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CRISPR And the Looming Bio-Disruption

We’ve now entered the second phase of the Fifth Techno-Economic Revolution, following the painful transition phase that began with the Dot-Com crash. The next 20 years will be a period of unprecedented rising affluence around the world.

As explained in our book, Ride the Wave, three of the most important technologies enabled by this revolution are Genomics, Bio-reengineering and Synthetic Life. These technologies are the result of a rapidly accelerating learning process over the past 60+ years. We began to understand the basic rudiments of the genetic code in the 1950s and by the 1970s, we were able to painstakingly read DNA segments and splice genes. In the 1990s, we succeeded in sequencing the first human genome at a cost of over $1 billion. In the 2000s, we made that process routine and began dramatically reducing the costs, However, one of the biggest problems with the therapeutic use of this technology remained the high error-rate involved in editing genes.

Then, just five short years ago, Jennifer Doudna, a biochemist at the University of California, Berkeley and French microbiologist, Emmanuelle Charpentier, startled the bio-world with a new technology called CRISPR-Cas9. That technology essentially solves gene editing-error problems and opens-up many new possibilities. Soon after it was first re- ported in the journal Science, CRISPR-Cas9 ushered in the long-anticipated moment when humans could, for the first time, bioengineer themselves.
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CRISPR is a tool that enables scientists to target a specific area of a gene, working like the search-and- replace function in Microsoft Word, to remove an “undesired” section and insert a “desired” sequence.

Despite ongoing legal disputes over commercial rights, CRISPR has increasingly become the tool-of- choice for those seeking to modify genes in humans and other organisms. Among other things, it has been used in experiments to:

- make mosquitoes resistant to malaria,
- genetically modify plants to be resistant to disease,
- explore the possibility of engineered pets and livestock, and
- potentially treat human diseases including hemophilia and leukemia.

However, CRISPR is still in its infancy. General safe- ty issues which still need to be worked out include the possibility of “off-tar- get” edits that occasionally occur in stretches of DNA outside the intended location. This could be devastating if it happened in a human, although scientists believe that fine-tuning CRISPR should eliminate this problem.
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As the discoverer of the CRIS- PR technology, Doudna is both thrilled by its potential and apprehensive that CRISPR might be used for evil, that fear has motivated her efforts to make sure the world is aware of the potential downsides, even as researchers revel in its possibilities.

For instance, she fears that CRIS- PR will be used to edit the so- called “germline cells” in human sperm, eggs, and embryos, thereby creating “designer people.” These alterations would then be passed down to children and subsequent generations, with unpredictable consequences.

In 2015, Doudna helped spearhead a global summit, in Washington, D.C, attended by 500 scientists, ethicists, and others from 20 countries. It ended with the organizers issuing a statement that endorsed the eventual use of germline editing, but only in a very narrow set of cases where CRISPR could be used to edit out horrific diseases. And then, only after a host of ethical and safety issues are resolved.

More recently, an international committee convened by the National Academy of Sciences issued a report that highlighted concerns with human germline genetic engineering, but laid out a set of safeguards and oversight procedures. That report was widely regarded as opening the door to embryo-editing research.
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Beyond this general consensus among leading researchers, there are a number of existing limits ? both policy-based and scientific ? which create barriers to implanting an edited embryo to achieve the birth of a child. For instance, there is a federal ban on funding gene editing research in embryos. In some states, there are also total bans on embryo research, regardless of how funded. In addition, the implantation of edited

human embryos would be regulated under federal human research regulations, as well as the Food, Drug and Cosmetic Act and potentially, the federal rules regarding clinical laboratory testing.

In addition to the regulatory barriers, scientists using the current technology are a long way from having the scientific knowledge necessary to design children. Most characteristics we might be interested in redesigning ? such as intelligence and personality, as well as athletic, artistic and musical ability are much too complex for today’s techniques.

Furthermore, there is still a long way to go between the ability to edit one gene in an embryo and cures for most genetic diseases and disorders.

This is not to say that these barriers won’t be over- come. But fortunately, we have a reasonable amount of time to consider the issues before the use of CRISPR becomes a mainstream medical practice.

Given this trend, we offer the following forecasts for your consideration.

First, by 2030 we will be forced decide when and how we should use CRISPR and related technologies.

That means answering big questions including:

Should there be limits on the types of things you can edit in an embryo?

If so, what should they entail?

How should we regulate access to embryo editing for serious diseases?

Who should be able to use this technology? And,

Who gets to set the limits and control access to the technology?

Mankind needs to debate and come to grips with the implications of creating a new line of elite super-humans. The implications are far scarier than any threat posed by artificial intelligence.

Second, the decision to put in place restrictions will raise objections from both potential parents and IVF providers.

Today, the use of assisted reproductive technologies is largely unregulated in the U.S. Imposing greater restrictions will certainly be challenged in the courts. And,
Third, the biggest source of disruption lies in the use of this technology by scientists operating in countries, that lack advanced regulatory controls.
Keep in mind that even though this technology was invented here, we cannot control what happens in other countries. Even in the United States, it can be difficult to craft guidelines that re- strict research society finds objectionable, while al- lowing other important research to continue. China is perhaps the most likely source of breakthroughs to undermine the OECD consensus.

References
1. Science. Vol. 337, Issue 6096, pp. 816-821. Aug 17, 2012. Martin Jinek1,2,*, Krzysztof Chylinski3,4,*, Ines Fonfara4, Michael Hauer2,†, Jennifer A. Doudna1,2,5,6,‡, Emmanuelle Charpentier4,‡ A Programmable Dual-RNA?Guided DNA Endonuclease in Adaptive Bacterial Immunity.

http://science.sciencemag.org/content/337/6096/816

2. Medium.com. David Ewing Duncan. Jun 1, 2016. It’s Time to Believe in Synthetic Biology.

https://medium.com/neodotlife/q-a-enriquez-1c7d47c4a6ea

3. Nature Biotechnology. 07 December 2015. Andrew Hammond, Roberto Galizi, Kyros Kyrou, Alekos Simoni,Carla Siniscalchi, Dimitris Katsanos, Matthew Gribble, Dean Baker, Eric Marois, Steven Russell, Austin Burt, Nikolai Windbichler, Andrea Crisanti & Tony Nolan.
4. A CRISPR-Cas9 gene drive system targeting female reproduction in the malaria mosquito vector Anopheles gambiae.

http://www.nature.com/nbt/journal/v34/n1/full/nbt.3439.html?foxtrotcallback=true

5. Cell: Molecular Therapy Nucleic Acids. February 08, 2017. Oliver Brabetz, Vijay Alla, Linus Angenendt, Christoph Schliemann,Wolfgang E. Berdel, Maria-Francisca Arteaga, & Jan- Henrik Mikesch. RNA-Guided CRISPR-Cas9 System-Mediated Engineering of Acute Myeloid Leukemia Mutations. Cell: Molecular Therapy Nucleic Acids, Volume 6, p243?248.

http://www.cell.com/molecular-therapy-family/nucleic-acids/fulltext/S2162-2531(17)30001-X