvester on Twitter @JoepSylvester.

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Geisinger experts say gene editing progress, but have concerns – Sunbury Daily Item

Kathiresan and Topol on Genomics of Heart Disease – Medscape

Focusing on Heart Attacks Among the Young

Eric J. Topol, MD: Hello. I’m Eric Topol, editor-in-chief of Medscape. I’m privileged today to speak with Sekar Kathiresan from the Broad Institute, who heads up the Center for Genomic Medicine at Massachusetts General Hospital, which is not even a year old, and who also is on the faculty at Harvard Medical School. Sek, you’ve done some remarkable things to advance our knowledge in cardiovascular genomics. In fact, you’re my go-to guy.

I’d like to start with your background and how you got into this area. You grew up in Pittsburgh, went to Penn for undergrad, and then to Harvard?

Sekar Kathiresan, MD: I graduated from Harvard Medical School in ’92 and have stayed there since. I did internal medicine (clinical cardiology) training, and I was a chief resident in medicine at Mass General. I started my research training in 2003 after all those years of medical school and clinical training. It was originally supposed to be just a 2-year stint in genetic epidemiology, but I ended up liking it so much that I spent 5 years as a postdoctoral fellow2 years at the Framingham Heart Study and 3 years at the Broad Institute, learning human genetics. I got all of the foundation for genetics research during that experience.

I started my own lab in 2008. The whole time, we’ve been focused on trying to understand why some people have heart attacks at a young age, specifically looking at the genetic basis for premature myocardial infarction (MI).

Dr Topol: In addition, you’ve established worldwide collaborations of people doing similar things. How did you start that?

Dr Kathiresan: That’s an interesting story. I started in this work in 1997 as an intern at Mass General, recruiting patients who’d had an MI prior to the age of 50 for men and 60 for women. A faculty member there, Chris O’Donnell, started that project and got me involved. Over the subsequent 6 or 7 years of my clinical training, we recruited about 500 such patients at Mass General. I realized quickly that it wasn’t going to be a sufficient sample size to make the kind of observations needed to understand the biology of the disease. It’s a complex disease; a few patients were not going to help solve the problem.

In the mid-2000s I worked with David Altshuler. He was my mentor, and he encouraged me to reach out to people around the world who had similar collections of patients. As a postdoctoral fellow, I emailed investigators in Malm, Sweden, who had a similar collection. They had published their findings. I said, “Do you want to work with us?” They invited me to Malm, and I went. We ended up partnering with six or seven other investigators to start what we called the Myocardial Infarction Genetics Consortium. That’s been the foundation for all of our work on heart attack genetics.

Around the same time, I started a similar consortium for looking at cholesterol level genetics. That has now expanded to more than 50 centers around the world.

Dr Topol: There is a real misconception that heart attacks and coronary disease are tightly interwoven with lipids and cholesterol, but plenty of people who have virtually normal or even better-than-average lipid profiles wind up having heart attacks. Where do you see this field going in terms of better understanding the non-LDL cholesterolor other lipidfoundation for MIs?

Dr Kathiresan: I’ll share with you what we have learned about heart attack genetics over the past 10 years. Doing something unbiased, in the sense of looking across the genome and asking, “Where in the genome is there risk for heart attack in terms of cases versus controls?”, we have learned that several previously known pathways show up. For example, one of the top results in any genetic analysis for heart attack is LDL cholesterol and several genes related to LDL cholesterol. In addition, we’ve been able to clarify some controversies in the lipids area.

It was unclear when I got into the field which of the twoHDL, the so-called “good cholesterol,” or triglycerideswas more important. When I was in medical school I was taught that anything that raised the good cholesterol must be good for you. Our genetics have shown that is not the case. Basically, HDL cholesterol is a very good marker of risk but it’s unlikely to be a causal factor. We published a genetics study[1] a couple of years ago that challenged the conventional wisdom and suggested that drugs that raise HDL are not going to work. We actually had a hard time publishing that study; it took a couple of years, but since then, there have been five randomized control trials of medicines that have tried to raise HDL cholesterol.

Dr Topol: It’s been a big bust.

Dr Kathiresan: It turns out that we probably were on the wrong side of the seesaw. When HDL is down, triglycerides are up. People thought that HDL was what was important. The genetics now strongly point to triglycerides-rich lipoproteins.

