Lulu and Nana, the Faces of Human Genome Editing
By Elisa Núñez Acosta
Published in Spanish online: http://www.comoves.unam.mx/numeros/articulo/246/edicion-genetica-en-humanos-la-gran-controversia
A new form of genome editing could cure numerous diseases, but it also has complex technical, legal, and ethical implications. Everything depends on how and what it is used for. “Two Chinese girls called Lulu and Nana arrived in the world crying as healthy as any other baby,” announced in a You Tube video, Dr. He Jiankui, professor at the University of Science and Technology of China, on 25th November 2018. In this video the scientist narrated the gestation of the girls starting with an in vitro fertilization procedure. He and his team obtained sperm from the father, who was infected with the human immunodeficiency virus (VIH), and eggs from the mother, who was not infected. The eggs were fertilized in a laboratory. From each fertilized egg a one celled zygote was created, which immediately duplicated into two, four, eight cells… until a blastocyst was formed. A blastocyst is a fiveday old embryo with approximately 200 cells. As a point of comparison, an adult human body is composed of about 37 000 000 cells. In He´s experiment, at the fertilization moment, when the egg and spermatozoid come together, a protein with instructions to modify the zygote genetic information was added. Then, two formed embryos were implanted into the mother´s uterus. Months later, Lulu and Nana were born.
Editing or Not Editing
For years scientists and philosophers have been warning the scientific community about the risk of creating embryos genetically modified for pregnancy purposes. In 2015 experts from around the world came together at the first Summit on Human Genome Editing in order to discuss, among other things, the possibility of genetically editing human embryos. At the end of the meeting the organizing committee wrote a statement which established the irresponsibility of performing genome editing on germline cells – in other words, those that can pass down their genetic information to offspring, such as eggs and spermatozoids– before the problematic issues of the effectiveness and the safety of this technique are overcome and a consensus about its appropriateness be reached. The statement finishes by highlighting that currently those issues have not been overcome for clinical application. The ethics topic related to the use of this technology is still pending.
Genome editing technology modifies the DNA of a cell or an organism in order to change its characteristics. Editing the DNA chain is similar to editing the frame forming a film stock: it is cut in the precise place where you want to make a modification, then you can cut a fragment out and another one can be inserted to replace it. The most common and efficient technique in editing the genome is called CRISPR (pronounced “crisper”, an acronym for “clustered regularly interspaced short palindromic repeats”).
In order to perform genome editing it is necessary at first to recognize the specific DNA region to be modified. However, other similar regions can exist in the genome so similar to that you want to change, so that changes are made at the place you chose and accidentally at those similar other places you did not want to do it. As a result, it could bring undesirable negative consequences.
Applications and Warnings
On the one hand, genome editing can be used to understand human genes functions. For instance, how embryos develop, the relationship between some diseases and genes, and the evolution of diseases such as cancer with an important genetic component.
On the other hand, a potential clinical application is used to cure heritable diseases caused by mutations in a unique gene, which are known as monogenic diseases. Currently, more than 10 000 of these kinds of monogenic diseases affecting millions of people are known. This technology has been used to study different diseases and to experiment in developing effective treatments, for example, fighting the infection caused by HIV and the neurodegenerative Huntington Disease. With this purpose no cell or organism from human species are used, but rather mice.
Genome editing can be made into two kind of cells: somatic and germline cells. Almost all cells of the human body are somatic, for example, skin, liver, muscles, bones, and blood cells. The genetic changes made in this these kinds of cells affect only the organism in which the procedure was made. They are not transmitted to the human offspring. Thus, if some unpredictable or undesirable modifications occur, the consequences will affect only the host organism in which the change was performed. When this technique is applied to germline cells, such as an egg or spermatozoid, it works differently, since the changes could pass down to the offspring. Thus, if genome editing causes negative consequences, they will be passed down, affecting future generations. Experiments in zygotes formed from either four or eight cells have been done, as well as in older embryos, but they have never been implanted for pregnancy.
Some countries have approved the creation of human embryos to use in scientific experiments if donors are informed of how their donation will be used. the use their cell will have. Research groups use supernumerary human embryos, which are the remaining embryos from assisted reproduction treatments. In some countries, scientists are asked to justify the necessity and utility of the embryos use. They are also asked to limit the number of embryos used and to use other kinds of cells or embryos of other species before doing the experiments in human embryos.
Legislation regulating the use of human embryos for experiments vary from country to country. In some of them, such as Mexico, there is no law regarding the use of embryos in genome editing. However, no where in the world is the implantation of genetically edited embryos for pregnancy legally approved.
