New Gene Editing Technology Promises
Most Monumental Advance of Humankind Into the Future
January 26, 2016
Story at-a-glance
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Research has radically improved the CRISPR gene
editing technology, which is likely the most
significant health technology ever introduced, with
many unknown dangers
A number of companies are now developing new drugs
to cure genetic-driven disorders with CRISPR
technology
CRISPR makes three categories of DNA alterations
possible: embryonic modification to eliminate
genetic disease; alterations to protect against
future disease; and genetic enhancement of human
form and function
By Dr. Mercola
In his 1932 sci-fi novel "Brave New World," Aldous Huxley
explored what life might be like in AD 2540 — a world in which
children are born in government owned baby hatcheries.
In his world, human freedom is virtually non-existent, as
each individual is genetically engineered and psychologically
conditioned to fulfill a specific role within one of the five
societal classes.
Over 500 years before his prediction, we're already seeing
the germination of some of his projections.
The technical development that is taking medicine by storm is
CRISPR (clustered regularly interspaced short palindromic
repeat) — a gene editing tool that has the most profound
potential to change the health world as we know it that I have
ever encountered.
A layman's explanation of the technology and its potential
ramifications is presented in the video above. In the past, talk
about altering the human genome was relegated to philosophical
discussions; now it's becoming a reality. A "Brave New World"
indeed!
Drug Companies Race to Develop Gene Editing Drugs
According to MIT Technology Review,1
the pharmaceutical industry is "doubling down" on CRISPR for
novel drug development. CRISPR Therapeutics has entered a joint
venture with Bayer to create drugs for blood disorders and
blindness using this gene editing technology.
Two other startups aiming to put CRISPR technology to use in
drug development are Editas Medicine and Intellia Therapeutics.
According to the featured article, "dealings over the past year
have revealed broad disease areas where drugmakers see
opportunities for applying the new tool."
At present, any therapy based on CRISPR technology would have
to involve three steps: Remove cells from your body; alter the
DNA, and then reintroduce the cells into your body.
CRISPR hold the promise to transform the human species in ways
yet unknown and it has quickly gone from being written about
only in scientific journals to receiving global media attention.
It is sometimes called the Microsoft Word of gene editing for
its low cost and ease of use for researchers.
Specificity — The Ultimate Challenge of Genetic Modification
All three CRISPR startups are also working on technologies
for editing the genome right inside your body, without having to
take out and reinsert the cells.
This presents a far greater challenge, and while it would
broaden the range of diseases that could be addressed, it may
also be far more dangerous, with any number of potential side
effects.
As noted in the featured article:
"'The ultimate need' of any of the players trying to
make CRISPR drugs is for technologies that can increase
CRISPR's specificity, so that it edits only the target DNA
sequence ...
The basis of CRISPR technology is a biological system
some bacteria use to remove unwanted viral DNA sequences ...
One of the molecules that locates and cuts the DNA has
evolved to be somewhat nonspecific so it can be flexible
enough to address a range of different viruses...
Once the system is specific enough, there could be
several ways to get it into the right cells, such as by
using viral vectors or nanoparticles. Delivering it to the
right tissue might be as simple as licensing a syringe for
injecting into the eyeball, or a stent for delivering the
drug to the heart ...
But none of the players trying to make CRISPR drugs
have yet been able tackle all three challenges — delivering
the drug to the tissue, the cells, and ultimately to the
target sequence with the necessary specificity ..."
One Step Closer to 'Designer Babies'
On January 6, researchers announced the discovery of a
technique that renders CRISPR more precise — an important step
for those who seek to employ the technique in human embryos to
"weed out" inherited diseases and the like.
By modifying an enzyme called Cas9, the gene-editing
capabilities are significantly improved; in some cases reducing
the error rate to "undetectable levels." As reported by Nature:2
"Researchers use CRISPR — Cas9 to make precise
changes to genomes that remove or edit a faulty gene. It has
worked on nearly every creature on which they have tested
it, including human embryos.
The technique relies on an enzyme called Cas9 that
uses a 'guide RNA' molecule to home in on its target DNA.
Cas9 cuts the DNA at that site, and the cell's
natural DNA repair machinery then takes over to mend the cut
— deleting a short fragment of DNA or stitching in a new
sequence in the process.
But the technology is not infallible: sometimes the
Cas9 enzyme creates unwanted mutations.
As CRISPR inches out of the laboratory and towards
the clinic — with debates raging over whether it should be
deployed in embryos — researchers have pushed to reduce the
error rate. The latest study moves the field closer to that
goal ..."
