Some scientists make no sense to me

There was an opinion piece published in Nature recently called Don’t edit the human germ line. It’s written by leading scientists (Edward Lanphier, Fyodor Urnov, Sarah Ehlen Haecker, Michael Werner& Joanna Smolenski) in somatic cell gene therapy, and to me it reads like they’re very concerned that the association between gene therapy in adults and the concerns about making designer babies would lead to public outcry over gene therapy. Basically they’re trying to shut down germline engineering so they don’t look guilty by association (especially given the same techniques would likely be employed).

The authors do point out a lot of technical issues with embryonic genetic manipulation, namely that any errors or side-effects might not appear until years later. Which is fair, in my opinion. I still think it’s pretty likely that people won’t genetically modify the human embryo until the technology for doing so in consenting adults is well established.

But in the article, the scientists make a few stupid statements. Like saying

We are not, of course, making a comparison between the replacement of faulty mitochondrial DNA in an egg or embryo with healthy DNA from a female donor and the use of genome-editing in human embryos. In mitochondrial transfer, the aim is to prevent life-threatening diseases by replacing a known and tiny fraction of the overall genome.

I don’t see why they wouldn’t make this comparison, because it seems basically identical to me. I will concede that editing the mitochondrial DNA component of the genome is technically a lot easier than editing a small component the nucleic DNA component (due the former already being isolated in the cytoplasm). But ethically, it doesn’t matter if you’re trying to edit the mitochondrial DNA or a gene contained in the nucleic DNA, you’re still aiming “to prevent life-threatening diseases by replacing a known and tiny fraction of the overall genome”.

The scientists also seem to tie themselves in a loop with two parts of their argument. The first is this:

Philosophically or ethically justifiable applications for this technology — should any ever exist — are moot until it becomes possible to demonstrate safe outcomes and obtain reproducible data over multiple generations.

Aside from the extreme lack of foresight in doubting the obvious benefits of germline genetic engineering*, this seems a fair point. While the science is in its infancy, it seems wise to be very cautious. But combine this point with a point made in their closing argument:

A voluntary moratorium in the scientific community could be an effective way to discourage human germline modification and raise public awareness of the difference between these two techniques.

Hardly a suprise, given the title of the article, that the scientists are against germline engineering. But how is anyone going to be able to :”demonstrate safe outcomes and obtain reproducible data over multiple generations” if there’s a moratorium and it’s illegal to do those experiments?

Basically these scientists, instead of trying to address the concerns the public has over the ‘scary’ idea of designer babies, are just trying to say “Yeah, designer babies are scary but that’s not what we’re doing at all, so please keep funding us”.

*There are a whole host of genetic diseases that have to be fixed before the development of organs and tissues, so our only option to cure these would be to edit the genome of a gamete (sperm or egg) or embryo. There would be no way to use somatic cell gene therapies after birth for these conditions, especially for those conditions that often result in death shortly after birth. In most but not all cases you could, as the authors suggest, use pre-implantation genetic diagnosis (PGD) to select only for embryos without these mutations. But in some cases both parents might be affected by a recessive genetic condition, so there would be no embryo without the mutation to choose, thus ruling out PGD as an option.

Performance-enhancement in sports with Arthur Caplan

Following the recent (albeit technically not yet published until the 28th of March) article by Leon Kass and Eric Cohen, Arthur Caplan’s piece on performance enhancements in sport, titled ‘A Shot In the Rear‘ (perhaps because he views it as a pain in that area?), which was published last week at Science Progress. In it, he specifically looks at arguments set out by John Harris – who is pro-enhancement – and Michael Sandel – who is anti-enhancement. Caplan then ends up siding, for the most part, with Sandel.

Here is the crux of Caplan’s argument:

Sport is only sport if it is measuring human abilities, as varied as those may be. Sport also links the results achieved to training, will, and effort. Outcomes don’t define sport—the process leading to outcomes does. That is why short circuiting your way to success by pills or hormones as Jones, Bonds, and Clemens did undercuts their performance since both process and outcome are required in assessing performance. […] The definition of sport is human effort based on talent and training leading to performance.

In a sense, this is very similar to that argument of Leon Kass and Eric Cohen. But it is equally refutable, because all that these three people (four if you count Sandel) are doing is defining sport as something that can’t have enhancements (well, performance enhancements at least. I don’t know how they would view a drug that makes you enjoy training, or makes you strive harder. I’m guessing they would come up with something though). They could equally just say “sport is defined as an enhancement-free activity” and be done with it.