Curing fatal diseases
Genetic editing has also been used in patients with health conditions that are not heritable and for which there is no available treatment. This is the case of Layla, a baby born in July 2014, who was diagnosed with leukemia, a type of cancer in the blood cells, when she was three months old. The white globules or leukocytes are a kind of blood cell that normally helps to fight infectious diseases. Layla´s leukocytes were not working properly because of the leukemia, so that her destiny was to die.
Layla´s parents, Lisa and Ashleigh were told to be ready for the worst, and to take the baby to palliative care. However, the parents chose to try a novel treatment that had not been tried in humans yet, since this was the last chance. This treatment only had been tried experimentally in mice, and it was about to be injected into the baby blood cells edited genetically. The purpose of the treatment was that Layla would develop her own healthy leukocytes. “It was scary to think that this treatment had never been tried in humans previously. But Layla was sick, in pain, and we had to do something”, said Ashleigh.
The cells to inject into Layla were leukocytes from a healthy donor, which were genetically edited in a laboratory. Because of these modifications the cells acquired basically two new characteristics that would help Layla to fight against the cancer: (1) an increased resistance to cancer medication (chemotherapy), which usually is so toxic that it kills the cells with cancer, as well as, the healthy cells, and (2) the ability to destroy the cells with cancer. Before applying the injection, it was necessary to discuss the procedure with the ethics committee of the hospital. Finally, in 2015 doctors applied the treatment to Layla, who kept having chemotherapy to help eliminate cancer. After a couple of weeks, doctors announced that the procedure had been successful, eliminating the cancer cells from Layla.
Afterwards, in order to be sure that Layla would have a stock of healthy white globules, a bone marrow transplant was performed. Layla will must probably be required to use medicines for the rest of her life with constant vigilance. In 2017 it was reported that after 18 months of therapy intervention, the baby reminded healthy.
Even if this new treatment does bring hope, doctors cautions that this technology may not be a good option for every cancer patient. However, if it is successfully replicated it could represent an important advance in the field of leukemia therapy.
The big controversy
Human genome editing is used for different purposes, which brings complex technical, legal and ethical consequences. He´s experiment was aimed at modifying DNA on the one-celled zygotes Lulu and Nana, so that the changes made could be passed down to their off-spring causing irrevocable changes in the human species. These changes included those intentionally made, and at the same time, those potentially dangerous occurred spontaneously and non-intentionally.
He released his experiment to the scientific community during the second Summit on Human Genome Editing held in Hong Kong three days after He´s experiment was launched on You Tube. The Organizing Committee highlighted the existence of two published guides regarding the appropriate conditions on using human genome editing in clinic. These documents established a discussion in the scientific community and required benefit-risk evaluation to be accomplished before approving a clinical essay.
Furthermore, medical justification and lack of other available treatments were necessary conditions in order to obtain approval. Finally, the Committee reiterated that transparency during the essay´s execution was fundamental. In contrast He´s experiment was lacking medical justification, since He claims it was carried out in order to prevent Lulu and Nana from inheriting VIH infection from the father. However, many treatments to avert this infection already exist. Moreover, if the girls became sick suitable medicine would be available. Thus, He´s medical justification does not account for the performance of his experiment.
In addition, Dr. He made public his experiment much later than he had started it, almost at the same time when the babies were born. Finally, it is not clear if Lulu and Nana’s parents were clearly aware about the purpose, potential benefits, and risks of the procedure performed on the two babies zygotes.
At the aforementioned summit the physiology and medicine Nobel prize winner, David Baltimore said: “I think that the process was not transparent. We knew about it once the babies were born. Personally, I do not think it was medically necessary… I think it is a failure of the scientific community autoregulation because of the lack of transparency”. More than 100 scientists, mostly from China, signed a letter establishing that the use of CRISPR in He’s experiment was risky and unjustified.
The concerns regarding the human genome editing are as varied as the cultures, religions and beliefs could be around the world. Another ethics concern is that Professor He highlighted the stigma that people with HIV suffer in China, as one of his motives to genetically modify the zygote’s babies.
However, does human DNA modification in order to prevent the HIV infection resolve stigma? Or in opposition, does “genetic correction” strengthen the stigma issue?
The potential use of genome editing in order to enhance the human race is quite alarming, for instance, in order to create babies more intelligent or with selected traits, such as height or eye and skin color.
Current national and international legislation on new technologies may protect, among other things, health, moral and ethical interests of people. Now, more than ever the development of legislation is essential in order to take advantage of this and to prevent the potential risks and misuses.
Dr. He plans continuously to check the health of Lulu and Nana until they are 18 years old, and later if permitted. We will have to wait to know what Lulu and Nana think about the genetic modifications performed on them when they were only one-cell zygotes, as well as the impact on their health. Only then, we will see the consequences of one of the most controversial experiments in history.
