How did scientists edit the genes of human embryos?

  • How Did Scientists Edit the Genes of Human Embryos? Scientists have successfully altered a piece of defective DNA in human embryos to prevent them from developing heart disease. It's the first time a mutation that causes a common inherited disease has been fixed using a gene-editing tool. The trial's success raises the prospect of gene editing being used to prevent thousands of inherited conditions from being passed down through generations in the future. The procedure is highly controversial and there is no question of the technique being used to create babies with the genetic modification, as this would be illegal in both the US and the UK. The research, published in the journal Nature, was carried out by scientists in the US at Oregon Health and Science University and the Salk Institute and at the Institute for Basic Science in South Korea. Embryos used by the scientists were allowed to develop for five days before the experiment was stopped. Had they been allowed to develop further, the babies and any future descendants would no longer have been at risk from the heart disease. Dr Shoukhrat Mitalipov, from Oregon Health and Science University (OHSU) in Portland, said “Every generation on would carry this repair because we have 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.” The scientists focused on editing the gene that causes hypertrophic cardiomyopathy, a common disorder that affects about one in 500 people and can cause the heart to suddenly stop beating. The embryos were editing using a powerful gene-editing tool called Crispr-Cas9, which works by precisely snipping away the defective piece of DNA from embryos containing the mutation.Once the gene was removed, the embryo's own repair systems replaced them with the healthy version.

New U.S. Experiments Aim To Create Gene-Edited Human Embryos

How Did Scientists Edit the Genes of Human Embryos?

Dieter Egli, a developmental biologist at Columbia University, and Katherine Palmerola examine a newly fertilized egg injected with a CRISPR editing tool.

Rob Stein/NPR

A scientist in New York is conducting experiments designed to modify DNA in human embryos as a step toward someday preventing inherited diseases, NPR has learned.

For now, the work is confined to a laboratory. But the research, if successful, would mark another step toward turning CRISPR, a powerful form of gene editing, into a tool for medical treatment.

A Chinese scientist sparked international outrage in November when he announced that he had used the same technique to create the world's first gene-edited human babies. He said his goal was to protect them from infection with HIV, a claim that was criticized because there are safe, effective and far less controversial ways of achieving that goal.

In contrast, Dieter Egli, a developmental biologist at Columbia University, says he is conducting his experiments “for research purposes.” He wants to determine whether CRISPR can safely repair mutations in human embryos to prevent genetic diseases from being passed down for generations.

So far, Egli has stopped any modified embryos from developing beyond one day so he can study them.

“Right now we are not trying to make babies. None of these cells will go into the womb of a person,” he says.

How Far Are We from (Accurately and Safely) Editing Human Embryos?

We can already edit genes in human embryos. We can even do it in a way to pass the edits down generations, fundamentally changing a family’s genetic makeup.

Doing it well, however, is far more difficult.

It’s impossible to talk about human germline genome editing without bringing up the CRISPR baby fiasco.

Over a year ago, a rogue Chinese scientist performed an edit on fertilized human embryos that, in theory, makes them resistant to HIV infection.

Two twin girls were born, and both had multiple unplanned edits in their genome with unknown health consequences—consequences that may be passed on to their offspring.

The brash attempt at making scientific history clearly shows that, ethics and morality issues aside, when it comes to germline editing—that is, performing gene edits in egg, sperm, or the embryo—we’re simply technologically not there.

Make no mistake: CRISPR may one day wipe out devastating genetic diseases throughout entire family lines, or even the human race. But to harness its power responsibly, there are plenty of technical challenges we need to master first.

This week, Rebecca Lea and Dr. Kathy Niakan at the Human Embryo and Stem Cell Laboratory at the Francis Crick Institute in London, UK, laid out those challenges in a sweeping article in Nature.

CRISPR as a gene editor is getting more specific and efficient by the day, they explained.

However, for it to gradually move into germline editing, we also need to understand how the tool tangos with cells during early human development.

