Image copyright Getty Images Image caption Scientists looked at the genes of people with pulmonary arterial hypertension to find out what was causing the condition

Scientists say they have identified genes that cause a deadly heart condition that can only be cured by transplants of the heart or lungs.

Pulmonary arterial hypertension kills 50% of those affected within five years, but little was known about what caused the condition in some people.

Now experts say they have discovered five genes that cause the illness.

The findings could lead to earlier detection of the disease and ultimately new treatments, researchers say.

Pulmonary arterial hypertension (PAH) currently affects around 6,500 people in the UK and causes the arteries carrying blood from the heart to their lungs to stiffen and thicken, ultimately leading to heart failure.

It is often diagnosed in people who have other heart or lung conditions, but it can affect people of any age and in about a fifth of people there is no obvious cause.

The only "cure" is a transplant of the heart and particularly the lungs, but there is a waiting list for organ transplants and the body will often ultimately reject them, particularly in the case of lungs.

For this latest research, published in Nature Communications, scientists carried out the largest ever genetic study of the disease by analysing the genomes - the unique sequence of a person's DNA - of more than 1,000 PAH patients for whom the cause of the illness was unknown.

They found that mutations in five genes were responsible for causing the illness in these people, including in four genes that were not previously known to be involved in the disease.

In people with the condition these genes fail to effectively produce the proteins that are required for the structure, function and regulation of the body's tissues, researchers found.

Nick Morrell, the lead author of the paper and professor at the British Heart Foundation, told BBC News: "Identifying the nature of these new genes and mutations in the new genes tells you what causes the disease.

"It allows you to design and come up with potential new ways of treating the disease because you have really well-grounded knowledge about what's actually causing it in cases where you find these mutations," he explained.

'People should be more aware'

Image caption Wendy Callaghan was diagnosed with the condition five years ago

Wendy Callaghan, from west London, was diagnosed with PAH in 2013 after doctors became concerned about her persistent chest infection.

Her sister died from the condition 27 years ago at the age of 36, and her grandmother also died from a similar heart condition.

Wendy, who participated in the trial, has been told she has the genetic version of the illness and is now waiting to learn if her daughters and grandchildren have inherited the same deadly condition.

The 58-year-old said: "Even children can get it. People should be more aware of it and look out for the signs and persist with it if they think their child is not well.

"Especially as it does run in families, some people if they don't know they've got it could be passing those genes on to the next generation," Wendy added.

The research was part of a pilot study for the 100,000 Genomes Project - a huge initiative focused on understanding the genetics of cancer and rare diseases.

Prof Morrell said such genetic studies were helping to transform our understanding of rare diseases.

He said: "Often people with rare diseases go to lots of different specialists, everybody is scratching their head a bit, we don't know what the cause is, therefore it's hard to find a treatment for it.

"Now being able to [genetically] sequence people with rare diseases at scale allows you to push the genetics into the clinic and into the families, and it also gives you a cause for the disease which you can potentially do something about," he said.

Darren Griffin, professor of genetics at the University of Kent, who was not involved in the study, said the research was "one of the big successes" of the 100,000 Genome Project.

He said: "By studying the role of rare genetic variation in diseases, we come to a better understanding of the disease pathology itself, which can aid in early diagnosis and in tailoring treatment regimes."

Follow Alex on Twitter. </s> LONDON (Reuters) - Lung cancer can lie dormant for more than 20 years before turning deadly, helping explain why a disease that kills more than 1.5 million a year worldwide is so persistent and difficult to treat, scientists said on Thursday.

Two papers detailing the evolution of lung cancer reveal how after an initial disease-causing genetic fault -- often due to smoking -- tumor cells quietly develop numerous new mutations, making different parts of the same tumor genetically unique.

By the time patients are sick enough to be diagnosed with cancer, their tumors will have developed down multiple evolutionary pathways, making it extremely hard for any one targeted medicine to have an effect.

The findings show the pressing need to detect lung cancer before it has shape-shifted into multiple malignant clones.

“What we’ve not been able to understand before is why this is really the emperor of all cancers and one of the hardest diseases to treat,” said Charles Swanton, an author on one of the papers from Cancer Research UK’s London Research Institute.

“Previously, we didn’t know how heterogeneous these early-stage lung cancers were.”

Lung cancer is the world’s deadliest cancer, killing an estimated 4,300 people a day, according to the World Health Organization. Around 85 percent of patients have non-small cell lung cancer (NSCLC), the type analyzed in the two studies.

To get a clearer understanding of the disease, the two groups of British and American scientists looked at genetic variability in different regions of lung tumors removed during surgery and worked out how genetic faults had developed over time.

What they found was an extremely long latency period between early mutations and clinical symptoms, which finally appeared after new, additional faults triggered rapid disease growth.

