BODYBUILDER BEAGLES, GLOW IN THE DARK MASTIFFS, RETURN OF THE WOOLY MAMMOTH, A POTENTIAL CURE FOR CANCER & GENETICALLY MODIFIED HUMANS
IT WOULD BE IMPOSSIBLE TO BELIEVE IF IT WEREN’T TRUE
40,000 years of breeding and inbreeding have created an obsession with a purebred ideal — and riddled dogs with health problems that shorten their lifespans and diminish their hearing, digestion, or other basic abilities. Now that many of these disorders could at least theoretically be repaired using gene-editing techniques like CRISPR, Ishee wants to help breeders do exactly that, creating healthier dogs that can still be considered purebred.
That’s where the bioluminescent puppies come in. Yes, you read that correctly.. Glow in the dark dogs. It has already been done in mice. If he can edit dog genes to make the animals glow, he reasons, perhaps he can convince breeders that the technique could be used for more practical purposes. First on his list would be to eliminate a bladder disorder in Dalmatians called hyperuricemia. That’s a painful buildup of uric acid crystals that is caused by a mutation in a gene associated with the dogs’ black spots and often requires surgery. It could be an excellent candidate for a CRISPR fix.
Ishee is, in many ways, the quintessential biohacker. Homeschooled from the fifth grade, he does his research in a shed in his backyard. He has already gotten in trouble with the Food and Drug Administration, which has declared every intentional genomic edit — and therefore every individual edited animal — to be an “experimental drug” that requires extensive testing. The agency informed Ishee in 2016 that he could neither give away nor sell any of the edited dogs without its approval.
There’s no question that Ishee’s ideas are inspired, but he’s still a long way from successfully editing dogs, even after several attempts at glowing puppies. And even if he can pull that off, his most significant obstacle may still be ahead: convincing breeders obsessed with creating the best show dogs that gene editing could help them. All this makes Ishee’s story — his struggle to do innovative research while navigating bioethical tensions and regulators trying to monitor a fast-developing technology — a telling case study in the gap between what biohackers can imagine and what they can achieve.
“I love dogs,” Ishee tells me before his presentation in Oakland. “It’s really just as simple as that. I want to fix them.” He grew up around dogs; his great-grandfather and grandfather were breeders, and his brother is too. He balances his own work breeding mastiffs with a job in Mississippi’s oil industry.
What frustrates him about traditional dog breeding is its reliance on trial and error. He describes it as a “very, very blunt tool, like trying to carve stone with an anvil on a stick.” It’s also slow. Dogs’ heat cycles are months apart, and it takes years for successive generations of puppies to mature. Through Google Scholar, YouTube, and extensive reading, he essentially taught himself graduate-level biology and began tinkering with gene editing. He buys his raw chemicals on Amazon and eBay; gets enzymes and genetic material from other sites and from fellow biohackers.
He isn’t quite ready to use CRISPR on dog embryos yet. For now he’s experimenting with “sperm-mediated gene transfer.” In that process, specially prepared dog sperm is mixed with foreign DNA and is altered by it. Then he uses that sperm to inseminate female dogs. So far, he’s been using his own mastiffs. His first four attempts all failed; three of them resulted in miscarriages. But Ishee sees those as positive signals, theorizing that the genes he added for luminescence integrated and affected fetal development.
Now he has two more attempts under way to try to figure out exactly why it hasn’t worked. In these current experiments, he mixed in a different and simpler gene, one that codes for fluorescence in jellyfish and that he hopes will not disrupt the dogs’ development. If this technique produces glowing puppies, he sees no reason why subsequent CRISPR projects couldn’t work.
BODYBUILDER BEAGLES
Elsewhere in the world, scientists in China have claimed that they were the first to use gene editing to produce customized dogs. They created a beagle with double the amount of muscle mass by deleting a gene called myostatin. The dogs have “more muscles and are expected to have stronger running ability, which is good for hunting, police (military) applications.”
RETURN OF THE WOOLY MAMMOTH?
Then there are those applications of CRISPR that verge on science fiction. Rather than harnessing gene-editing technology to create organisms never before seen on Earth, some scientists aim to do exactly the opposite and leverage gene editing to resurrect extinct animals that once existed long ago. Dinosaurs are sadly out of the question, as imagined by Michael Crichton in Jurassic Park — DNA breaks down far too quickly to rebuild the genome of any dinosaur species — but not so with the wooly mammoth. Using extremely well-preserved frozen tissue samples, geneticists have already succeeded in deciphering the letter-by-letter sequence of the wooly mammoth genome, enabling a direct comparison to the genome of the modern-day elephant, its closest relative.
