Faster, Higher, Stronger, CRISPR!

Here is a paper that I couldn’t pass by – “Correction of a pathogenic gene mutation in human embryos” (open access!) from Nature.

It’s been a little over two years since the first attempt to use CRISPR-Cas9 to correct beta-thalassemia in non-viable human embryos. At the time that manuscript was rejected from both Nature and Science on ethical ground. Today the ethical consensus seems to have settled to that modifying human germline cells is OK unless you want to enhance otherwise normal human embryo. So now everyone is doing that anyway. And the last ethical barrier to CRISPR-babies is actual implantation of genetically corrected embryo in clinical settings.

In the paper linked in the beginning, the authors corrected the mutation of cardiac myosin-binding protein C (cMyBP-C), a key factor in 40% of hypertrophic cardiomyopathy (HCM). HCM in turn is a frequent cause of sudden death in young athletes. Current state-of-the-art for preventing this disease is preimplantation genetic diagnosis (PGD) in the context of in vitro fertilization (IVF).

Long story short, the team led by Prof. Mitalipov from OHSU has seemingly figured out how to perform gene editing in the safest way. The first key trick was to deliver pre-formed Cas9-sgRNA ribonucleoproteine (not the plasmids or viruses). And the second trick was to do that via microinjection simultaneously with fertilization. The timing was crucial as the editing had to be done before DNA duplication machinery would start running full-speed.

The most positive news is that in zygotes DNA repair mechanism was much more well-behaving than in induced stem cells. But at the same time it’s a rather tricky point. So far we don’t know how similar DNA repair efficiencies are in different people. It’s hard to extrapolate anything from n = 1 sample. A more mixed news is that embryos used mother’s DNA as a template for repair, rather than external DNA supplied together with Cas9-sgRNA complex. This prompted some relief that there will be no ‘designer-babies’ in the nearest future (more on that later). But this also means the technology won’t be able to edit homozygous embryos. So overall, the answer to the question ‘is CRISPRing embryos a clinic-ready technology?’ is usual ‘more studies are needed’.

If you think about it, inability to use external DNA for repairing Cas9-cut genes casts a significant shadow over CRISPR perspectives for reproduction biology. That means the technology is very close to being redundant to IVF/PGD combo. The only advantage it will provide is, in authors’ words:

targeted gene correction can potentially rescue a substantial portion of mutant human embryos, thus increasing the number of embryos available for transfer

Since there is only one embryo to be implanted anyway, having to choose between, let’s say, 10 and (up to) 20 is not such a big deal. But who knows, maybe this limitation is just a matter of optimization and not another biological dogma. Again, n = 1 is not a sample size to draw serious conclusions.

Regarding the ‘designer-babies’, however, I wouldn’t be too comforted by the Mitalipov’s paper. Because the definition of ‘design’ can be different. Many physical features can be easily manipulated by doing gene knockout, with no external DNA needed. The question is though ‘Do we really need to enhance physical or mental parameters of humans in the world full of robots?‘ Surprisingly or not, many people still think that we do. That’s why bioethics will remain a major obstacle in reproductive biology, even in China. I’ll leave this quote (about PGD/IVF) as a nice illustration of current state of ethical consensus on genetic manipulation with human embryos:

[…] some families ask to weed out the mutation that renders many Asians unable to process alcohol, something that could affect the ability to take part in the often alcohol-fuelled Chinese business lunches. “They want their son to be able to drink,” says Lu. “We say no.”

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What’s so special about synthesis?

On Tuesday a piece form Phillip Ball appeared in Nature, with provocative question ‘Why synthesize?’ addressed to organic chemists, and particularly to adepts of total synthesis. And, you know what, after reading it, I didn’t feel like the author answered the question − for each argument he provides a counterargument. So the take home message I got was the following:

even though molecule-building is sure to remain a crucial part of the chemical enterprise, conventional organic synthesis need not be the only, or even the best, way to do it

When I started learning about organic chemistry, the book “Organic synthesis: the science behind the art” was one of the strongest inspiration sources for the subsequent choice of the major. This perception of the organic synthesis as the art is something that triggered my interest but what’s causing awkward feelings nowadays.

Like architecture, chemistry deals in elegance in both design and execution.

What exactly is meant by “elegance” of synthesis? “Beauty is in the eyes of the beholder” says the old proverb. So isn’t it disturbing that organic chemists themselves are the only ones who appreciate the elegance of total synthesis?

In my current opinion arranging synthetic steps in a reasonable manner is an engineering and project management problems, but by no means is it the art. There’s no more elegance in designing the synthetic scheme than in designing any other sophisticated multi-step experiment. So why don’t call microbiology the art, too? Why setting up the culturing of stubborn microorganisms producing natural products is different? After all, it’s often the same trial and error process yield a couple milligrams of the product in the end.

For me the synthesis is a means, not the goal. It’s a chemist’s way of solving problems. But other scientists may be interested in solving the same problems, too. So indeed, the synthesis is not the only and often not the best way to do it. That’s why chemists should focus on how to make it the best way. In this I’m staying with George Whitesides’s philosophy that simplicity should be the major goal. But that doesn’t make organic chemists unique among other scientists. That’s why I’d rephrase the following quote from Phillip Ball:

We need to avoid romanticizing an imagined bygone age […]

We [organic chemists] need to avoid romanticizing an imagined uniqueness of our field and train a broader look on problem solving.

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