In a groundbreaking experiment, an international team of scientists on Wednesday officially reported the successful elimination of a genetic disease from human embryos.

Its potentially a huge step for medicine -- but also a controversial one. While these embryos, which a team led by researchers at the Oregon Health and Science University edited using a novel gene-editing procedure known as CRISPR-Cas9, were destroyed rather than implanted into a womb, some say this type of genetic manipulation opens the door to other possibilities in human engineering.

Below are answers to some of the common questions about this research.

In short, this experiment showed that it is potentially possible to correct a genetic disease in an embryo with a high chance of success. In order to show this, the researchers created human embryos designed to have a specific genetic mutation responsible for a type of heart disease known as hypertrophic cardiomyopathy. This genetic disease, which occurs in one out of 500 people, can cause sudden death, as well as a host of other cardiac problems such as heart failure and arrhythmias.

Using a technique known as CRISPR-Cas9, the scientists were able to target the faulty genes as the cells in the embryo divided -- swapping them out for a properly functioning form of the gene. What was novel about this study is that researchers were able to nudge the embryo to use its own native machinery to perform the repair with a high degree of efficiency using a correct form of the gene already present in the cell. In this particular experiment, the researchers used CRISPR-Cas9 on 58 embryos containing the mutation. After the procedure, they found that the mutation was corrected in 42 embryos -- a success rate of 72 percent.

If a feat similar to that seen in this experiment could be achieved in an afflicted embryo that was allowed to develop into a person, it would prevent the condition in this individual -- and it would also prevent their future sons and daughters from inheriting this condition as well.

Moreover, there are thousands of genetic diseases, ranging from cystic fibrosis to sickle cell anemia, for which such a procedure could be relevant. Tests currently exist to diagnose many diseases prior to birth; however, at this time there is no therapy in use that actually alters the DNA of embryos prior to birth. Of course, the use of such a technique would inevitably raise the prospect of exerting all kinds of control over human reproduction -- as well as a host of new ethical questions.

Its not likely, at least for now. Currently, the U.S. Food and Drug Administration is barred from reviewing investigational medical studies involving editing of human embryos -- something which would be required in order to proceed with moving this research into practice. Additionally, the National Institutes of Health, which is an important source of science research funding in the United States, will not financially support research on gene editing of embryos. The research in this study was not supported by funding from the National Institutes of Health.

Right now, it is unclear. Importantly, even though this experiment was considered to be successful, it is not known how this method would perform in other cases -- for example, a case in which both copies of the gene were mutated rather than just one, which was the case in this experiment. Also, since the scientists destroyed these embryos at a very early stage of development, it is not possible to tell for sure how viable these embryos would actually have been in the long run, or whether there would have been any unforeseen complications with their development.

But along with these scientific questions are also big ethical questions -- ones that will only be answered as scientists, ethicists and the public reflect further on this groundbreaking step.

Will Garneau, M.D., is an internal medicine resident at the Johns Hopkins Hospital.

The rest is here:
Groundbreaking study demonstrates promise and controversy of gene editing in embryos - ABC News

Using a powerful gene-editing technique, scientists have rid human embryos of a mutation responsible for an inherited form of heart disease thats 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 erase a disease-causing mutation not only from the DNA of the primary subject but from the genes of his or her progeny as well.

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

Scientists ultimate goal is to fix gene mutations that lead to debilitating or fatal diseases, and to prevent the propagation of those mutations to future generations. Study leader Shoukhrat Mitalipov, a biologist at OHSU, said the new findings might correct genetic variants that can cause breast and ovarian cancer, cystic fibrosis and muscular dystrophy in those who inherit them.

But others fret that the technique may be used for less noble purposes, such as creating designer babies with desired traits like green eyes, an athletic build or an aptitude for mathematics.

In the United States, the Food and Drug Administration currently forbids any use of germ-line editing outside of a research setting.

But recent history has shown that people who want access to such techniques can find people willing to perform them in venues where theyre able to do so, said Jeffrey Kahn, who directs Johns Hopkins Universitys Berman Institute of Bioethics.

It will happen whether we discuss it or not, and we need to talk about these things before they happen, said Kahn. Thats now.

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 the time being.