We have LDL and we have triglyceride-rich lipoproteins. The other key factor in the lipids space is something called lipoprotein(a). The genetics are compelling that these three things are very important for heart attack. The surprising thing has been that of the 55 gene regions we’ve identified for heart attack, only about 40% point to things that we already knew about. Another 60% don’t relate to any of the known risk factors, like blood pressure or cholesterol, suggesting that there are new mechanisms for atherosclerosis. As a community, we need to figure those out.

Dr Topol: For example, the common variant of 9p21, a 60 kb noncoding region, has nothing known to do with cholesterol, and we are still working on what it really means, right?

Dr Kathiresan: Yes. At Scripps, you played a big role in trying to sort that out. It’s been 10 years and it’s been very challenging. None of this is going to be easy. Cholesterol was hypothesized to play a role in heart attack more than 100 years ago, and some people are still debating the role of LDL cholesterol. This isn’t going to be straightforward, but it does suggest that there are lots of other mechanisms.

Dr Topol: That’s obviously very important because Brown and Goldstein, the famous Nobel Laureates who were instrumental in the development of statins at the turn of the century, published an editorial in Science, “Heart Attacks: Gone With the Century?”[2] That was the notion that statins would be widely used and that we would stamp out heart attacks. That hasn’t exactly happened, although there has been a reduction in large ST-elevation infarcts.

Dr Kathiresan: There are a couple of issues. Their hypothesis is sound; it says that if you start treatment early enough, and if the LDL is low over an extended period of time (30-40 years), you won’t develop atherosclerosis. They based that hypothesis on model organism work but also on human genetics. People who carry mutations that naturally lower their LDL to very low levels lifelong rarely develop atherosclerosis. Societies like rural China, where LDL is very low, have very little atherosclerosis. It is a very good hypothesis and we still have to test it. We don’t know.

Dr Topol: If you could do it at birth…

Dr Kathiresan: If we could do it safely…

Dr Topol: And safelyright.

Dr Kathiresan: Even if you do that, there are still several other elements or pathways. We are seeing now, in the United States at least, a transition from risk that was driven over the past century by blood pressure, smoking, and LDL, to this century, when risk is basically being driven by abdominal adiposity, insulin, and triglyceridesthe cardiometabolic axis. That’s what we’re seeing with the obesity epidemic. LDL levels are coming down and heart attack rates have come down as a result, but we have the countervailing force of cardiometabolic disease. That’s where triglyceride-rich lipoproteins come ininsulin and so forth. This is on an incredible rise in the United States and also worldwide.

Dr Topol: One of the most seminal studies in the three decades during which I studied cardiology and coronary heart disease was one that you and your colleagues published last November in the New England Journal of Medicine.[3] In that study, you had the genetic risk scores, so you knew the various polygenic markers and could separate people into low, moderate or intermediate, and high risk, and you showed the titration of high riskwhich has never been done before, genomicallywith better lifestyle.

A Cell editorial[4] published very soon after your paper said that diet and exercise will save us all.

I want to get your thoughts about this. These days, if people knew that they were at high risk without any connection to family history, blood pressure, or LDL, they could benefit from this knowledge and this could be a way to promote, for them in particular, a healthy lifestyle.

Dr Kathiresan: Thank you for your kind words about the paper. The work started with a very simple observation. In my preventive cardiology clinic at Mass General, we have patients who come in and say, “My father died of a heart attack at age 50. I am doomed.” They feel that DNA is destiny for this disease. We wanted to address that if you are at high genetic risk, can you overcome or counterbalance that risk with a favorable, healthy lifestyle? We’ve known for many years that a favorable lifestyle is associated with a reduced risk for coronary heart disease. In the context of genetic risk, how do they interact?

We found that if you are at high genetic risk, based on 50 different DNA markers, you could cut that risk in half by having a favorable lifestyle that included not smoking, regular fruit and vegetable intake, maintaining an ideal weight, and so forth. It was a very sobering message in some sense and a good public health messagethat if you are at high genetic risk based on, let’s say, family history, you should not take this DNA-as-destiny approach. Rather, you do have control over your health, specifically by trying to practice these healthful behaviors.

Dr Topol: It transcends the Framingham Risk Score era because now you have a way to gauge risk and it can be titrated, so it was a big step forward. I also want to get into the idea that you can protect your heart disease risk naturallythat is Mother Nature. Previously you’ve talked about APOC3 and a startling finding about these homozygotes that you identified in Pakistan. Would you tell us that story?