CRISPR May Be Used to Alter Future Generations
According to an earlier article in MIT Technical Review,3
the notion of genetically modifying humans is no longer a
science fiction fantasy, and while many will probably shudder at
the idea, "to people facing a devastating inherited disease,
engineering humanity sounds like a good thing."
In December last year, hundreds of scientists and ethicists
met in Washington, D.C. at the National Academy of Sciences to
discuss the sanctioning of "germ-line engineering," meaning the
altering of DNA in sperm, eggs, or embryos, in order to remove
or correct genetic defects.
CRISPR now provides the means to do so, but just because we
can, should we tinker with the human genome? After all,
there are just as many hazards as there are opportunities with
this technology.
Genetic diseases and defects could be eradicated, and any
number of diseases might be cured once they strike; on the other
hand, introduced errors might leave a child worse off, or cause
unintended generational effects, and then there are potential
societal ramifications such as those presented in Huxley's book.
Three Categories of Genetic Manipulation of the Human Race
With CRISPR gene editing capabilities, three categories of
DNA alterations become possible.4
Science and society will ultimately have to face and address the
need and ethical requirements for all of them:
Embryonic DNA is corrected to eliminate genetic defects
associated with inheritable disease. (While this use has the
greatest support, some scientists argue that using germ-line
gene editing to eliminate genetic disease is unnecessary,5
since the technology to test and choose embryos free of
genetic disease already exists, and is regularly used in IVF
clinics.)
The alteration of genes to protect a person against
future disease or diseases.
Genetic enhancement, in which genes are installed or
modified to change a person's appearance, or physical or
mental potential.
At present, about 40 countries around the world have banned
the genetic engineering of human embryos; 15 of 22 European
countries prohibit germ line modification.6
According to MIT:
"Many experts at the [National Academy of Sciences]meeting seem to be leaning toward endorsing an
indefinite moratorium on any effort to create
gene-modified babies, calling the technology too new,
too unsafe, and too limited in medical use, a position that
has been endorsed by the Obama administration.
But when MIT Technology Review reached out to several
families who've dealt with devastating genetic illnesses,
all said they approved of using the technology as quickly as
possible.
That could create a potential clash between desperate
families and cautious scientists and politicians...Others
warn of a slippery slope toward 'consumer eugenics' and
out-of-control changes to the gene pool. 'Although gene
editing is in its infancy, it is likely that the pressure to
use it will increase,' says David Baltimore, a Nobel
Prize-winning professor at the California Institute of
Technology who is leading the deliberations in Washington."
The Danger of Unintended Effects
In "Understanding the Unintended Effects of Genetic
Manipulation,"7
the Nature Institute brings forth a number of thought-worthy
issues. Genetic engineering or genetic modification of an
organism is of course done with a specific objective or effect
in mind.
However, the sheer complexity of the genome, be it plant,
animal or human, is such that unintended or "non-target" effects
frequently occur. There's also the issue of "pleiotropic
effects" which refers to effects due to a gene affecting more
than one characteristic.
The fact that we have identified the effects of many genes
does not mean we've teased out ALL effects of each and every
gene. Such ignorance could do a great deal of harm when
tinkering with the human genome.
Another factor that may prove to be exceptionally dangerous
when we're talking about experimenting with the human genome is
the current lack of
scientific integrity. As science has gotten more complex, it
has also decreased in quality and transparency.
As noted by the Nature Institute:
"[N]ontarget effects are not always reported in
research reports. As Dougherty and Parks (1995) write,
'Organisms that do not perform as expected are discounted as
defective or atypical in some way, are not the subject of
study, and frequently are not reported in the literature. It
is important, therefore, to recognize that most published
works represent a selected subset of transgenic organisms
that have been produced.
These built-in biases have hindered our understanding
of how transgene expression impacts the endogenous [host]
gene' and, I would add, how the organism as a whole can be
affected by the genetic manipulation."
Clearly, once we start talking about human subjects, the
ramifications to humanity of discounting those with unintended
anomalies as "defective" and tossing them out of the study could
be severe. Far more severe than giving the go-ahead to
transgenic plants that may be harmful if you eat them in
significant amounts over a lifetime.
The Nature Institute only discusses the genetic engineering
of plants, not animals or humans, but once you know what can go
wrong in a plant, it becomes easier to evaluate the potential
risks of tinkering with the genetic code of a human being, which
is infinitely more complex than a plant.
Take for example the transgenic potato. A study designed to
screen for potential non-target effects in a GE potato, in which
the pathway for sugar breakdown was altered, found the potato
had altered levels of nearly all metabolites
(substances) they tested using metabolic profiling — in this
case, 88.
This was a complete surprise, because many of these
substances, such as amino acids, were "not known to be related
to the sugar breakdown pathway targeted by the genetic
manipulation."