The data, they argue, will not only let us zoom into the creation of human life. It will also help “inform the debate about potential safe and effective clinical uses of this technology,” and truly unlock the doors to the human genome for good.

Why ‘Play God’ With Our Genetic Source Code?

Correcting dangerous genetic mutations is one reason to pursue germline editing, but CRISPRing human embryos can also unveil insights into the very first stages of human embryo development.

Research shows that trying to understand how human embryos form by studying mice might not be the best route, especially when it comes to using those results to tackle infertility and other medical problems. With CRISPR, we have insight into these early stages that were previously completely unattainable.

We might only solve infertility issues, but perhaps also allow same-sex couples to have genetic children in the future.

Another argument is that couples already screen for life-threatening mutations during IVF, and using CRISPR on top of that is unnecessary. Not true, the authors argued.

When both parents carry a similar mutation that robs them of the ability to have a healthy child, CRISPR—not selection during IVF—is the answer.

“Ultimately, providing more options for patients empowers them to make the choice that is best for their family and circumstances,” they said.

Why Genome Editing in Embryos Is So Hard

This is where it gets complicated.

The big one: we’re still trying to tease out how CRISPR works in cells that form the embryo, in hopes that we can cut down on potential mistakes.

Let me explain: all cells in the body have a “cell cycle,” somewhat analogous to a person’s life cycle. Many “checkpoint” life events happen along the way. The cell could decide to divide and have kids, so to speak, or temporarily halt its cycle and stop its own aging. During a cycle, the cell’s DNA dramatically changes in number and packaging in preparation for its next stage in life.

The problem? The way CRISPR works heavily depends on the cell cycle. Although dubbed an “editor,” CRISPR actually vandalizes the genome, creating breaks in the DNA strands. What we call “gene editing” is the cell’s DNA repair system kicking into high gear, trying to patch up the mess CRISPR left behind.

Adult cells that can’t be repaired stop their own life cycle at a checkpoint for the greater good. In embryos, however, cells aren’t nearly as altruistic. Their checkpoints aren’t fully developed, so they might continue to develop even with severe mutations.

Zooming back to the full picture, it means that the resulting early-stage embryo may keep accumulating damage, until it fails in the mother’s womb.

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What is Human Gene Editing?

Genome editing is a way of making changes to specific parts of a genome.

Scientists have been able to alter DNA since the 1970s, but in recent years, they have developed faster, cheaper, and more precise methods to add, remove, or change genes in living organisms.

Researchers are working to develop therapies that use gene editing to treat children or adults for a range of conditions, including sickle cell, hemophilia, and some forms of cancer and blindness.

Since 2015, a few laboratories have been experimenting with a far more controversial use of CRISPR: editing the genomes of early human embryos, eggs, and sperm.

If edited embryos are used to start a pregnancy, the changes affect every cell in the body of any resulting child, that child’s offspring, their offspring, and so on.

Dozens of countries already prohibit any attempt to start a pregnancy with edited embryos, yet some scientists seem eager to proceed.

In November 2018, researcher He Jiankui from Shenzhen, China announced the birth of the first gene-edited babies: twin girls publicly referred to as Lulu and Nana. In a reckless and widely condemned experiment, He had edited the DNA of two embryos and used them to start a pregnancy. The babies were born prematurely and their current health status is unknown.

These utterly unethical experiments have pushed the issue of human genome editing to the forefront of media, scientific, and public discussion and debate. Any discussion of how we might use this technology in the future needs to consider the serious societal consequences of human genome editing.

This includes examining the rise of vast economic inequalities and the resurgence of overt xenophobia and racism in many parts of the world.

It also includes acknowledging our eugenic histories and the present-day systemic oppression of women, people of color, Indigenous people, LGBTQ people, and people with disabilities, particularly as they relate to reproduction and ideas about who is “fit” to reproduce.

Human genome editing is not just a scientific issue.

