Victor Hugo once observed, “there is nothing more powerful than an idea whose time has come.” Not long ago, the world asked whether it can have read privileges to view its own genetic file of life. The answer, wrested from regulating bodies and crusty institutions by the expanding clientele of companies like 23andMe, was a resounding yes. Rapid advances in the ability to make edits under this file system have now forced the hand of researchers around the world into penning a moratorium, a temporary ban on germ-line gene editing. Once again, the world asks, if not now, then when?
The answer no longer comes exclusively from funding bodies picking winners and losers, or from journals holding sway over any knowledge they can sequester and trickle out as they see fit. The question is simply too rich. We need look no further than Nature magazine to see that the tables have turned. The first reference in their widely read commentary on the issue is not to an article in another peer-reviewed journal, but rather an article from the people, an article in the popular science publication MIT Tech Review.
The article notes that while some countries have responded to the argument over who can do what to whose genome, and at which positions with an indefinite ban, other countries will simply do. In fact they have already done, in monkeys, and in human embryos beset with genetic predispositions for ovarian or breast cancer. The gene editing techniques that can now be used to police our entire genome, potentially in any cell of the body, can also hit you right in the family jewels — the germ cells. The techniques have names like zinc finger nucleases or TALENs, but the one that has caused the biggest stir is called CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats).
The primary reason for much of the commotion is that CRISPR isn’t all that hard. It’s RNA tag can target specific DNA sequences with decent accuracy, and its on board protein nuclease can cut out the offending region and prepare the wound for repair systems in the cell to act. The main problems right now are that it doesn’t always do its job, it doesn’t always do it only where its supposed to, and it takes finite time to do it. If used not just in static cells, or germ cells in waiting, but in the rapidly dividing cells of say, a developing embryo, then all bets are off. It can still work, but if it catches a dividing cell in the act, when its pants are down so to speak, there is much less predictability.
What is a bit curious, disturbing actually, is that amid all the fuss over editing a little part of one protein in the singular nuclear genome of a cell, places like Britain are in the process of bankrolling related, but much more reckless procedures under the guise of fertility — namely, the mitochondrial transfer procedures that generate what is essentially a three parent embryo. Against the normal background that is our potluck of genetic recombination, many people who potentially stand to benefit from things like CRISPR are asking, what exactly is the problem?
While it is illegal in Britain to modify even a single base pair in human gametes (eggs or sperm), as could conceivably be done in the creation of an IVF embryo, you might now knock yourself out restocking your egg with what ever mitochondria you want. Never mind that empowering the egg in this way potentially introduces 16.5 giga base pairs of new DNA, (as compared with 3.4 giga base pairs nuclear DNA), albeit with ample redundancy.
To better understand some of the issues involved in this kind of germ modification, I would suggest availing yourself of the two articles linked in the next sentence. They highlight some concerns with mitochondrial mutations, heteroplasmy (different brands of mitochondria in the same cell or organism), and potential pitfalls in the elective crafting ofartisanal mitochondrial children. At the center of this issue is a new technique being made available by a company called OvaScience. Their ‘Augment’ procedure takes mitochondria not from a stranger’s egg, or even from somatic cells of the husband, but from supporting cells right next to the egg within the mother’s own defaulting ovaries.
It remains to be seen whether the mitochondrial DNA from these cells is of sufficiently better quality then that in the neighboring eggs. In particular, whether these cells are privy to the selective genetic bottlenecks that the egg is subjected to in vetting its mitochondrial suitors, or whether it is this very bottleneck that is the root cause issue. The founders of the company have made some intriguing discoveries regarding these cells, not least dispelling the myth that a woman is born with all the eggs she will ever have. In mentioning new work at OvaScience (and other places) what the Tech Review article, like many others, misses is that the ability to edit mitochondrial genomes as we would the nuclear is now coming into full view.
Instead of talking about ongoing work at places like OvaScience to do things analogous to CRISPR in stem cells — cells which could be turned into eggs (and might begin to skirt some issues that fall under the rubric of ‘germ cell law’) — we should probably be talking about editing single points in mitochondria. Especially if we have already green-lighted editing the entire mitochondria all at once through complete transfer. One researcher now looking at these issues is Juan Carlos Izpisua Belmonte from the Salk Institute in California. He is evaluating gene-editing techniques to modify the mitochondria in unfertilized eggs to later be used in IVF. If successful, we will soon have concerns even more immediate then CRISPR in germ cells.
At the heart of the issue is the fact that the proteins that make up the respiratory chain that powers our cells are mosaics. In other words, as researcher Nick Lane would say, mitochondria are mosaics. They are built from two genomes, their own DNA and the nuclear DNA, which re-apportions proteins (many once upon a time their own) back to them. Getting this mix right is the premier issue in fertility and any subsequent development of the organism. When negative mutations occur in the subunits making up these respiratory proteins something predictable happens: They don’t fit so close anymore, and subsequently the electrons that need to be transported through them have a more difficult time tunneling through the reaction centers attempting to squeeze out every last drop of energy.
Mr. Lane passes down another quote to us in his forthcoming new book ‘The Vital Question,’ a book which makes much of this discussion a whole lot clearer. It comes from famous biophysicist Albert Szent-Györgyi, and it is a fitting conclusion to our remarks here on tinkering with the file system of life: “Life is nothing but an electron looking for a place to rest.”
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