American researchers have announced the successful repair of a human embryo's genes. As reported in the journal Nature, they used CRISPR-cas9. On one hand, their success represents an exciting breakthrough and on the other, it's a stark reminder of all we don't yet understand about human genetics. That's because the repair of the gene occurred in a way that researchers didn't anticipate.
The gene they repaired is MYBPC3. A mutation in it causes hypertrophic cardiomyopathy (HCM). With HCM, which is estimated to occur in 700,000 to 725,000 U.S. citizens — 1 in 500's heart muscle becomes thickened. Many people lead normal lives with it, with or without treatment. HCM isn't restricted to any particular group or gender, either, but the disease is especially worrisome in young people, where its first symptom can be sudden death — in fact, it's the most common cause of death in young athletes.
Word of the repair first appeared in i News, followed a week later by the peer-reviewed study in Nature. An international team authored the study, with scientists from Oregon, California, China, and South Korea. They were led by senior author Shoukhrat Mitalipov, director of the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University (OHSU).
Mitalipov previously made a name for himself by introducing the first cloned stem cells from monkeys, the first “three-parent" monkeys, and making embryonic cells from human skin cells.
Shoukhrat Mitalipov (UYGHUR HUMAN RIGHTS PROJECT)
The new study involved embryos created with eggs from 12 healthy females injected with sperm from a male with the MYBPC3 mutation. The team tried twice, using a cas9 enzyme targeting the mutation they sought to snip out. The cas9 enzyme was accompanied by a synthetic DNA template modeled after a normal MYBPC3 gene, but chemically tagged so it could be identified by researchers later.
CRISPR After Fertilization
In the first experiments, the scientists fertilized 54 eggs with the sperm, and then injected the cas9 enzyme and template post-fertilization.
In 36 of the embryos (66.7%), the mutation was repaired. Of the remaining 18 (33.3%), 5 embryos were simply not repaired. The other 13 were more troubling: They contained a “mosaic" of repaired and unrepaired genes that may represent a potential time bomb for subsequent generations, one of the reasons many are encouraging caution when modifying embryos. Bioethicist L. Syd M Johnson tells Big Think, “It's one thing to use experimental gene therapies in patients, where the modifications will be isolated to that individual. It's something else entirely to make genomic changes that could potentially be passed on to future generations, which is what happens when you alter an embryo."
If you carry the MYBPC3 mutation, there's a 50% chance your children will develop HCM. It only takes one parent having the mutation for offspring to acquire the condition.
CRISPR During Fertilization — and a Surprise
In the second round, the scientists injected the sperm, cas9, and the DNA template together, and the the result was a pronounced increase in their success rate. In 42 of the 58 embryos, 72.4%, the mutation was successfully snipped out and replaced by cells without the MYBPC3 mutation. And — most encouragingly — no mosaic embryos were produced.
But here's the surprise, and the reminder of how much there still is to learn. The replaced DNA in all 41 of the repaired embryos was not from the injected DNA template — instead it was non-synthesized, or “wild," MYBPC3 material from the maternal egg. “We were so surprised that we just couldn't get this template that we made to be used," Mitalipov tells New York Times. “It was very new and unusual."
It also allows Mitalipov to hedge a bit as to just exactly what he and his team have done. “Everyone always talks about gene editing," he says. “I don't like the word 'editing.' We didn't edit or modify anything. All we did was unmodify a mutant gene using the existing wild-type maternal gene." In other words, we didn't implant synthetic DNA in anyone. This is why the title of his paper is “Correction of a Pathogenic Gene Mutation in Human Embryos." To be fair, “unmodifying" something should really mean to just leave it alone, and it may be more accurate to say that his team simply snipped out a mutation and the embryo unexpectedly did the rest.
Moral Concerns
The study notes the potential for repairing embryos with undesirable mutations before they're implanted during IVF, and others agree that reducing the number of defective embryos would be a positive thing. Not everyone's comfortable with the idea though. There is the issue of the potential for engineering “designer babies." Hank Greely, director of the Center for Law and the Biosciences at Stanford notes, “If you're in one camp, it's a horror to be avoided, and if you're in the other camp, it's desirable."
“There's an additional worry that this technology might be used for nefarious purposes," says Johnson, “to advance eugenicist policies, for example, to 'weed out' undesirable traits or people." She adds, “It's a small conceptual step to move from so-called undesirable traits to undesirable humans. Humans have an unfortunate history of taking that step."
(WINSLOW ANDERSON)
Going Forward
Mitalipov's next step is to see if he can similarly “unmodify" other mutations, including some that are trickier to target than MYBPC3s. The legal terrain in the U.S is not exactly welcoming of such efforts, with the Food and Drug Administration prohibited from permitting clinical trials of germline engineering, and the National Institutes of Health not funding research on gene-editing in humans. (Mitalipov's work was funded by OHSU, the Institute for Basic Science in South Korea, and some private foundations.) This may be starting to change, though — a committee of the National Academy of Sciences, Engineering and Medicine has recently endorsed the modification of human embryos for the purposes of repairing mutations that would otherwise lead to a serious condition if there's no other known remedy.
