In my book, which I will now shamelessly promote – The Skeptics’ Guide to the Future – my coauthors and I discuss the incredible potential of information-based technologies. As we increasingly transition to digital technology, we can leverage the increasing power of computer hardware and software. This is not just increasing linearly, but geometrically. Further, there are technologies that make other technologies more information-based or digital, such as 3D printing. The physical world and the virtual world are merging.

With current technology this is perhaps most profound when it comes to genetics. The genetic code of life is essentially a digital technology. Efficient gene-editing tools, like CRISPR, give us increasing control over the genetic code. Arguably two of the most dramatic science and technology news stories over the last decade have been advances in gene editing and advances in artificial intelligence (AI). These two technologies also work well together – the genome is a large complex system of interacting information, and AI tools excel at dealing with large complex systems of interacting information. This is definitely a “you got chocolate in my peanut butter” situation.

A recent paper nicely illustrates the synergistic power of these two technologies – Interpreting cis-regulatory interactions from large-scale deep neural networks. Let’s break it down.

Cis-regulatory interactions refer to several regulatory functions of non-coding DNA. Coding DNA, which is contained within genes (genes contain both coding and non-coding elements) directly code for amino acids which are assembled into polypeptides and then folded into functional proteins. Remember the ATCG four letter base code, with three bases coding for a specific amino acid (or coding function, like a stop signal). This is coding DNA. Noncoding DAN regulates how coding DNA is transcribed into proteins.

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CRISPR has been big scientific news since it was introduced in 2012. The science actually goes back to 1987, but the CRISPR/Cas9 system was patented in 2012, and the developers won the Noble Prize in Chemistry in 2020. The system gives researchers the ability to quickly and cheaply make changes to DNA, by seeking out and matching a desired sequence and then making a cut in the DNA at that location. This can be done to inactivate a specific gene or, using the cells own repair machinery, to insert a gene at that location. This is a massive boon to genetics research but is also a powerful tool of genetic engineering.

There is also the potential for CRISPR to be used as a direct therapy in medicine. In 2023 the first regulatory approval for CRISPR as a treatment for a disease was given to treatments for sickle cell disease and thalassemia. These diseases were targeted for a technical reason – you can take bone marrow out of a patient, use CRISPR to alter the genes for hemoglobin, and then put it back in. What’s really tricky about using CRISPR as a medical treatment is not necessarily the genetic change itself, but getting the CRISPR to the correct cells in the body. This requires a vector, and is the most challenging part of using CRISPR as a medical intervention. But if you can bring the cells to the CRISPR that eliminates the problem.

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The technology of CRISPR (clustered regularly interspaced short palindromic repeat) continues to advance as a rapid pace. A recent study, Cas9/Nickase-induced allelic conversion by homologous chromosome-templated repair in Drosophila somatic cells, provides the potential for a new method of treating certain kinds of genetic diseases. This approach also appears to be safer, with fewer off-site genetic changes, but still has to be tested in humans.

CRISPR works by pairing it with a guide RNA (gRNA) that targets a specific sequence in the DNA, and with a Cas9 endonuclease which will cleave the DNA at the target site. The normal DNA repair machinery will then fix the cut, but there are two basic pathways for this to happen. The first pathway (nonhomologous end joining – NHEJ) blindly reconnects the ends together, creating the potential for the introduction of random mutations at the repair site. This is considered an error-prone repair pathway. The other pathway is homology-directed repair (HDR), which uses the other copy of the DNA as a template, and is therefore much less prone to error. Remember, every cell has two of every somatic chromosome, one from each parent, and therefore two copies of every gene.

The researchers in the current study wanted to know if the HDR pathway could be exploited to not only repair the cleaved DNA but also to make the repaired copy of the gene look like the other copy, the “homologous” gene. Some genetic conditions or traits are dominant and others recessive. A dominant trait will manifest if an organism has only one copy of that trait, which a recessive trait requires that both copies of the gene have the trait. The classic example is eye color (this is an oversimplifcation, but demonstrates the point). Brown eye color is the dominant allele (gene version), while blue is recessive. A person with one brown and one blue allele will have brown eyes (dominant). You need two blue alleles to have blue eyes (recessive).

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Last year I wrote about CRISPR On-Off – this is a system for using the genetic modification tool, CRISPR, in order to turn the expression of a gene off and then back on again, without altering the gene itself. Now researchers have published a similar application of CRISPR, using a different mechanism to turn on the expression of silenced genes. Their technique shows the power of CRISPR as a modifiable platform. The research also used AI to design the new system, again showing how artificial intelligence is being used to dramatically speed up the pace of research.

The new technique also uses CRISPR (Clustered regularly interspaced short palindromic repeats), which was derived from bacteria that use it as part of their immunity against viruses. CRISPR is like a carrier, which can be attached to a specific stretch of DNA. It will then find that stretch of DNA within a genome and target it. CRISPR can also be attached to a variety of proteins, most famously CAS9, which can then perform some function when it gets to its target. CAS9 is a DNA splicer, so a CRISPR-CAS9 system can target a desired stretch of DNA and splice it. This can be used to disrupt a gene, or it can be used to create a location for the insertion of a new gene or gene modification, which requires a separate process involving the DNA repair mechanism.

