Where do we draw the line?
With the recent announcement of a scientist who genetically edited babies, controversy has been plentiful. If you haven’t followed the story too closely, you might be wondering many things. What exactly happened? Why does it matter? What does it mean for the future? Should there be repercussions?
In order to understand why the announcement of babies who were genetically edited has created such a stir, we need to first look at how this is even possible. CRISPR-Cas9 is a genome editing tool that makes it possible to make alterations on DNA to supply a needed gene or disable one that is causing problems. It’s not the first gene-editing tool, but it is the cheapest, easiest, most accessible and most accurate one available. Before its development, geneticists used chemicals or radiation to cause mutations in DNA, but they had no way of controlling where in the mutation would happen. Scientists have been using the concept of gene targeting to make changes in specific places in the genome for a while, but they could only remove or add whole genes or single bases. While this has been beneficial in the study of genes and genetics, it takes a long time to create a mutation and it’s expensive. Besides CRISPR-Cas9, there are two main other methods of gene targeting, known as transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs). TALENs and ZFNs aren’t as precise or quick though. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats, which is used to describe particular types of DNA sequences present in bacterial genomes as a component of their immune system. These sequences allow the bacteria to protect themselves from invaders, like viruses. The way it does this is when the first time a virus invades a bacterium, it stores a small piece of the virus’s genome in its own and transcribes it into strands of RNA that will recognize the viral DNA if it invades again. These RNA strands send special enzymes, CRISPR-assisted proteins (Cas), to the known DNA piece in the attacking virus. The enzyme chops up the DNA, which kills the virus. Geneticists have harnessed this mechanism to make targeted changes in DNA. An easy way to think of it is by comparing it to a document where you can find and replace typos. So, CRISPR finds the mistake and then the enzyme Cas9 cuts it out and replaces it with a new DNA sequence using a piece of RNA called guide RNA (gRNA). This is a small piece of pre-designed RNA sequence (about 20 bases long) located within a longer RNA scaffold. The scaffold part attaches to DNA and the pre-designed sequence directs Cas9 to the right part of the genome. This makes sure that the Cas9 enzyme cuts at the right point in the genome. The guide RNA is designed to find and bind to a specific sequence in the DNA because it has bases that are complementary to those of the target DNA sequence. So, the gRNA should only bind to the target sequence and no other regions. However, not all 20 bases need to match for the gRNA to be able to attach. This can occur because a sequence that might have 19 of the 20 complementary bases may exist somewhere completely different in the genome. This opens up the potential for the gRNA to attach there instead of or as well as at the targeted sequence. This would lead to the Cas9 enzyme cutting at the wrong site and inserting the desired mutation in the wrong location. While this mutation might not present any problems to the individual, it could affect a key gene or another important part of the genome. Scientists are trying to find a way to have even better accuracy than we have now in order to prevent this possible mismatch. One idea is to create, more specific gRNAs using our knowledge of the DNA sequence of the genome and the off-target behavior of different versions of the Cas9-gRNA complex. The other option is using of a Cas9 enzyme that will only cut a single strand of the target DNA rather than both. So, there would need to be two Cas9 enzymes and two gRNAs to be present in the same place for the cut to be made, which would decrease the chances of the cut being made in the wrong place. Note, CRISPR-Cas9 can be used to alter multiple genes at once, which is helpful for diseases that involve more than one gene.
The technology has many potential uses. It could be used to help wildlife populations. When an invading predator animal enters a territory, it can devastate other animal populations. So, conservationists are excited about the possibility of using CRISPR-Cas9 to introduce a genetic code into the invading predator’s population that would make it more challenging for them to reproduce. This would help to decrease their numbers, which would give the other animals a chance to repopulate. The technology could be used in agriculture to help create plants that are resistant to mildew, fungus and drought, which would have a significant impact. In fact, the US Department of Agriculture recently gave permission for a common white mushroom that is genetically edited so that it would be resistant to browning to be sold without GMO regulation because developers are removing the gene that causes the browning rather than adding new genetic material. Livestock could also be influenced in a variety of ways, but one that is currently being developed by a group of scientists is to engineer milk cows that don’t grow horns. This is in hopes of saving the cows from having their horns removed with hot irons, which is done to prevent injury to the cows and farmers, but is a painful procedure. Public health officials are hopefully that they can use CRISPR-Cas9 to make it more difficult for mosquitoes to spread destructive diseases, such as malaria or Zika, to human beings. This could be done by making mosquitoes resistant to the disease itself or altering their genetic code so that they stop reproducing altogether.