In the case of some ex-smokers, the initial genetic faults that started their cancer dated back to the time they were smoking cigarettes two decades earlier. But these faults became less important over time and more recent mutations were caused by a new process controlled by a protein called APOBEC.

The research was published in the journal Science.

Ramaswamy Govindan of Washington University School of Medicine, who was not involved in the studies, said better understanding of such genetic alterations was key to developing more effective treatments.

There are also hopes for a new generation of immunotherapy drugs that boost the immune system’s ability to detect and fight tumors, which could be particularly applicable to lung cancer.

“The large number of mutations may be the tumor’s Achilles heel because every time a new mutation forms there is a chance for the immune system to recognize it,” Swanton told Reuters.

Immunotherapy drugs from companies such as Bristol-Myers Squibb, Merck & Co, Roche and AstraZeneca are already undergoing tests in lung cancer, with data on Bristol’s medicine Opdivo due later this year.

Apart from better drugs, a critical challenge is to find improved ways to detect lung cancer before it develops the multiple genetic faults that eventually trigger rapid tumor growth and spread.

Currently, doctors use computerized tomography (CT) to detect lung cancer -- but by the time a nodule is big enough to be spotted it on a scan it may contain a billion genetically diverse cancer cells.

For the future, oncologists are pinning hopes on a new approach, known as liquid biopsy, that may be able to detect signs of cancer much earlier from DNA circulating in the blood.

The current prognosis for NSCLC is grim, with most patients diagnosed when the disease has already spread and only around 15 percent surviving for at least five years after that. </s> Image copyright OHSU Image caption Pictures of the genetically modified embryos

Scientists have, for the first time, successfully freed embryos of a piece of faulty DNA that causes deadly heart disease to run in families.

It potentially opens the door to preventing 10,000 disorders that are passed down the generations.

The US and South Korean team allowed the embryos to develop for five days before stopping the experiment.

The study hints at the future of medicine, but also provokes deep questions about what is morally right.

Science is going through a golden age in editing DNA thanks to a new technology called Crispr, named breakthrough of the year in just 2015.

Its applications in medicine are vast and include the idea of wiping out genetic faults that cause diseases from cystic fibrosis to breast cancer.

Heart stopper

US teams at Oregon Health and Science University and the Salk Institute along with the Institute for Basic Science in South Korea focused on hypertrophic cardiomyopathy.

The disorder is common, affecting one in every 500 people, and can lead to the heart suddenly stopping beating.

It is caused by an error in a single gene (an instruction in the DNA), and anyone carrying it has a 50-50 chance of passing it on to their children.

In the study, described in the journal Nature, the genetic repair happened during conception.

Sperm from a man with hypertrophic cardiomyopathy was injected into healthy donated eggs alongside Crispr technology to correct the defect.

It did not work all the time, but 72% of embryos were free from disease-causing mutations.

Eternal benefit

Dr Shoukhrat Mitalipov, a key figure in the research team, said: "Every generation on would carry this repair because we've removed the disease-causing gene variant from that family's lineage.

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

There have been multiple attempts before, including, in 2015, teams in China using Crispr-technology to correct defects that lead to blood disorders.

But they could not correct every cell, so the embryo was a "mosaic" of healthy and diseased cells.

Their approach also led to other parts of the genetic code becoming mutated.

Those technical obstacles have been overcome in the latest research.

However, this is not about to become routine practice.

The biggest question is one of safety, and that can be answered only by far more extensive research.

There are also questions about when it would be worth doing - embryos can already be screened for disease through pre-implantation genetic diagnosis.

However, there are about 10,000 genetic disorders that are caused by a single mutation and could, in theory, be repaired with the same technology.

Prof Robin Lovell-Badge, from the Francis Crick Institute, told the BBC: "A method of being able to avoid having affected children passing on the affected gene could be really very important for those families.

"In terms of when, definitely not yet. It's going to be quite a while before we know that it's going to be safe."

Nicole Mowbray lives with hypertrophic cardiomyopathy and has a defibrillator implanted in her chest in case her heart stops.

But she is unsure whether she would ever consider gene editing: "I wouldn't want to pass on something that caused my child to have a limited or painful life.

"That does come to the front of my mind when I think about having children.

"But I wouldn't want to create the 'perfect' child, I feel like my condition makes me, me."

Ethical?

Darren Griffin, a professor of genetics at the University of Kent, said: "Perhaps the biggest question, and probably the one that will be debated the most, is whether we should be physically altering the genes of an IVF embryo at all.

"This is not a straightforward question... equally, the debate on how morally acceptable it is not to act when we have the technology to prevent these life-threatening diseases must also come into play."

The study has already been condemned by Dr David King, from the campaign group Human Genetics Alert, which described the research as "irresponsible" and a "race for first genetically modified baby".

