By:
Susan A. Ehrlich, J.D., LL.M. (biotechnology & genetics)
Judge
(ret.), Arizona Court of Appeals
(*Editor’s Note: This article is
being specially published by the International Judicial Monitor in
recognition that developments in the sciences, just as developments in government policies, often affect the
judiciary and the kind of cases that are presented in courts. An example of the
validity of this observation is DNA, the discovery and research of which has led to many cases, both
civil and criminal, in which DNA evidence and questions about its applicability are
presented to judges. The singular development discussed in this article is one that
very well may become an issue for judges in the not too distant future.)
Humans have been genetic engineers since
ancient times by using selective breeding of plants and animals, but orthodox
selective breeding is a lengthy and often-times costly matter of trial and
error or even of chance. In the 21st Century, though, new means of
genetic engineering have the vast potential for bettering the human condition
and the biosphere to an exponentially increasing degree. However, these
instruments also carry a significant risk of transforming our planet in
unforeseen ways. The recent discovery and use of CRISPR is revolutionizing
this aspect of molecular biology and genetics.
CRISPR is the abbreviation for Clustered Regularly Interspersed Short
Palindromic Repeats, and it is the description of a new and more precise
genetic technology. This technology is based on an enzyme complex that binds
to and splices DNA at precise locations so that CAS 9 target a dysfunctional
gene by deleting and then repairing or replacing the problematic sequence.
One version of the CRISPR process relies on Cas9 to guide a sequence
of RNA bases (a “guide” RNA strand) designed to target a desired DNA sequence
so that Cas9, an endonuclease, is the enzyme that breaks a nucleotide chain
into shorter chains by cleaving the internal bonds that link the nucleotides.
The guide strand acts rather like a genetic GPS (Global Positioning System) so
that Cas9 can grasp the DNA and slice it as precisely as if it were a scalpel,
thereby deleting the targeted DNA and enabling substitution by a repaired or
new DNA sequence.
Another version, announced in September 2015, is designed to make the
CRISPR technology even more simple and more precise. Cpf1, a protein, needs
only one RNA molecule to cut the DNA, not two as are necessary to use Cas9, and
it is able to cut the DNA at different places, which allows more options when
selecting a site to edit.
This then is the new tool for genetic engineering that is simple,
quick, flexible and inexpensive, and it may be the most significant development
in genome engineering since the discovery of the polymerase chain reaction
(PCR) technology, the gene-amplification technique discovered thirty years
ago. The CRISPR technology also appears to work well on eukaryotic (viz.
human) cells, including human embryonic stem cells.
The CRISPR technology becomes all the more momentous when employed in
conjunction with gene-drive methodology, which allows a CRISPR-engineered
mutation on one chromosome to copy itself to its partner chromosome in every
generation so that almost all of the offspring will inherit the change. This
lets the change be manifest in each succeeding generation, thereby eventually
changing an entire population by assuring that the new genetic element is
inherited more often than it would be from conventional random chromosome
assortment at fertilization. The time required to spread the change through
the population depends, however, on the time between successive generations –
for humans, centuries because of their long generation time; for mosquitoes and
common fruit flies, days because of their shorter generation time – and on how
many drive-containing organisms are released into the population. Obviously,
gene drives only work in species that reproduce sexually such as animals,
insects and most plants but not in bacteria or viruses.
Most of what researchers hope to accomplish using the CRISPR
technology is neither deleterious to humans or to nature nor notably
controversial. Rather, the list of what the CRISPR technology could be used to
accomplish already is lengthy, including:
- making
pharmaceuticals that are new or more effective, pharmaceuticals that are better
targeted to the person and condition for which the pharmaceutical is being
employed for improved therapeutic responses, pharmaceuticals that are more
readily proven to be safe and effective, pharmaceuticals that are less
expensive, and pharmaceuticals that are easier to store and transport in
less-than-ideal conditions and circumstances;
- replacing or
repairing aberrant or dysfunctional genes such as the ones associated with
(causing or modifying) conditions such as β-thalassemia (a deadly blood
disorder), sickle-cell anemia, Huntington’s disease or cystic fibrosis;
- replacing or
repairing genes that increase the likelihood of an undesirable disorder such as
blindness, cancer or heart disease;
- stopping cancer
cells from multiplying;
- making cells
resistant to viruses such as HIV;
- effecting changes
in stem cells in order to produce specific tissues;
- manufacturing a
range of high-value but biochemically challenging and expensive bioproducts;
- reducing
dependence on petrochemicals and developing alternative fuels that are less
damaging to the environment, less expensive, safer and renewable;
- producing hardier
livestock and poultry in more humane conditions and without unnecessary feed
additives; and
- engineering
disease-resistant and drought-resistant crops such as wheat, rice, corn, sugar beets,
soybeans and various root vegetables such as cassava to feed or improve the
health of millions of malnourished and hungry people on a warming planet.
