Scientists from China have recently published research on their attempts to genetically modify human embryos. Emphasis on the word "attempts". What exactly did they do and why is it causing such a stir?
- Liang, Puping, et al. "CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes." Protein & Cell (2015): 1-10.
- "Chinese Paper on Embryo Engineering Splits Scientific Community" (DOI: 10.1126/science.aab2547)
- "Chinese Scientists Edit Genes of Human Embryos, Raising Concerns" (Article, New York Times)
- "Critics Lash Out at Chinese Scientists Who Edited DNA in Human Embryos" (Article, NPR)
- "Public interest group calls for strengthening global policies against human germline modification" (Article, Genetics and Society.Org)
- Baltimore, David, et al. "A prudent path forward for genomic engineering and germline gene modification." Science 348.6230 (2015): 36-38.
- What is beta thalessemia? (Informational Article, NIH)
- Lanphier, Edward, et al. "Don't edit the human germ line." Nature 519.7544 (2015): 410.
A paper originally published online in early April in Protein & Cell has served as a catalyst to the scientific community's discussion on the ethics and morality of research on human embryos and gene-editing technology. The authors of the study, Junjiu Huang and colleagues at Sun Yat-sen University in Guangzhou, detail in the paper their attempts to use a new gene-editing technology called CRISPR/Cas-9 to edit a particular gene in human embryos.
What is CRISPR?
So let's take a step back and talk about CRISPR, a novel gene-editing technology that exploits a bacterial immune system to cut and paste genes in an organism. Other than making you crave a nice bag of chips, CRISPR is an acronym that stands for "clustered regularly interspaced short palindromic repeats". What does that mean?
So back in the 1980s, scientists noticed that bacteria have these tiny chunks of palindromic DNA that were repeated many times with little spaces of DNA in between these repetitions. Just like regular palindromes, palindromic DNA reads the same backwards as it does forwards. The spacers between these palindromic sequences match DNA segments of certain viruses, supposedly that the bacteria or their ancestors had dealt with before. When bacteria are under attack, the spacer DNA is transcribed into RNA and an enzyme-RNA structure is formed that binds to DNA strands that are complementary to the spacer's sequence. When a matching DNA strand is found by this enzyme, the enzyme opens up the double helix, makes cuts on both sides, effectively breaking the DNA strand and disabling the viral DNA. If the bacteria survives the attack, it can make a new piece of spacer DNA and integrate it into its own genome to be passed down to future generations of bacteria babies.
Researchers are trying to harness this "cut and paste" method of gene editing to edit DNA segments at a more precise level. By making a cut in a cell's DNA, a specific DNA snippet can be inserted into the gap by researchers. A cell can repair this cut in the DNA strand, but there is the possibility that if it does not repair it perfectly, the edited gene could be disabled. While this may be unlikely as the body has many proofreading elements incorporated into DNA maintenance and synthesis, the possibility still remains. Nonetheless, the development of this new technology may prove to be very useful in the development of clinical therapies, especially for common and rare genetic diseases.
How was it used in this study?
Huang and his colleagues were attempting to use CRISPR to edit the hemoglobin-B gene (HBB) in 86 human embryos that were donated for research by couples at an in vitro fertilization clinic. These embryos were specifically selected because they were not viable in the first place, having an extra set of chromosomes as a result of polyspermy. Polyspermy, or the phenomenon of an egg being fertilized by more than one sperm, resulted in triploid embryos that would not produce viable embryos. The researchers used these embryos to try and edit the HBB gene as a preventive technique against a blood disorder called beta thalassemia, in which the HBB gene is mutated, resulting in the body's reduced production of hemoglobin. Hemoglobin, as you may well know, is a protein in red blood cells that carries oxygen to your cells throughout your body. And as you may imagine, low levels of hemoglobin lead to low oxygen levels in various parts of the body, causing weakness, fatigue, and an increased risk of developing abnormal blood clots.
After carrying out these genetic edits, the researchers found that only 28 of the 71 surviving embryos that were tested were actually successfully edited. Unfortunately, these 4 embryos were what's called "mosaic", meaning that only some of the cells in the embryo actually had the correct genetic edits in their DNA. The edited embryos also had a great deal of other problems associated with the genetic editing, including mutations in genes other than the targeted HBB, which could have proven to be harmful.
Why the controversy?
One might wonder how this research ever got off the ground. In the United States, most research involving living organisms and/or living cells need to pass research ethics boards at the university, national and/or international levels. If research involves the use of animal models, researchers must get their project approved by IACUC (Institutional Animal Care and Use Committees), who must ensure that the research is worth the use of animals and that all animals used in research are treated humanely. Now the use of animals in research is another episode all on its own, but the point here is that there are a lot of people you have to go through as a researcher to make sure your research is ethical, safe, and necessary. And rightfully so lest we perpetuate the mad scientist stereotype. So how did this research ever get footing?