Dr Yalda Jamshidi, a reader in genomic medicine at St George's University of London, said: "The study is the first to show successful and efficient correction of a disease-causing mutation in early stage human embryos with gene editing.

"Whilst we are just beginning to understand the complexity of genetic disease, gene-editing will likely become acceptable when its potential benefits, both to individuals and to the broader society, exceeds its risks."

The method does not currently fuel concerns about the extreme end of "designer babies" engineered to have new advantageous traits.

The way Crispr is designed should lead to a new piece of engineered DNA being inserted into the genetic code.

However, in a complete surprise to the researchers, this did not happen.

Instead, Crispr damaged the mutated gene in the father's sperm, leading to a healthy version being copied over from the mother's egg.

This means the technology, for now, works only when there is a healthy version from one of the parents.

Prof Lovell-Badge added: "The possibility of producing designer babies, which is unjustified in any case, is now even further away."

Follow James on Twitter. </s> (CNN) Scientists are getting one step closer to snipping inherited genetic diseases out of human offspring using a gene-editing technique called CRISPR.

For the first time, scientists said, they corrected a gene mutation linked to inherited heart conditions in human embryos using the approach. A study demonstrating the technique was published in the journal Nature on Wednesday (PDF).

Last week, the MIT Technology Review released the first news of this scientific feat, describing the research as the first-known attempt at creating genetically modified human embryos in the United States.

However, Juan Carlos Izpisua Belmonte, a co-author of the study, described it as the first in the world to demonstrate gene-editing to be safe, accurate and efficient in correcting a pathogenic gene mutation in human embryos. Previous attempts by Chinese researchers were unsuccessful at achieving this without safety concerns.

"This is the first that has been demonstrated as safe and working," said Belmonte, a professor at the Salk Institute for Biological Studies' gene expression laboratory in La Jolla, California.

"All cells of the embryo were corrected," he said. "It seems to be working from these samples that we have chosen, but we need to do much more basic research with many other genes."

The study was a collaboration between the Salk Institute, the Oregon Health & Science University in Portland and Korea's Institute for Basic Science.

Scientists estimate that more than 10,000 human diseases may result from mutations to a single gene occurring in all cells of the body, according to the World Health Organization

Cutting and correcting gene mutations

The study used 75 human zygotes in which the father carried a mutation on the MYBPC3 gene, Belmonte said. The eggs used to produce the zygotes did not carry that gene mutation. The researchers noted that they received informed consent from the donors of the eggs, sperm and embryos used in the study.

Hypertrophic cardiomyopathy also is thought to be the most common inherited or genetic heart disease in the US, according to the Centers for Disease Control and Prevention

Newly fertilized eggs before gene editing, left, and embryos after gene editing and a few rounds of cell division.

In a lab dish, the researchers used CRISPR, a gene-editing technique, to remove the harmful MYBPC3 mutation from the human zygotes. Then, the zygotes' own DNA-repair mechanism replaced what was cut out with a copy of a MYBPC3 gene from the mother, which did not carry a mutation, Belmonte said.

"A male research subject known to be heterozygous for this gene mutation was recruited for the study, as were several healthy young egg donors," Dr. Paula Amato, an obstetrician-gynecologist at Oregon Health & Science University, said Tuesday. She was a co-author of the study.

"CRISPR was introduced at the time of sperm injection," she said. "Then, DNA repair of the embryos was assessed."

The researchers found that about 72% of zygotes were properly and safely corrected on the MYBPC3 gene, Belmonte said.

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This method significantly differed from studies in which scientists used the CRISPR tool to replace what was cut out with whatever the scientists desired.

"The previous human studies done in China had very small numbers, and one of them used abnormal embryos," Amato said. "So we think this is the first, largest study from which you could draw some reasonable conclusions."

Some gene-editing attempts in human embryos have been problematic, resulting in an issue called mosaicism , in which the corrections made in one gene failed to replicate once that cell divided into two cells, those two cells divided into four cells and so on.

"So when the baby is born, all the cells do not have the mutation anymore. ... This study, it shows that we can correct the embryo and then, after the division, all the cells are corrected, so there's not what we call mosaicism," said Belmonte, who is also a member of the National Academies of Sciences, Engineering and Medicine's committee on human gene editing.

This year, the academies published a report on human genome editing that addressed potential applications of the technology, including the possible prevention or treatment of inherited diseases or conditions.

The future of gene editing

Though the researchers have expressed enthusiasm around their new study, they also noted that the findings must be replicated in followup research before this gene-editing approach can move forward to clinical trials.

"The fact that it is, apparently, a new and poorly understood mechanism and it is not the now standard CRISPR 'cut and replace' method adds to the time needed for research into its safety and effectiveness," said Hank Greely, professor of law and genetics at Stanford University, who was not involved in the new study.

Yet future research can come with some political challenges, Amato said.