The national governments of the United States, the European Union
countries, China and other nations have spent billions of dollars or the
monetary equivalents on research to these ends as have numerous private
entities.
Not all of the proposed uses of the CRISPR technology are salutary,
however. While the preponderance of less-benign outcomes are likely to be
consequences of accidents, poor planning or design, or poor containment
precautions or procedures, a few may be forthrightly malign. Think of
species-specific bio-weaponry. The use of CRISPR-engineered organisms against
humans, livestock and poultry, seafood or crops, or in the air or water
supplies, would precipitate illness and death, including illness and death of
unknown etiology, shortages and the ruination of commerce, undoubtedly
accompanied by civil unrest and the deterioration of structures of governance.
While this high-consequence, low-probability outcome is not inconceivable, our
perspective on these new genetic technologies such as CRISPR should be grounded
in scientific reality, not Hollywood scenarios.
Well short of an apocalypse, researchers already are using the CRISPR
technology to edit genes in organisms from bacteria to non-viable human
embryos. One researcher used the process in mice to correct a mutation
associated with tyrosinaemia, a human metabolic disease, a key step toward
using the technology for human gene therapy. Another researcher modified a
virus to carry CRISPR-engineered components into mice that, upon inhaling the
virus, precipitated the engineering of mutations that modeled lung cancer, a
key step in addressing human lung cancer.
A furor was provoked, though, when scientists at the Sun Yat-sen
University in Guangzhou, China, used the CRISPR technology to edit non-viable
human embryos to disable a gene for β-thalassemia. The current
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limitations of the technology became evident when the process worked in only
some of the embryos, when the engineered mutations appeared in parts of the
genome other than in those regions that had been targeted, and because there
were “mosaics” in which a single embryo had the changes in only some of the
cells. These and other Chinese researchers since have announced that they
fully intend to continue to pursue this type of research using the CRISPR
technology to edit non-viable human embryos.
The United States already bans federal funding for research that
destroys human embryos or creates them for research purposes. This prohibition
would not, however, apply to the kind of research conducted by the Chinese
because those scientists used non-viable human embryos.
Neither the United States nor China has passed a law banning germline
genetic engineering in humans, but the administration of United States
President Barack Obama has declared that “altering the human germline for
clinical purposes is a line that should not be crossed at this time.” (“A Note
on Genome Editing,” Dr. John P. Holdren, Assistant to the President for Science
and Technology, May 26, 2015.) The United States National Institutes of
Health shortly before had refused to fund such research. (Its director, Dr.
Francis Collins, declared with specific reference to the CRISPR technology that
“The concept of altering the human germline in embryos for clinical purposes
has been debated over many years from many different perspectives, and has been
viewed almost universally as a line that should not be crossed.” (“Statement on
NIH funding of research using gene-editing technology in human embryos,” April
29, 2015.)
The Hinxton Group, an “International Consortium on Stem Cells, Ethics
& Law,” recently stated that while research with human embryos “has
tremendous value to basic research” and should be permitted, the technology “is
not sufficiently developed to consider human genome editing for clinical
reproductive purposes at this time,” thus leaving open that “there may be
morally acceptable uses” under future circumstances. (“Statement on Genome
Editing Technologies and Human Germline Genetic Modification,” September 9,
2015.) It made no mention regarding whether such engineering
violates at least the spirit if not the letter of the United Nations’ Universal
Declaration on the Human Genome and Human Rights (1998).
In the United Kingdom, the extent of the use of CRISPR technology for
research involving human embryos is about to be tested. The Human
Fertilisation & Embryology Authority has received an application from
researchers at The Francis Crick Institute in London to use the CRISPR
technology in one of its projects to look at the earliest stages of human
development. The embryos would be those that remain after IVF (in vitro
fertilization) treatment has ended, donated with informed consent, and
destroyed after the research is completed rather than being implanted. The
researchers’ intent is to understand how the human genome develops
successfully.