While all of these advancements would be remarkable, the most influential would be the impact CRISPR-Cas9 would have directly on humans. There is the opportunity to cure some of the awful diseases that have plagued humanity for years. Many diseases, like cancer, are genetically caused. Also, single-gene disorders, such as Huntington’s disease, fragile X syndrome and cystic fibrosis, can have ravaging effects on a person’s life and even cause early death. Additionally, it may be able to be used as a new form of treatment for HIV. A team of US scientists were able to use it to edit the HIV genome out of immune cells called T cells from an HIV patient. Unfortunately, they also reported that the editing can prompt the HIV virus to mutate, which might make it harder to treat. Due to all the positive possible outcomes, the use of CRISPR-Cas9 to edit genes in somatic (non-reproductive) cells is uncontroversial because of the numerous benefits and the fact that we know that the changes are confined to the person that is undergoing the gene editing. Most Americans are onboard with this type. However, despite the support, only recently has the process been tried in adults to treat deadly diseases and it’ll be many years before CRISPR-Cas9 is used routinely in humans because of the work needing to be done to eliminate the off-target effects. The debate surrounding gene editing comes from the potential to alter germline (reproductive) cells because if sperm, eggs or embryos were to be edited, the changes could then be inherited. Since the technique is so new, scientists have no idea what unforeseen consequences could take place in the genetically altered babies. Many scientists, ethicists and policymakers fear that if babies could be genetically engineered to have certain desirable traits, like being athletic or looking a certain way. The ability to create these designer babies probably isn’t far off. The concern is that there will be places that are less regulated and people are going to try to see what they can do with the technology. Right now, the consensus among these groups is that if scientists use genetic editing tools on human embryos, those embryos shouldn’t then be transferred to a woman to establish a pregnancy until we know exactly how to control the editing process and we have in place policies to dictate exactly what can and can’t be edited. Currently, it is illegal in the United States and many other countries to purposely alter the genes of human embryos. However, it’s not against the law to do so in China, even if it’s opposed by many researchers there.
This is where the most recent development in the genetic editing story begins. On November 25, 2018, a research scientist, Dr. He Jiankui, in China released a video online stating that he has created the world’s first genetically edited babies. He said he altered embryos for seven couples during fertility treatments and it had resulted in one pregnancy and birth of twin girls at the time of his announcement. The parents involved in the study declined to be identified or interviewed and Dr. Jiankui would not say where they lived or where the work was done. Also, he didn’t provide any evidence or data to back up his assertions and has not published anything in any scientific journals. This means there is no way to independently confirm his claim. Dr. Jiankui said he practiced editing mice, monkey and human embryos in the lab for several years and has applied for patents on his methods while working at his two genetic companies and Southern University of Science and Technology in Shenzhen after receiving his education from Rice and Stanford universities in the US. His previous work is known to many experts in the field and they feel that it is entirely possible he has altered the DNA of a human embryo.
So, what gene did Dr. Jiankui change? And why? It’s a gene called CCR5 and it forms a protein doorway that allows HIV to enter a cell. His goal wasn’t to cure or prevent someone from inheriting the disease from their parents, but to try to give the babies a trait that most people don’t naturally have, which is the ability to resist possible future infection with HIV. Dr. Jiankui used couples for his study in which all of the men had HIV and all of the women did not. It’s essential to note that there is an incredibly small risk of transmission of HIV to the baby when it’s the father who is infected because the virus isn’t in the sperm, but in the semen (which can infect the mother). In addition, the fathers in the study had their infections deeply suppressed by the standard HIV medicines. Also, there are simple ways to keep the virus from infecting offspring that doesn’t involve altering genes. Dr. Jiankui said what appealed to the couples affected by HIV was a chance to have a child that could be prevented from having a similar fate. In order to accomplish his aim, the gene editing took place during in vitro fertilization. The first part is similar to the standard in vitro process, which is to separate the sperm from the semen (thus decreasing the chance of the mother being infected with HIV) and then place a single sperm into a single egg to create an embryo. The next part is where it branches into the gene editing portion. After the editing was done and once the embryos were three to five days old, a few cells were removed and checked to see if it worked. According to Dr. Jiankui, he personally made sure the goals of the study were clear explaining to the participants that embryo gene editing had never been tried before and carried risks. Ultimately, it was up to the couples if they want to use edited or unedited embryos for their pregnancy attempts.
Once he made his announcement, he sparked a public outcry around the world for several reasons. When most scientists announce a groundbreaking development, they provide data that can back up their claims and be reviewed by academic peers. Dr. Jiankui did neither of these. In addition, this kind of gene editing is banned in most countries since the technology is still experimental and the potential for unforeseen side-effects in the babies and their offspring could be numerous. One potential problem in this particular situation is that the deleted CCR5 gene has many more functions than just aiding HIV in infecting cells. It plays a role in helping white blood cells (a key part of your immune system) function properly and is thought to have a key part in preventing West Nile virus and flu infections. By removing it from the genome, it makes the person more vulnerable to these diseases. Another area of concern is that genes don’t exist in isolation. Since they are constantly interacting with each other, any changes can have major effects on the organism as a whole resulting in an alteration of the overall behavior of the cells. Also, it’s highly unlikely that a scientist would realize if any off-target changes occurred because they might not be obvious until the baby is born or not appear until later in life. Furthermore, all of these unknown genetic changes can be passed on to future generations. An additional fear from scientists is a condition called mosaicism, which is when some cells, but not all cells, of an individual carry a genetic change because of gene editing. This can result in unexpected diseases.
