Stem Cell Year-in-Review 2016
If we picked one word to define the past year in the stem cell field, it would have to be ‘therapy.’
While many important developments impacted the field, two that garnered significant public, political and scientific attention in 2016 were the proliferation of clinics using unproven stem cell “therapies,” and the steps forward in therapeutic modification of human oocytes (unfertilized eggs) through a process called mitochondrial replacement therapy (MRT).
Within the stem cell field, unproven stem cell therapies, or “treatments” that lack rigorous scientific proof of their safety and effectiveness, have been a growing concern. Clinics often offer these types of treatments directly to consumers, marketing them online or in recruiting seminars, often at substantial cost. The treatments typically use autologous stem cells (those obtained from one’s body) to treat everything from bad knees to incurable disease such as ALS or Parkinson’s. In some countries, this phenomenon traditionally has been called stem cell tourism because it involved travel to another country with less stringent regulations to obtain treatment. Two publications1,2 in 2016 debunked that concept, showing these clinics are found throughout the world. The U.S. alone has an estimated 570 clinics. That puts the U.S. among the countries with the highest number of such clinics, along with India, Mexico, China, Australia, United Kingdom, Thailand, Malaysia and Germany.
Like many countries, the U.S. struggles to regulate unproven stem cell therapies. In 2016, the Food and Drug Administration (FDA), the branch of government charged with regulating cellular therapies, took action to address these issues, proposing revised guidelines that could change how stem cells, especially autologous stem cells, are regulated. The ISSCR was among the organizations and individual scientists that supported the need for careful oversight and regulation of the therapeutic application of stem cells. The FDA has yet to issue a final ruling, but a Perspective article written by three FDA executives published in the New England Journal of Medicine may provide insight into their thinking.
Another big story in 2016 was the first reported use of MRT in humans. This relatively new technology has shown to be effective in animal models for intercepting mitochondrial disease before it’s passed from mother to child. The approach works by replacing the mother’s mutant mitochondria responsible for disease with healthy mitochondria from a donor. The chimeric oocytes (that contain the mother’s nuclear DNA and the donor’s mitochondria) then undergo fertilization through standard IVF methods.
A U.S. fertility specialist reported the birth of a baby boy from a mother who was a carrier for mitochondrial disease that lead to the death of her previously-born children. The MRT procedure is not approved in the U.S., so doctors performed it in Mexico, which led to many concerns within and outside the scientific community. Among them, how do regulatory agencies and the scientific community deal with procedures approved in some countries but not others? Whether and how should we advance human health using technology that alters a natural state? How far should science be applied in influencing health-related outcomes?
This concern was also brought to the forefront of the scientific and public consciousness when a report by Chinese scientists described the use of CRISPR-Cas to modify a gene in human embryos making them resistant to HIV infection [to learn more about CRISPR-Cas, read our previous blog]. Although the embryos were not viable and not intended for clinical use, this proof-of-principle research raised ethical concerns and emphasized the need to continue to have discussions on the scientific and social impact of this technology and its use in countries around the world.
While 2016 saw many articles on unproven stem cell therapies, and the controversial use of MRT, there were many positive stories about potential stem cell-derived therapies that are successfully moving into the clinic for testing. Interventions for macular degeneration, stoke, cancers, and sickle cell disease, among others, are in approved clinical trials in California (U.S.), London, Japan, and elsewhere. These trials, unlike the unproven therapies, have been approved by the appropriate regulatory agencies and will be rigorously tested so that the risks and benefits are more fully understood before (hopefully) being made available to patients. We look forward to continued advances in 2017 that support the rigorous, ethical standards set forth in the 2016 Guidelines for Stem Cell Research and Clinical Translation, and help address issues of human health around the world.
While many important developments impacted the field, two that garnered significant public, political and scientific attention in 2016 were the proliferation of clinics using unproven stem cell “therapies,” and the steps forward in therapeutic modification of human oocytes (unfertilized eggs) through a process called mitochondrial replacement therapy (MRT).
Within the stem cell field, unproven stem cell therapies, or “treatments” that lack rigorous scientific proof of their safety and effectiveness, have been a growing concern. Clinics often offer these types of treatments directly to consumers, marketing them online or in recruiting seminars, often at substantial cost. The treatments typically use autologous stem cells (those obtained from one’s body) to treat everything from bad knees to incurable disease such as ALS or Parkinson’s. In some countries, this phenomenon traditionally has been called stem cell tourism because it involved travel to another country with less stringent regulations to obtain treatment. Two publications1,2 in 2016 debunked that concept, showing these clinics are found throughout the world. The U.S. alone has an estimated 570 clinics. That puts the U.S. among the countries with the highest number of such clinics, along with India, Mexico, China, Australia, United Kingdom, Thailand, Malaysia and Germany.
