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Posts Tagged ‘CRISPer-Cas9

Broadening the Debate: Societal Discussions on Human Genetic Editing

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By: Courtney Pinard, Ph.D.

Licensed via Creative Commons

In one of the most impressive feats of synthetic biology so far, researchers have harnessed the ability of bacteria to fight and destroy viruses, and have been able to precisely and cheaply edit genetic code using a genetic technology called clustered, regularly-interspaced short palindromic repeats (CRISPR) and CRISPR-associated endonuclease protein 9 (Cas9). CRISPR has been used to find and detect mutations related to some of the world’s most deadly diseases, such as HIV and malaria. Although CRISPR holds great promise for treating disease, it raises numerous bioethical concerns, which were sparked by the first report of deliberate editing of the DNA of human embryos by Chinese researchers. Previous blog posts have described scientific discussion surrounding the promise of CRISPR. At least three scientific research papers per day are published using this technique, and biotech companies have already begun to invest in CRISPR to modify disease-related genes. However, the use of CRISPR, or any genetic editing technology, to permanently alter the genome of human embryos is an issue of concern to a much broader range of stakeholders, including clinicians, policymakers, international governments, advocacy groups, and the public at large. As CRISPR moves us forward into the realm of the newly possible, the larger global, social and policy implications deserve thorough consideration and discussion. Policies on human genetic editing should encourage extensive international cooperation, and require clear communication between scientists and the rest of society.

There is no question that CRISPR has the potential to help cure disease, both indirectly and directly. CRISPR won the Science Breakthrough of the Year for 2015, in part, for the creation of a “gene drive” designed to reprogram mosquito genomes to eliminate malaria. Using CRISPR-Cas9 technology, investigators at the Universities of California (UC) have engineered transgenic Anopheles stephensi mosquitoes to carry an anti-malaria parasite effector gene. This genetic tool could help wipe out the malaria pathogen within a targeted mosquito population, by spreading the dominant malaria-resistant gene in 99.5% of progeny. The gene snipping precision of CRISPR can also treat certain genetic diseases directly, such as certain cancers, and sickle cell disease. CRISPR can even be used to cut HIV out of the human genome, and prevent subsequent HIV infection.

There are limitations of CRISPR, which include the possibility of off-target genetic alterations, and unintended consequences of on-target alterations. For example, the embryos used in the Chinese study described above, were non-viable, less than 50% were edited, and some embryos started to divide before the edits were complete. Within a single embryo, some cells were edited, while other cells were not. In addition, researchers found lack of specificity; the target gene was inserted into DNA at the wrong locus. Little is known about the physiology of cells and tissues that have undergone genome editing, and there is evidence that complete loss of a gene could lead to compensatory adaptation in cells over time.

Another issue of concern is that CRISPR could lead scientists down the road to eugenics. On May 14th 2015, Stanford’s Center for Law and the Biosciences and Stanford’s Phi Beta Kappa Chapter co-hosted a panel discussion on editing the human germline genome, entitled Human Germline Modification: Medicine, Science, Ethics, and Law. Panelist Marcy Darnovsky, from the Center for Genetics and Society, called human germline modification a society-altering technology because of “the potential for a genetics arms race within and between countries, and a future world in which affluent parents purchase the latest upgrades for their offspring.” Because of its potential for dual use, genetic editing was recently declared a weapon of mass destruction.

In response to ethical concerns, the co-inventor of CRISPR, Dr. Jennifer Doudna, called for a self-imposed temporary moratorium on the use of CRISPR on germline cells. Eighteen scientists, including two Nobel Prize winners, agreed on the moratorium. Policy recommendations were published in the journal Science. In addition to a moratorium, recommendations include continuing research on the strengths and weaknesses of CRISPR, educating young researchers about these, and holding international meetings with all interested stakeholders to discuss progress and reach agreements on dual use. Not all scientists support such recommendations. Physician and science policy expert Henry Miller disagrees on a moratorium, and argues that it is unfair to restrict the development of CRISPR in germline gene therapy because we would be denying families cures to monstrous genetic diseases.