Dr Kathiresan: You wrote many years ago about protective mutations. When we think about genetics, we think automatically about risk, but actually there is a big value of genetics in finding people who are naturally protected because of a mutation, and the main value is that you could hopefully develop a medicine that might mimic that mutation. If you can do that, then you can transfer the benefit that nature gave just to that one rare person to the entire population. That’s the concept.

There’s a very good example in the cardiovascular space with the gene PCSK9, where this held true. We set out a couple of years ago to ask whether there are other examples. The first that we found was the gene apolipoprotein C3. This is a gene that has been known about for 30 or more years. It’s a gene that puts a break on your body’s ability to handle dietary fat. When we eat a McDonald’s burger, right after the meal, the triglyceride level goes up two- to threefold. The body has to clear that fat and the APOC3 protein actually dampens your ability, or puts a break on your body’s ability, to clear it.

We found that about 1 in 150 people in the United States have a favorable mutation that gets rid of one of the two gene copies of APOC3. These individuals have lost a “bad guy” in their blood, and therefore they have lower lifelong triglyceride levels and about a 40% lower risk for heart attacks. That immediately suggested that if you could develop a medicine that got rid of APOC3, you might be able to reduce risk for heart attack.

One of the other key features of this paradigm is finding individuals who lack both copies of that gene. Sometimes you would call them “human knock-outs.” Why do you want to know that? If there’s a person walking around who naturally lacks both copies of that gene, and they are healthy, then that immediately says that you could pretty safely treat somebody with an inhibitor of that protein and not have a lot of adverse effects. It’s not a complete predictor, but it’s pretty close.

We set out to find these individuals. We looked at more than 100,000 people in the United Sates of European ancestry and did not find a single person who lacked both copies of APOC3. It turns out that there are people in whom both copies are gone, but that property tends to happen more when the parents of a child are closely related to each otherfor example, first-cousin marriage. In some parts of the world, it is actually fairly common. It’s not taboo as it is in the United States. Pakistan is a country with the highest proportion of marriages that involve parents who are closely related. We went to an investigator in Pakistan, a collaborator who had recruited a large study of heart attacks there, and we did sequencing of APOC3 in more than 20,000 people. We found four individuals who completely lacked the gene.

Dr Topol: It was striking that these people, first with low triglycerides, also had no triglyceride elevation when they ate a fatty meal.

Dr Kathiresan: It’s fascinating. This was a small fishing village. My collaborator, Danish Saleheen, had a mobile truck to do studies. They went out to the fishing village and recruited family members in whom gene copies were present and those with both copies gone. They gave both groups of individuals a fat challenge and then took blood samples every hour for 6 hours. In all of the people who had APOC3, the triglyceride levels went up (like they would in you and me), but in the people who didn’t have the gene, the triglyceride levels did not budge at all after the fatty meal. This gives us some insight as to why people are protected from heart attack.

Dr Topol: It’s interesting, because it flies in the face of so many studies where they lowered triglyceride levels and findings were very disappointingthere was little clinical effect. But this is a different target, of course.

Dr Kathiresan: That’s the issue. There were lots of studies over the years (particularly with fibrates and fish oils, for example). In randomized controlled trials, those two medicines lowered triglycerides but they were unable to show that they lowered risk for heart attack. The challenge is that we don’t really know what the molecular targets are for those two drugs, and triglyceride metabolism is complex. You can imagine waysand there are actually waysthat you can lower the triglyceride level, but counteract that with other bad things where the net effect might be no effect on disease risk. The way you lower the triglycerides will mattermaybe a little less so than for LDL. It looks like almost any way you lower LDL (although there are some exceptions there too) makes a difference in terms of heart disease risk. For triglycerides, it matters how you lower them.

We are seeing that there are several genes (APOC3 and a couple of others) in the pathway where there is naturally occurring genetic variation, pointing to these genes as being the way to lower triglycerides if you want to lower risk for heart attack.

Dr Topol: That’s phenomenal. What we are seeing here is starting to really crack the big three: Lp(a), APOC3 (and other triglycerides), and LDL. We’re going to see the lipid story become amplified. There is still going to be this other…

Dr Kathiresan: Residual risk.

Dr Topol: That’s going to be an interesting enigma.

Dr Topol: Where are you going next? How are you going to keep building this? This foundation of knowledge has been extraordinary. You have been working on it for a decade. What can you do to expand this now?

