Regulating The CRISPR Revolution

Credit: Sciencenews,org

The government of New Zealand recently announced an ambitious plan, to eliminate rats, possums and stoats from the nation’s ecosystem, in order to protect wildlife (through both eliminating competition for resources, as well as disease spread by these animals). As Singularity Hub explained, this initiative is possible, thanks to what’s known as a “gene drive.”

A gene drive takes advantage of the fact that most animals have two copies of each same gene, and sometimes, these copies are different variants. On occasion, a variant might have been edited to promote a desired trait, let’s say, infertility (so that pests can’t reproduce). Normally, any offspring of a parent who held this gene, would end up containing both the infertility gene, as well as the normal gene.

A gene drive seeks to remove the natural version of the gene (using genetic engineering techniques), and replace it exclusively with the edited gene, which will then be passed on to future generations. If an animal with the edited gene breeds with a normal animal, the gene drive seeks to again replace any natural genes with only the edited variant. In a matter of around 10 generations, 100% of a species would carry this gene (in this instance, with an inability to reproduce, the animal would become extinct).

If all of this sounds a bit fanciful, keep in mind that versions of this approach have already been successfully implemented . Dr. Anthony James of the University of California at Irvine, and Dr. Valentino Gantz, at the University of California, San Diego, were able to spread a gene for resistance to malaria, through generations of mosquitoes, at a 99% efficacy rate. This gene isn’t really useful to mosquitoes themselves, and so under the laws of evolution, it should have ceased being passed along after a certain number of generations. Yet, thanks to this gene drive, the opposite happened.

American scientists aren’t the only ones who’ve been working on mosquito gene alteration. Dr. Austin Burt at Imperial College London, and his team of collaborators, carried out a succesful gene drive to target female reproduction in mosquitoes, such that future generations of mosquitoes might eventually become extinct.

James and Gantz’s team, as well as Burt’s, were able to implement this gene drive thanks to CRISPR, and more specifically Cas9, a gene-editing, technology which makes it easier to splice and make changes to DNA. Cas9 (which stands for CRISPR associated protein 9), plays a major role in why CRISPR offers such a revolutionary method for sustainable gene editing.

Because Cas9 can snip any DNA sequence, it can be added to mosquitoes in the embryo stage, to insert a malarial antibody (which helps to ensure a resistance to malaria, in James’ and Gantz’s experiment), or a gene to hinder reproduction (in Burt’s study). This Cas9-centered approach was made possible in part thanks to a 2015 experiment by Gantz, and his UC San Diego colleague, Dr. Ethan Bier. They used Cas9 to conduct a gene drive to spread albinism among fruit flies.

There’s little question that these findings are revolutionary, and can have a transformative impact on our planet. After all, who wouldn’t want to stop the spread of malaria, or prevent the growth of diseases, which threaten to harm the remarkable wildlife found in New Zealand?

The problem is, it isn’t quite that simple. Elimination of mosquitoes (or at least engineering their immunity to disease) might have a positive overall impact, especially given their role in spreading diseases like malaria and Zika to humans. Yet, these insects are also a source of food and flower pollination, and we simply don’t understand enough about their role in our ecosystem, to accurately predict the long-term consequences of their elimination. How might New Zealand’s efforts to curb certain species, impact it’s environment balance? While rats and possums aren’t keystone species, that is, absolutely critical to our environment, each plays a role of note in our world, and the eventual impact of their absence, remains uncertain.

Let’s also keep in mind that scientific experimentation and advancement, is rarely limited to just one specific area. If genetic engineering of wildlife poses concerns, what about attempting similar techniques on human beings? In April 2015, researchers at Yat-sen University in China, led by Dr. Junjiu Huang, published a paper, announcing that CRISPR had been used to modify some non-viable human embryos. The Yat-sen team removed a gene sequence which carried the blood disorder Beta thalassemias, and inserted a healthy sequence in it’s place. The study at Yat-sen University ultimately was of limited effectiveness (only a small fraction of the embryos initially tested, ended up with the healthy sequence), although one rather concerning byproduct of this experiment, was that CRISPR also “unintentionally caused mutations in other parts of the genome.” In other words, CRISPR carried some unpredictable results, making genetic changes that weren’t expected.

Huang’s research created quite a stir within the scientific community. The prominent science journal Nature, refused to publish these results, in part because of ethical concerns, while a number of well-known geneticists wrote a piece in the journal Science, counseling scientists to avoid running CRISPR techniques on human embryos.

Why was Huang’s experiment so controversial? Lots of the researchers who criticized Huang’s work in Nature, were advocates of and experts in human genome modification, primarily for the purpose of preventing disease. However, their personal research, and that which they endorsed, focused primarily on editing of somatic cells (i.e. T cells).