While the possibilities suggested by the study's success are obvious, the results weren't perfect, and there's more work to be done. As Gaétan Burgio told WIRED, “This is a remarkable paper that shows how much the field has progressed in just the last year or two. But I think for now everyone needs to chill down a bit."
Johnson notes, “We are talking about the future of the human species here. Before we rush headlong into a future where germline genetic modifications of humans might be possible, it's important to consider whether that's a future we really want, how the use of the technology will be controlled, who will have access to it, and how human individuals and the diversity of our species will be protected."
Ash deposits of some of North America's largest volcanic eruptions.
The end of the world as we know it
Panoramic view of Yellowstone National Park
Image: Heinrich Berann for the National Park Service – public domain
Of the many freak ways to shuffle off this mortal coil – lightning strikes, shark bites, falling pianos – here's one you can safely scratch off your worry list: an outbreak of the Yellowstone supervolcano.
As the map below shows, previous eruptions at Yellowstone were so massive that the ash fall covered most of what is now the western United States. A similar event today would not only claim countless lives directly, but also create enough subsidiary disruption to kill off global civilisation as we know it. A relatively recent eruption of the Toba supervolcano in Indonesia may have come close to killing off the human species (see further below).
However, just because a scenario is grim does not mean that it is likely (insert topical political joke here). In this case, the doom mongers claiming an eruption is 'overdue' are wrong. Yellowstone is not a library book or an oil change. Just because the previous mega-eruption happened long ago doesn't mean the next one is imminent.
Ash beds of North America
Ash beds deposited by major volcanic eruptions in North America.
Image: USGS – public domain
This map shows the location of the Yellowstone plateau and the ash beds deposited by its three most recent major outbreaks, plus two other eruptions – one similarly massive, the other the most recent one in North America.
Huckleberry Ridge
The Huckleberry Ridge eruption occurred 2.1 million years ago. It ejected 2,450 km3 (588 cubic miles) of material, making it the largest known eruption in Yellowstone's history and in fact the largest eruption in North America in the past few million years.
This is the oldest of the three most recent caldera-forming eruptions of the Yellowstone hotspot. It created the Island Park Caldera, which lies partially in Yellowstone National Park, Wyoming and westward into Idaho. Ash from this eruption covered an area from southern California to North Dakota, and southern Idaho to northern Texas.
Mesa Falls
About 1.3 million years ago, the Mesa Falls eruption ejected 280 km3 (67 cubic miles) of material and created the Henry's Fork Caldera, located in Idaho, west of Yellowstone.
It was the smallest of the three major Yellowstone eruptions, both in terms of material ejected and area covered: 'only' most of present-day Wyoming, Colorado, Kansas and Nebraska, and about half of South Dakota.
Lava Creek
The Lava Creek eruption was the most recent major eruption of Yellowstone: about 640,000 years ago. It was the second-largest eruption in North America in the past few million years, creating the Yellowstone Caldera.
It ejected only about 1,000 km3 (240 cubic miles) of material, i.e. less than half of the Huckleberry Ridge eruption. However, its debris is spread out over a significantly wider area: basically, Huckleberry Ridge plus larger slices of both Canada and Mexico, plus most of Texas, Louisiana, Arkansas, and Missouri.
Long Valley
This eruption occurred about 760,000 years ago. It was centered on southern California, where it created the Long Valley Caldera, and spewed out 580 km3 (139 cubic miles) of material. This makes it North America's third-largest eruption of the past few million years.
The material ejected by this eruption is known as the Bishop ash bed, and covers the central and western parts of the Lava Creek ash bed.
Mount St Helens
The eruption of Mount St Helens in 1980 was the deadliest and most destructive volcanic event in U.S. history: it created a mile-wide crater, killed 57 people and created economic damage in the neighborhood of $1 billion.
Yet by Yellowstone standards, it was tiny: Mount St Helens only ejected 0.25 km3 (0.06 cubic miles) of material, most of the ash settling in a relatively narrow band across Washington State and Idaho. By comparison, the Lava Creek eruption left a large swathe of North America in up to two metres of debris.
The difference between quakes and faults
The volume of dense rock equivalent (DRE) ejected by the Huckleberry Ridge event dwarfs all other North American eruptions. It is itself overshadowed by the DRE ejected at the most recent eruption at Toba (present-day Indonesia). This was one of the largest known eruptions ever and a relatively recent one: only 75,000 years ago. It is thought to have caused a global volcanic winter which lasted up to a decade and may be responsible for the bottleneck in human evolution: around that time, the total human population suddenly and drastically plummeted to between 1,000 and 10,000 breeding pairs.