Effort can matter, but it doesn’t define sport. Fun can also matter, but that also doesn’t define sport. Sport is mostly, though probably not entirely, about outcomes. I would have thought that was obvious.

If sport wasn’t about outcomes, why do people make a bigger deal about breaking a world record than breaking a personal best (sometimes, the personal best may actually exceed the record, but was recorded without an official being present to corroborate it)? That’s because it is more of an achievement to be the best in the world than it is to have the most willpower, effort and determination. Effort is secondary to performance.

If sport wasn’t about outcomes, why do athletes retire when their body can’t perform as well anymore, even though their will and determination is still present? Perhaps it is because they know that performance is what the sports fans want to see, not effort.

If sport wasn’t about outcomes, why do sporting authorities accept (even in a limited manner) enhancements in equipment such as lighter bicycles, lycra bodysuit/bodyskin costumes or faster performance engines in cars, rather than force athletes to use the same outdated equipment? Perhaps it is because if the average Joe on the street can drive/ride/swim faster than the people at competing at an international level, then there is little desire to even watch the sport (unless perhaps a family member was competing or similar). And so it will also be when the typical citizen has bionic limbs that allow him to run faster than any pro sprinter and lift more than any pro-weightlifter, or when the typical citizen has genetically-enhanced reflexes allowing her to view a fencing or judo competition as if it were slow-motion dancing.

These bioethicists need to face the facts. Sport is mostly about performance, and in that view the individual athlete will become less important. I predict that the most popular sports of the future will become more like motor racing – the final achievement will be a result of the athlete’s ability to ‘drive’ his or her genetically-enhanced cyborg body to victory, in addition to the geneticists, pharmacologists and cyberneticians in the support team.

Those with germline-modified mitochondria walk among us

A news article on the mitochondrial transplants I blogged about previously has the headline: “First disease-free babies could be born in three years as doctors create embryo from THREE parents”

But, and I kick myself for not remembering (or, more accurately, rediscovering) a certain fact earlier – that babies have been born with genetic material from three parents over ten years ago. Let me tell you the story of the real first baby (technically, an embryo, although a healthy baby did result – see below) created from three parents. This story comes from the following source: J. Cohen et al “Birth of Infant after Transfer of Anucleate Donor Oocyte Cytoplasm into Recipient Eggs” The Lancet 350(9072): pp186-187, July 1997

In 1996-7, Jacques Cohen and his team from the Institute for Reproductive Medicine and Science at the Saint Barnabas Medical Center in Livingston, New Jersey (in the USA) were treating a 39-year old, whose efforts as assisted reproduction had all failed. She was offered, and consented to, a cytoplasm transfer. Ooplasm, containing mitochondria and all the other organelles and chemicals present in the cytoplasm of an oocyte, from the eggs of a 27-year old donor was extracted with a pipette and inserted into the eggs of the patient. The patient’s eggs were fertilised with her husband’s sperm, and four embryos were implanted. A single impregnation resulted, and a healthy baby girl (weighing 4356g) was born as a result.

The thing is, the researchers report the following:

We compared nuclear and mitochondrial DNA fingerprinting profiles from aspirated amniocytes with those from both parents and the egg donor, […] Donor mitochondria had been displaced by homologous mitochondria before 16 weeks’ gestation.

So, technically this wasn’t germline engineering, or at least wasn’t a ‘successful’ example of it. The now 11-year old girl currently contains none of the donor mitochondria, so can’t pass any but her own mitochondria to any children she may have. But the same is not the case in the other children (17 of them, I believe) born as a result of the same technique in that medical centre and others across America (as far as I know, it hasn’t happened outside of the US, but I could easily be wrong). According to the following article: Barritt et al “Mitochondria in human offspring derived from ooplasmic transplantation: A brief communication” Human Reproduction 16(3):pp513-516, March 2001

mtDNA fingerprinting analysis performed on blood samples from 1 year old children following ooplasmic transfer detected mitochondrial polymorphisms in which both alleles were present in the hypervariable region of the mitochondrial genome. […] These are the first reported cases of germline mtDNA genetic modification which have led to the inheritance of two mtDNA populations in the children resulting from ooplasmic transplantation. These mtDNA fingerprints demonstrate that the transferred mitochondria can be replicated and maintained in the offspring, therefore being a genetic modification without potentially altering mitochondrial function.

So, these children are actually the first germline-modified children to be born, as far as I know. But I shouldn’t use the words ‘germline genetically modified’, because since these words were used, the FDA tightened their restrictions on the procedure. In a meeting of the Biological Response Modifiers Advisory Commitee on May 9,2002, the FDA changed regulations to require each procedure to gain approval from the FDA before going ahead (read the minutes of the meeting here, or the full transcript here).