Geneticists have made tremendous progress in their applications of CRISPR with T cells. It has been used to remove HIV genes “from the genomes of mice and rats infected with the virus”, and to restore sight to blind rats. In November 2016, a team led by Dr. Lu You, an oncologist at Sichuan University in China, injected a cancer patient with cells that contained CRISPR-edited genes, in an attempt to both test the safety of this use of CRISPR, and to explore how these treatments might actually work. This effort is being followed by the world’s first CRISPR clinical trial, where researchers, led by Dr. Edward Stadtmauer, will remove T cells from cancer patients, and perform several CRISPR edits, testing both safety and effectiveness.

Embryonic editing might offer excellent opportunities for scientific advancement, but also, increased chances of unpredictable changes or cuts, being made elsewhere in the genome (as happened with some of the embryos in Huang’s work) These modifications might not be known until after birth of the embryo, and could well be passed on to an embryo’s future children, creating additional risks for generations to come.

Observers have also raised the prospect of “designer babies”, basically, future human children, who have been engineered to either lack or carry certain traits. There are a number of ongoing efforts around CRISPR-based germ-line engineering (editing of egg and sperm DNA, or of embryos themselves), being conducted by scientists at Harvard, MIT, and several universities and companies abroad.

According to Luhan Yang, a postdoctoral researcher at Harvard, these efforts might make it possible to one day eliminate familial vulnerability to genetic diseases like cystic fibrosis, or protect future generations against infection, Alzheimer’s, or even simple aging. Other researchers hope to use CRISPR-based embryonic cell modifications to reverse autism.

Yet, there are also some morally troubling aspects, to this sort of research. What if research advances far enough that some (wealthier) families use these tools to engineer specific traits, such as a certain eye color, or physical strength or agility, or intelligence (to the extent that physique and intelligence are genetic traits)? What does it mean for social and economic inequality, when families of means, can provide their children with yet another powerful advantage, from the day they were born? How about the unforeseen consequences of genetic modifications, as has occurred with both plants and animals? How much more impactful would such missteps be in humans, who have, as a whole, been “optimized” through millions of years of evolution.

As a solution, we ought to implement some basic parameters, applicable on an international basis (let’s remember that Dr. Huang’s research is being conducted in China, not the United States) , to regulate genetic modification and engineering, across species (both humans and animals), and types of research (i.e. gene drives in insects, or T cell and embryonic cell modification in humans). At their core, these rules must balance the drive for innovation and progress, with an eye to the very real risks posed by human interference, in the code of life.

What might this regulatory structure look like? First, we would need to bring together nations across the globe, to ratify a treaty, whereby they agree to implement the recommendations of a panel of experts, assigned to develop guidelines around these questions.

This panel will be made up of a broad cross-section of expert scientists, both geneticists and physicians, who focus on somatic, as well as germline (including embryonic) editing/modification. To this group we will add prominent bioethicists, who are tasked with grappling with complex ethical issues, in both biology and medicine. While expertise in one’s respective field, ought to be the most important requirement for membership on this panel, it also makes sense to select individuals from a fairly broad range of nations, so that their recommendations are not questioned as the biased, unfair assessments, of scientists from a few select nations.

These individuals will need to periodically (perhaps every 18 months or so), offer a consensus view, around what sort of experimental research ought to be permitted (and restricted), as well as any notable risks on the horizon, particularly in terms of germline modification practices. Given the difficulties that people seem to have in reaching unanimous agreement on even simple matters, the group should be allowed to make recommendations based on substantial, although not necessarily unanimous agreement. 

For this reason, any recommendations issued by this panel, ought to carry the support of at least 2/3 of all members, with dissenting members offering their own thoughts on how to proceed (sort of like those justices who end up in the minority in a US Supreme Court ruling).

Next, those nations who were signatories to the treaty (and ideally, the treaty can be expanded to include as many nations as possible), will ensure compliance by scientists within their borders. In a sense, this might not be so hard, because scientists typically publish the results of their work, for peer review, making it possible to catch violations. Yet, we can also imagine rogue scientists, quietly abetted by nations which choose to look the other way, given the potential for profit. That must be prevented.

It’s not hard to see the challenges (and the potential flaws) in this entire process. The international community has faced serious challenges in reaching actionable agreements around issues like climate change, and the proliferation of nuclear weapons. Genetic modification isn’t likely to be any less contentious (or easy to enforce), particularly when a country whose scientists are unhindered by these rules, might stand to gain billions of dollars, by successfully commercializing certain technologies. Also, given that humans aren’t very good at predicting the future, what’s to say that scientists don’t end up completely overlooking potential risks of genetic modification?

When it comes to biological innovation, we are living in an incredibly interesting time. CRISPR/Cas9 are starting to make it possible to alter the code of human life, in a way that can fundamentally change human and animal existence. Some of these changes might be very positive. Yet, such power also carries the potential for massive missteps, with potentially catastrophic consequences. Let’s proceed with caution.