Image: USGS – public domain
So, what are the chances of something that massive happening anytime soon? The aforementioned mongers of doom often claim that major eruptions occur at intervals of 600,000 years and point out that the last one was 640,000 years ago. Except that (a) the first interval was about 200,000 years longer, (b) two intervals is not a lot to base a prediction on, and (c) those intervals don't really mean anything anyway. Not in the case of volcanic eruptions, at least.
Earthquakes can be 'overdue' because the stress on fault lines is built up consistently over long periods, which means quakes can be predicted with a relative degree of accuracy. But this is not how volcanoes behave. They do not accumulate magma at constant rates. And the subterranean pressure that causes the magma to erupt does not follow a schedule.
What's more, previous super-eruptions do not necessarily imply future ones. Scientists are not convinced that there ever will be another big eruption at Yellowstone. Smaller eruptions, however, are much likelier. Since the Lava Creek eruption, there have been about 30 smaller outbreaks at Yellowstone, the last lava flow being about 70,000 years ago.
As for the immediate future (give or take a century): the magma chamber beneath Yellowstone is only 5 percent to 15 percent molten. Most scientists agree that is as un-alarming as it sounds. And that its statistically more relevant to worry about death by lightning, shark, or piano.
Strange Maps #1041
Got a strange map? Let me know at strangemaps@gmail.com.
Stoicism can help overcome anxiety
Are you a worrier? Do you imagine nightmare scenarios and then get worked up and anxious about them? Does your mind get caught in a horrible spiral of catastrophizing over even the smallest of things? Worrying, particularly imagining the worst case scenario, seems to be a natural part of being human and comes easily to a lot of us. It's awful, perhaps even dangerous, when we do it.
But, there might just be an ancient wisdom that can help. It involves reframing this attitude for the better, and it comes from Stoicism. It's called "premeditation," and it could be the most useful trick we can learn.
Practical Stoicism
Broadly speaking, Stoicism is the philosophy of choosing your judgments. Stoics believe that there is nothing about the universe that can be called good or bad, valuable or valueless, in itself. It's we who add these values to things. As Shakespeare's Hamlet says, "There is nothing either good or bad, but thinking makes it so." Our minds color the things we encounter as being "good" or "bad," and given that we control our minds, we therefore have control over all of our negative feelings.
Put another way, Stoicism maintains that there's a gap between our experience of an event and our judgment of it. For instance, if someone calls you a smelly goat, you have an opportunity, however small and hard it might be, to pause and ask yourself, "How will I judge this?" What's more, you can even ask, "How will I respond?" We have power over which thoughts we entertain and the final say on our actions. Today, Stoicism has influenced and finds modern expression in the hugely effective "cognitive behavioral therapy."
One of the principal fathers of ancient Stoicism was the Roman statesmen, Seneca, who argued that the unexpected and unforeseen blows of life are the hardest to take control over. The shock of a misfortune can strip away the power we have to choose our reaction. For instance, being burglarized feels so horrible because we had felt so safe at home. A stomach ache, out of the blue, is harder than a stitch thirty minutes into a run. A sudden bang makes us jump, but a firework makes us smile. Fell swoops hurt more than known hardships.
What could possibly go wrong?
So, how can we resolve this? Seneca suggests a Stoic technique called "premeditatio malorum" or "premeditation." At the start of every day, we ought to take time to indulge our anxious and catastrophizing mind. We should "rehearse in the mind: exile, torture, war, shipwreck." We should meditate on the worst things that could happen: your partner will leave you, your boss will fire you, your house will burn down. Maybe, even, you'll die.
This might sound depressing, but the important thing is that we do not stop there.
Stoicism has influenced and finds modern expression in the hugely effective "cognitive behavioral therapy."
The Stoic also rehearses how they will react to these things as they come up. For instance, another Stoic (and Roman Emperor) Marcus Aurelius asks us to imagine all the mean, rude, selfish, and boorish people we'll come across today. Then, in our heads, we script how we'll respond when we meet them. We can shrug off their meanness, smile at their rudeness, and refuse to be "implicated in what is degrading." Thus prepared, we take control again of our reactions and behavior.
The Stoics cast themselves into the darkest and most desperate of conditions but then realize that they can and will endure. With premeditation, the Stoic is prepared and has the mental vigor necessary to take the blow on the chin and say, "Yep, l can deal with this."
Catastrophizing as a method of mental inoculation
Seneca wrote: "In times of peace, the soldier carries out maneuvers." This is also true of premeditation, which acts as the war room or training ground. The agonizing cut of the unexpected is blunted by preparedness. We can prepare the mind for whatever trials may come, in just the same way we can prepare the body for some endurance activity. The world can throw nothing as bad as that which our minds have already imagined.
Stoicism teaches us to embrace our worrying mind but to embrace it as a kind of inoculation. With a frown over breakfast, try to spend five minutes of your day deliberately catastrophizing. Get your anti-anxiety battle plan ready and then face the world.
Jonny Thomson teaches philosophy in Oxford. He runs a popular Instagram account called Mini Philosophy (@philosophyminis). His first book is Mini Philosophy: A Small Book of Big Ideas.