The genetic engineering of human embryos highlights the ethical, legal
and social implications of using the CRISPR technology to not only make
heritable changes to the human genome but to other species as well. How and to
what degree can the CRISPR technology provoke unforeseen changes? There is the
potential for the unintended consequences of the genetic modification, the potential
for unknown interactions. Among the possibilities are not only those shown by
the Chinese research, e.g., the failure of the process in non-targeted regions
of the genome and single-embryo mosaics, but the possibility that the genome
could be cut at an unintended site or the mutated gene itself could mutate in
an unexpected way. Perhaps most importantly, what may be intended as a
beneficent removal of a deleterious gene could have genomic ramifications that
are completely unforeseen, e.g., there is a protective effect of the
sickle-cell gene against malaria morbidity and mortality.
Additionally, we too many times have seen the ill results when an
alien species is introduced into an environment for an advantageous purpose.
Similarly, a species with a genome changed through the ready use of the CRISPR
technology could adversely affect an entire ecosystem whether the species be
“improved” or whether it be removed. In other words, there could be an
unintended cascade of disruptive consequences detrimental if not destructive to
the ecosystem. We necessarily must be humble and both cognizant and accepting
of the limitations of our present knowledge, humans having, as the psychologist
Daniel Kahneman wrote, “an almost unlimited ability to ignore our ignorance.”
(Thinking, Fast and Slow. Farrar, Straus and Giroux 2011, page 201.)
Much depends on cultural values and ethical judgments. This actually
is exemplified by the differing approaches to the research with non-viable
human embryos of the Chinese researchers versus the United States and European
researchers. Concerns about a eugenics movement or about what constitutes
“genetic dysfunction” and by whose definition have been heard if genes one day
can be readily substituted, one normal gene for another normal gene but one
that is “preferred”. But what are the constraints as reflected in different
cultures and among those with differing values, values often illustrated by
regulatory environments, and how can mutual acceptance be found, especially if
the values are in ethical juxtaposition?
Indeed, the development of the CRISPR technology necessitates a new
approach to governance, particularly the regulatory and oversight framework.
The foundation, of course, is for the researchers to accept full responsibility
not only for their technical and investigative work but for the social and
ethical implications and ramifications of their research. This means demanding
of themselves and each other a culture of responsibility. At a minimum, every
possible effort has to be undertaken to incorporate rigorous confinement
strategies to reduce any risk that the use of the technology could result in a
released or escaped organism that could infiltrate and change, perhaps
devastate, any native population no matter whether through inadvertence,
negligence or malice. A culture of responsibility also entails that all
personnel undergo screening and oversight as a regular course of participating
in research utilizing the CRISPR technology.
Apart from the research environment, regulations should be the
calibrated result of practical assessments of the benefits, risks and
precautions attendant to the use of the CRISPR technology beginning at the
earliest time with the identification of research along a continuum of categories
from research with minimal risk to dual-use research of concern, defined in the United States Government Policy for Institutional Oversight of Life
Sciences Dual Use Research of Concern, as “research that,
based on current understanding, can be reasonably anticipated to provide
knowledge, information, products, or technologies that could be directly
misapplied to pose a significant threat with broad potential consequences to
public health and safety, agricultural crops and other plants, animals, the
environment, materiel, or national security.” There has to be a continuing
process of evaluation and revision, but it is imperative that the research not
be strangled by excessive and unjustifiable regulatory burdens.
Wise governance always is informed by a meaningful and vigorous public
discussion. This is true not only with reference to the use of the CRISPR
technology but because the ultimate success of science depends to a crucial
degree on the validity bestowed upon research by the public. The uses of the
technology therefore cannot be decided by the researchers alone but needs to be
steered by them and others with varying expertise and cultural values. A
dynamic discussion therefore has to include the communities of researchers,
health-care providers, regulatory agents and policy-makers, those involved in
the political processes and all members of the public, including the
do-it-yourself proponents, to consider the benefits and risks, and to provide
insight and guidance for the responsible use of this revolutionary technology.
Ultimately, the uses of new technologies are matters for the larger global
society. As of this writing, however, outside the arena of intellectual
property, the incipient use of the CRISPR technology has not prompted an adequate
consideration and development of appropriate regulatory and legal guidance in
any nation, and certainly not in the requisite international context, telling
those of us law-educated individuals that we must engage, fulfilling our
responsibilities by providing our particular expertise in the essential
discussions of fairness, equity and justice, and the modeling of dynamic
governance structures.
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