Like many countries, the U.S. struggles to regulate unproven stem cell therapies. In 2016, the Food and Drug Administration (FDA), the branch of government charged with regulating cellular therapies, took action to address these issues, proposing revised guidelines that could change how stem cells, especially autologous stem cells, are regulated. The ISSCR was among the organizations and individual scientists that supported the need for careful oversight and regulation of the therapeutic application of stem cells. The FDA has yet to issue a final ruling, but a Perspective article written by three FDA executives published in the New England Journal of Medicine may provide insight into their thinking.
Another big story in 2016 was the first reported use of MRT in humans. This relatively new technology has shown to be effective in animal models for intercepting mitochondrial disease before it’s passed from mother to child. The approach works by replacing the mother’s mutant mitochondria responsible for disease with healthy mitochondria from a donor. The chimeric oocytes (that contain the mother’s nuclear DNA and the donor’s mitochondria) then undergo fertilization through standard IVF methods.
A U.S. fertility specialist reported the birth of a baby boy from a mother who was a carrier for mitochondrial disease that lead to the death of her previously-born children. The MRT procedure is not approved in the U.S., so doctors performed it in Mexico, which led to many concerns within and outside the scientific community. Among them, how do regulatory agencies and the scientific community deal with procedures approved in some countries but not others? Whether and how should we advance human health using technology that alters a natural state? How far should science be applied in influencing health-related outcomes?
This concern was also brought to the forefront of the scientific and public consciousness when a report by Chinese scientists described the use of CRISPR-Cas to modify a gene in human embryos making them resistant to HIV infection [to learn more about CRISPR-Cas, read our previous blog]. Although the embryos were not viable and not intended for clinical use, this proof-of-principle research raised ethical concerns and emphasized the need to continue to have discussions on the scientific and social impact of this technology and its use in countries around the world.
While 2016 saw many articles on unproven stem cell therapies, and the controversial use of MRT, there were many positive stories about potential stem cell-derived therapies that are successfully moving into the clinic for testing. Interventions for macular degeneration, stoke, cancers, and sickle cell disease, among others, are in approved clinical trials in California (U.S.), London, Japan, and elsewhere. These trials, unlike the unproven therapies, have been approved by the appropriate regulatory agencies and will be rigorously tested so that the risks and benefits are more fully understood before (hopefully) being made available to patients. We look forward to continued advances in 2017 that support the rigorous, ethical standards set forth in the 2016 Guidelines for Stem Cell Research and Clinical Translation, and help address issues of human health around the world.
Second Chinese team reports gene editing in human embryos
Study used CRISPR technology to introduce HIV-resistance mutation into embryos.
In April 2015, a different China-based team announced that they had modified a gene linked to a blood disease in human embryos (which were also not viable, and so could not have resulted in a live birth)2. That report — a world first — fuelled global deliberations over the ethics of modifying embryos and human reproductive cells, and led to calls for a moratorium on even such proof-of-principle research.
At the time, rumours swirled that other teams had conducted similar experiments. Sources in China told Nature’s news team that a handful of papers had been submitted for publication. The latest paper, which appeared in the Journal of Assisted Reproduction and Genetics on 6 April, might be one of these. Nature’s news team has asked the paper’s corresponding author, stem-cell scientist Yong Fan, for comment, but had not heard from him by the time of this report.
Fan’s team used CRISPR–Cas9 genome editing to introduce into some of the embryos a mutation that cripples an immune-cell gene called CCR5. Some humans naturally carry this mutation (known as CCR5Δ32) and they are resistant to HIV, because the mutation alters the CCR5 protein in a way that prevents the virus from entering the T cells it tries to infect.
Genetic analysis showed that 4 of 26 human embryos targeted were successfully modified. But not all the embryos’ chromosomes harboured the CCR5Δ32 mutation — some contained unmodified CCR5, whereas others had acquired different mutations.
George Daley, a stem-cell biologist at Children’s Hospital Boston in Massachusetts, says that the paper’s main advance is the use of CRISPR to introduce a precise genetic modification successfully. “This paper doesn’t look like it offers much more than anecdotal evidence that it works in human embryos, which we already knew,” he says. “It’s certainly a long way from realizing the intended potential” — a human embryo with all its copies of CCR5 inactivated.
“It just emphasizes that there are still a lot of technical difficulties to doing precision editing in human embryo cells,” says Xiao-Jiang Li, a neuroscientist at Emory University in Atlanta, Georgia. He thinks that researchers should work out these kinks in non-human primates, for example, before continuing to modify the genomes of human embryos using techniques such as CRISPR.
Fan's team writes in the paper that proof-of-principle experiments for human-embryo editing such as theirs are important to conduct while the ethical and legal issues of germline modification are being hashed out. “We believe that any attempt to generate genetically modified humans through the modification of early embryos needs to be strictly prohibited until we can resolve both ethical and scientific issues,” they write.
