Google Genomics could prove more significant than any of these moonshots. Connecting and comparing genomes by the 1000s, and soon by the millions, is what’s going to propel medical discoveries for the next 10 years.
this will save so many lives it’s not even funny. we’re of course very very early into this. kinda like the internet in 1995 when larry & sergey were fresh-faced students at stanford, and there were 20k web sites.
and yes, obviously doing the right thing privacy wise is a big big big responsibility.
If somatic mutations are common in healthy bodies, then biomedical researchers can no longer assume that DNA aberrations point toward the causes of disease. Doctors won’t be able to trust that the DNA found in a blood or saliva sample actually reflects the gene sequences in the heart or the liver. Should somatic variation turn out to be not just common but also good for you, it will undermine the longstanding presumption that the healthiest genome gets replicated with perfect fidelity. The most highly functional bodies may be the ones that permit a little mutation, that encourage a certain amount of genetic wildness and disorder within
not only are you 90% bacterial, but the human parts of you can’t get their shit together.
within our bodies our cells are not all created equal at the genomic level. In other words, we are mosaics.
During a new infection, the bacterial DNA was found to mutate at 40-50x the average rate. All of the bacterial DNA mutated quickly, but the changes manifested most prominently in the cell’s outer membrane proteins, helping them avoid detection by human defense cells.
From the moment life gained a foothold on Earth the diversity of organisms has been written in a DNA code of 4 letters. The latest study moves life beyond G, T, C and A and introduces 2 new letters of life: X and Y.
and here’s P and Z:
Researchers have shown that 2 synthetic nucleotides called P and Z fit seamlessly into DNA’s helical structure, maintaining the natural shape of DNA. Moreover, DNA sequences incorporating these letters can evolve just like traditional DNA, a first for an expanded genetic alphabet. The new nucleotides even outperform their natural counterparts. When challenged to evolve a segment that selectively binds to cancer cells, DNA sequences using P and Z did better than those without.
more on Z and other noncanonical bases:
Z and other modified DNA bases seem to have evolved to help viruses evade the defenses with which bacteria degrade foreign genetic material. The eternal arms race between bacteriophages and their host cells probably provides enough selection pressure to affect something as seemingly “sacrosanct” as DNA. “Right now, everyone thinks the modifications are just protecting the DNA. People almost trivialize it.” But something more may be at work: The triple bond of Z might add to DNA’s stability and rigidity, and perhaps influence some of its other physical properties. Those changes could carry advantages beyond hiding from bacterial defenses and could make such modifications more broadly significant. After all, no one really knows how many viruses may have played with their DNA like this. “Standard genome sequencing methods for looking for biological diversity in nature would fail to find these, because we are looking in a way that assumes a common biochemistry that is not present.”
Researchers have sequenced the whole genomes of 2500 people from Iceland. They have genotyped ~120k Icelanders. They can impute whole genome sequence down to variants with less than 0.1% frequency.
On the plan to sequence all icelanders, to find patterns of disease.
In the trove of data, Decode found rare mutations that dramatically increase the risk for Alzheimer’s, gallstones, atrial fibrillation, and liver and thyroid diseases—mutations that appear to be the result of “knocked out” or missing pieces of DNA. Perhaps most intriguing is the detective work that lies ahead. Decode identified 1171 knocked out genes, present in nearly 8% of the 104K people studied. The next step is to work backward—in the opposite direction one normally goes in genetics research—and cross-reference these knockouts with medical records and phenotypical data and try to determine the impact of these mistakes in nature.
Scientists estimate that among all the viruses that infect all the animals of the world there may be around 800K which could, in the right circumstances, jump from their habitual hosts into humans and start spreading. Could all of them be identified, too, and sentry posts set up that would provide news of their incursions? The Global Immunological Observatory would ideally test every tiny sample of blood for 100Ks of distinct antibodies. Considering how hard large-scale testing for just sars-cov-2 has proved, this might seem impossibly ambitious.
After the pandemic, there will still be new strains of flu and other viruses to code. There will be a backlog of sequencing work for cancer and prenatal health and rare genetic diseases. There will be an ongoing surveillance effort for SARS-CoV-2 variants. An even bigger job, moreover, involves a continuing project to sequence untold strains of microbes, a project that Ginkgo has been involved with in search of new pharmaceuticals.
now that sequencing is cheap, it will move out of the lab and in situ:
Multiple appliances could benefit from integration with sequencing
sensors, including air conditioning or the main water supply to monitor harmful pathogens
2022-05-04: Bill Gates on how to prevent the next pandemic. He also wrote a book about it. Strangely, he has a misplaced belief in the WHO, which completely failed us.