So far, the ethical debate has been mostly among scientists and academics. In her article published last December in The Hill Congress Blog, Darnovsky asks: “Where are the thought leaders who focus, for example, on environmental protection, disability rights, reproductive rights and justice, racial justice, labor, or children’s welfare?” More of these voices will be heard as social and policy implications catch up with the science.

In early February, the National Academy of Sciences and National Academy of Medicine held an information-gathering meeting to determine how American public attitudes and decision making intersect with the potential for developing therapeutics using human genetic editing technologies. The Committee’s report on recommendations and public opinion is expected later this year. One future recommendation may be to require Food and Drug Administration (FDA) regulation of genetic editing technology as a part of medical device regulation. Up until recently, the FDA has been slow to approve gene therapy products. Given the fast pace of CRISPR technology development, guidelines on dual use, as determined by recommendations from the National Academies, should be published before the end of the year. So far, U.S. guidelines call for strong discouragement of any attempts at genome modification of reproductive cells for clinical application in humans, until the social, environmental, and ethical implications are broadly discussed among scientific and governmental organizations.

International guidelines on the alteration of human embryos are absolutely necessary to help regulate genetic editing worldwide. According to a News Feature in Nature, many countries, including Japan, India, and China, have no enforceable rules on germline modification. Four laboratories in China, for example, continue to use CRISPR in non-viable human embryonic modification. Societal concerns about designer babies are not new. In the early 2000s, a Council of Europe Treaty on Human Rights and Biomedicine declared human genetic modification off-limits. However, the U.K. now allows the testing of CRISPR on human embryos.

In a global sense, employing tacit science diplomacy to developments in synthetic biology may mitigate unethical use of CRISPR. Tacit science diplomacy is diplomacy that uses honesty, fairness, objectivity, reliability, skepticism, accountability, and openness as common norms of behavior to accomplish scientific goals that benefit all of humanity. The National Science Advisory Board for Biosecurity (NSABB) is a federal advisory committee that addresses issues related to biosecurity and dual use research at the request of the United States Government. Although NSABB only acts in the U.S., the committee has the capacity to use tacit science diplomacy by providing guidance on CRISPR dual use concerns to both American citizen and foreign national scientists working in the U.S.

Under tacit science diplomacy, scientific studies misusing CRISPR would be condemned in the literature, in government agencies, and in diplomatic venues. Tacit science diplomacy was used when the Indonesian government refused to give the World Health Organization (WHO) samples of the bird flu virus, which temporarily prevented vaccine development. After five years of international negotiations on this issue, a preparedness framework was established that encouraged member states to share vaccines and technologies. A similar preparedness framework could be developed for genetic editing technology.

Institutional oversight and bioethical training for the responsible use of genetic editing technology are necessary, but not sufficient on their own. Tacit science diplomacy can help scientists working in the U.S. and abroad develop shared norms. Promoting international health advocacy and science policy discussions on this topic among scientists, government agencies, industry, advocacy groups, and the public will be instrumental in preventing unintended consequences and dual use of genetic editing technology. 


Written by sciencepolicyforall

March 9, 2016 at 9:01 am

Is the human germline off limits?

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By: Thomas Calder, Ph.D.

Licensed via Creative Commons

A new genetic engineering technology, known as CRISPR-Cas9, is allowing scientists to edit the human genome faster and easier than ever thought possible. This technology has the potential to treat and even cure several major diseases such as sickle-cell anemia, HIV, and many forms of cancer. As a result, many labs around the world are rushing to better understand the CRISPR-Cas9 system so they can eventually advance the technology into the clinic. However, such unparalleled potential comes with a risk. CRISPR-Cas9 could be used to alter the genetic code of germline cells, which are reproductive cells that could then pass these alterations onto further generations. This has scientists and the public asking the controversial question: is editing the human germline ethical?

