1. Sledge, George W. Jr. MD

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Wrangel Island is a small, miserable place in the Arctic Ocean, a land where the temperature stays below freezing for 9 months per year. It has few permanent residents (a Russian weather station and a few park rangers), though the odd scientist drops in every now and then. Some 3,700 years ago, had you visited the place, you would have seen a strange sight. This is where the last woolly mammoths roamed, and died.

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George W. Sledge, Jr... - Click to enlarge in new windowGeorge W. Sledge, Jr., MD. GEORGE W. SLEDGE, JR., MD, is Professor of Medicine and Chief of the Division of Oncology at Stanford University. He also is

Their forbearers had long since died out on the mainland, likely the result of an invasive species that had spread from Africa to Northern Eurasia and the Americas. Wherever that species (we call them "wise man" in their Latin formulation) went, large animals died with frightening suddenness. But Wrangel Island, separated from the mainland by rising waters some 12,000 years ago, and not exactly what one would consider prime real estate, remained a refugee for those last mammoths.


Elsewhere, human beings had already created the first civilizations and were writing epics in Akkadian. But on Wrangel Island, the woolly mammoths were declining. Species confined to islands frequently undergo reduction in size over time, known as insular dwarfism. Think of Shetland ponies, or the "Hobbits" found on Flores Island off the coast of Southern Asia, or dwarf mammoths in the Channel Islands off the coast of France. The Wrangel Island mammoths do not appear to have been insular dwarfs, but they were genetically stressed.


We've learned this as a result of genomic analyses comparing the Wrangel Island mammoths with their mainland ancestors, as recently published in PLoS Genetics. Small in number-perhaps as few as 300 breeding members in that sad remnant-they were severely inbred and had accumulated numerous genetic defects, with significant loss of heterozygosity, increased deletions affecting gene sequences, and increased premature stop codons. The paper's authors call it "genomic meltdown."


Their hair, for instance, was not the coarse dark hair of their woolly mammoth ancestors, but rather a soft cream-colored, satiny coat lacking an inner core and therefore deficient as an insulator. One can imagine them standing there shivering as Arctic blasts bore down on Wrangel Island. Did this lead to their eventual extinction, or did our ancestors, visiting in boats, do them in? We don't know for certain, though harpoons and other human artifacts on the island have been dated to ~1700 BC. For whatever reason, the Wrangel Island woolly mammoths went extinct. We will never see their like again.


Or maybe we will. George Church at Harvard has inserted woolly mammoth genes into Indian elephant cells using CRISPR technology. The list of edits is up to 45 genes, genes that would allow a tropical elephant to survive on the Siberian plains. Similar efforts are underway in Russia and Korea. Perhaps elephant-mammoth hybrids will walk the Earth in a few years. The Russians have already established a Pleistocene Park.


I feel conflicted about this. Part of me, the eternally curious 15-year-old part of me that loves gee-whiz science, finds this attempt at de-extinction (a neologism of the CRISPR age) a thoroughly enthralling prospect. The other part of me, rather like Jeff Goldblum's character in Jurassic Park, finds all this quite frightening.


And frightening, not for the reason stated by Goldblum's character ("they had their time, and their time is over" was the gist of the argument), but because of the technology itself. For with CRISPR technology, we are at an inflection point in human history, that point where humans intentionally, directly alter the genomes of insects, mammals, and fellow humans.


CRISPR technology has advanced rapidly in the past few years. I wrote about this in a previous blog, but let me briefly revisit the technology. CRISPR is a bacterial defense system designed to snip out viruses attacking the bacterial genome. The CRISPR/Cas9 system has been adapted to mammalian cells and allows one to subtract or insert highly specific gene sequences. If one does this with stem cells, one can permanently change the genetic makeup of an organism. It works, sort-of, in human ova.


CRISPR/Cas9 has gone from obscurity to ubiquity in an astonishingly short time. Since the Doudna and Charpentier breakthrough paper in 2012, here are the number of PubMed citations: three in 2012; 78 in 2013; 315 in 2014; 715 in 2015; and 1,465 in 2016. As I write this in mid-April, 689 CRISPR/Cas9 papers have already been published in 2017. The technology is cheap, easy to learn, and powerful to use. It is a true new paradigm, an overused term but appropriate for once.


The big questions right now are:


* When will CRISPR's discoverers/inventors fly to Stockholm?


* Which discoverers/inventors will get the Nobel?


* Who will win the patent wars over the use of CRISPR/Cas-9 in mammalian cells?