If we’re going to make COVID-19 the last pandemic, the world needs to get to work right away on 3 key areas:
1. Make and deliver better tools.
1 key step is to create a library of antiviral compounds that are designed to attack common respiratory viruses, so that we can more easily find out if an existing drug will work in the event of an outbreak. We should also expand incentives for generics manufacturers to create low-cost versions of new drugs. We also need to support work on new types of tests that make it easier to collect samples and turn around results quickly, like better versions of the rapid antigen tests that many of us now take at home for COVID or even handheld devices that health workers can use to easily test people in their community.
2. Improve disease monitoring.
Creating the GERM—Global Epidemic Response and Mobilization—team is one of the most important steps we can take to stop the next pandemic. GERM will play a crucial role in virtually every aspect of pandemic prevention, but improving monitoring will be the most significant part of their mandate.
3. Strengthen health systems.
There are steps that countries at every income level should consider, like improving primary health care and deciding in advance of a crisis who will oversee what. Governments and donors also need a global forum where they can coordinate action with poor countries.
By feeding biological data about the various types of bats — their diet, the length of their wings, and so on — into their computer, they created a model that could offer predictions about the bats most likely to harbor betacoronaviruses. They found over 300 species that fit the bill.
Since that prediction in 2020, researchers have indeed found betacoronaviruses in 47 species of bats — all of which were on the prediction lists produced by some of the computer models they had created for their study. It was striking the way simple features such as body size could lead to powerful predictions about viruses. “A lot of it is the low-hanging fruit of comparative biology”.
The long story of sequencing the coelacanth genome, the fish most closely related to us (but not our direct ancestor)
When it turned up unexpectedly, the coelacanth was the biological find of the century. And now it is showing why. Its biographer tells the best fish story in 380 ma
CRISPR allows for much better genetic engineering than previous approaches and is a huge deal. It even works in human cells. Probably Nobel prize material. 2015-06-11: 1000x CRISPR
It is now possible to record a human genome (differences relative to a reference is only 2 megabytes. This is instead of 9 terabytes for a human genome with image data. CRISPR improvements are getting to 1 off target in 1 in 100 trillion (10^14) to 1 in 10 million trillion (10^19)
Editas plans to deliver the CRISPR technology as a gene therapy. The treatment will involve injecting into the retina a soup of viruses loaded with the DNA instructions needed to manufacture the components of CRISPR, including a protein that can cut a gene at a precise location. To treat LCA, the company intends to delete 1000 DNA letters from CEP290 in a patient’s photoreceptor cells.
CRISPR is far too important to become entangled in the same web of confusion that has made G.M.O.s such a toxic issue. We ought to have learned something from those troubling and extended shouting matches; scientists, politicians, and everyone else needs to join in on this debate now. Society has no choice but to come to terms with both the potential benefits and the possible risks. That will require a big change: today, there isn’t even really a regulatory mechanism capable of governing products like CRISPR.
2016-03-09: Improvements to CRISPR subtypes like Cpf1 and now Cas9 are happening very quickly. This should reduce errors and increase the power of these gene editing technologies. 2016-10-14: CRISPR corrects sickle cells
Sickle cell disease is a genetic disorder caused by a mutation in one of the hemoglobin genes, which causes deformation of red blood cells and results in occlusion of blood vessels, severe pain crises, and progressive organ injury. To correct the mutation that causes this disease, DeWitt et al. modified hematopoietic stem cells from sickle cell disease patients using a CRISPR/Cas9 gene editing approach. The authors showed that the corrected cells successfully engrafted in a mouse model and produced enough normal hemoglobin to have a potential clinical benefit in the setting of sickle cell disease.
Do you think that the medical applications of CRISPR in themselves can inform basic science?
For sure. CRISPR technology has been widely adopted by all kinds of scientists, including people like me. I was never doing anything with genome editing before CRISPR came along.
In my lab we’ve had a project over the last few years working on Huntington’s chorea, a degenerative neurological disease. The mutation that causes the disease is a single codon — 3 base pairs in the DNA — that gets repeated many times. If the codon gets repeated too many times, it leads to a defective protein that causes this disease. That’s been known for a long time, but the challenge was, how do you fix it?
We’ve been working on a way to deliver the CRISPR into mouse neuronal cells to make the necessary edits. But one of the curious things that’s come out of that line of work is that we found that only neuronal cells in the mouse brain were getting edited, not [the supportive glial] cells called astrocytes.
These cells are a lot smaller, so it could be that they don’t have enough surface area to take up the CRISPR protein efficiently. Or maybe they don’t respond to DNA cutting and editing in the same way as other cells.
2019-03-01: CRISPR error rates. Gene Editing Is Trickier Than Expected
how many errors are too many? Cells are prone to making their own mistakes—on the order of 1 every 1M-100M base pairs, with more for skin cells, and fewer for sperm and eggs. Does it matter if an overactive gene editor makes that number closer to 1 in 500K?