Scientists aren’t the only ones concerned. Individuals and families of those with severe, life-limiting disease fear the announcement risks undermining the very careful research being undertaken to explore the safety and future potential uses of genome editing to provide help to those who need it. They fear that experiments like this will set back the entire field. There is no question that science functions under a social license where scientists work within limits defined by broader community interests. If these boundaries are ignored, a justified public backlash will occur.
An important consideration in the discussion is the fact that the lifetime risk of contracting HIV is extremely low, there are many means of prevention and it’s no longer incurable. Since men with HIV do not infect embryos and there are ways for them to have children without infecting their offspring or partners, many scientists feel that Dr. Jiankui put these children at a huge risk for only a marginal gain making it an unwarranted endeavor. In order to edit human genes, most scientists feel the procedure should only be done to deal with serious unmet needs in medical treatment. The process needs to be well monitored with full consent in place and has to be well tracked. Most scientists assumed that, when this type of genetic editing technology would first be used in humans, it would be used to get rid of mutations tied to a single gene that were certain to cause a person pain and suffering once they were born. Also, it would be the used as a last resort in hopes to provide a better quality of life for that individual. Since Dr. Jiankui used it to, as he put it, “close a door” that HIV might one day travel through, it has led some to believe that this project was more about testing the technology than serving an acute medical need. When it comes to preventing HIV, there are safer and easier ways to do it than gene editing. The thought is that we don’t need genome editing to prevent HIV, we need to make existing protective measures, like PrEP, and treatments more widely accessible.
Due to the public outcry after Dr. Jiankui’s announcement, China’s national health commission had their branch in the southern Guangdong province investigate the claims. During the investigation, Dr. Jiankui provided some data but no definitive proof to aid in the investigation and said he had permission to do the work from the ethics board of the hospital, Shenzhen Harmonicare, but they deny ever being involved. However, the investigation found that Dr. Jiankui and his team had edited the genes of human embryos and then implanted the embryos in female volunteers as he had claimed. One volunteer gave birth to twin girls in November and another volunteer is now pregnant. The investigation also states that starting in 2016, Dr. Jiankui had intentionally evaded supervision, used unsafe and ineffective methods, forged documents (including ethical review materials) and financed his work independently so he could shield it from the university where he works, the local authorities and the hospital where the trial was carried out. According to the report, Dr. Jiankui had violated state regulations, but the specific laws that he has broken were not made clear. Since the release of the report, Southern University of Science and Technology in Shenzhen rescinded Dr. Jiankui’s contract and canceled all of his teaching and research activities there.
The investigative report has raised several areas of major concern. The first is the conflict of interest that results when researchers who own companies, therefore, have a financial interest in the success of the technology, are in charge of the research. The second issue is that the report states the lab didn’t know they were dealing with HIV-positive patient samples (supposedly to protect the privacy of the patients involved). The third concern is that the researcher team involved in the study didn’t have any experience running clinical trials or training in physical sciences. The fourth problem that was found is despite Dr. Jiankui saying to the opposite, the patients might not have been adequately briefed on the experimental nature of the trials. The fifth item was that an embryo with a known failure in the editing process was transferred into woman, which is highly suggestive that the researchers were actually interested in testing the safety and efficacy of the technology and not providing genetic resistance to HIV for the babies.
Ironically, the second international summit on human gene editing took place in Hong Kong at the same time that the announcement took place. Most of the top geneticists where present and they issued a statement that confirmed their stance on the issue, which was first published in 2015. They feel that any genetic editing on sperm, egg or embryo cells shouldn’t go on to become pregnancies yet because it’s still too risky and there are too many unknowns. This case serves as a warning to all of us that we need to have tough laws, that are enforced, on gene editing because the legal responsibility in some areas, like China, can be unclear, which means the penalties for any violations are usually light. In order to have a chance a better regulation, we need to have an international treaty that can help guide the process of deciding if and when it is safe to use this type of genetic editing in humans. This shouldn’t make it impossible to accomplish this, but allow the science enough time to progress so that the chances of off-target mutations are reduced to acceptable and accurately measurable levels while maintaining appropriate safeguards and having been through thorough ethics reviews.
Ever since the CRISPR molecule came on the scene when it was discovered in bacteria in 2012, it has significantly altered our perception of what the future could look like. However, it’s definitely not perfect yet! Scientists have been waiting with trepidation for the day when it would be used to create a genetically altered human being. Now that time has come, there needs to be a substantial amount of scientific and ethical issues resolved before it should be used to change a genome of an embryo and its future descendants. Without these issues being taken care of, making mistakes during gene editing could result in the creation of new genetic diseases. So, for the time being making a baby from gene-edited embryo is an ethical line that should not be crossed until we know for sure the technology is proven safe and have had discussions as to what benefit any changes would provide to society.