Artificially Introduced Genetic Errors That Can Change the Human Species

 A study by the Francis Crick Institute in London revealed that gene editing experiments carried out so far generated accidental mutations in 16% of cases

 

Errors introduced by gene editing could be passed from generation to generation

He Jiankui looked nervous. The Chinese researcher at the Southern University of Science and Technology in Shenzhen has been working on a top-secret project for the past two years, and was about to take the podium at the International Summit on Human Genome Editing to announce the results.

The audience watched anxiously. People started filming on their phones. The biologist had created the first genetically modified babies in the history of mankind. After 3.7 billion years of continuous evolution undisturbed by natural selection, a life form had taken its innate biology into its own hands.

 

The result was twin girls who were born with altered copies of a gene known as CCR5, which the scientist hoped would make them immune to HIV. But things were not what they seemed.

"He convinced me for the first five or six minutes, he seemed very sincere," said Hank Greely , a professor of law at Stanford University and an expert in medical ethics, who watched the conference live online in November 2018. " And then, as I progressed, I became more and more suspicious. "

A genetic invention

In the years that followed, it became clear that He's project was not as innocent as it seemed. He had violated laws, falsified documents, misled the babies' parents about the risks, and failed to perform proper safety tests.

He Jiankui received a three-year prison sentence for "illegal medical practices"AFP Agency

All of this left many experts appalled - he was described as "monstrous" and "amateur" - and the investigator is now in prison. However, most serious of all were the mistakes he made . It turns out that the babies involved, Lulu and Nana, weren't gifted with carefully edited genes after all. Not only are they not necessarily immune to HIV, but they were accidentally endowed with versions of CCR5 that are totally made up.

They probably don't exist in any other human genome on the planet. And yet such changes are inheritable: they could be passed on to your children, your children's children, etc. In experiments with genetically modified animals, this field was found to be riddled with errors and misunderstandings.

From rabbits altered to be thinner that inexplicably ended up with much longer tongues, to cattle modified to lack horns that were endowed with bacterial DNA (including some genes that confer resistance to antibiotics).

16%

Recently, researchers at the Francis Crick Institute in London found that editing the genetics of human embryos can have unintended consequences. Analyzing data from previous experiments, they found that about 16% had accidental mutations that would not have been detected by standard tests.

 

Why are these errors so common? Can they be remedied? And how could they affect future generations? This may seem like a problem for the future. After all, He's work was widely condemned and designer babies are illegal in many countries, at least for now.

For years, Lulu, Nana, and a mysterious third baby, whose existence was only confirmed during the scientist's trial, were the only gene-edited people on the planet. But this could be about to change, thanks to "somatic cell" editing.

What is it?

It is a new technique that is being developed to treat a variety of devastating diseases, from obscure metabolic disorders to the leading cause of childhood blindness.

Somatic Cell Editing Could Cure Many Diseases, But It Has Its Risks

The technology is considered to represent a breakthrough in the management of some of the most difficult-to-treat inherited disorders , as well as common diseases such as cancer. It works like this: instead of altering a person's genome while it is a fertilized egg or early embryo, this method alters ordinary cells, such as those of specific organs, such as the eye.

This means that the changes should not be inherited by the next generation. But, as with all gene edits, it is not that simple. "Let's say we're injecting a genome editor into the brain to target neurons in the hippocampus," explained Krishanu Saha , a bioengineer at the University of Wisconsin-Madison who is currently part of a consortium investigating the safety of this technique.

"How do we make sure those genome editors don't travel to the reproductive organs and end up altering a sperm or an egg?" At the moment , it is not yet known how likely this is, but Saha explained that it is something they are studying carefully, especially since it appears that the treatment will be much more available over the next decade.

 

A gene editor was injected into humans for the first time last year, as part of a landmark clinical trial. If reproductive cells were to end up being altered, "certainly, we would have individuals who have new genetic variants that could potentially be very problematic."

A failed experiment

But first, let's go back to gene-edited Chinese babies, for a master class on what can go wrong when the technique is handled without due caution. He's goal was to give girls a version of the CCR5 gene that is naturally present in about 1% of northern Europeans.

When people with this gene are exposed to HIV, the virus cannot enter the system and they are therefore immune. This was the goal, but it didn't work out as the scientist expected. Instead, both Lulu and Nana carry new CCR5 genes, which are completely different from the normal gene.

Nana carries two altered genes, while Lulu has one altered and one normal. "We have never seen these CCR5 proteins before and we do not know their function in the context of a human ," Saha said, adding: "We are basically doing that experiment now."

Today most gene editing uses "Crispr", a kind of genetic scissors developed in 2012 by Nobel Prize winning scientists Emmanuelle Charpentier and Jennifer A Doudna.

The technology relies on the immune system of many bacteria. When they encounter a potential viral threat , they copy and paste some of the virus' DNA into their own genome, then use it to develop a pair of scissors that can identify that exact sequence. If they ever find it again, they just cut it out and disable it.

This is pretty much the same process for editing human cells: Scientists use a guide sequence to show the Crispr system where to join and cut, allowing them to precisely target certain genes and cut out unwanted segments. The cell's own repair system repairs the break, leaving a perfectly altered genome. However, this does not always go according to plan.

Unwanted changes

In the case of the Chinese babies , he altered a sequence that turned out to be similar to the one he was supposed to be cutting. It's a common problem - a recent study found that editing caused unwanted changes more than half the time.

While it is believed that Nana's two CCR5 genes could protect her from HIV, one of Lulu's two genes kept its natural version, meaning it could be susceptible to the virus. The experiment not only ended up inventing new mutations, but it did not alter all cells.

