Human 2.0 – Gene drives: “hey … we’re just messing with evolution, ok?”

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8 March 2017 – So Quartz has started to run this list called must-know science terms and frankly it is bitch to keep up. Basically they are doing it because science “will play a larger role in public discourse than it has in the past, at least in the U.S.”

One term I spotted because I have been doing a lot of reading on it: gene drive. Brian Grossman over at Zeitguide, Jennifer Kuzman over at Nature magazine, Kevin Esfelt at MIT Media Lab, and Michael Spector (a writer and former Washington Post science editor and expert on synthetic biology) have pulled together a lot of information so herein a guide, supplemented by my other sources.

What is a gene drive? It’s a revolutionary new way to use CRISPR. Crisp-wha? OK, first, a refresher on CRISPR. It stands for “clustered regularly interspaced short palindromic repeats.” Yes, I know. An awkward name but a memorable acronym.

In brief, CRISPR has two components. The first is essentially a cellular scalpel that cuts DNA. The other consists of RNA, the molecule most often used to transmit biological information throughout the genome. It serves as a guide, leading the scalpel on a search past thousands of genes until it finds and fixes itself to the precise string of nucleotides it needs to cut. And as my genetics prof pointed out, it has been clear at least since Louis Pasteur did some of his earliest experiments into the germ theory of disease, in the nineteenth century, that the immune systems of humans and other vertebrates are capable of adapting to new threats.

Scientists discovered these bits of repeated genetic material in bacteria 30 years ago, but more recently figured out how to turn it into a cheap, fast and precise gene editing tool. There’s a much more comprehensive explanation of CRISPR here in Quanta magazine.

So in short, CRISPR works like a cut-and-paste function for bits of DNASo, what if you put a cut-and-paste function into a gene? Here’s why scientists would want to do that.

When two organisms mate, their offspring inherit chromosomes from both parents, so a trait has only a 50% chance of being expressed in the offspring, and a 25% chance in the next generation, and so on. So genetic modifications fade away. When a chromosome has a gene drive on it, however, the gene drive snips out the undesirable DNA from the unmodified parent’s chromosome. Then the offspring’s genetic machinery repairs the damage by pasting in the modified bit of DNA.

Suddenly, scientists can almost 100% ensure that new bit of DNA is inherited by all offspring. That means, theoretically, the genetic change could spread through a whole population in the wild, or at least until some other evolutionary change or resistance sets in.

In labs, this has been tested on fruit flies, mosquitoes, and yeast, and scientists hope to use this technique to wipe out humanity’s worst enemies or save endangered species. Scientists already have their sights set on eradicating malaria-spreading mosquitoesand have raised millions in funding, including $75 million from Bill Gates.

NOTE:  I received the most comprehensive briefing on CRISPR at the Imperial College Festival in London last year. The Festival is held every May and if you live in/near London (or will be there during those dates) and love science … GO! Almost very facet/area of science is covered over the 2-day event, all done by students and faculty. Three years ago I attended a presentation on the incredible Rosetta space probe mission that was launched by the European Space Agency, with Philae, its lander module, which performed a detailed study of a comet last year.  Launched in 2004 (with technology built and tested in 2002) it performed nearly flawlessly.  Wrap your brain around that: launched with technology 14 years old, on a 12 year flight/mission into space … the planning/specs/trouble-shooting, etc. boggles the mind.

Sorry. I digress … back to CRISPR.

Gene drives may get their first mammalian application in New Zealand in the coming years, where invasive rodents have devastated flightless bird populations. To exterminate an invasive species of mice, a team of scientists altered a subset of mouse genomes so that the animals only reproduce males. If there are no female mice to breed with, the population will gradually die out.

But not everyone is convinced such interventions are a good idea. One is Neill Gemmell, a researcher at the University of Otago in New Zealand, who noted in a Nature piece:

“I think there are actually a hell of a lot of things that could go wrong. If you think you are just going to release things and they are going to eradicate for you, it’s a big mistake,”

And it is not surprising that messing with evolution is highly controversial. The science journals and popular press are replete with ethicists, environmentalists and conservationists opinion, split on the issue of tinkering with genes in the wild even in the name of saving endangered species or saving human lives. Scientists are trying to model how the genetic change will spread, or not, but let’s just say that anyone squeamish about GMO corn isn’t likely to support CRISPR-ed rodents.

The potential impact of CRISPR on the biosphere is obviously profound. Activists have been arguing that governments should ban gene drives until the impacts are better understood and regulations set in place. A coalition of environmental activists called for a global moratorium on gene drives at the UN Convention on Biodiversity in December, but their calls were rejected and the final agreement just “urged caution.”

And for my lawyer readers, an interesting note. Last year CRISPR was a topic at the annual mega-artificial intelligence conference sponsored by the AAAI. The conference promotes research in almost every aspect of AI and there is a tremendous exchange of information among AI researchers, practitioners, scientists, lawyers, IT specialists, engineers and scores of people in affiliated disciplines. There are diverse tracks … technical track, legal track, student abstracts, poster sessions, invited speakers, tutorials, workshops, exhibit/competition programs, etc.