The CRISPR system dramatically reduced the cost and time necessary to make alterations to a genome. The technology is also rapidly progressing, because research using CRISPR is now available to many more labs and researchers. There are other payloads other than CAS9 that can be used, for example. Researchers are also learning how to tweak the speed vs accuracy of CRISPR.

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Each year 6-7 billion male chicks are culled, because only females are needed for egg laying. Many other animals are also culled because one sex is desired either for food production or research. There are many research questions that are sex specific, and therefore large numbers of a single sex of a specific strain of mice may be required. Culling is a crude way to achieve these ends, and raises concerns about humanely treating animals.

For these reasons researchers have been looking for ways to achieve high degrees of sex selection in animals more efficiently and humanely. A new study published in Nature Communications seems to have made a significant advance in this direction, using CRISPR-Cas9 (a gene-editing system) to create a sex-selection system for either male or female mice that operates with 100% efficiency. The idea is clever – insert one half of a CRISPR-Cas9 kill switch into the X-chromosome of a female mouse, then insert the other half into either the X or Y chromosome of a male mouse. Only those embryos that get both halves of the CRISPR-Cas9 system (either XX or XY) will be killed at the early embryo stage.

This approach has been used before, in insects and zebrafish, but never in mammals. There are also other methods for sex selection that don’t rely on culling, such as sperm sorting, but this approach is not very efficient, and doesn’t work in birds where the females gametes determine sex. This new system has proven 100% effective in mice, and should easily port to other mammals such as pigs and cattle. The researches targeted a gene, the Top 1 gene, that codes for an enzyme critical for early DNA replication in a developing embryo. Inactivating this gene is a “suicide switch” for the embryo. This gene is also highly conserved, and the reason why it should work in all mammals, not just mice.

The researchers discovered that the early activity of this suicide switch has a specific advantage in sex-selection systems – it actually increases the yield (not just the ratio) of the desired sex compared to unselected litters. This happens because is many mammals with litters of multiple offspring, the females overproduce eggs, and not all eggs implant in the uterus. Therefore, if the eggs of the undesired sex are killed very early on more eggs from the desired sex can implant in the uterus and develop.

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I know I just wrote about CRISPR, the powerful gene-editing tool that can make targeted specific alterations to genes, but there is another CRISPR news item I wanted to write about. A recent study published in the NEJM reports the results of a treatment trial using a CRISPR-Cas9 treatment injected into the blood. This is an important proof of concept with implications for the clinical impact of CRISPR.

The study itself involved a rare genetic disease called Transthyretin amyloidosis, also called ATTR amyloidosis, which results from the creation of a misfolded protein that causes damage primarily to nerves and heart tissue. From a genetics point of view, this is conceptually straightforward – turn off the gene making the toxic protein and that should fix the problem. CRISPR is really good at that – it can target the specific gene and then makes cuts in that gene to permanently disable it.

While CRISPR technology is extremely powerful, perhaps the bigger challenge is getting the CRISPR-Cas9 into the desired cells. It is easy to do this in vitro (outside the body in a test tube or dish) but harder to get the CRISPR to the correct cells in a living organism. For this we have been relying primarily on viral vectors, viruses which infect cells, delivering the CRISPR.

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Bonus points for anyone who has managed to commit to memory what the CRISPR acronym stands for – Clustered Regularly Interspaced Short Palindromic Repeats. I still have to look it up each time to make sure I get it right, but I’m getting there. I first wrote about CRISPR in 2015. It is a method of editing genes derived from bacteria. CRISPR itself is a means of targeting a specific sequence of DNA; you load it with the desired gene sequence and it will find the corresponding sequence in the DNA. Of course, it has to do something once it gets there, so CRISPR is also combined with a payload, such as Cas9, which are molecular scissors that will cut the DNA a the targeted location.

Since the potential for the CRISPR-Cas9 system in genetic engineering was realized, the technology has been on a steep climb of advancement. This was a new platform, one that had the advantage of being relatively quick, easy, and cheap. This means that genetics researchers round the world were all able to play with their new toy, and not only find uses for it but find ways to improve it. The basic technology slices DNA at a desired location. One limitation of this technology, as accurate as it is, there are still off-target effects. But researcher have already started to unpack how to make CRISPR slower but more accurate (vs faster but less accurate). They know how to dial in the accuracy, and it’s likely this aspect of the technology will improve further.

Also, once you make a slice in the DNA this can have a couple of effects. If all you want to do is kill the cell (like a cancer cell) you just make a bunch of slices and be done with it. If you want to inactivate a single gene your job may also be done. However, if you want to edit the gene then there is another step. You need to coax the cell into using its own repair mechanism to fix the break in the DNA while simultaneously inserting a new bit of DNA into the break. This is full gene editing, and while it’s still a bit tricky, it is much faster and cheaper than other methods.

