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.