One speaker noted that CRISPR has become a household name for molecular biologists around the world. Researchers have eagerly co-opted the system “to insert or delete DNA sequences in genomes across ALL kingdoms of life”.

And the principal developers and investigators involved in the seminal work on CRISPR have become scientific celebrities: they are profiled in major newspapers, star in documentaries and are rumoured to be contenders for a Nobel prize. But not so the students and postdocs who have toiled at the bench to make CRISPR genome editing a reality. They certainly reap benefits from their work: support and reflected glory from their supervisors, as well as expertise in a coveted technique. But some also face a difficult transition to becoming independent scientists as they try to establish themselves in a hypercompetitive field.

And so gene editing has become a subject of fierce debate and a bitter, high-stakes patent battle. Researchers and institutes have been jostling aggressively to make sure that they are credited for their share of the work in everything from academic papers to news stories. Said the speaker: “I get a lot of phone calls from lawyers about what I did and when. Jeez. Like I need this”.

Concluding thoughts

 

When the first draft of the Human Genome Project was published, in 2001, the results were expected to transform our understanding of life. In fundamental ways, they have; the map has helped researchers locate thousands of genes associated with particular illnesses, including hundreds that cause specific types of cancer.

To understand the role that those genes play in the evolution of a disease, however, and repair them, scientists need to turn genes on and off systematically and in many combinations. Until recently, though, altering even a single gene took months or years of work.

So, inevitably, the CRISPR technology will permit scientists to correct genetic flaws in human embryos. It freaks us out. Any such change will infiltrate the entire genome and eventually be passed down to children, grandchildren, great-grandchildren, and every subsequent generation. That raises the possibility, more realistically than ever before, that scientists will be able to rewrite the fundamental code of life, with consequences for future generations that we may never be able to anticipate. Vague fears of a dystopian world, full of manufactured humans, long ago became a standard part of any debate about scientific progress. Yet not since J. Robert Oppenheimer realized that the atomic bomb he built to protect the world might actually destroy it have the scientists responsible for a discovery been so leery of using it.

My genetics prof summarized as follows:

For much of the past century, biology has been consumed with three essential questions: What does each gene do? How do we find the genetic mutations that make us sick? And how can we overcome them?

 

With CRISPR the answers have become attainable, and we are closing in on a sort of “grand unified theory of genetics”. And while CRISPR is not the first system to help scientists pursue that goal, it is the first that anyone with basic skills and a few hundred dollars’ worth of equipment can use.

 

And just as artificial intelligence developments have collapsed application time in so many areas, so has CRISPR in genetics. Normally, it takes years for genetic changes to spread through a population. That is because, during sexual reproduction, each of the two versions of any gene has only a fifty per cent chance of being inherited. But a “gene drive” – which is named for its ability to propel genes through populations over many generations – manages to override the traditional rules of genetics. A mutation made by CRISPR on one chromosome can copy itself in every generation, so that nearly all descendants would inherit the change. A mutation engineered into a mosquito that would block the parasite responsible for malaria, for instance, could be driven through a large population of mosquitoes within a year or two. If the mutation reduced the number of eggs produced by that mosquito, the population could be wiped out, along with any malaria parasites it carried.

Michael Specter, who frequently writes about AIDS and is a synthetic biology expert, noted:

Modern medicine already shapes our genome, by preserving genes that might otherwise have been edited out of our genome by natural selection. Today, millions of people suffer from myopia, and many of them are legally blind. Were it not for the invention of glasses, which have turned poor eyesight largely into a nuisance rather than an existential threat, the genes responsible for myopia might be less prevalent than they are today. The same could be said about many infectious diseases, and even chronic conditions like diabetes.

 

Humans also carry genes that protect us from one disease but increase our susceptibility to others, and it’s impossible to predict the impact of changing all or even most of them. The aids virus often enters our blood cells through a protein called CCR5. One particular genetic variant of that protein, called the Delta32 mutation, prevents H.I.V. from locking onto the cell. If every person carried that mutation, nobody would get aids. So why not introduce that mutation into the human genome? Several research teams are working to develop drugs that do that in people who have already been infected.

 

Geo-engineering disturbs everybody. And once you go down that path, it may not be so reversible. CRISPR technology offers a new outlet for the inchoate fear of tinkering with the fundamentals of life. There are many valid reasons to worry.

But it is essential to assess both the risks and the benefits of any new technology. Quoting Michael Spector again:

Most people would consider it dangerous to fundamentally alter the human gene pool to treat a disease like aids if we could cure it with medicine or a vaccine. But risks always depend on the potential result. If CRISPR helps unravel the mysteries of autism, contributes to a cure for a form of cancer, or makes it easier for farmers to grow more nutritious food while reducing environmental damage, the fears, like the many others before them, will almost certainly disappear.

 

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