Dr Kathiresan: The lab has worked on three elements during the past 10 years: discovery of new genes, understanding how they work, and then translating those findings to improve cardiac care. I see genomics and informed cardiac care going in two ways. One is identifying a subset of individuals who are at much higher risk, based on the genome. We are pretty good at that right now and I think there will be broad uptake over the next 10 years.

We’ll then be able to find a subset of individuals early in life, based on their DNA sequence, who are at three-, four-, or 10-fold higher risk for heart attack. Then the question becomes, what do you do for those patients? We’ve already shown the value of lifestyle and probably a statin, but then the key question is, what else is there? Can we develop a medicine in the nonlipid space that can have dramatic benefit? That’s what I see in the next 10 years.

Dr Topol: That would be exciting. We will ultimately get there as we learn more.

Now, you are big on Twitter.

Dr Kathiresan: No bigger than you.

Dr Topol: I enjoy following you. You are great to follow because you are one of my favorite educators. We can learn a lot from Twitter. What do you like about it? Sometimes, of course, you are tweeting about the Steelers, but when you are not tweeting about the Steelers or politics, what do you enjoy about Twitter?

Dr Kathiresan: I love what you just said. Every day I learn something new on Twitter. It’s a little bit of a double-edged sword. We all know about social media; it’s quite addictive. I could sometimes spend an inordinate amount of time on it. That aside, I learn a lot and it’s mostly about science. It’s things that I would not have seen. On your feed, you transfer an incredible amount of information daily, and there are lots of other opinions. Often now it is the place for immediate news, whether it’s science news or other news.

A good example: A couple of weeks ago, the topline results from the randomized controlled trial of the PCSK9 antibody were announced. I knew they were going to be announced because it was a 4 PM release by Amgen at the close of the market, so I’m waiting.

Dr Topol: The first look is going to be on Twitter.

Dr Kathiresan: Exactly. A day later it will show up in The New York Times.

Dr Topol: The pulse of our field, as you say; the amount of information that you can get through Twitter in science and biomedicineour worldis quite extraordinary, and it’s just as surprising that a lot more physicians and researchers don’t use it.

Dr Kathiresan: Two of the healthiest areas are genomics and cardiovascular medicine. There’s a tremendous amount of cardiology on Twitter, and of course, genomics is way ahead of a lot of other fields.

Dr Topol: It seems that way. It’s some of my favorite stuff.

This has been really fun. I just cannot say enough about how much you have accomplished in such a short time to advance the field. [Heart disease is] still right there as the number-one cause of death and disability, and we still have a long way to go, although cancer is catching up and may soon overtake it in the United States.

Thanks so much for joining us. And thanks to all of you for joining us for this conversation. It got a little deep into the pathophysiology and genomics of coronary disease, but it’s certainly an area that we are going to continue to build on.

Follow Dr Kathiresan on Twitter @skathire and Dr Topol @EricTopol

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Kathiresan and Topol on Genomics of Heart Disease – Medscape

Rohan Silva: The genetic revolution is happening in a tiny office or coffee shop near you – Evening Standard

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Rohan Silva: The genetic revolution is happening in a tiny office or coffee shop near you – Evening Standard

Joyce Harper The Conversation – The Conversation UK

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Joyce Harper is Professor of Human Genetics and Embryology at University College London in the Institute for Womens Health where she is head of the Reproductive Health Department, Principal Investigator of the Embryology, IVF and Reproductive Genetics Group, Director of Education and Director of two MSc programmes – Prenatal Genetics and Fetal Medicine and Reproductive Science and Womens Health. She has been working in the fields of IVF and reproductive genetics since 1987 and written over 170 scientific papers and published two textbooks. Her research includes preimplantation genetic diagnosis, factors affecting preimplantation development, comparison of in vivo and in vitro development, differences in culture media, embryo selection methods, sperm DNA damage and social and ethical issues surrounding IVF and reproductive genetics including gamete donation, surrogacy, social egg freezing, religious views to ART and fertility education and awareness.

Joyce is passionate about public engagement to discuss all aspects of womens health, including wellbeing. She has established a public engagement group with daily posts http://www.globalwomenconnected.com. Joyce is writing a book covering womens health from birth to death. She is deputy chair of the UK Fertility Education Initiative, trying to improve fertility awareness in the UK and a member of the Fertility Arts Education Project Steering Group.