This is a classic case of not knowing what we don't know. In
addition to that, they found 9 substances in the transgenic
potato that didn't exist in the non-GE potatoes — another
surprise, since the creation of these substances had not been
part of the intended, target effect.
CRISPR Technology Completely Ignores Epigenetics
It's worth noting that CRISPR technology also ignores
epigenetic effects, for which there is a solid scientific
foundation. "The Central Dogma" of molecular biology states that
biological information is transferred sequentially and only in
one direction (from DNA to RNA to proteins).
The ramification of buying into the central dogma is that it
leads to belief in absolute determinism, which leaves you
utterly powerless to do anything about the health of your body;
it's all driven by your genetic code, which you were born with.
However, scientists have shattered this dogma and proven it
false. You actually have a tremendous amount of control over how
your genetic traits are expressed — from how you think to what
you eat and the environment you live in.
You may recall the Human Genome Project, launched in 1990 and
completed in 2003, the mission of which was to map out all human
genes and their interactions. The idea was that this would then
serve as the basis for curing virtually any disease. Alas, not
only did they realize the human body consists of far fewer genes
than previously believed, they also discovered that these genes
do not operate as previously predicted.
In 1988, experiments by John Cairns, a British molecular
biologist, produced compelling evidence that our responses to
our environment determine the expression of our genes. A radical
thought, for sure, but one that has been proven correct on
multiple occasions since then.
CRISPR Also Being Used in Creation of Transgenic Insects
Another application for CRISPR is for so-called "gene drive"
in transgenic insect disease vectors. In a recent report,8
the Institute of Science in Society (ISIS) discusses the
creation of transgenic mosquitoes, carrying genes against a
malarial pathogen.
Using CRISPR/Cas9, a gene drive was created that makes
virtually all progeny of the male transgenic mosquitoes carriers
of this anti-malaria gene. However, the transgene was found to
be unstable in female mosquitoes, and key safety issues were
also raised, including the following:
"'To what extent and over what period of time might
crossbreeding or lateral [i.e., horizontal] gene transfer
allow a drive to move beyond target populations? Might it
subsequently evolve to regain drive capabilities in
populations not originally targeted?' This is crucial in the
light of the instability of the gene drive in transgenic
female mosquitoes reported.
When these females bite animals including humans,
there is indeed the possibility of horizontal gene transfer
of parts, or the entire gene-drive construct, with
potentially serious effects on animal and human health. Cas9
nuclease could insert randomly or otherwise into the host
genome, causing insertion mutagenesis that could trigger
cancer or activate dominant viruses ...
Finally, the ecological risks of gene drives are
enormous, so warns conservation scientists from Australia's
Commonwealth Scientific and Industrial Research Organization
... As the gene drive can in principle lead to the
extinction of a species, this could involve the species in
its native habitat as well as where it is considered
invasive. As distinct from conventional biological control,
which can be applied locally, there is no way to control
gene flow.
They point out that because the CRISPR/Cas gene drive
remains fully functional in the mutated strain after it is
created, the chance of off-target mutations also remain and
the likelihood increases with every generation.
'If there is any risk of gene flow between the target
species and other species, then there is also a risk that
the modified sequence could be transferred and the adverse
trait manifested in nontarget organisms.' (This commentary
has not even begun to consider horizontal gene flow, which
would multiply the risks many-fold.)"
Too Much, Too Fast
The ISIS report makes it clear that CRISPR technology raises
"unprecedented concern over safety and ethics." According to the
report, the issue "came to a head" after a team of Chinese
researchers used the technology to create the first genetically
modified human embryos.
While CRISPR/Cas9 effectively cut the intended gene target,
it also affected other non-target sites, and in the end,
"untoward mutations" were created. According to the researchers:
"Taken together, our work highlights the pressing
need to further improve the fidelity and specificity of the
CRISPR/Cas9 platform, a prerequisite for any clinical
applications of CRISPR/Cas9-mediated editing."
There's no doubt that gene editing technology is here to stay
(unless something truly devastating cuts its popularity short).
It certainly has the potential to do good, but it also has the
potential to be misused and abused — especially since it's far
cheaper than any previous methods.
For better or worse, medicine and reproductive technology is
about to take a massive leap; we're quickly entering an era
where the human genome can be tinkered with for any number of
reasons. Unfortunately, if genetically engineered foods are any
indication, such a leap may turn out to be just another factor
in our own undoing.
If this topic interests you, you can learn more about the
history of this revolutionary technology in a paper9
published in the journal Cell earlier this month. A commentary10
on the paper can also be found on the science blog Genotopia.