This controversy is not new, as genetic engineering technologies have been around since the 1980’s. Zinc-finger nucleases (ZFNs) were discovered in the 1980’s and were determined to have genome-editing capabilities during 1996-2003. ZFNs are DNA cutting enzymes that can be engineered to target specific segments of DNA, and can thus alter sections of the human genome. Designing ZFNs proved to be difficult, so many scientists were excited when different genome-editing enzymes, TAL effector nucleases (TALENs), were found in 2009-2010 to be easier to engineer than ZFNs. Both ZFNs and TALENs have the same shortcoming though. They require scientists to design proteins specifically for a targeted segment of DNA, which then requires validation of each newly designed protein. Thus, these technologies are highly impractical for editing the genome on a large-scale.

The CRISPR-Cas9 system was first discovered in 1987 by a Japanese lab, but it was not well understood until recent years. Scientists determined in 2005-2007 that bacteria harbor this DNA editing system to digest foreign viral DNA. In 2011-2012, scientists began to understand the basic essentials of this system so they could utilize it for genetic engineering. They discovered that Cas9 is a DNA cutting enzyme that can be targeted to specific DNA fragments with the help of a specially designed guide-RNA molecule. This system proved to be much easier to use that ZFNs and TALENs, because scientists did not have to design different enzymes for each targeted DNA fragment. Instead, they only had to engineer RNA molecules to match with targeted DNA fragments. With this approach, CRISPR-Cas9 can be used to target and alter any gene based on its genetic code, and it can even be used for genome-wide studies.

With the recent characterization of CRISPR-Cas9, a new frontier in science has begun. Scientists have designed guide-RNA molecules for every gene in the genome to determine which genes are essential for various diseases, such as many forms of cancer. This approach is exciting because it may lead to the discovery of new targets for drug-based therapy. Scientists are also creating animal models of various genetic diseases by causing disease-specific alterations in the genome of animals such as mice and monkeys. For humans, this research has focused on non-reproductive cells, but the efficacy of this technology is making the human germline a tempting target. Theoretically, scientists could use CRISPR-Cas9 in an embryo to remove a disease-causing gene and replace it with a healthy version of the gene. This approach has the potential to ward off deadly diseases—but is it ethical? Most importantly, is it safe?

Both questions are controversial. In terms of safety, many scientists currently agree that it is not safe to create a permanent genetic alteration that can be passed onto future children. One concern is that Cas9 could have off-target effects that could damage the human genome in unpredictable ways. Another concern is that scientists do not understand the genome well enough to start making changes to the code. According to a Perspective article in the journal Science, by scientists that attended an ethics discussion in January on the topic of editing the human germline, “there are limits to our knowledge of human genetics, gene-environment interactions, and the pathways of diseases (including the interplay between one disease and other conditions or diseases in the same patient).” Also, side-effects from altering the genetic code of an embryo might not be noticeable until that embryo turns into a grown child, many years into the future. Therefore, more information on the human genome is necessary before genetic engineering of the human germline can be considered safe.

These safety concerns factor into the ethics debate, but other concerns are also drawing attention. While CRISPR-Cas9 is currently being proposed to prevent debilitating diseases, the use of this technology might start a slippery slope that could lead to the creation of “designer-babies.” For example, the genome of an embryo could be altered to impart a different eye color, hair color, or higher level of intelligence. These changes are certainly not worth the risk of side-effects, but some parents might pursue these options to provide their child with a “leg up”. Other ethical questions include:

  • Would the use of this technology be regulated?
  • Would a child be monitored if he/she was genetically modified as an embryo? Would the child’s future offspring be monitored?
  • Which parts of society would have access to this technology? Would use of this technology lead to a greater divide between the poor and wealthy?

The CRISPR-Cas9 technology is advancing quickly, so scientists need to act now to reach a consensus on these ethical issues. Many scientists have already called for a moratorium on editing the human germline in the short-term. This would provide time for scientists to engage with the bioethics community and the public to discuss the ethical, social, and legal implications of altering the human genome.

The genetic engineering capabilities of CRISPR-Cas9 is exciting. Millions of lives could benefit from this new technology. It could cure certain cancers, prevent diabetes, ward of many age-related diseases, and even stop HIV from causing AIDS. But scientists must use extra caution when editing the human germline, because any negative effects that arise could last for many generations into the future.


Written by sciencepolicyforall

April 15, 2015 at 11:02 am