Joyce has had many senior roles in the European Society of Human Reproduction and Embryology (ESHRE), including establishing the ESHRE PGD Consortium. She is chair of the HFEA Horizon Scanning Group and an advisor to the HFEA Science and Clinical Advances Advisory Committee. She is on the Board of the British Fertility Society. She is a member of the Nuffield Council for Bioethics working group on genome editing.

For further information see http://www.joyceharper.com.

1987

Kings College London, PhD

1984

Queen Elizabeth College, BSc

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Joyce Harper The Conversation – The Conversation UK

Shrinking Bat DNA and Elastic Genomes – Quanta Magazine

Parsing the creatures 2 billion base pairs, Feschotte and his colleagues did stumble on something strange. We found some very weird transposons, he said. Because these oddball parasite sequences didnt appear in other mammals, they were likely to have invaded after bats diverged from other lineages, perhaps picked up from an insect snack some 30 to 40 million years ago. Whats more, they were incredibly active. Probably 20 percent or more of the bats genome is derived from this fairly recent wave of transposons, Feschotte said. It raised a paradox because when we see an explosion of transposon activity, wed predict an increase in size. Instead, the bat genome had shrunk. So we were puzzled.

There was only one likely explanation: Bats must have jettisoned a lot of DNA. When Kapusta joined Feschottes lab in 2011, her first project was to find out how much. By comparing transposons in bats and nine other mammals, she could see which pieces many lineages shared. These, she determined, must have come from a common ancestor. Its really like looking at fossils, she said. Researchers had previously assembled a rough reconstruction of the ancient mammalian genome as it might have existed 100 million years ago. At 2.8 billion base pairs, it was nearly human-size.

Next, Kapusta calculated how much ancestral DNA each lineage had lost and how much new material it had gained. As she and Feschotte suspected, the bat lineages had churned through base pairs, dumping more than 1 billion while accruing only another few hundred million. Yet it was the other mammals that made their jaws drop.

Mammals are not especially diverse when it comes to genome size. In many animal groups, such as insects and amphibians, genomes vary more than a hundredfold. By contrast, the largest genome in mammals (in the red viscacha rat) is only five times as big as the smallest (in the bent-wing bat). Many researchers took this to mean that mammalian genomes just dont have much going on. As Susumu Ohno, the noted geneticist and expert in molecular evolution, put it in 1969: In this respect, evolution of mammals is not very interesting.

But Kapustas data revealed that mammalian genomes are far from monotonous, having reaped and purged vast quantities of DNA. Take the mouse. Its genome is roughly the same size it was 100 million years ago. And yet very little of the original remains. This was a big surprise: In the end, only one-third of the mouse genome is the same, said Kapusta, who is now a research associate in human genetics at the University of Utah and at the USTAR Center for Genetic Discovery. Applying the same analysis to 24 bird species, whose genomes are even less varied than those of mammals, she showed that they too have a lively genetic history.

No one predicted this, said J. Spencer Johnston, a professor of entomology at Texas A&M University. Even those genomes that didnt change size over a huge period of time they didnt just sit there. Somehow they decided what size they wanted to be, and despite mobile elements trying to bloat them, they didnt bloat. So then the next obvious question is: Why the heck not?

Feschottes best guess points at transposons themselves. They provide a very natural mechanism by which gain provides the template to facilitate loss, he said. Heres how: As transposons multiply, they create long strings of nearly identical code. Parts of the genome become like a book that repeats the same few words. If you rip out a page, you might glue it back in the wrong place because everything looks pretty much the same. You might even decide the book reads just fine as is and toss the page in the trash. This happens with DNA too. When its broken and rejoined, as routinely happens when DNA is damaged but also during the recombination of genes in sexual reproduction, large numbers of transposons make it easy for strands to misalign, and that slippage can result in deletions. The whole array can collapse at once, Feschotte said.

This hypothesis hasnt been tested in animals, but there is evidence from other organisms. Its not so different from what were seeing in plants with small genomes, Leitch said. DNA in these species is often dominated by just one or two types of transposons that amplify and then get eliminated. The turnover is very dynamic: in 3 to 5 million years, half of any new repeats will be gone.