In a bid to make the experiment relevant to the real-life problems faced by parents who carry disease-causing mutations, the researchers focused on a gene variant that causes inherited hypertrophic cardiomyopathy.

In this condition, a parent who carries one normal and one mutated copy of the MYBPC3 gene has a 50-50 chance of passing the faulty copy 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 in which one parent carries a gene like this, a couple will often seek the assistance of fertility doctors to minimize the risk of passing the mutation on to a child. A womans eggs and mans sperm meet in a lab using in vitro fertilization. Then specialists inspect the resulting embryos, cull the ones that have inherited an unwanted mutation, and transfer unaffected embryos into a womans 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.

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 study authors reported.

The fix was made possible by a system known as CRISPR-Cas9, which has been sweeping through biology labs because it greatly simplifies the gene-editing process. It uses a small piece of RNA and an enzyme to snip out unwanted DNA and, if desired, replace it with something better.

If the process is found to be safe for use in fertility clinics, it could potentially decrease the number of cycles needed for people trying to have children free of genetic disease, said Dr. Paula Amato, a coauthor and professor of obstetrics and gynecology at Oregon Health and Science University.

The team encountered several scientific surprises along the way. 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.

Mitalipov called these exciting and surprising moments. But he cautioned that there is room to improve the techniques for producing mutation-free embryos. Clinical trials would have to wait until the DNA editing showed a near-perfect level of efficiency and accuracy, he said, and could be limited by state and federal regulations.

There is still a long road ahead, said Mitalipov, who heads the Center for Embryonic Cell and Gene Therapy at OHSU.

Oregon Health & Science University

Human embryos developing into blastocysts after being injected with a gene-correcting enzyme and sperm carrying a mutation for a potentially fatal disease of the heart muscle.

Human embryos developing into blastocysts after being injected with a gene-correcting enzyme and sperm carrying a mutation for a potentially fatal disease of the heart muscle. (Oregon Health & Science University)

Oregon Health & Science University

Individual blastomeres within the early embryos two days after the co-injection. Each new cell in the developing embryos was uniformly free of the disease-causing mutation.

Individual blastomeres within the early embryos two days after the co-injection. Each new cell in the developing embryos was uniformly free of the disease-causing mutation. (Oregon Health & Science University)

Biologists, fertility doctors and ethicists have long anticipated that scientists would one day manipulate the DNA of human embryos. Now that the milestone has been reached, it 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 the understanding of genetic repair on many fronts. Hynes, who was not involved with the research effort, said he was pleasantly surprised by the Oregon-based teams clever modifications and their outcomes.

Its likely to become feasible, technically not tomorrow, not next year, but in some foreseeable time. Less than a decade, Id say, said Hynes, 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 system, said the new research highlights a prospective use of gene editing for one inherited disease and offers some insights into the process. But she questioned how broadly the experiments results would apply to other inherited diseases.

Doudna also said she does not believe using germ-line editing to improve efficiency at fertility clinics meets the criteria laid out by the National Academies of Sciences, which urged that the technology be explored only in cases in which its needed essentially as a last resort.

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

Doudna said she feared 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 theres broad societal consensus, and that just hasnt happened, she said. This study underscores the urgency of having those debates. Because its coming.

Kristyna Wentz-Graff/Oregon Health & Science University

Study leader Shoukhrat Mitalipov with coauthors Hong Ma, left, and Nuria Marti-Gutierrez.

Study leader Shoukhrat Mitalipov with coauthors Hong Ma, left, and Nuria Marti-Gutierrez. (Kristyna Wentz-Graff/Oregon Health & Science University)

The study authors a multinational team of geneticists, cardiologists, fertility experts and embryologists from OHSU, the Salk Institute in La Jolla, and labs in South Korea and China tested 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, the researchers simultaneously performed two steps that had never been combined in a lab: fertilizing the eggs with sperm and introducing the CRISPR-Cas9 repair machinery.

The resulting embryos took up the gene-editing program so efficiently and uniformly that, after five days of incubation, 72.4% of the 58 embryos tested were free of the MYBPC3 mutation. By comparison, when there was no attempt at gene editing, just 47.4% of embryos were free of the mutation responsible for the deadly heart condition.