It is a political and social justice issue that intersects with the concerns of multiple movements, including disability rights, LGBTQ rights, reproductive rights and justice, racial justice, environmental justice, and health justice. Read on to learn more about human genome editing and why everyone should have a say in the decisions we make about whether and how to use this powerful technology.

Scientist reports first gene editing of humans

academic     Relating to school, classes or things taught by teachers in formal institutes of learning (such as a college).

AIDS     (short for Acquired Immune Deficiency Syndrome) A disease that weakens a body’s immune system, greatly lowering resistance to infections and some cancers. It is caused by the HIV germ. (See also HIV)

bioethics     A code of conduct for research in biology and medicine. To be ethical, people should treat others fairly, avoid cheating or dishonesty in any form and avoid taking or using more than their fair share of resources (which means, to avoid greed).

Bioethics applies this idea to research. It focuses on how to avoid putting others at risk without first alerting people to the potential dangers — and having them choose to accept such risks without coercion.

A person who works in this field is known as a bioethicist.

cancer     Any of more than 100 different diseases, each characterized by the rapid, uncontrolled growth of abnormal cells. The development and growth of cancers, also known as malignancies, can lead to tumors, pain and death.

Cas9     An enzyme that geneticists are now using to help edit genes. It can cut through DNA, allowing it to fix broken genes, splice in new ones or disable certain genes.

Cas9 is shepherded to the place it is supposed to make cuts by CRISPRs, a type of genetic guides. The Cas9 enzyme came from bacteria.

When viruses invade a bacterium, this enzyme can chop up the germs DNA, making it harmless.

cell     The smallest structural and functional unit of an organism. Typically too small to see with the unaided eye, it consists of a watery fluid surrounded by a membrane or wall. Depending on their size, animals are made of anywhere from thousands to trillions of cells. Most organisms, such as yeasts, molds, bacteria and some algae, are composed of only one cell.

colleague     Someone who works with another; a co-worker or team member.

commentary     (in science) An opinion piece, often written to accompany — and add perspective to — a paper by others, which describes new research findings.

CRISPR

Experiments that led to the first gene-edited babies: the ethical failings and the urgent need for better governance

1Bioethics Center, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand

Find articles by Jing-ru Li

1Bioethics Center, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand

Find articles by Simon Walker

1Bioethics Center, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand

Find articles by Jing-bao Nie

2School of Humanities and Social Sciences, Peking Union Medical College, Beijing 100730, China

Find articles by Xin-qing Zhang

The rapid developments of science and technology in China over recent decades, particularly in biomedical research, have brought forward serious challenges regarding ethical governance.

Recently, Jian-kui HE, a Chinese scientist, claimed to have “created” the first gene-edited babies, designed to be naturally immune to the human immunodeficiency virus (HIV). The news immediately triggered widespread criticism, denouncement, and debate over the scientific and ethical legitimacy of HE’s genetic experiments.

China’s guidelines and regulations have banned germline genome editing on human embryos for clinical use because of scientific and ethical concerns, in accordance with the international consensus. HE’s human experimentation has not only violated these Chinese regulations, but also breached other ethical and regulatory norms.

These include questionable scientific value, unreasonable risk-benefit ratio, illegitimate ethics review, invalid informed consent, and regulatory misconduct. This series of ethical failings of HE and his team reveal the institutional failure of the current ethics governance system which largely depends on scientist’s self-regulation.

The incident highlights the need for urgent improvement of ethics governance at all levels, the enforcement of technical and ethical guidelines, and the establishment of laws relating to such bioethical issues.

Keywords: Jian-kui HE, Human germline gene editing, Human immunodeficiency virus (HIV), Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9, Ethical review

With the support of central and local governments and various institutions, science and technology in China has been advancing rapidly over recent decades, particularly in the area of biomedical research. With this progress, numerous and extensive ethical challenges have arisen and will continue to arise.