"First of all, there are regulations regarding use of federal funds for embryo research, so the (US National Institutes of Health) does not currently support embryo research, so that's one barrier. The other barrier is, the (US Food and Drug Administration) is prohibited from considering any clinical trials related to germline genetic modification," she said.

In this new study the embryos were only allowed to mature to day three after fertilization before they were disaggregated, or isolated into various components, for further analysis.

In the far-off future, a clinical trial could include transplanting corrected embryos into a uterus with the goal of establishing pregnancy and then monitoring the embryos as they develop into children.

Still, "it is way too early to contemplate implanting the edited embryos for the purpose of actually establishing a pregnancy," said Dana Carroll, a professor of biochemistry at the University of Utah who was not involved in the new study but has used CRISPR in his own research.

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"The genome editing tools are currently not sufficiently efficient and specific to be reliable, and regulatory and oversight processes have not been established," Carroll said, adding that the work on the new study was "well-done" and "well-presented."

"The authors have made an important discovery regarding the repair of CRISPR-induced DNA breaks in human eggs just at the time of fertilization," he said.

"This information will help to guide ongoing research, and it demonstrates that research on early-stage human embryos will be necessary to establish safe and effective procedures in the long run," he said. "There is still a lot of work to do to understand repair processes in very early embryos and to optimize the use of the CRISPR reagents, but this study makes a valuable contribution."

Some CRISPR critics have argued that gene editing may give way to eugenics and to allowing embryos to be edited with certain features in order to develop so-called designer babies

However, the researchers wrote in their study that they hope CRISPR could be considered as an alternative option to preimplantation genetic diagnosis, also known as PGD, for couples at risk of passing on an inherited disease.

'This opens up the possibility for those embryos'

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When only one parent carries a heterozygous mutation on a gene, about half of the embryos from that parent should be mutation-free while the others would have the mutation. Selectively, the parents' doctor would chose the healthy embryos to be implanted and discard the embryos with the mutations, Belmonte said.

Sometimes, "a couple that wants to have a baby and they have a mutation, they may not have enough embryos to choose from," he said. This is when CRISPR can come in.

"This technology, independent of the embryos that are there, it would go on and correct all of them. ... This opens up the possibility for those embryos," he said. "That's important because after the first implantation, if it doesn't work, you can do it again."

The researchers wrote in their study, "PGD may be a viable option for heterozygous couples at risk of producing affected offspring. In cases when only one parent carries a heterozygous mutation, 50% of embryos should be mutant. In contrast, targeted gene correction can potentially rescue a substantial portion of mutant human embryos, thus increasing the number of embryos available for transfer."

Nonetheless, using CRISPR in that way remains a long way off.

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Shoukhrat Mitalipov, director of the Oregon Health & Science University's Center for Embryonic Cell and Gene Therapy, helped lead the new study. In 2013, Mitalipov and his colleagues reported the first success in cloning human stem cells , reprogramming human skin cells back to their embryonic state. In 2007, a research team led by Mitalipov announced that they created the first cloned monkey embryo and extracted stem cells from it.

Now, when it comes to using CRISPR to correct gene mutations in embryos, Mitalipov said Tuesday, "We've done some ground work. ... There is still a long road ahead, and it's unclear at this point when we will be allowed to move on." </s> An analysis of the DNA of 300,000 people in the UK - the biggest of its kind - identified almost 80 genes that could be involved in the devastating condition. The mental illness blights the lives of sufferers and their families. It is second-leading cause of death among 15 to 29 year-olds. Although environmental factors play a role in many cases of depression genetics are also known to be crucially important. Lead author Dr David Howard, of Edinburgh University's Centre for Clinical Brain Sciences, said drugs that target the genes could improve mental health.

He said: "This study identifies genes that potentially increase our risk of depression - adding to the evidence it is partly a genetic disorder. "The findings also provide new clues to the causes of depression and we hope it will narrow down the search for therapies that could help people living with the condition." Depression can be crippling - impairing the ability to sleep, work or even eat. Antidepressants can often takes weeks or months to kick-inDr Howard's team used data from the UK Biobank - which contains health information on half a million people - to scan participants' genetic code for areas of DNA connected to depression. Such scans are popular for finding genes that affect risk of diseases - but depression has proven largely resistant to this approach. Only a handful of potential ones have previously been identified.

Dr Howard and colleagues confirmed the findings by examining anonymised data held by the personal genetics and research company 23andMe - used with the donors' consent. The study, published in the journal Nature Communications, sheds light on why some people may be at higher risk of a disorder that affects one in five people in the UK every year. It is the leading cause of disability globally. Life events - such as trauma or stress - can contribute to its onset but it's not clear why certain individuals are more vulnerable. Some of the pinpointed genes are involved in the function of synapses - tiny connections between brain cells that enable communication through electrical and chemical signals. Prof Andrew McIntosh, who leads the lab's research group, said: "Depression is a common and often severe condition that affects millions of people worldwide.