Thats not the case for larger genomes. What we see in big plant genomes and also in salamanders and lungfish is a much more heterogeneous set of repeats, none of which are present in [large numbers], Leitch said. She thinks these genomes must have replaced the ability to knock out transposons with a novel and effective way of silencing them. What they do is, they stick labels onto the DNA that signal to it to become very tightly condensed sort of squished so it cant be read easily. That alteration stops the repeats from copying themselves, but it also breaks the mechanism for eliminating them. So over time, Leitch explained, any new repeats get stuck and then slowly diverge through normal mutation to produce a genome full of ancient degenerative repeats.

Meanwhile, other forces may be at play. Large genomes, for instance, can be costly. Theyre energetically expensive, like running a big house, Leitch said. They also take up more space, which requires a bigger nucleus, which requires a bigger cell, which can slow processes like metabolism and growth. Its possible that in some populations, under some conditions, natural selection may constrain genome size. For example, female bow-winged grasshoppers, for mysterious reasons, prefer the songs of males with small genomes. Maize plants growing at higher latitudes likewise self-select for smaller genomes, seemingly so they can generate seed before winter sets in.

Some experts speculate that a similar process is going on in birds and bats, which may need small genomes to maintain the high metabolisms needed for flight. But proof is lacking. Did small genomes really give birds an advantage in taking to the skies? Or had the genomes of birds flightless dinosaur ancestors already begun to contract for some other reason, and did the physiological demands of flight then shrink the genomes of modern birds even more? We cant say whats cause and effect, Suh said.

Its also possible that genome size is largely a result of chance. My feeling is theres one underlying mechanism that drives all this variability, said Mike Lynch, a biologist at Indiana University. And thats random genetic drift. Its a principle of population genetics that drift whereby a genetic variant becomes more or less common just by sheer luck is stronger in small groups, where theres less variation. So when populations decline, such as when new species diverge, the odds increase that lineages will drift toward larger genomes, even if organisms become slightly less fit. As populations grow, selection is more likely to quash this trait, causing genomes to slim.

None of these models, however, fully explain the great diversity of genome forms. The way I think of it, youve got a bunch of different forces on different levels pushing in different directions, Gregory said. Untangling them will require new kinds of experiments, which may soon be within reach. Were just at the cusp of being able to write genomes, said Chris Organ, an evolutionary biologist at Montana State University. Well be able to actually manipulate genome size in the lab and study its effects. Those results may help to disentangle the features of genomes that are purely products of chance from those with functional significance.

Many experts would also like to see more analyses like Kapustas. (Lets do the same thing in insects! Johnston said.) As more genomes come online, researchers can begin to compare larger numbers of lineages. Four to five years from now, every mammal will be sequenced, Lynch said, and well be able to see whats happening on a finer scale. Do genomes undergo rapid expansion followed by prolonged contraction as populations spread, as Lynch suspects? Or do changes happen smoothly, untouched by population dynamics, as Petrovs and Feschottes models predict and recent work in flies supports?

Or perhaps genomes are unpredictable in the same way life is unpredictable with exceptions to every rule. Biological systems are like Rube Goldberg machines, said Jeff Bennetzen, a plant geneticist at the University of Georgia. If something works, it will be done, but it can be done in the most absurd, complicated, multistep way. This creates novelty. It also creates the potential for that novelty to change in a million different ways.

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Shrinking Bat DNA and Elastic Genomes – Quanta Magazine

Amyloid precursor protein associated with AD may also be linked to intelligence in children – News-Medical.net

August 2, 2017

Rare mutations in the amyloid precursor protein (APP) have previously been shown to be strongly associated with Alzheimer’s disease (AD). Common genetic variants in this protein may also be linked to intelligence (IQ) in children, according to recent research performed at the University of Bergen, Norway.

Results of the research were published online today in the Journal of Alzheimer’s Disease. Senior author Dr. Tetyana Zayats is a researcher at the KGJebsen Centre for Neuropsychiatric Disorders at the University of Bergen.

The study analyzed genetic markers and IQ collected from 5,165 children in the Avon Longitudinal Study of Parents and Children. The genetic findings were followed up in the genetic data from two adult datasets (1) 17,008 cases with AD and 37,154 controls, and (2) 112,151 individuals assessed for general cognitive functioning. The function of the genetic markers was analyzed using reporter assays in cells.

Brain cells communicate via synapses containing hundreds of specialized proteins. Mutations in some of these proteins lead to dysfunctional synapses and brain diseases such as epilepsy, intellectual disability, autism or AD. Dr. Zayats and co-workers at the University of Bergen examined a subgroup of these proteins that have been implicated in synaptic plasticity and learning (the ARC complex). They found that a variation in DNA sequence within the gene encoding a member of this group of proteins, amyloid beta precursor protein (APP) was associated with non-verbal (fluid) intelligence in children, which reflects our capacity to reason and solve problems. In adults, this variation revealed association with AD, while the overall genetic variation within the APP gene itself appeared to be correlated with the efficiency of information processing (reaction time).