Bioethics and governance of ethical issues in China have also developed quickly to meet these challenges, but they have not kept pace. A more robust system of ethical governance is now required. This need is made clearly evident in the genetic experimentation recently undertaken by Jian-kui HE and his team.

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HE claims to have produced the world’s first germline gene-edited babies, and that these babies are naturally immune to the human immunodeficiency virus (HIV). These claims are yet to be confirmed independently.

Irrespective of whether they are proved correct, they raise a large number of serious global ethical concerns.

These concerns are complex and interrelated but may be broadly mapped into the following four categories: (1) key issues related to biomedical research ethics; (2) broader political, socio-cultural and transcultural issues; (3) fundamental ethical problems on germline gene-editing reproduction itself; and (4) fundamental questions about the moral goals of science and technology. This paper will not cover each of these broad categories but will focus on the first and the third. After we briefly outline the Chinese responses to HE’s announcement, we will argue that his experimentation breaches many well-established Chinese and international ethical norms relating to human germline editing and clinical research. We also discuss the institutional ethical failings involved in this case and what they mean for the systems of ethical governance in China and conclude that improvements are urgently needed.

On 25 November 2018, two days before the Second International Summit on Human Genome Editing in Hong Kong, Jian-kui HE, a Chinese researcher of the Southern University of Science and Technology, released a video on YouTube announcing that he and his colleagues have “created” the world’s first genetically altered babies, Lulu and Nana.

HE explained the details of his experiment in his address at the Hong Kong conference. HE and his team had recruited eight couples through an HIV volunteer group named Baihualin (BHL) China League (one couple later withdrew from the research).

All the male participants are HIV-positive, and all female participants are HIV-negative. The participants’ sperm was “washed off” to get rid of HIV and then injected into eggs collected from the female participants.

By using clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9, a gene editing technique, they disabled a gene called CCR5 in the embryos, aiming to close the protein doorway that allows HIV to enter a cell and make the subjects immune to the HIV virus.

The process led to at least one successful pregnancy and the birth of the twin baby girls.

The news was rapidly reprinted by Chinese media. At first, HE’s research was promoted as a dramatic scientific advancement.

For example, People’s Daily Online, the most influential newspaper in the Chinese mainland, described HE’s research as “a historical breakthrough in the application of gene editing technology for disease prevention” (SinaTech, 2018).

However, as more detailed information about HE’s research was unveiled by the media, its legitimacy was increasingly challenged by scientists, bioethicists, lawyers, and the general public, both in China and internationally.

On the night of 26 November, 122 Chinese scientists issued a statement strongly condemning HE’s action as unethical.

They stated that while CRISPR-Cas is not a new technology, it involves serious off-target risks and associated ethical considerations, and so should not be used to produce gene-altered babies.

They described HE’s experiment as “crazy” and “a huge blow to the global reputation and development of Chinese science”.

The Scientific Ethics Committee of the Academic Divisions of the Chinese Academy of Sciences posted a statement declaring their opposition to any clinical use of genome editing on human embryos, noting that “the theory is not reliable, the technology is deficient, the risks are uncontrollable, and ethics and regulations prohibit the action”. The Chinese Academy of Engineering released a statement on 28 November, calling on scientists to improve self-discipline and self-regulation, and to abide by corresponding ethical principles, laws, and regulations. Finally, the Chinese Academy of Medical Sciences published a correspondence in The Lancet, stating that they are “opposed to any clinical operation of human embryo genome editing for reproductive purposes” (Wang et al., 2018).

At the Second International Summit on Human Genome Editing in Hong Kong, Ren-zong QIU, an eminent Chinese bioethicist, described HE’s research as “a practice with the least degree of ethical justifiability and acceptability”.

QIU described that HE’s research was conducted on healthy embryos with the aim of making the baby immune to the HIV virus, and this constitutes gene enhancement for medical purposes.

This further indicates the cavalier nature of HE’s research, as there is currently broad opposition to the idea of gene enhancement, and national or international agreement seems a long way off.