"These new findings help us better understand the causes of depression and show how the UK Biobank study and big data research has helped advance mental health research. "We hope the UK's growing health data research capacity will help us to make major advances in our understanding of depression in coming years." The study was funded by the Wellcome Trust as part of Stratifying Resilience and Depression Longitudinally - a £4.7 million project to better understand the condition. Last year a much smaller study of almost 2,000 people suggested depression could be caused by a single mutation. The Dutch and Russian team found the NKPD1 gene accounted for a 4 per cent rise in the risk of experiencing symptoms of worthlessness, a lack of concentration and fatigue. </s> Using a powerful gene-editing technique, scientists have rid human embryos of a mutation that causes an inherited form of heart disease often deadly to healthy young athletes and adults in their prime.

The experiment marks the first time that scientists have altered the human genome to ensure a disease-causing mutation would disappear not only from the DNA of the subject on which it’s performed, but from the genes of his or her progeny as well.

The controversial procedure, known as “germ-line editing,” was conducted at Oregon Health & Science University using human embryos expressly created for the purpose. It was reported Wednesday in the journal Nature.

The new research comes less than six months after the National Academies of Science, Engineering and Medicine recommended that scientists limit their trials of human germ-line editing to diseases that could not be treated with “reasonable alternatives” — at least for now.

In a bid to make the experiment relevant to real-life dilemmas faced by parents who carry genes for inherited diseases, the researchers focused their editing efforts on a mutation that causes inherited hypertrophic cardiomyopathy.

In this genetic condition, a parent who carries one normal and one faulty copy of a the MYBPC3 gene has a 50-50 chance of passing that mutation on to his or her offspring. If the child inherits the mutation, his or her heart muscle is likely to grow prematurely weak and stiff, causing heart failure and often early death.

In diseases where one parent carries such an “autosomal dominant” mutation, a couple will often seek the assistance of fertility doctors to minimize the risk of passing such a mutation on to a child. A woman’s egg production is medically stimulated, and eggs and sperm meet in a lab — a process called in vitro fertilization. Then embryologists inspect the resulting embryos, cull the ones that have inherited an unwanted mutation, and transfer only unaffected embryos into a woman’s uterus to be carried to term.

In the new research, researchers set out to test whether germ-line gene editing could make the process of choosing healthy embryos more effective and efficient by creating more of them.

In the end, their experiment showed it could. The targeted correction of a disease-causing gene carried by a single parent “can potentially rescue a substantial portion of mutant human embryos, thus increasing the number of embryos available for transfer,” the authors wrote in Nature. Co-author Dr. Paula Amato, an Oregon Health & Science University (OHSU) professor of obstetrics and gynecology, said the technique “could potentially decrease the number of cycles needed for people trying to have children free of genetic disease” if it’s found safe for use in fertility clinics.

Along the way, though, many of the researchers’ findings were scientifically surprising. Long-feared effects of germ-line editing, including collateral damage to “off-target” genetic sequences, scarcely materialized. And “mosaicism,” a phenomenon in which edited DNA appears in some but not all cells, was found to be minimal.

The study’s lead author, OHSU biologist Shoukhrat Mitalipov, called these “exciting and surprising moments.” But he cautioned that “there is room to improve” the techniques demonstrated to produce mutation-free embryos. As for conducting human clinical trials of the germ-line correction, he said those would have to wait until results showed a near-perfect level of efficiency and accuracy, and could be limited by state and federal regulations.

Eventually, Mitalipov said, such germ-line gene editing might also make it easier for parents who carry other gene mutations that follow a similar pattern of inheritance — including some that cause breast and ovarian cancers, cystic fibrosis and muscular dystrophy — to have healthy children who would not pass those genes to their own offspring.

“There is still a long road ahead,” predicted Mitalipov, who heads the Center for Embryonic Cell and Gene Therapy at the Portland university.

The research drew a mix of praise and concern from experts in genetic medicine.

Dr. Richard O. Hynes, who co-chaired the National Academies’ report issued in February, called the new study “very good science” that advances understanding of genetic repair on many fronts. Hynes, who was not involved with the latest research effort, said he was “pleasantly surprised” by researchers’ “clever modifications” and their outcomes.

“It’s likely to become feasible, technically — not tomorrow, not next year, but in some foreseeable time. Less than a decade, I’d say,” said Haynes, a biologist and cancer researcher at MIT and the Howard Hughes Medical Institute.

UC Berkeley molecular and cell biologist Jennifer Doudna, one of pioneers of the CRISPR-Cas9 gene-editing technique, acknowledged the new research highlights a prospective use of gene editing for one inherited disease and offers some insights into the process.