“This study has potential implications for our understanding of the normal function of these synaptic proteins as well as their involvement in disease” said Dr. Zayats.

APP encodes the amyloid- precursor protein that forms amyloid–containing neuritic plaques, the accumulation of which is one of the key pathological hallmarks in AD brains. However, it is unclear how these plaques affect brain functions and whether they lead to AD.

“Our understanding of biological processes underlying synaptic functioning could be expanded by examining human genetics throughout the lifespan as genetic influences may be the driving force behind the stability of our cognitive functioning,” Dr. Zayats commented.

Genetic correlation between intelligence and AD has also been found in large-scale genome-wide analyzes on general cognitive ability in adults. Several genes involved in general intelligence have previously reported to be associated with AD or related dementias. Such overlap has also been noted for the APP gene, where a coding variant was shown to be protective against both AD and cognitive decline in elderly.

“While this is only an exploratory study, in-depth functional and association follow up examinations are needed,” Dr. Zayats noted. “Examining genetic overlap between cognitive functioning and AD in children – not only adults – presents us with a new avenue to further our understanding of the role of synaptic plasticity in cognitive functioning and disease.”

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Amyloid precursor protein associated with AD may also be linked to intelligence in children – News-Medical.net

Genome Sequencing Shows Spiders, Scorpions Share Ancestor – Laboratory Equipment

In collaboration with scientists from the U.K., Europe, Japan and the United States, researchers at the Human Genome Sequencing Center at Baylor College of Medicine have discovered a whole genome duplication during the evolution of spiders and scorpions. The study appears in BMC Biology.

Researchers have long been studying spiders and scorpions for both applied reasons, such as studying venom components for pharmaceuticals and silks for materials science, and for basic questions such as the reasons for the evolution and to understand the development and ecological success of this diverse group of carnivorous organisms.

As part of a pilot project for the i5K, a project to study the genomes of 5,000 arthropod species, the Human Genome Sequencing Center analyzed the genome of the house spider Parasteatoda tepidariorum a model species studied in laboratories and the Arizona bark scorpion Centruroides sculpturatus, the most venomous scorpion in North America.

Analysis of these genomes revealed that spiders and scorpions evolved from a shared ancestor more than 400 million years ago, which made new copies of all of the genes in its genome, a process called whole genome duplication. Such an event is one of the largest evolutionary changes that can happen to a genome and is relatively rare during animal evolution.

It is tremendously exciting to see rapid progress in our molecular understanding of a species that we coexist with on planet earth. Spider genome analysis is particularly tricky, and we believe this is one of the highest quality spider genomes to date, said Stephen Richards, associate professor in the Human Genome Sequencing Center, who led the genome sequencing at Baylor.

Similarly, there also have been two whole genome duplications at the origin of vertebrates, fuelling long-standing debate as to whether the duplicated genes enabled new biological complexity in the evolution of the vertebrate lineage leading to mammals. The new finding of a whole genome duplication in spiders and scorpions therefore provides a valuable comparison to the events in vertebrates and could help reveal genes and processes that have been important to our own evolution.

While most of the new genetic material generated by whole genome duplication is subsequently lost, some of the new gene copies can evolve new functions and may contribute to the diversification of shape, size, physiology and behavior of animals, said Alistair McGregor, professor of evolutionary developmental biology at Oxford Brookes University and lead author of the research. Comparing the whole genome duplication in spiders and scorpions with the independent events in vertebrates reveals a striking similarity. In both cases, duplicated clusters of Hox genes have been retained. These are very important genes that regulate development of body structures in all animals, and therefore can cause evolutionary changes in animal body plans.

The study also found that the copies of spider Hox genes show differences in when and where they are expressed, suggesting they have evolved new functions.

McGregor explains that these changes may help clarify the evolutionary innovations in spiders and scorpions including specialized limbs and how they breathe, as well as the production of different types of venom and silk, which spiders use to capture and kill their prey.

Many people fear spiders and scorpions, but this research shows what a beautiful part of the evolutionary tree they represent, said Richard Gibbs, director of the Human Genome Sequencing Center and the Wofford Cain Chair and professor of molecular and human genetics at Baylor.