The news also attracted the attention of the general public in China. Though most people do not fully understand the science behind the procedure, they are concerned about the welfare and health of the twin girls, and the potential adverse consequences to humanity.

The authorities in China promised a stringent investigation of HE’s research.

Nan-ping XU, vice minister of China’s Ministry of Science and Technology, noted that China “explicitly banned” clinical procedures of gene-editing on human embryos for reproductive purposes and ordered a halt to the “scientific activities of relevant personnel”. China’s National Health Commission has requested the Guangdong Provincial Health Commission to investigate and verify HE’s assertions.

What’s the right way for scientists to edit human genes? 5 essential reads

Since scientists first figured out how to edit genes with precision using a technology called CRISPR, they’ve been grappling with when and how to do it ethically. Is it reasonable to edit human genes with CRISPR? What about human genes in reproductive cells that pass the edits on to future generations?

The International Commission on the Clinical Use of Human Germline Genome Editing convened on Aug. 13 to hash out guidelines about editing human embryos. The goal is to provide a framework that researchers around the globe can consult to ensure their work is in line with scientific consensus.

An earlier U.S. National Academies committee had already released recommendations in 2017. They called for caution – but were ambiguous enough for Chinese scientist He Jiankui to suggest he’d followed them even as he produced twin girls with CRISPR-edited genomes late last year.

Here are five stories from our archive that explore how to ethically develop and regulate a potentially risky new technology.

1. A voluntary pause

No one denies the power of the CRISPR editing tool. It could allow doctors to one day cure genetic diseases, whether in adults who are living with medical conditions or in embryos that have not yet even been born. But there’s a lot of lab work yet to be done, as well as many conversations to be had, about the right way to proceed.

In 2015, a group of prominent scientists called for a voluntary freeze on germline editing – that is, changing sperm, eggs or embryos – until ethical issues could be resolved.

Chemical biologist Jeff Bessen wrote that this approach has precedents in the scientific community, where many think it makes sense to take things slow and place “the right emphasis on safety and ethics without hampering research progress.”

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2. Stringent hurdles before proceeding

The National Academies’ 2017 report was meant to provide the scientific community with definitive guidance on the issue.

Rosa Castro, a scholar of science and society, explained that the report gave the green light to modifying body cells and a yellow light to modifying reproductive cells that would allow the changes to be inherited by future progeny. The report’s goal was to ensure that “germline genome editing will be used only to prevent a serious disease, where no reasonable alternatives exist, and under strong supervision.”

3. Science marches on

By later that year, a research group announced they’d successfully used CRISPR to modify human embryos, though the edited embryos weren’t implanted in women and were never born.

Bioethics and public health professor Jessica Berg wrote about the importance of working out the ethical issues of gene editing before researchers take the critical step of allowing modified embryos to develop and be born as babies.

“Should there be limits on the types of things you can edit in an embryo? If so, what should they entail? These questions also involve deciding who gets to set the limits and control access to the technology.

“We may also be concerned about who gets to control the subsequent research using this technology. Should there be state or federal oversight? Keep in mind that we cannot control what happens in other countries.

“Moreover, there are important questions about cost and access.”

4. Babies born with edited genomes

Most of the world reacted with shock in 2018 when a Chinese researcher announced he’d edited the germline cells of embryos that went on to become twin baby girls. His stated goal was to protect them from HIV infection.

This development seemed to many researchers to be in violation of at least the spirit of the 2017 guidelines around human gene editing. Biomedical ethicist G. Owen Schaefer described the central objection: that the procedure was simply too risky, with the potential for unexpected and harmful health effects later in the girls’ lives outweighing any benefit.

He wrote that the “CRISPR babies” are “part of a disturbing pattern in reproduction: rogue scientists bucking international norms to engage in ethically and scientifically dubious reproductive research.”