Now, George Church and colleagues are using CRISPR to convert specific genes in elephant cells into their wooly mammoth counterparts, prioritizing those genes implicated in functions like temperature sensation, fat tissue production, and skin and hair development. Organizations like the Long Now Foundation hope to bring genetic engineering to bear on many more such de-extinction efforts, with a focus on passenger pigeons, great auks, and gastric-brooding frogs, all of which were directly or indirectly wiped off the planet by human actions. You can actually follow Church and the Harvard’s teams progress at the Woolly Mammoth Project
A POTENTIAL CURE FOR GENETIC DISEASE
Notwithstanding the numerous exciting developments in plant and animal applications, the greatest promise of CRISPR technology is arguably to cure genetic diseases in human patients
CRISPR offers the possibility of this ideal treatment. In dozens of proof-of-concept studies already published, scientists have successfully leveraged CRISPR in cultured human cells to eradicate the mutations that cause sickle cell disease, beta-thalassemia, hemophilia, Duchenne muscular dystrophy, blindness, and countless other genetic disorders.
CRISPR has been injected into mouse and canine models of human disease, and achieved lasting and effective reversal of disease symptoms. And physicians have already tested the first gene-editing-based treatments in patients, though it is too early to say whether or not the treatments were efficacious.
CURE FOR CANCER?
In a parallel and equally exciting avenue of research, CRISPR is being combined with a promising (and Nobel Prize-winning) new avenue of cancer treatment, known as cancer immunotherapy. Here, human immune cells are enhanced with genetic engineering, endowing them with specialized molecules that can hunt down markers specific to cancer, and then potently eliminate cancerous cells from the body.
In a remarkable first, Layla Richards, a one-year-old patient from London who was suffering from acute lymphoblastic leukemia, the most common type of childhood cancer, was cured in 2015 using a combination of gene-edited immune cells and bone marrow transplant. Chinese scientists have since initiated clinical trials in dozens of other patients using gene-edited immune cells to treat cancer, and additional trials are imminent in the US and Europe.
To be sure, many challenges remain before the full potential of CRISPR-based disease cures can be realized. For one, the tricky problem of delivery remains: how to deliver CRISPR into the body and edit enough of an adult patient’s forty trillion cells to have a lasting effect, and to do so safely without any adverse effects.
Additionally, the edits need to be introduced with an extreme level of accuracy, so that other genes are not inadvertently perturbed while the disease-associated mutation is being repaired. Early reports highlighted the risk of so-called off-target effects, in which CRISPR induced unintended mutations, and, given the permanent nature of DNA changes, the bar must be set very high for a gene-editing therapy to be proven safe.
In 2015, for the first time ever, human embryos were subjected to precision gene editing. The resulting embryos were not implanted to establish pregnancies, and those initial experiments were not particularly successful at achieving the desired edits, but, nevertheless, the red line had been crossed.
Many fear that the first humans to be born with engineered DNA mutations may be just around the corner. researchers in China have actually proceeded to human clinical trials using CRISPR much faster than has been possible in the United States. Normally, the clinical trial process to test any new therapy requires several very well studied stages. The first stage is to test in animals to make sure that there’s complete safety. Then it goes into very limited testing in human beings, just for safety, and then proceeds from there. Apparently in China, they took the animal data and they went right into therapeutic trials in human beings. And the most recent reports that are that somewhere between 80 and 100 people are already being tried, or already being tested using CRISPR.
We know that in China, they’re using CRISPR for cancer therapy. That’s the example where cells are taken out of the body, their immune cells are manipulated with CRISPR and then they’re re-infused. It’s too early to tell if it’s successful or not. But there is a lot of concern that the regulatory authorities in China have been extremely permissive with allowing these technologies to move forward.
With regulatory authorities so lax in China, a Chinese scientist recently claimed he had produced the world’s first gene-edited babies although there has been no research published to support his claims, his actions would be a sensational breach of international scientific conventions. Although gene editing holds promise to potentially correct dangerous disease-causing mutations and treat some medical conditions, there are many safety and ethical concerns about editing human embryos.
The scientist, He Jiankui, said he used Crispr, a gene-editing technique, to alter a gene in human embryos — and then implanted the embryos in the womb of a woman, who gave birth to twin girls in November. That is illegal in many countries, including the United States. China has halted Dr. He’s research and is investigating whether he broke any laws there. Among the concerns are whether the couples involved in Dr. He’s research were adequately informed about the embryo editing and the potential risks involved.
Dr. He says he has submitted his research to a scientific journal. But nothing has been published yet, and he announced the births of the twins before his research could be peer-reviewed by fellow scientists. He also appears to have taken other secretive steps that defy scientific standards. Changing the genes in an embryo means changing genes in every cell. If the method succeeds, the baby will have alterations that will be inherited by all of the child’s progeny. And that, scientists agree, is a serious undertaking that must be done with great deliberation and only to treat a serious disease for which there are no other options — if it is to be done at all.
Bodybuilder beagles, and genetically modified dogs has already happened. CRISPR is moving scientific advancement faster than we can keep up with. Glow in the dark dogs, genetically modified humans, plants and animals all sounds like science fiction. But, believe it or not, it’s already happening. It’s a frightening thought that we don’t know what the ramifications will end up being. We could either be eradicating disease and curing genetic defects in animals, or we could unknowingly be risking them all, us included, by playing God.
We’re living in a very exciting and terrifying time.
BULLY KING Magazine