Daley sees a stark contrast between Fan’s work and research approved in February by UK fertility regulators that will allow CRISPR genome editing of human embryos. Those experiments, led by developmental biologist Kathy Niakan at the Francis Crick Institute in London, will inactivate genes involved in very early embryo development, in hopes of understanding why some pregnancies terminate. (The work will be done in viable embryos, but the researchers' licence requires that experiments be stopped within 14 days.)
Earlier this year, developmental biologist Robin Lovell-Badge, also at the Francis Crick Institute, told Nature that he thought that the carefully considered UK approval might embolden other researchers who are interested in pursuing embryo-editing research. “If they've been doing it in China, we may see several manuscripts begin to appear,” he said.
Whereas Niakan's work is answering questions intrinsic to embryology, Fan's work is establishing proof of principle for what would need to be done to generate an individual with resistance to HIV, Daley adds. “That means the science is going forward before there’s been the general consensus after deliberation that such an approach is medically warranted," he says.
Early-stage human embryos have been edited by scientists.
Researchers in China have reported editing the genes of human embryos to try to make them resistant to HIV infection. Their paper1 — which used CRISPR-editing tools in non-viable embryos that were destroyed after three days — is only the second published claim of gene editing in human embryos.In April 2015, a different China-based team announced that they had modified a gene linked to a blood disease in human embryos (which were also not viable, and so could not have resulted in a live birth)2. That report — a world first — fuelled global deliberations over the ethics of modifying embryos and human reproductive cells, and led to calls for a moratorium on even such proof-of-principle research.
At the time, rumours swirled that other teams had conducted similar experiments. Sources in China told Nature’s news team that a handful of papers had been submitted for publication. The latest paper, which appeared in the Journal of Assisted Reproduction and Genetics on 6 April, might be one of these. Nature’s news team has asked the paper’s corresponding author, stem-cell scientist Yong Fan, for comment, but had not heard from him by the time of this report.
HIV resistance
In the paper, Fan, who works at Guangzhou Medical University in China, and his team say that they collected a total of 213 fertilized human eggs between April and September 2014. The fertilized eggs, donated by 87 patients, were unsuitable for implantation as part of in vitro fertility therapy, because they contained an extra set of chromosomes.Fan’s team used CRISPR–Cas9 genome editing to introduce into some of the embryos a mutation that cripples an immune-cell gene called CCR5. Some humans naturally carry this mutation (known as CCR5Δ32) and they are resistant to HIV, because the mutation alters the CCR5 protein in a way that prevents the virus from entering the T cells it tries to infect.
Genetic analysis showed that 4 of 26 human embryos targeted were successfully modified. But not all the embryos’ chromosomes harboured the CCR5Δ32 mutation — some contained unmodified CCR5, whereas others had acquired different mutations.
George Daley, a stem-cell biologist at Children’s Hospital Boston in Massachusetts, says that the paper’s main advance is the use of CRISPR to introduce a precise genetic modification successfully. “This paper doesn’t look like it offers much more than anecdotal evidence that it works in human embryos, which we already knew,” he says. “It’s certainly a long way from realizing the intended potential” — a human embryo with all its copies of CCR5 inactivated.
“It just emphasizes that there are still a lot of technical difficulties to doing precision editing in human embryo cells,” says Xiao-Jiang Li, a neuroscientist at Emory University in Atlanta, Georgia. He thinks that researchers should work out these kinks in non-human primates, for example, before continuing to modify the genomes of human embryos using techniques such as CRISPR.
Ethics of experiments
Tetsuya Ishii, a bioethicist at Hokkaido University in Sapporo, Japan, sees no problem with how the experiments were conducted — a local ethics committee approved them, and the egg donors gave their informed consent — but he questions their necessity. “Introducing CCR5Δ32 and trying repair, even in non-viable embryos, is just playing with human embryos,” Ishii says.Fan's team writes in the paper that proof-of-principle experiments for human-embryo editing such as theirs are important to conduct while the ethical and legal issues of germline modification are being hashed out. “We believe that any attempt to generate genetically modified humans through the modification of early embryos needs to be strictly prohibited until we can resolve both ethical and scientific issues,” they write.
Daley sees a stark contrast between Fan’s work and research approved in February by UK fertility regulators that will allow CRISPR genome editing of human embryos. Those experiments, led by developmental biologist Kathy Niakan at the Francis Crick Institute in London, will inactivate genes involved in very early embryo development, in hopes of understanding why some pregnancies terminate. (The work will be done in viable embryos, but the researchers' licence requires that experiments be stopped within 14 days.)
Earlier this year, developmental biologist Robin Lovell-Badge, also at the Francis Crick Institute, told Nature that he thought that the carefully considered UK approval might embolden other researchers who are interested in pursuing embryo-editing research. “If they've been doing it in China, we may see several manuscripts begin to appear,” he said.
Whereas Niakan's work is answering questions intrinsic to embryology, Fan's work is establishing proof of principle for what would need to be done to generate an individual with resistance to HIV, Daley adds. “That means the science is going forward before there’s been the general consensus after deliberation that such an approach is medically warranted," he says.
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