5. Rules and regs don’t guarantee ethical work

Whatever the outcome of the current meeting, there may be a distinction between sticking to the rules and doing what’s right. Arizona State professor of life sciences J. Benjamin Hurlbut and applied ethicist Jason Scott Robert underscored this point after Chinese scientist He Jiankui claimed he checked off the boxes laid out by the 2017 guidelines.

“Public debate about the experiment should not make the mistake of equating ethical oversight with ethical acceptability. Research that follows the rules is not necessarily good by definition.”

Guidelines and expectations can help define what the scientific community finds acceptable. But complying with the routines of oversight doesn’t guarantee a project is ethical. That’s a much more complicated question.

Editor’s note: This story is a roundup of articles from The Conversation’s archives.

Russian ‘CRISPR-baby’ scientist has started editing genes in human eggs with goal of altering deaf gene

An earlier version of this story and its headline incorrectly stated that Denis Rebrikov had started editing eggs from a woman with a mutation that causes deafness.

Denis Rebrikov plans to soon publish his experiments to repair genes in human eggs.Credit: Andrey Rudakov/Bloomberg/Getty

Russian biologist Denis Rebrikov has started gene editing in eggs donated by women who can hear to learn how to allow some deaf couples to give birth to children without a genetic mutation that impairs hearing.

The news, detailed in an e-mail he sent to Nature on 17 October, is the latest in a saga that kicked off in June, when Rebrikov told Nature of his controversial intention to create gene-edited babies resistant to HIV using the popular CRISPR tool.

Rebrikov’s latest e-mail (see box) follows a September report in Russian magazine N+1 that one deaf couple had started procedures to procure eggs that would be used to create a gene-edited baby — but the eggs that Rebrikov has edited are from women without the genetic mutation that can impair hearing. He says the goal of the experiments is to better understand potentially harmful ‘off-target’ mutations, which are a known challenge of using CRISPR–Cas9 to edit embryos.

In his e-mail to Nature, Rebrikov makes clear that he does not plan to create such a baby yet — and that his previously reported plan to apply this month for permission to implant gene-edited embryos in women has been pushed back.

Instead, he says that he will soon publish the results of his egg experiments, which also involved testing CRISPR’s ability to repair the gene linked to deafness, called GJB2, in bodily cells taken from people with this mutation. People with two mutated copies of GJB2 cannot hear well without interventions, such as hearing aids or cochlear implants. Rebrikov says these results will lay the groundwork for the clinical work.

Rebrikov adds that he has permission from a local review board to do his research, but that this does not allow transfer of gene-edited eggs into the womb and subsequent pregnancy.

Apart from the deaf couple who agreed to start undergoing procedures, he is in discussion with four other couples in which both would-be parents have two mutated GJB2 genes, he says. Rebrikov says he wants to help couples such as these to have a child with unimpaired hearing.

Rebrikov also provided further information about the couple who agreed to the procedures in his most recent e-mail. In September, N+1 had reported that the couple didn’t sign a consent form and had backed away from the idea of creating a gene-edited child, citing personal reasons.

But Rebrikov now says that this is only a temporary hurdle. He notes that the woman who donated the eggs has taken a one-month ‘pause’ while she gets a cochlear implant.

Rebrikov also emphasized that he will not move forward without approval from the Ministry of Health of the Russian Federation. “I will definitely not transfer an edited embryo without the permission of the regulator.”

That might not come soon. Last week, the ministry released a statement saying that production of gene-edited babies is premature. Rebrikov says “it is hard to predict” when he will get permission, but it will be after all the necessary safety checks.

Doubling down

Rebrikov shot to fame in June with the news of his plans to make HIV-resistant babies. The news shocked international researchers, who feared that he was following in the footsteps of Chinese scientist He Jiankui, who announced the controversial birth of the world’s first babies, twin girls, with edited genomes last year.

Rebrikov plans to use CRISPR to disrupt the same gene that He did — CCR5. The protein made by the CCR5

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