The researchers believe their method prompted the embryos to rely on the healthy maternal copy of the gene as a model for fixing the MYBPC3 mutation, and not a repair template that used DNA from the sperm donors normal version of the gene. Only one of the 42 embryos used the introduced template for repair. The scientists contrasted this process to stem cells, which do use repair templates.

The embryos cells divided normally as they matured to the blastocyst stage, the point at which they would usually be ready for transfer to a womans uterus. After extensive testing, the embryos were used to make embryonic stem-cell lines, which are stored in liquid nitrogen and can be used in future research.

Researchers also noted that genetic mosaicism a concern raised by earlier experiments in gene-editing was virtually absent from 41 of the 42 embryos that were free of the disease-causing mutation.

MITs Hynes said such findings offer important insights into how human embryos grow, develop and respond to anomalies, and will help families facing infertility and inherited illnesses.

Human embryogenesis is clearly different from that of a mouse, which we know a lot about, Hynes said. That needs to be studied in human embryos, and theres no other way to do it.

At the same time, he downplayed fears that embryologists would soon tinker with such attributes as looks, personality traits and intelligence in human children.

Were not looking at designed babies around the corner not for a long time, he said.

melissa.healy@latimes.com

@LATMelissaHealy

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UPDATES:

3:50 p.m.: This story has been updated with comments from Jeffrey Kahn of Johns Hopkins Universitys Berman Institute of Bioethics.

This story was originally published at 10 a.m.

Excerpt from:
In a first, scientists rid human embryos of a potentially fatal gene ... - Los Angeles Times

WASHINGTON -- For the first time, researchers in the U.S. have safely repaired a disease-causing gene in human embryos, targeting a heart defect best known for killing young athletes a big step toward one day preventing a list of inherited diseases. The breakthrough is also prompting debate about the ethics of altering DNA for generations to come.

Scientists from Oregon Health and & Science University used the gene-editing tool CRISPR to target the mutation that causes hypertrophic cardiomyopathy, a common genetic heart disease that can cause sudden cardiac death and heart failure.

The research, published in the journal Nature, demonstrates a new method of fixing a disease-causing mutation and preventing it from being passed down to future generations.

"Every generation on would carry this repair because we've removed the disease-causing gene variant from that family's lineage," senior author Shoukhrat Mitalipov, Ph.D., who directs the Center for Embryonic Cell and Gene Therapy at OHSU in Portland, Oregon, said in a statement. "By using this technique, it's possible to reduce the burden of this heritable disease on the family and eventually the human population."

The successful experiment involved altering defective embryos in a lab; they were not implanted or allowed to develop.

This type of gene editing technology is already used every day in fields ranging from agriculture to drug development. The tools enable scientists to alter the DNA of living cells from plants, animals, and now, potentially, even humans more precisely than ever before. Think of it as a biological cut-and-paste program. Here is a closer look at the science.

While scientists have long been able to find defective genes, fixing them has been so cumbersome that it's slowed development of genetic therapies. There are several gene editing methods, but a tool called CRISPR-Cas9 has sparked a boom in research as laboratories worldwide adopted it over the past five years because it's faster, cheaper, simple to use with minimal training and allows manipulation of multiple genes at the same time.

Pieces of RNA are engineered to be a guide that homes in on the targeted stretch of genetic material. The Cas9 is an enzyme that acts like molecular scissors to snip that spot. That allows scientists to delete, repair, or replace a particular gene.

The fresh attention comes from research involving human embryos. In laboratory experiments, a team lead by Oregon researchers used CRISPR to successfully repair a heart-damaging gene in human embryos, marking a step toward one day being able to prevent inherited diseases from being passed on to the next generation. But there's wide agreement that more research is needed before ever testing the technique in pregnancy.

The biggest everyday use of CRISPR so far is to engineer animals with human-like disorders for basic research, such as learning how genes cause disease or influence development and what therapies might help.

But promising research, in labs and animals so far, also suggests gene editing might lead to treatments for such diseases as sickle cell, cancer, maybe Huntington's by altering cells and returning them to the body. Another project aims to one day grow transplantable human organs inside pigs.

Safety is a key question because gene editing isn't always precise enough; there's the possibility of accidentally cutting DNA that's similar to the real target. Researchers have improved precision in recent years, but out-of-body treatments like using cells as drugs get around the fear of fixing one problem only to spark another.