But Doudna questioned how broadly the experiment’s promising results would apply to other inherited diseases. She said she does not believe the use of germ-line editing as a means to improve efficiency at infertility clinics meets the criteria laid out by the National Academies of Science, which urged that the techniques only be explored as treatment for diseases with “no reasonable alternative.”

“Already, 50% of embryos would be normal,” said Doudna. “Why not just implant those?”

Doudna said she worried that the new findings “will encourage people to proceed down this road” before the scientific and ethical implications of germ-line editing have been fully considered.

“A large group of experts concluded that clinical use should not proceed until and unless there’s broad societal consensus, and that just hasn’t happened,” Doudna said. “This study underscores the urgency of having those debates. Because it’s coming.”

What is clear is that the researchers — a multinational team of geneticists, cardiologists, fertility experts and embryologists from OHSU and from labs in South Korea and China — tried a number of innovations in an effort to improve the safety, efficiency and fidelity of gene editing. And most yielded promising results.

After retrieving eggs from 12 healthy female volunteers, researchers simultaneously performed two steps that had never been combined in a lab: At the same moment that they fertilized the eggs with the sperm of a man who carried a single copy of the mutated gene, they introduced the CRISPR-Cas9 repair machinery.

The resulting embryos took up the genetic-editing program so efficiently and uniformly that, after five days of incubation, 72.4% of the embryos (42 of 58) created and tested were free of the MYBPC3 mutation. By comparison, when sperm carrying the single mutation was used to fertilize eggs without any genetic manipulation, just 47.4% of embryos were free of the mutation linked to the deadly heart condition. </s> Scientists have been tinkering with the DNA in humans and other living things for decades. But one thing has long been considered off-limits: modifying human DNA in any way that could be passed down for generations.

Now, an international team of scientists reports they have, for the first time, figured out a way to successfully edit the DNA in human embryos — without introducing the harmful mutations that were a problem in previous attempts elsewhere. The work was published online Wednesday in the journal Nature.

"It's a pretty exciting piece of science," says George Daley, dean of the Harvard Medical School, who was not involved in the research. "It's a technical tour de force. It's really remarkable."

The research is ultimately aimed at helping families plagued by genetic diseases. The new experiment used a powerful new gene-editing technique to correct a genetic defect behind a heart disorder that can cause seemingly healthy young people to suddenly die from heart failure.

The experiment corrected the defect in nearly two-thirds of several dozen embryos, without causing potentially dangerous mutations elsewhere in the DNA.

None of the embryos were used to try to create a baby. But if future experiments confirm the techniques are safe and effective, the scientists say the same approach could be used to prevent a long list of inheritable diseases.

"Potentially, we're talking about thousands of genes and thousands of patients," says Paula Amato, an associate professor of obstetrics and gynecology at Oregon Health & Science University in Portland. She was a member of the scientific team from the U.S., China and South Korea.

Other diseases that might ultimately benefit from such an approach include Huntington's disease, cystic fibrosis, perhaps an inherited form of Alzheimer's disease and cases of breast and ovarian cancer caused by mutations in the BRCA genes.

Nonetheless, the work is setting off alarm bells among critics around the world.

"I think it's extraordinarily disturbing," says Marcy Darnovsky, who directs the Center for Genetics and Society, a genetics watchdog group in Berkeley, Calif. "It's a flagrant disregard of calls for a broad societal consensus in decisions about a really momentous technology that could be used good, but in this case is being used in preparation for an extraordinarily risky application."

"If irresponsible scientists are not stopped, the world may soon be presented with a fait accompli of the first [genetically modified] baby," says David King, who heads the U.K-based group Human Genetics Alert. "We call on governments and international organizations to wake up and pass an immediate global ban on creating cloned or GM babies, before it is too late."

Amato and others stress that their work is aimed at preventing terrible diseases, not creating genetically enhanced people. And they note that much more research is needed to confirm the technique is safe and effective before anyone tries to make a baby this way.

But scientists hoping to continue the work in the U.S. face many regulatory obstacles. The National Institutes of Health will not fund any research involving human embryos (the new work was funded by Oregon Health & Science University). And the Food and Drug Administration is prohibited by Congress from considering any experiments that involve genetically modified human embryos.

Nevertheless, the researchers say they're hopeful about continuing the work, perhaps in Britain. The United Kingdom has permitted genetic experiments involving human embryos forbidden in the United States.

"If other countries would be interested, we would be happy to work with their regulatory bodies," says Shoukhrat Mitalipov, director of the Oregon Health & Science University's Center for Embryonic Cell and Gene Therapy.

One major concern is safety to a developing embryo — whether genetically modified human embryos would indeed produce healthy babies. But on a broader level, any changes made in the DNA of an embryo would be passed down for generations. That raises fears that any mistakes in the editing that inadvertently caused new diseases could become a permanent part of that family's genetic blueprint.