The number of stories and journal articles about how CRISPR DNA-editing technology works, has worked, and is planned to work are beyond counting. How about an article about how to stop it in its tracks? That’s this one, just published in Cell from a multicenter team in Cambridge and New York. It describes a screening program for small-molecule inhibitors of S. pyogenes Cas9 (spCas9), because one would want some ways (not all of which currently exist) to turn its effects off in given places and at given times.
The teaser zooms in on the stomach-stabbing self-experimentations of biohackers like Josiah Zayner and Aaron Traywick. DIY Crispr is just one subplot in the larger narrative about what happens when nature can be minutely controlled, when humans might even preside over their own evolution. Their cameras also follow scientists like Jennifer Doudna and Kevin Esvelt and the first patients in an experimental gene therapy trial to treat hereditary blindness. “Our main hope is to create a discussion around these technologies. People might come away excited. Or they might be scared. But at least that means they’re talking and learning and understanding what’s coming.”
One of the most compelling arguments against CRISPR gene editing, namely the potential for misuse, can also be considered the most compelling argument for CRISPR gene editing. Banning progress on gene editing technology may create a black market, but the continuation of research on gene editing will allow the scientific community to control its use and ensure patient safety
2022-03-07: Another similar claim of a 4000x improvement. The new paper doesn’t mention BNANC, so who knows if these improvements stack. Probably not.
Researchers discovered how some of these errors can happen. Usually, the Cas9 protein is hunting for a specific sequence of 20 letters in the DNA code, but if it finds one where 18 out of 20 match its target, it might make its edit anyway. To find out why this occurs, the team used cryo-electron microscopy to observe what Cas9 is doing when it interacts with a mismatched sequence. To their surprise, they discovered a strange finger-like structure that had never been observed before. This finger reached out and stabilized the DNA sequence so the protein could still make its edit. Having uncovered this mechanism, the team tweaked this finger so that it no longer stabilized the DNA, instead pushing away from it. That prevents Cas9 from editing that sequence, making the tool 4000x less likely to produce off-target mutations. The team calls the new protein SuperFi-Cas9.
“With this new system we’re seeing a structure and function unlike anything that’s been observed in CRISPR systems to date”.
While other CRISPR systems bind to their target sequence, make their cut, and then stop, when Cas12a2 binds to its target, it seems to “activate,” transforming in shape.
“It’s a change in structure that’s extraordinary to observe — a phenomenon that elicits audible gasps from fellow scientists”. Once activated, the protein can bind to any genetic material that comes near it, whether its single-stranded RNA, single-stranded DNA, or double-stranded DNA. Cas12a2 then starts shredding the material, making multiple cuts in indiscriminate locations.
Because the genetic material can belong to the bacteria itself, the result can be cellular death. CRISPR causes the infected cell to self-destruct — rather than let it become a virus factory.
Microbiologists were learning more about an unusual group of bacteria that use molecular spikes to pierce a hole in the membranes of host cells. The bacteria then transport proteins through the perforation and into the cell, exploiting the host’s physiology in their favor. Using the artificial-intelligence program AlphaFold, which predicts protein structures, the team designed ways to modify the tail fibre so that it would recognize mouse and human cells instead. They then loaded the syringes with various proteins, including Cas9 and toxins that could be used to kill cancer cells, and delivered them into human cells grown in the lab, and into the brains of mice. Similar to the early days of CRISPR–Cas9 research, the bacterial syringes are studied by only a handful of labs, and their roles in microbial ecology are only beginning to be understood.
That’s really what inspired us to develop base editing in 2016 and then prime editing in 2019. These are methods that allow you to change a DNA sequence of your choosing into a different sequence of your choosing, where you get to specify the sequence that comes out of the editing process. And that means you can, for the first time in a general way, programmable change a DNA sequence, a mutation that causes a genetic disease, for example, into a healthy sequence back into the normal, the so-called wild type sequence, for example. So base editors work by actually performing chemistry on an individual DNA base, rearranging the atoms of that base to become a different base.
epigenetics can work on the scale of hours and 100s of genes, truly massive.
When the No. 2 cichlid saw that he was now No. 1, he responded quickly. He underwent massive surges in gene expression that immediately blinged up his pewter coloring with lurid red and blue streaks and, in a matter of hours, caused him to grow some 20%. It was as if Jason Schwartzman, coming to work 1 day to learn the big office stud had quit, morphed into Arnold Schwarzenegger by close of business.
Earth has fewer species than we think
More and more, biologists are discovering that organisms thought to be different species are, in fact, but 1. A recent example is that the formerly accepted 2 species of giant North American mammoths (the Columbian mammoth and the woolly mammoth) were genetically the same but the 2 had phenotypes determined by environment.
Gregor J. Rothfuss 