Altering genes in sperm, eggs or embryos can spread those changes to future generations, so-called "germline" engineering. But it's ethically charged because future generations couldn't consent, any long-term negative effects might not become apparent for years, and there's concern about babies designed with enhanced traits rather than to prevent disease.

Earlier this year, an ethics report from the prestigious National Academy of Sciences opened the door to lab research to figure out how to make such changes but said if germline editing ever is allowed, it should be reserved for serious diseases with no good alternatives and performed under rigorous oversight.

Where you live determines if, or what kind of, research can be performed on human embryos. Some countries, especially in Europe, ban germline research. Britain allows basic lab research only.

In the U.S., scientists can perform laboratory embryo research only with private, not federal taxpayer, funding, as the Oregon team did. Any attempt to study germline editing in pregnant women would require permission from the Food and Drug Administration, which is currently prohibited by Congress from reviewing any such request.

Researchers also are using gene editing to hatch malaria-resistant mosquitoes, grow strains of algae that produce biofuels, improve crop growth, even make mushrooms that don't brown as quickly.

More:
Gene editing fixes harmful mutation in human embryos - CBS News

Every human on earth is unique our genes are different, we eat different things, we live in different places. As a result, medical treatments tend to work differently on different people. Depending on your genes, a drug might cure your sickness or it might cause a side effect that makes you sicker.

In the past, many of humanitys individual variations were invisible to us, but today, new technology offers us a way to peer into each persons genome, allowing doctors to personalize treatments for each patient. This approach, called precision medicine, has been a major focus of research and investment in the last few years.

But precision medicine only works if scientists have studied people who are similar to you. If your genes are rare or unusual compared to those researchers have examined in the past, you could end up getting the wrong treatment. Since the vast majority of genetics studies are done on people of European ancestry, members of other racial groups may lose out on the benefits of precision medicine entirely. Those same groups already often receive worse health care in the United States than people of European descent get, and personalized medical treatment could make the gap in care larger.

Precision medicine is based on the idea that genes can be linked to diseases. To study this, scientists assemble a group of people, some with a disease and some without, and identify their genetic differences. If particular differences are common among the people who have the disease and absent from the people without it, then scientists can infer that those genetic patterns might be involved in the disease.

But each person has their own catalogue of genetic characteristics. Some are common in people of certain ancestral backgrounds and rare in those from other backgrounds. If scientists exclusively study individuals of one ethnic group, they may not know how to refine their treatments for a person from a different group.

A 2009 analysis of the studies that can link a genetic variant to a disease or trait showed that fully 96 percent of participants were of European descent. In a 2016 commentary in the journal Nature, Alice Popejoy and Stephanie Fullerton, respectively a graduate student and a professor at the University of Washington, showed that these studies had grown more diverse and people of European ancestry now account for 81 percent of research subjects. Things are getting better, and its still pretty darn slow, Fullerton said in an interview. And of the progress that has been made, much of it is attributable not to an increase in diversity in U.S. research but to studies conducted in Asian countries, which involve local participants.

Disparities in biomedical research exacerbate an existing gap in U.S. health care. African-Americans and Latinos are less likely to have health insurance and more likely to suffer from chronic diseases. Even controlling for wealth differences between populations, African-Americans receive worse health care.

The science underlying precision medicine threatens to make these disparities worse because it could leave any genetic differences that primarily affect nonwhite groups unstudied. Some genetic differences are prevalent in one population and rare in another. A prominent example is a gene called APOL1. Differences in this gene are common in people whose ancestors are from sub-Saharan Africa but rare in those of other backgrounds. Some of these variations increase the risk of developing kidney disease more than sevenfold, but they also seem to confer protection against African sleeping sickness. Knowing a patients APOL1 genetic makeup might be useful for guiding kidney disease treatment, and APOL1 is likely one of many genes that must be studied within a nonwhite population.

Its possible to solve the problem of underrepresentation. The National Institutes of Health fund a number of large-scale genetic research projects in the United States, and scientists there consider this a major issue. We are aware of this situation, and work is being funded to rectify the situation, said Charles Rotimi, an investigator at NIH. He pointed to initiatives like Human Heredity and Health in Africa and the Population Architecture using Genomics and Epidemiology Consortium. These projects are developing more diverse study populations to address the underrepresentation of people of non-European ancestries, in some cases going to African countries to collect genetic data. In the United States, individual investigators can also apply for smaller-scale NIH grants to study particular diseases.

