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.

Patent on human cancer gene struck down

At last! Finally somebody has a clue! Maybe this will lead to the invalidation of the patents over the 20-something% of (protein-coding) human genes currently patented.

On Myriad Genetics Inc patent claims on two breast and ovarian cancer genes, U.S. District Judge Robert Sweet ruled that they were invalid:

Sweet said he invalidated the patents because DNA’s existence in an isolated form does not alter the fundamental quality of DNA as it exists in the body nor the information it encodes.

He rejected arguments that it was acceptable to grant patents on DNA sequences as long as they are claimed in the form of “isolated DNA.”

“Many, however, including scientists in the fields of molecular biology and genomics, have considered this practice a `lawyer’s trick’ that circumvents the prohibitions on the direct patenting of the DNA in our bodies but which, in practice, reaches the same result,” he said.

The judge said his findings were consistent with Supreme Court rulings that have established that purifying a product of nature does not mean it can be patented.

And, I can’t believe I’m going to say this, but I agree with somebody at the Center for Genetics and Society:

“The evidence has mounted that human gene patents are doing more harm than good,” and resulted more by accident than a well-thought-out policy, said Jesse Reynolds, a policy analyst at the Center for Genetics and Society. The center is a nonprofit policy research group advocating for oversight and responsible use of biotechnologies.

The Myriad patent “was particularly troublesome” because it was so broadly worded, Reynolds said.

Reading the court ruling, “I saw nothing that limited it to Myriad’s patents,” Reynolds said. It boiled down to this, he said: “Natural things aren’t patentable; inventions are.” [emphasis mine]

Damn straight! If and when you make your own human genes, with enhanced function or resistance to mutation or whatever, then sure, patent away. As the ruling says, you can only patent a gene that has ‘markedly different’ characteristics from a natural gene. A silent or conservative mutation won’t cut it. You’d have to do something like, take a gene from another animal, and put it in humans with the right enhancers, promotor and introns to have it properly expressed in human tissue. Then it has a ‘markedly different characteristic’, namely, specific expression in human tissue rather than in the original animal.

I’ve got no problem with people walking around with patented genes in their body, or even people being born with a genome that is partially owned by somebody. That’s necessary for biotech companies to make money from human gene therapy and human enhancement. I’ve just got a problem with people trying to claim as their own something that evolved naturally before they were even born.

Let’s just hope this holds up in the Supreme Court, where this case will inevitably end up.

Super-strong genetically-engineered monkeys

Scientists from Ohio State University and the Center for Gene Therapy at Ohio’s Nationwide Children’s Hospital have successfully demonstrated the genetic enhancement of muscle growth in monkeys (Kota et al. 2009).

In brief, the researchers used a viral vector (AAV1, adeno-associated virus 1) containing the human gene for follistatin, a glycoprotein which encourages muscle growth (by blocking myostatin). Researchers injected this vector into the right quadriceps muscle of macaque monkeys, thereby permanently genetically modifying that muscle to produce more follistatin.

Isolated quadriceps muscles from the left-hand unmodified (control) side and the right-hand genetically-modified (CMV-FS) side of a macaque monkey.

As expected, muscle size and strength increased over a 3 month period after treatment, and was maintained at that enhanced level for a year (the effects of the enhancement likely would have lasted for the rest of the monkeys’ lives, but the monkeys were killed after a year for autopsy). Quadriceps circumference increased from around 16-17cm to about 21cm. In addition, twitch strength (force produced by rapid muscle contraction) increased by about 25% and tetanic strength (force produced by sustained contraction) by 12.5%. This increase was not correlated with any change to other organs or hormones.

As always, there are a few caveats. Firstly, drugs were used to suppress the immune systems of the monkeys for two weeks prior to the injections,  in order to increase the efficiency of the viral vector and to avoid immune reactions (the immune system attacks viruses, even relatively harmless ones like AAV).

Second, mystatin inhibition can reduce the elasticity of tendons (Mendias et al, 2007), increasing risk of injury. My solution was to limit the modifications of myostatin to myocytes (muscle cells), rather than tenocytes (tendon cells). This most recent study attempted to do just that, by using a muscle creatine kinase promoter to control expression of the inserted follistatin trangene (therefore, only cells that also express creatine kinase would express the follistatin insert, and I assume tenocytes don’t express much creatine kinase). With this extra limitation, however, the researchers did not see as dramatic increases in muscle growth as those I presented above (which were from a vector that would be expressed in any cell).

Nonetheless, this study shows a successful localised insertion of a transgene in monkeys and a permanent increase in muscle size and overall strength, without any changes to other organs or levels of testosterone (or other hormones). I’m sure a good workout at the gym has some benefits to health (specifically cardiac health) that wouldn’t be mimicked by changes to follistatin or myostatin, but regardless this is another step towards super-strength and other enhancements.