Darnovsky and others also worry that modifying human DNA in an embryo could give rise to "designer babies." That's when parents pick and choose the traits of their children to try to make them smarter, taller, stronger or have other traits that make them seem superior. That's not yet technically possible. But critics fear scientists are already moving in that direction.

"The scenario is that you would have fertility clinics advertising to people who wanted to engineer their future children so that they could be presented as 'enhanced' — as biologically better than everyone else," Darnovsky says. "It's not a world we want to build. It's not a world we want to live in."

Unscrupulous researchers could also rush the technology into fertility clinics to try to start creating babies they can bill as genetically enhanced before the technology has even been proved safe, and before a societal consensus has been reached about what applications should be permitted.

"This is a strong statement that we can do genome editing," says Harvard's Daley. "The question that remains is: 'Should we?' We need a deeper public discourse around the ethical implications of this technology."

Darnovsky and some scientists argue that many couples who carry genetic diseases already have safer alternatives to this sort of gene editing. Couples carrying genetic diseases can go through in vitro fertilization (IVF) and have their embryos tested before being implanted in the womb.

"I will admit to experiencing a sense of puzzlement," says Fyodor Urnov, an associate director at the Altius Institute for Biomedical Sciences, a nonprofit research institute in Seattle.

"The question I have is: 'Why did you folks bother, given that there is a safe, effective, approved and ethical way to attain exactly the goal you have set out to do without any of the significant logical and ethic hurdles of having to edit a human embryo?" Urnov says.

Amato and the other scientists on the international team say their approach could offer an alternative for couples for whom those standard options won't work or are less desirable. But they agree the work should only move forward with careful regulatory oversight to prevent abuse.

"Anytime there's a new technology there's a potential for misuse. We have to acknowledge that," Amato says. "Personally I don't feel that's a reason not to pursue the research if you think there's a potential benefit that outweighs that risk. And I think if you can prevent serious disease in future generations, that makes it worthwhile to pursue this."

The advance was first reported last week in Technology Review, a magazine published by the Massachusetts Institute of Technology. But the details were withheld and the researchers did not elaborate until the scientific paper had finished being vetted by other scientists for publication in Nature.

For their experiments, the scientists obtained sperm from a donor carrying a mutation for the heart disorder cardiomyopathy. They then used that sperm to fertilize dozens of eggs obtained from healthy women.

At the same time as fertilization, the researchers injected a powerful, microscopic gene-editing tool known as CRISPR-Cas9. The new technique makes it much easier than previous approaches to make very precise changes in DNA.

Several scientists likened the approach to doing surgery on fetuses when they are in the womb. But this takes that idea much further and involves repairing damaged DNA at a molecular level in the womb.

"This is nano-surgery," says George Church, a prominent Harvard geneticist who also was not involved in the research. "You're doing it with the finest possible scalpel."

The editing tool very accurately cut into a mutated gene known as MYBPC3, which causes cardiomyopathy. To the researchers' surprise, the cut triggered the embryos to repair the defective gene on their own. This is a process that had previously been unknown, the scientists say.

"The most exciting moment was when we realized the mechanism of repair," Amato says. "It was fixing itself."

The researchers then let the embryos develop for several days so they could analyze them to see how well the experiments worked. In one part of the experiments involving 58 embryos, the approach corrected the mutation in more than 70 percent of the embryos, the researchers reported.

"The gene defect was corrected with high efficiency," Amato says.

In addition, a detailed genetic analysis of the embryos concluded that the gene editing had not caused safety problems.

"I think this is a significant advance," Church says. "This is important."

In 2015, Chinese scientists reported trying to edit the DNA of embryos for the first time, also using CRISPR-Cas9. But that experiment involved embryos that could never develop normally. And while those researchers did succeed in editing the targeted defect, it also produced unintended defects elsewhere in the embryos' DNA.

The scientists who conducted the new experiments say they think they avoided those problems by injecting CRISPR at the same time the eggs were being fertilized by sperm.

"That was key," Mitalipov says.

Alta Charo, a bioethicist at the University of Wisconsin, dismissed concerns about the work leading to designer babies.

"This is not the dawn of the era of the designer baby," says Charo, who co-chaired a committee formed by the National Academies of Sciences and the National Academy of Medicine to determine whether such experiments should be permissible. The committee concluded earlier this year that gene editing of human embryos could be allowed in rare cases when no other options are available — but only to treat diseases.

"I do not think that the constant drumbeat about the fear of designer baby is warranted, Charo says. "What this is, is a possible step toward being able to edit the DNA in human embryos that's reliable and precise."

In the meantime, scientists in Britain have won approval to use CRISPR to edit the DNA in healthy human embryos to learn more about normal human development. A team in Sweden has started similar experiments.