Costs have now dropped rapidly enough from tens of millions of dollars to merely a few thousand dollars for this genomic analyses to now be performed on any species, Richards said. There is still so much more to learn about the life on earth around us, and I believe this result is just the beginning of understanding the molecular make up of spiders.

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Genome Sequencing Shows Spiders, Scorpions Share Ancestor – Laboratory Equipment

Marc Malandro of Pitt’s Innovation Institute leaving for Chan Zuckerberg Initiative – Pittsburgh Post-Gazette


Pittsburgh Post-Gazette
Marc Malandro of Pitt's Innovation Institute leaving for Chan Zuckerberg Initiative
Pittsburgh Post-Gazette
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Scientists Claim to Disprove Biblical Account of Canaanites – The Jewish Press – JewishPress.com (blog)

Photo Credit: Youtube

{Originally posted to the Elder of Ziyon website}

A new DNA study has just been released that says that ancient Canaanites were not annihilated by the Children of Israel, but are the ancestors of todays Lebanese.

A new genetic study from the Wellcome Trust Sanger Institute has found that far from being destroyed, the Canaanites morphed into the inhabitants of modern Lebanon.

Scientists in the United Kingdom-based genetic research center sequenced the genomes of five 4,000-year-old Canaanite individuals and compared them to other ancient and present-day populations, including a sample of 99 modern Lebanese.

The results, published July 27 in the American Journal of Human Genetics, show that 93 percent of the ancestry of modern Lebanese ancestry comes from the Canaanites.

Had they been destroyed by the Israelites, though, it would have been a form of patricide.

The study took the DNA of human remains in Sidon and compared it to those of modern Lebanese:

Uncertainties also surround the fate of the Canaanites: the Bible reports the destruction of the Canaanite cities and the annihilation of its people; if true, the Canaanites could not have directly contributed genetically to present-day populations. However, no archaeological evidence has so far been found to support widespread destruction of Canaanite cities between the Bronze and Iron Ages: cities on the Levant coast such as Sidon and Tyre show continuity of occupation until the present day.

We sampled the petrous portion of temporal bones belonging to five ancient individuals dated to between 3,750 and 3,650 years ago (ya) from Sidon, which was a major Canaanite city-state during this period.

Only one problem: the Children of Israel never conquered Sidon, or many other Canaanite cities, nor did they destroy the Canaanites according to the Bible.

God indeed commanded the destruction of the Canaanites (Deuteronomy 20:17) but the beginning of Judges shows that it never happened (NIV translation, easier to understand than JPS)

27 But Manasseh did not drive out the people of Beth Shan or Taanach or Dor or Ibleam or Megiddo and their surrounding settlements, for the Canaanites were determined to live in that land. 28 When Israel became strong, they pressed the Canaanites into forced labor but never drove them out completely. 29 Nor did Ephraim drive out the Canaanites living in Gezer, but the Canaanites continued to live there among them. 30 Neither did Zebulun drive out the Canaanites living in Kitron or Nahalol, so these Canaanites lived among them, but Zebulun did subject them to forced labor. 31 Nor did Asher drive out those living in Akko or Sidon or Ahlab or Akzib or Helbah or Aphek or Rehob. 32 The Asherites lived among the Canaanite inhabitants of the land because they did not drive them out. 33 Neither did Naphtali drive out those living in Beth Shemesh or Beth Anath; but the Naphtalites too lived among the Canaanite inhabitants of the land, and those living in Beth Shemesh and Beth Anath became forced laborers for them. 34 The Amorites confined the Danites to the hill country, not allowing them to come down into the plain. 35 And the Amorites were determined also to hold out in Mount Heres, Aijalon and Shaalbim, but when the power of the tribes of Joseph increased, they too were pressed into forced labor.

Indeed, David bought cedar trees from Sidon and Tyre to build the Temple.Queen Jezebel was the daughter of the king of Sidon and swayed her husband Ahab into worshiping false gods.

All the study proved is that Sidon was never destroyed and todays Lebanese descended from ancient Phoenicians, which everyone pretty much knew already.

The DNA tests actually prove the Biblical account that the Israelites never conquered Sidon. These scientists had an agenda beyond science.

Original post:

Scientists Claim to Disprove Biblical Account of Canaanites – The Jewish Press – JewishPress.com (blog)


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