It turns out that the project had actually been reviewed by Huang's university ethics board. The paper claims that the research had complied with both international and national ethical standards. In fact, the reason why researchers used abnormal embryos that would otherwise be discarded is "because ethical concerns preclude studies of gene editing in normal embryos". Yet, Huang told Nature News that the paper was rejected by Science and Nature in part because of ethical concerns.
Indeed, current international guidelines developed by stem cell researchers allow for experiments with human embryos as long as the cells are not allowed to grow for more than 14 days. With regards to gene editing, though, more than 40 countries and several international human rights treaties already ban germline gene modification.
Harvard molecular geneticist George Church claims that the consensus among the scientific community regarding discarded embryos has long been acceptable. The only thing that makes this research different is the integration of new CRISPR technology. Church did not object to the published research but claims that the results were expected, claiming that researchers had not used the latest version of the gene-editing technology, resulting in the undesired effects in the defective embryos.
Other folks in the scientific community have been more critical of the research itself. A commentary published in Science by David Baltimore, molecular biologist and president emeritus of CalTech in Pasadena, along with 17 co-authors have openly called for scientists to "strongly discourage...attempts at germline genome modification for clinical application in humans." Dr. George Daley, a stem cell researcher at Harvard, shared similar sentiments, saying that "this is an unsafe procedure and should not be practiced at this time, and perhaps never." Interestingly enough, he mentioned that he's worried what happened with cloning technology would happen with gene editing technology. When cloning techniques were being developed back in the day, there was a clear consensus in the international community that it was unacceptable to clone a human being. Despite this, there were cases of some researchers trying.
The Center for Genetics and Society in Berkeley, California have straight out called for a halt to experiments like this one. Executive Director of the Center, Marcy Darnovsky, commented that,
The medical risks and social dangers of human germline modification cannot be overstated. Creating genetically modified human beings could easily lead to new forms of inequality, discrimination and societal conflict.
So what went wrong?
In a comment published in Nature in early March, Edward Lanphier, Fyodor Urnov and colleagues discuss the future of genetic editing with regards to the human genome. Genetic editing technology has actually been very revolutionary in the field of biology, but as Lanphier and his colleagues discuss, there are only certain types of cells we should be using the technology on. There are two general classifications of cells in eukaryotic (multicellular) animals: somatic cells and germ cells. Somatic cells are cells that make up your epidermis (skin) or your immune cells (like WBCs). Germ cells are divided into eggs and sperm, which believe it or not, are individual cells all on their own. Lanphier and colleagues mention that while genetic editing can serve as a powerful tool for developing treatments for human diseases like HIV/AIDS, sickle-cell anemia, and several forms of cancer, the research that is involved in developing these technologies for clinical use are focused on somatic cells (such as white blood cells). The current gene editing technology is not meant for germ line cells. Here are some quotes from the actual article they wrote, which I'll put in the show notes on the website for you.
In our view, genome editing in human embryos using current technologies could have unpredictable effects on future generations. This makes it dangerous and ethically unacceptable. Such research could be exploited for non-therapeutic modifications. ...At this early stage, scientists should agree not to modify the DNA of human reproductive cells. Should a truly compelling case ever arise for the therapeutic benefit of germline modification, we encourage an open discussion around the appropriate course of action.
Some scientists, including Rudolf Jaenisch, an MIT biology professor, do not see the application of CRISPR technology in human embryos whatsoever, even with the good intentions to prevent disease. If one parent has a disease gene, for instance, only half of the parent's embryos will inherit that gene simply due to the nature of gene distribution in embryos. If gene editing was used in human embryos specifically, it would have to be immediately after fertilization, in which case it would be too early to tell whether the embryo actually happened to receive that gene or not. According to Jaenisch, it would be "unacceptable to mutate normal embryos".
Despite their unsuccessful attempts to edit germline genes with precision, Huang and his colleagues are not dissuaded and have said that they will persist in their efforts. Some news reports have claimed that at least four other research groups in China are also involved in similar research, namely exploring genetic editing in human embryos. The conversation surrounding this type of research, however, has definitely been re-ignited or freshly fueled at the very least.
Now my job as an objective reporter of this kind of stuff is to keep my opinions out of the story, but I think it's safe to say that the best way forward is a careful discussion among members of the scientific community and the public. There needs to be more education surrounding this topic, and as many scientists have suggested, we need to start thinking of the repercussions of utilizing this type of technology in germline cells of the human embryo. Healthy communication never hurts.
And with that thought, I'll leave you with the conclusion from that commentary by David Baltimore and his colleagues, which I think sums up the issue at hand as we move forward:
At the dawn of the recombinant DNA era, the most important lesson learned was that public trust in science ultimately begins with and requires ongoing transparency and open discussion. That lesson is amplified today with the emergence of CRISPR-Cas9 technology and the imminent prospects for genome engineering. Initiating these fascinating and challenging discussions now will optimize the decisions society will make at the advent of a new era in biology and genetics.
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