One area illustrating challenges of balancing technology and nature is our attempts to understand genes and modify them to suit our purposes. In the past, this was time consuming with successful modification relying on screening of many subjects exposed to mostly random genetic engineering techniques. Now, we have the tools to modify genes and genomes systematically with specific changes to targeted sequences.
This technology, genome editing, is on the cusp of being a magic wand. It might radically transform human society and possibly entire ecosystems. It’s a now common technology that could turn out to be a flying car, antigravity, quantum computing level of development. That’s the opinion of this biologist. It is shared to some extent by famous biologists and entrepreneurs the world over. It’s not as extensive as swapping out or adding whole chromosomes, but it’s quite powerful nonetheless.
The origin story
To fully appreciate this technology, we have to go back into Earth’s ancient history. Development of the systems we use for gene editing began many millions, probably billions of years ago. To begin, we’ll look at the numbers.
There are more stars in the universe than there are sand grains on Earth. As far as we can tell, there are more bacterial cells on Earth than there are stars in the universe. Now, multiply that number by 10 for an estimate of how many viral particles there are on Earth. That’s a lot of biology and biochemistry.
Viruses have been infecting prokaryotic (bacteria and archaea) cells forever. A virus will inject its genetic material into a host cell, the biochemistry of which is then used to replicate the virus. This usually leads to lysis and death of the host cell. That is not advantageous for prokaryotes, so they have evolved ways to fight back.
Prokaryotes have long been known to possess innate immunity. That is, prokaryotes defend themselves through nonspecific actions against viruses in general. This typically involves marking the prokaryote’s own DNA as self through strategic addition of methyl molecules, and then attacking foreign DNA with endonucleases that cut viral DNA to pieces.
Over the last two decades, we have realized that many prokaryotes also utilize adaptive immunity. In this system, a bacterial or archaeal cell first survives exposure to a virus, perhaps through an innate immune response. Then, the prokaryote remembers this virus by incorporating a snip of the virus DNA into a specific region of its own genome. This region is known as CRISPR, or Clustered Regularly Interspaced Short Palindromic Repeats. The incorporated viral elements are labelled as CRISPR spacer elements. The CRISPR region of DNA is transcribed and processed like other DNA. The viral spacer DNA is held in a complex of bacterial proteins. If a remembered virus invades again, spacer transcripts will complement and bind to the same region of viral DNA. Then, CRISPR associated (CAS) proteins will attack the viral DNA.
Before telling how this system is being exploited by humans, we’ll finish this section with a reminder that biology is not so simple. The CRISPR CAS system requires multiple bacterial proteins expressed in a functioning biological system capable of RNA transcription, translation of RNA into amino acid sequences, and post-translational assembly of the amino acid sequences into protein complexes. Furthermore, evolution of both prokaryotes and viruses has led to infection measures, defensive counter measures, and continued adjustments on both sides. The CRISPR CAS system has even been expropriated by certain viruses to overcome bacterial defenses. Finally, even if a virus successfully infects a prokaryotic cell, it does not mean certain death for the host. In fact, viruses are important factors for transmitting genetic variation among prokaryotes. Thus, prokaryotes work at a population level to balance defending themselves from infection with receiving beneficial modifications from successful, yet nonlethal infections.
We can use this
As sequencing technology developed and prokaryotic sequences accumulated, we realized that many prokaryotes carried around strange regions of repeating host sequences interspersed with snippets of virus DNA. Smarter biologists than myself figured out that this was part of an adaptive immunity system. Then, bright biologists and technologists thought that maybe we can use this system to modify almost any genome. If we can get the CRISPR CAS system to work in other organisms, and if we replace the viral spacer with a target gene, then maybe we can get the CAS proteins to cut those genes. Plus, if we introduce a foreign gene with ends that look like the ends cut within the target gene, then maybe the cells own DNA repair system will ligate the foreign DNA into the cut region. With some diligent lab work, those maybes turned into reality.
In a six month period of 2012 and 2013, two papers were published demonstrating that the CRISPR/CAS system can make target cuts in specific locations in prokaryotes and eukaryotes. Nearly simultaneously, this system was used to introduce foreign DNA into specific locations within a host genome. In short, within a decade of realizing that prokaryotes harbor adaptive immunity systems, people were adapting this system to introduce targeted changes within multiple organisms spanning great evolutionary distances in the tree of life. It is hard to overstate the potential impacts this can have for humans and the rest of life on Earth.
Potential applications appear to limited by human imagination as much as limitations in the technology. The Gates Foundation is pushing to use this technology to eradicate malaria. In medicine, single gene disorders might be easy targets for modification. Research to use it to fight cancer is under way, as is editing in human embryos. But, it doesn’t stop there. Even more complex traits can be targeted. CRISPR/CAS has been used to successfully modify multiple genes nearly simultaneously, up to 62 genes in a pig genome in two weeks. Investors are rushing to finance agriculture startup companies that leverage CRISPR/CAS to accelerate development of improvements in our food. This technology might even be useful in bringing back extinct organisms, or at least traits from those organisms.
Enter Ethics
Just as genetic disorders might be reversed, so too can CRISPR/CAS be used to target traits that are more preferred, and not simply disorders. Could this be the start to an era of designer babies, and with that, will there be increased risks of discrimination and inequality. If we find genetic fixes to improve intelligence or physical performance, some parents will want that for their kids. Others might be at a disadvantage if they do not do it. But, what about the child? How can adults make decisions for the child before he or she can speak for themselves? Maybe we can mostly agree on eliminating disorders, such as sickle cell anemia, hemophilia, cystic fibrosis or muscular dystrophy, but what about changing eyecolor, skin color, height, or even personality traits?
As outlined in previous posts, we still have a long way to go to understand biological systems on Earth, which extends from our own bodies and microbiomes to terrestrial and marine ecosystems. We don’t know how gene modifications might propagate through these systems or what kind of effects will ultimately prevail. Ethics, caution and open minded research must be included in the process if there is any chance of obtaining short term benefits without also incurring the expense of uncontrollable destruction.
And, then there are intentionally destructive applications to manage. Military organizations will have to research how to weaponize genome editing. For example, it might be relatively easy to make influenza more contagious. Extrapolate this thinking to any pathogen, whether against humans or our food. The technology is straightforward. Tools are readily available to customize your own gene editing research. Most organizations might have ethics and refuse to support destructive or human research, but others certainly will.
Conclusion
Gene and genome editing are here. We can target specific and multiple genes for rapid modification. Technologically, it’s simple and repeatable. Sure there are complications and hurdles for each specific project, but this system has already been proven to be effective in many projects. Since it is still a young technology, we are only starting to see the impacts. Perhaps reality will not live up to the hype. Nothing suggests that it will not, though. On the contrary, all indications are that CRISPR/CAS or other yet to be developed genome editing technologies will have tremendous impacts across the globe for the foreseeable future.
The power of this technology suggests that we should proceed with caution. Meanwhile, economists, industrialists, capitalists, military strategists and technologists the world over realize that it would be foolish to sit back and let others get a head start in the race to exploit genome editing.