Even when scientists make a conscious effort to recruit a diverse study population, they can run into hurdles. For very good reason, minority populations can be more skeptical and concerned about being involved in biomedical research, said professor Danielle Dick of Virginia Commonwealth University, who studies how genetics contribute to a persons risk of substance abuse. The good reason Dick referred to is a long history of biomedical researchers mistreating people of color, including in the Tuskegee trials and through the forced sterilization of Puerto Ricans. Dicks team and others have tried to address issues of underrepresentation by visiting various hospitals to recruit Hispanic or African-American study participants, providing educational materials about genetics research, arranging to collect samples when patients may be off work, and taking other measures to encourage participation.

But the imbalance in samples is so severe, and the rush to develop precision medicine is so swift, that the problem may not be solved before treatments are developed, and as a result, those treatments will likely predominantly help people of European ancestry. The time horizon for a lot of therapies is typically in the 10- to 15-year range, Fullerton said. Could we solve it in that time frame? Possibly. But genetic differences may already be causing disparities in treatment results between groups. Some genetic variants that are common to certain racial or ethnic groups can affect a patients tolerance for drugs, for example, so knowing about a patients genetic code can guide a physicians prescription. Doctors are observing these phenomena in the clinic already, said Nishadi Rajapakse, an NIH administrator at the National Institute on Minority Health and Health Disparities.

Clinical differences in health care are only likely to become more severe as precision medicine advances. New drugs are already targeting certain genetic differences, although none that would function primarily in one ethnic group and not in others. In the long run, people of European ancestry could benefit from ever more specialized treatments while people of color are left behind.

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Medicine Is Getting More Precise For White People - FiveThirtyEight

Why it matters to you

Duchenne muscular dystrophy is a horrible disease which slowly attacks every muscle in the body. Gene therapy could help treat it -- whether you're a dog or a human.

As difficult as it is when our beloved pet dogs get old, its a whole lot worse if their decline is the result of a horrible disease like Duchenne muscular dystrophy, a genetic disorder characterized by progressive muscle degeneration and weakness. Fortunately, a team of gene-editing researchers from France and the U.K. have been working to develop gene therapy as an answer and its one that could help humans, too.

Their solution involves using gene therapy to restore muscle strength and stabilize clinical symptoms. This is achieved by way of a shortened version of the dystrophin gene, containing just 4,000 base pairs, which is combined with a viral vector and injected into patients.

Duchenne muscular dystrophy is a debilitating muscle-wasting disease affecting young boys and male animals, which is caused by inheritance of a damaged gene, George Dickson, professor of molecular cell biology at University of London, told Digital Trends. There is currently no very effective cure. Our work has involved producing a healthy functioning copy of the damaged gene in the lab, and then using a harmless virus to carry the gene into the affected muscles, a so-called gene therapy.

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The gene treatment has so far been tested on twelve golden retrievers affected by Duchenne muscular dystrophy. After a single dose, the dogs dystrophin production the protein responsible for maintaining the integrity and strength of muscles returned to its normal levels. Best of all, the trial was carried out a few years back, and all signs point to this being a lasting treatment. A paper describing the work was recently published in the journal Nature Communications.

We now have treated a number of dogs affected by this condition with a single round of gene therapy, Dickson continued. At the correct dose, the results have been very encouraging with dogs looking very active and healthy over 3 years after the treatment. The treatment involves a simple intravenous infusion, a one-off treatment, and we have been very pleased and quite surprised at how effective the gene therapy has been given that muscle is a major tissue spread all over the body.

Next up, the researchers hope to extrapolate the findings to human children, since they they are roughly the same weight and display similar clinical symptoms to canines.

The goal is to expand this gene therapy treatment into human patients, boys suffering from the Duchenne muscular dystrophy disease, Dickson said. We have to scale up production of the gene therapy medicine for human use, complete more safety tests, and then embark on recruiting patients into full-scale clinical trials.

Should all go according to plan, itll be another reminder of why gene therapy is the future of medicine as we know it.

More:
Man's best mend Gene therapy reverses muscular dystrophy symptoms in dogs - Digital Trends