 

This "mosaic" effect arises from the fact that it is easier to edit embryos than to alter a newly fertilized egg , which consists of a single cell. But when editing an embryo, not everything is necessarily affected uniformly by the edits: some cells will retain their original genetic makeup, while others will be altered.

As different organs and tissues develop, this variation remains, so if you had four initial cells, one of which was given a mutated CCR5, it could end up in 25% of the body's cells. In 2018, when the twins were born, CCR5 was primarily known for its ability to allow the HIV virus to enter cells.

Today, there is an emerging consensus that it has a variety of functions, including brain development, recovery from strokes , Alzheimer's disease, the spread of certain cancers, and the result of infection with other pathogens.

"We don't know how babies' lives will be affected, " Saha explained , adding, "how susceptible they will be to various types of infectious diseases and what this means in terms of current and future pandemics ."

In fact, typical CCR5 proteins are believed to protect against a variety of pathogens, including malaria, West Nile virus, tick-borne encephalitis virus, yellow fever, and respiratory viruses such as influenza, suggesting that editing may have robbed its subjects of a useful adaptation.

Gene editing often has unexpected results, like rabbits altered to be thinner that inexplicably ended up with much longer tongues

Alternatives

However, not all bad news. First, it is not certain that somatic cell editing necessarily alters reproductive cells; it is only a theoretical possibility. To find out if this is really happening, Saha and her team were working with laboratory mice, marking the altered cells with a red fluorescent protein so that they could see if injecting a mouse with an editor intended for, say, the brain will end up affecting its sperm or your eggs.

“We saw a lot of red blood cells in the brain. So far, we haven't seen anything in the reproductive organs, which is a good reassuring result , ”Saha said.

Second, not all somatic editing has to occur within the body. For some disorders, such as sickle cell anemia, the affected tissue - in this case, red blood cells - can be removed and treated outside the body. This means that the editor only finds the cells it targets, and there is almost no risk of mutations being passed down from generation to generation.

 

Finally, the use of this technique could be reduced to those who are not at risk of passing these changes to a new generation. For example, offering it only to patients who have passed the childbearing age or are nearing the end of their lives. According to Saha, there are likely many people who are willing to sacrifice the possibility of having children to improve their quality of life.

He believes the way forward is to make sure patients are well informed of the risks before agreeing to such procedures.

An intergenerational experiment

But let's say we end up with artificial errors in the human gene pool. Exactly how permanent could they become?

Will genetic errors pass from generation to generation?

According to Professor Greely, who wrote a book on the implications of He's project, the answer depends on what the edits do and how they are inherited. "They may just die or be overwhelmed by the vast sea of ​​normal genes and normal genetic variation," he said.

“Some people fear that if a change is made, eventually all human beings will bring that change. That's really unlikely unless the change is very, very beneficial . " The latter is, of course, a possibility. Whether a mutation is generated by editing error or natural errors, mutations are sometimes useful.

Some experts even suggested that CCR5 babies may have had their brains inadvertently enhanced. The argument stems from research showing that the natural version of the gene that most humans inherit - the kind that babies would have had - actually suppresses the brain's "neuroplasticity" or ability to grow and reorganize.

 

Some studies have shown that people who lack a normal CCR5 can recover from strokes more quickly and reportedly do better in school, while mice without a working version of this gene have better memory. However, there are some situations where rare mutations can spread widely, useful or not.

Take Huntington's disease, a heartbreaking condition that gradually stops normal brain function and eventually causes death. It is unusual for a genetic disease, because even if you have a healthy copy of the gene, you will develop the disease, which means that it would be expected to eventually go away .

However, in Lake Maracaibo, in northwestern Venezuela, there is a higher concentration of people with the disease than anywhere else in the world. There are two theories as to why this would be happening. One is that the disease typically materializes when people are in their 40s, that is, after most had children, and potentially the disease passed to them.

The second is the so-called Founder Effect, which distorts the distribution of genes in small populations by allowing the unusual genes of the "founders" - the first members of the community - to spread more widely than usual.

In some villages on Lake Maracaibo, in Venezuela, villagers have a 50% chance of inheriting Huntington's disease

Huntington's patients at Lake Maracaibo are believed to have started with a single woman, María Concepción Soto, who moved to the area from Europe in the early 1800s. She was a carrier of the deadly mutation that caused her, which she passed down to more than 10 generations of descendants, comprising more than 14,761 living people, as of 2004.

If Nana or Lulu moved to a less populated, low-migration area, such as an isolated island, or joined a religious group with strict rules on intermarriage, it is possible that their mutations would establish a relatively high prevalence in that community. In China, where they are believed to live , there are currently high rates of internal migration, so genes may be less likely to embed themselves.

Possible solutions

Beyond this, Saha points out that it can take many, many generations for any pattern in the distribution of genetic errors to be detected. There is an obvious solution, although there is no guarantee that the edited humans will agree with it : instead of allowing artificial mutations to spread, we could simply correct them, using the same technique that was used to create them in the first place.

 

"I think it's a real possibility," says Greely. "Or if a person has a healthy copy, like Lulu, they should be able to use embryo selection, to make sure their offspring don't get the altered version."

However, this solution is based not only on individual will, but also on a person knowing that their reproductive cells have been edited, as may not be the case with those who have undergone somatic editing due to a disease that manifests itself. in other parts of the body.

Given how little we know about the functions of certain genes in our current environment, Saha believes we need to be more cautious when making potentially millennial changes. ”I am amazed every day by how many different functions genes have; I try to be as humble as possible in terms of assuming that I know everything a genetic mutation would do in a human cell, "he said.

"These are genes that have been involved in our genome for thousands of years, if not longer, so knowing how they will work for humans in different contexts for the next hundred years is really challenging," he said.

To decide whether an issue is ethical, we may first need to understand what kind of future world it might remain in.