The only difference here between what I blogged about previously and the procedure discussed above is that the latter uses cytoplasmic transfer rather than nuclear transfer as in the former, but as I said in my previous blog on this, it is all relative to what is the defining characteristic of a cell – if a nucleus is the defining feature of a cell, then picking that up and putting in a different cell is actually a full cytoplasm transplant rather than nuclear transfer. (An analogy would be brain transplants vs body transplants – if personhood is localised in the brain, then a brain transplant is actually a body transplant).

Anyway, the point remains that the embryo created by British researchers is not the first to be created with three genetic parents. Let us hope that those members of the House of Commons in the UK are considering this fact when deciding whether to allow it in Britain.

Creating a knockout human

I said in my post about a possible genetic manipulation for viral immunity that a knockout human would “take too long and probably be unethical”. Well, I may have to eat my words (at least, the part about it taking too long). You see, I think there would be a way to make a knockout human in a shorter time than making a knockout mouse (of course, creating a knockout mouse with this method would be shorter still). I’ll explain how a knockout mouse is usually created, and then I’ll tell you the shortcut to be taken for long-lived creatures like humans.

Firstly, stem cells are isolated from a mouse embryo. These cells are genetically manipulated to insert a non-functional version of the gene of interest, hence “knocking out” the gene by overwriting it with a broken copy (a functional gene from another animal could be added to create a ‘knock in” mouse). The inserted gene is usually accompanied by a marker gene – a gene that can be detected (such as immunity to a toxic agent, which can be detected by growing the stem cells in a mixture containing that agent). Then, stem cells in which the gene has been successfully inserted are inserted into another (or the same) blastocyst, meaning that the mouse growing from that embryo will be a chimera – containing some cells that have been genetically modified and some that haven’t. If some of the germ cells (eggs or sperm) happen to have arisen from cells that have been genetically engineered, then those mice can be bred with another “knockout” mouse (or inbred) to create a mouse where both chromosomes contain genetically engineered genes.

This takes so long because to get your hands on a knockout mouse embryo requires you to wait for some mice to get old enough to breed. For mice, this is only about 5-8 weeks, but in humans it would be at minimum about 12 years and safely (and legally) at around 16/18/21 years. And not only is this a problem in terms of time, but forcing people to copulate, and specifying their partner, is a big ethical problem (even if we accept the ethical acceptability of genetic modification of humans). But this can be overcome, although it may bring up other ethical problems of its own.

The shortcut stems from the fact that we don’t actually need a man and a woman to create a child. Females would actually have all their primary oocytes (immature eggs) around 4-6 months before birth, but they mature and are released only after puberty. Likewise male embryos contain spermatogonia (although unlike in the female, they will be produced throughout life), which develop into spermatozoa after puberty. Turning primary oocytes into ova (mature eggs) is fairly simple to do in vitro, involving just a set of chemical signals (and has been done before to result in pregnancy). Turning spermatogonia into spermatozoa to achieve conception is harder, but it can be done in vivo (by putting the embryonic spermatogonia into a donor testicle, even one of a different species). So, one could possibly take a shortcut by performing some advanced IVF on germ cells harvested from the initial chimeric human embryos.

In solving this practical problem, numerous ethical issues could be raised. Firstly, one could object to creating a child whose genetic parents would have been embryos or foetuses at the time of conception (and need not even be implanted). Surely it is unethical to force two people to mate, but provided one accepts the discarding of embryos from IVF (and indeed normal reproduction), and also accepts abortion five months before birth, then why should this be an issue? If we can deny that the embryo or foetus is a person, or otherwise deny it a right to life, then we can surely deny the embryo or foetus the right to choose a sexual partner. One could also object to the xenotransplantation for maturation of human sperm (i.e. having human sperm grow in the testes of another animal), but this is likely a technical hurdle to be overcome, and so soon human sperm could be grown in a dish like we do for human eggs.

Perhaps an easier method, that gets around the above ethical hurdles, would be to transfer the nucleus of one of the genetically modified stem cells into an ovum and stimulate it to mature into a knockout human. This could negate the need to create the chimeric generation altogether. But, this is called cloning, and is frowned upon in most Western nations.