I don't know the answer to the first question, other than "soon," nor the second question (several folks have a claim), though the answer to the third question, according to a recent U.S. Patent and Trademark Office decision, is "the Broad Institute will get very rich for adapting other people's ideas." The lawsuits will probably land up at the Supreme Court.


Lots has been happening in this space of late that has nothing to do with patents. I've mentioned the plan to resurrect the woolly mammoth, but consider the mosquito. I hate mosquitoes, and I've never met anyone who speaks well of them. They seem to exist only to render us miserable. It is not enough that they ruin warm summer nights with their incessant buzz and their pernicious bites. They transmit malaria, a disease that afflicts tens of millions and kills many of those.


Humans evolved, in Africa and the Mediterranean, to resist the ravages of malaria. But in a "the cure is worse than the disease" sense, this evolution left us with sickle cell disease and its hematologic relatives.


So why not get rid of malaria-transmitting mosquitoes? One can use CRISPR/Cas-9 technology to create mosquitoes that are resistant to P. falciparum, the malarial parasite. That would be pretty cool. The problem is that if you dump a bunch of them into Sub-Saharan Africa, they will be outcompeted by the huge native mosquito population. In no time at all, the beneficial effects of the engineered population will dissipate and eventually disappear.


The scientific solution is called "gene drive" (a fine TED talks explanation can be seen at Gene drive involves the use of natural "selfish" homing endonuclease genes to promote the inheritance of specific genes. And it turns out you can use CRISPR/Cas9-based gene drive technology to engineer in genes that render mosquitoes resistant to malaria. Or-and this has also been done-you can engineer in a gene that renders female mosquitoes sterile.


Released into the wild, these engineered mosquitoes could spread throughout the world, eradicating the parent mosquito stock. One calculation suggests that were you to dump enough of these engineered mosquitoes into Sub-Saharan Africa, you could wipe out virtually all of the malaria-transmitting mosquitoes in the course of a year. An inflection point in human history: using science to drive an infection-transmitting, if unloved, species to extinction and replacing them with kinder, gentler relatives, albeit ones that still bite you at your neighborhood barbecue.


The engineered mosquitoes are waiting patiently in their inventor's lab. They've not been released into the wild. Lots of ethics committees lie ahead. Others are studying ways in which we might use gene drive to eliminate invasive species and return entire continents to their pre-invasion ecologic purity.


Meanwhile, those who guard us against things that go bump in the night are cogitating madly away on this. Last year, the latest Worldwide Threat Assessment of the U.S. Intelligence Community listed it as a potential bioterror weapon of mass destruction.


If you can engineer a mosquito tribe out of existence, what mad science CRISPR experiment might be used to, say, drive New England Patriot fans to the brink of extinction? I know, I'm sorry, bad example, but I'm sure you can concoct a more morally dubious use for the technology without great difficulty.


Does this sound too science-fictiony to you? Too like the movie, Gattaca, where the genetically engineered abuse the remnant normal human population? Too improbable? I'd like to think so, but this year's Intel Science Talent Search second-place awardee (with a $75,000 prize and an acceptance to Harvard) is an 18-year-old kid named Michael Zhang whose prize-winning science fair project is called "CRISPR-Cas9-based Virus-like Particles for Orthogonal and Programmable Genetic Engineering in Mammalian Cells." Just wait until next flu season. And I don't even want to know what the Talent Search's First Prize was for; Second Prize sounded scary enough.


The National Academy of Sciences (NAS) and the National Academy of Medicine have just released a thoughtful report on genome editing (you can, and should, see it at Not 2 years ago, a group of scientists that included CRISPR co-inventor Jennifer Doudna strongly discouraged the use of CRISPR technology on humans. The new report now gives a green light to genome editing for serious heritable medical conditions, under properly controlled, rigorous criteria. The same committee argued against genome editing for what they termed "enhancement," which of course is what I really want.


While we are a bit off, from both a technical and regulatory standpoint, from human genome editing, the NAS report opens the door on a new era in human history. The Israeli author Yuval Noah Harari recently published a fascinating book called Homo Deus: A Brief History of Tomorrow. Homo Deus makes the case that humanism has become the new religion of mankind, and that for the first time in our history as a species we have almost God-like powers to alter our own existence. Homo sapiens, if it does not succeed in cleansing the Earth of itself through stupidity, may transform into something unimaginable. And if that happens it will look back on this decade as the turning point.

Gattaca. Gattaca... - Click to enlarge in new windowGattaca. Gattaca

I'd still like to meet up with a woolly mammoth.


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