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."
Our hearts beat at a resting rate of 60 to 100 beats per minute. Lots of other things pulse, too. The colors we see and the pitches we hear, for example, are due to the different wave frequencies ("pulses") of light and sound waves.
Now, a study in the journal Geoscience Frontiers finds that Earth itself has a pulse, with one "beat" every 27.5 million years. That's the rate at which major geological events have been occurring as far back as geologists can tell.
A planetary calendar has 10 dates in red
Credit: Jagoush / Adobe Stock
According to lead author and geologist Michael Rampino of New York University's Department of Biology, "Many geologists believe that geological events are random over time. But our study provides statistical evidence for a common cycle, suggesting that these geologic events are correlated and not random."
The new study is not the first time that there's been a suggestion of a planetary geologic cycle, but it's only with recent refinements in radioisotopic dating techniques that there's evidence supporting the theory. The authors of the study collected the latest, best dating for 89 known geologic events over the last 260 million years:
- 29 sea level fluctuations
- 12 marine extinctions
- 9 land-based extinctions
- 10 periods of low ocean oxygenation
- 13 gigantic flood basalt volcanic eruptions
- 8 changes in the rate of seafloor spread
- 8 times there were global pulsations in interplate magmatism
The dates provided the scientists a new timetable of Earth's geologic history.
Tick, tick, boom
Credit: New York University
Putting all the events together, the scientists performed a series of statistical analyses that revealed that events tend to cluster around 10 different dates, with peak activity occurring every 27.5 million years. Between the ten busy periods, the number of events dropped sharply, approaching zero.
Perhaps the most fascinating question that remains unanswered for now is exactly why this is happening. The authors of the study suggest two possibilities:
"The correlations and cyclicity seen in the geologic episodes may be entirely a function of global internal Earth dynamics affecting global tectonics and climate, but similar cycles in the Earth's orbit in the Solar System and in the Galaxy might be pacing these events. Whatever the origins of these cyclical episodes, their occurrences support the case for a largely periodic, coordinated, and intermittently catastrophic geologic record, which is quite different from the views held by most geologists."
Assuming the researchers' calculations are at least roughly correct — the authors note that different statistical formulas may result in further refinement of their conclusions — there's no need to worry that we're about to be thumped by another planetary heartbeat. The last occurred some seven million years ago, meaning the next won't happen for about another 20 million years.
When I was a junior in college, my electromagnetism professor had an awesome idea. Apart from the usual homework and exams, we were to give a seminar to the class on a topic of our choosing. The idea was to gauge which area of physics we would be interested in following professionally.
Professor Gilson Carneiro knew I was interested in cosmology and suggested a book by Nobel Prize Laureate Steven Weinberg: The First Three Minutes: A Modern View of the Origin of the Universe. I still have my original copy in Portuguese, from 1979, that emanates a musty tropical smell, sitting on my bookshelf side-by-side with the American version, a Bantam edition from 1979.
Inspired by Steven Weinberg
Books can change lives. They can illuminate the path ahead. In my case, there is no question that Weinberg's book blew my teenage mind. I decided, then and there, that I would become a cosmologist working on the physics of the early universe. The first three minutes of cosmic existence — what could be more exciting for a young physicist than trying to uncover the mystery of creation itself and the origin of the universe, matter, and stars? Weinberg quickly became my modern physics hero, the one I wanted to emulate professionally. Sadly, he passed away July 23rd, leaving a huge void for a generation of physicists.
What excited my young imagination was that science could actually make sense of the very early universe, meaning that theories could be validated and ideas could be tested against real data. Cosmology, as a science, only really took off after Einstein published his paper on the shape of the universe in 1917, two years after his groundbreaking paper on the theory of general relativity, the one explaining how we can interpret gravity as the curvature of spacetime. Matter doesn't "bend" time, but it affects how quickly it flows. (See last week's essay on what happens when you fall into a black hole).
The Big Bang Theory
For most of the 20th century, cosmology lived in the realm of theoretical speculation. One model proposed that the universe started from a small, hot, dense plasma billions of years ago and has been expanding ever since — the Big Bang model; another suggested that the cosmos stands still and that the changes astronomers see are mostly local — the steady state model.
Competing models are essential to science but so is data to help us discriminate among them. In the mid 1960s, a decisive discovery changed the game forever. Arno Penzias and Robert Wilson accidentally discovered the cosmic microwave background radiation (CMB), a fossil from the early universe predicted to exist by George Gamow, Ralph Alpher, and Robert Herman in their Big Bang model. (Alpher and Herman published a lovely account of the history here.) The CMB is a bath of microwave photons that permeates the whole of space, a remnant from the epoch when the first hydrogen atoms were forged, some 400,000 years after the bang.
The existence of the CMB was the smoking gun confirming the Big Bang model. From that moment on, a series of spectacular observatories and detectors, both on land and in space, have extracted huge amounts of information from the properties of the CMB, a bit like paleontologists that excavate the remains of dinosaurs and dig for more bones to get details of a past long gone.
How far back can we go?
Confirming the general outline of the Big Bang model changed our cosmic view. The universe, like you and me, has a history, a past waiting to be explored. How far back in time could we dig? Was there some ultimate wall we cannot pass?
Because matter gets hot as it gets squeezed, going back in time meant looking at matter and radiation at higher and higher temperatures. There is a simple relation that connects the age of the universe and its temperature, measured in terms of the temperature of photons (the particles of visible light and other forms of invisible radiation). The fun thing is that matter breaks down as the temperature increases. So, going back in time means looking at matter at more and more primitive states of organization. After the CMB formed 400,000 years after the bang, there were hydrogen atoms. Before, there weren't. The universe was filled with a primordial soup of particles: protons, neutrons, electrons, photons, and neutrinos, the ghostly particles that cross planets and people unscathed. Also, there were very light atomic nuclei, such as deuterium and tritium (both heavier cousins of hydrogen), helium, and lithium.
Cosmic alchemy
So, to study the universe after 400,000 years, we need to use atomic physics, at least until large clumps of matter aggregate due to gravity and start to collapse to form the first stars, a few millions of years after. What about earlier on? The cosmic history is broken down into chunks of time, each the realm of different kinds of physics. Before atoms form, all the way to about a second after the Big Bang, it's nuclear physics time. That's why Weinberg brilliantly titled his book The First Three Minutes. It is during the interval between one-hundredth of a second and three minutes that the light atomic nuclei (made of protons and neutrons) formed, a process called, with poetic flair, primordial nucleosynthesis. Protons collided with neutrons and, sometimes, stuck together due to the attractive strong nuclear force. Why did only a few light nuclei form then? Because the expansion of the universe made it hard for the particles to find each other.
What about the nuclei of heavier elements, like carbon, oxygen, calcium, gold? The answer is beautiful: all the elements of the periodic table after lithium were made and continue to be made in stars, the true cosmic alchemists. Hydrogen eventually becomes people if you wait long enough. At least in this universe.
In this article, we got all the way up to nucleosynthesis, the forging of the first atomic nuclei when the universe was a minute old. What about earlier on? How close to the beginning, to t = 0, can science get? Stay tuned, and we will continue next week.
To Steven Weinberg, with gratitude, for all that you taught us about the universe.