"I think this needs to be tightly regulated," says Fredrik Lanner, a geneticist at the Karolinska Institute in Stockholm who is conducting those experiments. "This is very exciting. But it also could be a double-edged sword. So I think we really have to be extra cautious with this technology." </s> Mito Images/REX/Shutterstock

The numbers are in. We can now precisely count how many cancer-related DNA mutations accumulate in smokers’ organs over time.

On average, there is one DNA mutation per lung cell for every 50 cigarettes smoked, according to a new analysis. People who smoke a pack of 20 a day for a year generate 150 mutations per lung cell, 97 per larynx cell, 39 per pharynx cell, 18 per bladder cell and six per liver cell.

Epidemiological studies previously linked tobacco smoking with at least 17 classes of cancer, but this is the first time researchers have been able to quantify the molecular damage inflicted on DNA.

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Ludmil Alexandrov at Los Alamos National Laboratory in New Mexico and his colleagues achieved this by comparing tumour DNA from 2500 smokers and 1000 non-smokers. This allowed them to identify which mutations were associated with smoking.

Theoretically, every DNA mutation has the potential to trigger a cascade of genetic damage that causes cells to become cancerous. However, we still don’t know what the probability is of a single smoking-related DNA mutation turning into cancer, or which mutation types are likely to be more malignant. “This is research we are currently pursuing,” Alexandrov says.

Russian roulette

Some smokers never develop cancer despite accruing thousands of mutations, but this is purely down to luck, Alexandrov says. “Smoking is like playing Russian roulette: the more you play, the higher the chance the mutations will hit the right genes and you will develop cancer,” he says. “However, there will always be people who smoke a lot but the mutations do not hit the right genes.”

The team hopes their findings will deter people from taking up smoking and debunk the myth that social smoking is harmless. Every cigarette has the potential to cause genetic mutations, Alexandrov says.

Quitting smoking will not reverse these mutations – they leave permanent scars on DNA – but it will prevent the added risk of more mutations, he says.

There is good evidence that people who stop smoking have a significantly lower risk of premature death than those who continue, says Simon Chapman at the University of Sydney, Australia.

For example, a UK study that followed 35,000 men for half a century found that smoking shaved 10 years off average life expectancy. But quitting at age 30 mostly erased the risk of premature death, and giving up at 50 halved it.

“Many smokers believe there’s no point in quitting because the damage is already done,” says Chapman. “But if smokers quit by middle age, they can avoid nearly all the excess risk of tobacco-caused deaths.”

Journal reference: Science, DOI: 10.1126/science.aag0299 </s> In the landmark trials, the US and South Korean team demonstrated how they can use CRISPR technology (a revolutionary tool used to edit DNA) to successfully free the embryo from a faulty piece of DNA introduced by one of the parents at conception.

This opens the door to potentially tackle thousands of inherited diseases, but this study focused specifically on hypertrophic cardiomyopathy, a condition that causes the heart’s muscular wall to thicken and affects one in every 500 people worldwide.

Caused by an error in a single gene, anyone carrying it has a 50% chance of passing it on to their future children, but editing the DNA removes this risk.

Dr Shoukhrat Mitalipov, who worked on the study, wrote in the ‘Nature’ journal: “Every generation on would carry this repair because we’ve removed the disease-causing gene variant from that family’s lineage.

“By using this technique, it’s possible to reduce the burden of this heritable disease on the family and eventually the human population.”

Taking sperm from a male donor who has hypertrophic cardiomyopathy, and an egg from a healthy woman, the team injected the CRISPR technology at the point of fertilisation to carry out the genetic repairs.

Although it was not 100% successful, the attempt worked in 72% of the 58 embryos - the biggest success rate anywhere in the world so far.

The embryos were then allowed to develop for five days, before the experiment was stopped; as no work of this kind with modified embryos is actually permitted to carry children to term, it is only for purposes of “better understanding” human development.

This includes in the UK where, according to the UK Human Fertilisation and Embryology Authority (HFEA) 2016 licensing, embryos must be destroyed within 14 days and cannot be implanted into a woman after being altered.

A spokesperson for HFEA said: “UK researchers can apply for a license to edit human embryos in research, but offering it as a treatment is currently illegal.”

This is the first time such a trial has taken place outside of China, where laws are more relaxed.

But all previous Chinese trials (the most recent was in 2015) have not been this successful, and have resulted in “mosaic” cells that are a tapestry of healthy and unhealthy cells, as well as parts of the genetic code being mutated.

More work is needed to prove that gene editing would be safe to do in people, but even if it seems safe, scientists face major regulatory hurdles before clinical trials could start.

Today, people who carry certain genetic diseases can opt for IVF and have their embryos screened for harmful mutations but there are many ethical questions about the potential for creating “designer” babies that could be “edited” to have a specific intelligence, height, facial appearance or hair colour.
Scientists say that they have identified genes that cause deadly heart condition pulmonary arterial hypertension which kills 50% of those affected within five years.