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Our knowledge of genetics and the tools to engineer or modify genetics continues to rapidly progress. The most celebrated recent advance was CRISPR (clustered regularly interspaced short palindromic repeats), a bacteria-derived system that can easily target any sequence of DNA using a guide RNA. CRISPR is like the targeting system and it can be paired with various payloads, most commonly Cas9, which is an enzyme that will cut both strands of DNA at the desired location. CRISPR was actually discovered in 1993, but the CRISPR-Cas9 system was first used for gene editing in 2013, an advance that won the Nobel prize in chemistry in 2020.

We are still, however, on the steep part of the learning curve with this powerful technology, and now researchers have published perhaps the greatest advance since 2013 – a way to use CRISPR as an on-off switch for genes. At the very least this will revolutionize genetic research. But it also has incredibly therapeutic potential, although other hurdles remain for applications in living organisms.

Using CRISPR-Cas9 for gene editing basically comes in two forms, knocking in genes or knocking out genes. Knocking out genes is by far the easier of the two. CRISPR targets the gene you want to silence, or knock out, and Cas9 will make a double strand cut in the DNA. The cells natural repair mechanism, called non-homologous end joining (NHEJ), the joins to the two cut ends together. This repair mechanism, however, is very imprecise and frequently introduces errors. Many of those errors will cause a shift in the genetic sequence that essentially ruins to code, effectively turning off the gene. This change is permanent, and will be carried to all later generations.

Knocking in a gene is more difficult. You not only have to make the cut at the desired location, you have to provide the genes sequence you want inserted and you need a different DNA repair mechanism called homology-directed repair (HDR), which is more precise and preserves the genetic sequence so that the gene remains active. But NHEJ is much more common than HDR, and so the trick is finding ways to enhance HDR repair so that a new gene can be successfully inserted at the repair site.

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In the British Drama, Years and Years, they imagine the very near future. I do wonder what someone from 2010 would have thought about a tv show accurately depicting 2020. In any case, one of the throw-away lines of the show was that there are no more bananas. The writers did their research – that the Cavendish banana will disappear sometime in the 2020’s is extremely likely. It is being threatened by a fungus called Tropical Race 4 (TR4), which a century ago wiped out the previous commercial dessert banana, the Gros Michel (it’s not extinct, but cannot be grown commercially anymore).

TR4 is now on every continent that grows bananas. It is literally just a matter of time before the entire commercial Cavendish market is wiped out. TR4 and similar funguses also threaten other banana varieties (more like plantains) that provide a staple source of nutrition for large segments of the world (about 400 million people). So this is not just about no longer having access to a favorite dessert fruit – this can create a serious threat to food security in parts of the world.

Part of the problem is that all Cavendish banana plants are clones. The plants are triploid hybrids, which is why they don’t produce seeds. This also makes them sterile. They are reproduced by taking new shoots that grow off the underground bulb (or corm). For this reason the entire Cavendish industry is basically comprised of clones. This is the ultimate monoculture – which leaves them particularly susceptible to disease, such as TR4.

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Last year a Chinese researcher, Dr. He Jiankui, announced that he had altered the germ line DNA of two babies using the relatively new and powerful gene-editing technique known as CRISPR. Dr. He is back in the news because of a new study looking at the effect of a mutation similar to the one Dr. He created on the life expectancy of those with the natural variant. The study finds that those who are homozygous for the gene variant (the delta 32 mutation of the CCR5 gene) have a 21% greater all cause mortality than those without the variant. What this means for the two children is unclear, but does raise concern.

Dr. He took it upon himself, without proper oversight or approval, to use CRISPR to alter the CCR5 (C-C chemokine receptor type 5) gene of embryos he then used for IVF (in-vitro fertilization) on his patient. The father who donated the sperm for fertilization (the patient’s husband) is HIV positive, so He sought to make a genetic change to the eggs to prevent HIV infection from the father. CCR5 is a protein on white blood cells that is used by HIV as an important gateway into the cell. Without it HIV infection becomes much less likely. There are other gateways, so it is not perfect immunity, but those with the naturally-occurring delta 32 mutation of CCR5 seem to be immune to HIV as a result.

He’s plan was to alter the CCR5 gene in the embryos in a way similar to, but not identical to, the delta 32 mutation. This was apparently successful in preventing HIV infection in the resulting babies. He announced what he had done after their live and apparently healthy birth.

He received widespread criticism for what he did for several legitimate reasons. First and foremost is his unsanctioned use of CRISPR on humans. He essentially conducted illegal human research. Human research is carefully regulated, with international standards, in order to protect the rights of people from harm and exploitation. He bypassed these regulations and was acting as a rogue researcher. That in and of itself is a career-ender.

Further, the specific application that He chose was not necessary. There are already effective proven treatments to minimize the chance of HIV infection from infected sperm used in IVF. Using an experimental treatment instead of a proven standard treatment is also considered unethical.

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