Of course, we are likely to come up with much better methods of genetic interventions in mice, and soon I expect the knockout procedure will be replaced with something more efficient. The easiest, I think, would be finding a way to dedifferentiate (turn back) the genetically modified stem cells from pluripotency to totipotency, allowing them to develop into an embryo without forming the chimera. In fact, I would not be at all surprised if such a procedure had already been done recently (but won’t that upset the pro-life crowd – “every embryonic-stem cell is sacred”?).

So, bottom line is that I was wrong. But in my defence, the press release did report that one of the researchers said something even more incorrect. So you can all look at his comment to distract yourself from the fact that I said something wrong:

Dr. Sonenberg explained that the process of knocking out genes is not possible in humans, but the researchers are optimistic new pharmaceutical therapies will evolve from their research. [emphasis mine to increase the power of the distraction]

Mitochondrial transplant for human embryos

Apparently, British scientists have ‘created an embryo from three people’s DNA‘. I’m a bit behind on this story (chronologically, at least), but that shouldn’t matter. (UPDATE – this isn’t actually new. Babies were born with DNA from three people way back in 1998)

Researchers at Newcastle University took the nucleus from a human embryonic cell and transplanted it into an anucleated human cell. This served to swap the mitochondria (and other organelles in the cytoplasm) surrounding the nucleus from those of the mothers, to those of the donor. So, I would call it a mitochondria transplant, and rate it ethically similar to a heart transplant. If your child has a malformed heart, you have a heart transplanted from another person save her life. If you child would have mutated mitochondria (carrying muscular dystrophy, multiple sclerosis, heart disorders or one of many other mitochondria disorders), then why not replace those?

But I guess it must be an ethical problem for some because, technically, a child resulting from this would have DNA from three sources. Nuclear DNA would be a combination from mother and father, and mitochondrial DNA from the donor.

This has obviously caused a reaction, because Prof. Patrick Chinnery, one of the lead researchers, has said:

“Most of the genes that make you who you are are inside the nucleus. We’re not going anywhere near that.”

Personally, I say why not? But that’s not all. Chinnery also tried to distance himself from human genetic engineering by saying:

“We are not trying to alter genes, we’re just trying to swap a small proportion of the bad ones for some good ones.”

Of course, this is entirely genetic engineering. Under the category of ‘swapping bad genes for good ones’ would come transgenic humans (say, swapping human Pseudogene ΨGULO for the active gene found in monkeys, so humans would never get scurvy) or even swapping human chromosomes for entirely synthetic but ‘superior’ models.

Interestingly, the work is technically germline genetic engineering if the child is female. This is because any child born from a mother that has had the ‘mitochondria transplant’ will also have the same mitochondria (mitochondria from the father are found in sperm, and power the sperm all the way to the egg, but don’t actually contribute to fertilisation).

Legal Issues

So, with this in mind, let us look at the legality of the therapy. In Britain, this will be discussed in the House of Commons in March, and I will of course blog about anything interesting to come from that. In Canada, however, Bill C-6 ‘An Act Respecting Assisted Human Reproduction and Related Research‘ , which was actually approved four years ago and is current law in Canada, says the following in Section 5 (‘Prohibited Activities’):

No person shall knowingly for the purpose of creating a human being, create an embryo from a cell or part of a cell taken from an embryo or foetus or transplant an embryo so created into a human being.

So, this research would be illegal in Canada.

In Australian law, under the ‘Prohibition of Human Cloning for Reproduction‘ which I believe is still law (correct me if I’m wrong), under Part 2, Division 1, number 13:

A person commits an offence if:

(a) the person intentionally creates or develops a human embryo by a process of the fertilisation of a human egg by a human sperm outside the body of a woman; and

(b) the human embryo contains genetic material provided by more than 2 persons.

Maximum penalty: Imprisonment for 15 years.

So, certainly appears to be illegal here in Oz to save your child from mitochondrial disorders by ‘swapping’ mitochondrial genetic material.

I won’t look at the US, because reproduction is generally under state jurisdiction there. But I will look at the Council of Europe’s ‘Convention on Human Rights with Regard to Biomedicine‘, which states:

Article 13 – Interventions on the human genome

An intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants.

Which leads to a very interesting conclusion – In European countries that follow this convention, it is only legal to have a son free from mitochondrial disorders, because a daughter could pass on her healthy mitochondria to her children (and we wouldn’t want to ‘endanger human dignity’ or whatever the hell the CoE was thinking then they wrote this law. Time for an update, no?)

So, now I think we can all understand why Prof. Chinnery was trying to dodge the accusation of genetic engineering – because his research is pretty much illegal in most Western nations (and possibly Britain too, depending what the House of Commons thinks).