Enhancing memory and learning in mice

Recently, a review article by Yong‑Seok Lee and Alcino J. Silva was published in Nature Reviews Neuroscience, with the title ‘The molecular and cellular biology of enhanced cognition‘. If you are lucky enough to have a subscription, or know a library that can get this journal article for you, do.

The review lists 33 genetic modifications that lead to some level of enhanced memory and learning in mice. It also discuses the general methods by which these modifications work, focussing on enhancement of a form of neuronal plasticity known as long-term potentiation. NMDA receptors, the role of calcium as a messenger and the various enzymes and transcription factors that are recruited to create the cellular basis of a memory. The review also discusses other mechanisms, like epigenetics, growth factors, the involvement of glia, and also presynaptic signalling. Finally, the review looks at caveats in the current research in cognitive enhancement.

The authors also make a nod in the direction of bioethics, saying:

[I]t is also important to stress that memory enhancing manipulations raise a number of ethical issues that are outside of the scope of this Review, but that merit careful consideration and discussion^170,171.

For interests sake, references 170 and 171 are:

170: Rose, S. P. ‘Smart drugs’: do they work? Are they ethical? Will they be legal? Nature Rev. Neurosci. 3, 975–979 (2002).
171. Farah, M. J. et al. Neurocognitive enhancement: what can we do and what should we do? Nature Rev. Neurosci. 5, 421–425 (2004).

‘Genetic engineering’ implies an act of engineering

The term genetic engineering, according to Wiktionary, is the “the deliberate modification of the genetic structure of an organism.” Other definitions, especially those used by biotechnology regulators and lawmakers, often specify that genetic engineering refers only to modifications made by recombinant DNA technology, but I prefer the more broad usage. Genetic engineering is, as the name implies, the engineering of genetic material in living cells.

There are two processes which, I believe,  are mistakenly called genetic engineering: artificial selection (aka selective breeding) and PGD (pre-implantation genetic diagnosis, also known as embryo screening). Artificial selection refers to selective breeding of organisms with the desired traits (and, it is hoped, the desired genes) in order to breed more organisms with the desired traits. Pre-implantation genetic diagnosis is the term for determining the genetic makeup of human embryos before they are implanted for IVF, and usually implies choosing to implant the healthiest or more desirable of embryos.

These are both selective processes, and are often likened to genetic engineering, but often for different reasons. Selective breeding is often considered to be genetic engineering by those defending genetic modification of crops and livestock, as surely the traditional farming methods of the past couldn’t have been wrong (*cough cough*). On the other hand, PGD is often maligned as genetic engineering by those opposed to the idea, as surely genetic engineering of humans is to be vehemently opposed (*cough cough*). In fact, some proponents of human enhancement could even make both leaps at once, claiming that genetic engineering is just like the evolutionary processes of nature (only faster) and therefore that techniques like PGD are likewise just speeding up the natural selection of human embryos that occurs naturally.

But I strongly believe that a selective process is not a form of engineering. In most cases of selection, genomes are not first intentionally modified by human actions. Instead, modifications happen mostly randomly due to mutations and the natural forms of genetic recombination that occur during reproduction. This provides the variety on which breeders, farmers and parents/reproductive specialists can act to select which will be kept and which will be discarded. So, while these selective processes are intentional modifications of the proportions of certain genetic material in a population, they do not entail any intentional modification the genetic material of any individual organism. Selection is no more an act of genetic engineering than going shopping is an act of manufacturing.

Further, I’d be inclined to argue that cloning is also not a form of genetic engineering, as the genetic material is replicated intact rather than modified. Cloning is really just a very effective form of selective breeding, where every piece of genetic material within a particular cell is replicated in the cloned organism. Cloning, therefore, is no more an act of genetic engineering than using copy+paste is an act of writing.

All of this is really just semantics and word games, because it doesn’t really affect the ethical discussions on these issues. Equivocation is avoided, certainly, but appeals to the past, appeals to tradition, slippery slope arguments or arguments rooted in repugnance are also dubious moral arguments. Every new technology will have consequences, some similar to those seen in other technologies and some completely novel. Each technology should be evaluated individually, with comparisons used only when necessary and not stretched beyond reasonable limits.

Genetic enhancement of the human metabolism

Any living organism must be actively metabolising, or else it will not be able to sustain itself. Metabolism is the name given to the sum of all processes involved in producing and using energy, and forming and breaking down molecules, and disposing of the resultant waste. These can be divided into a number of steps, each catalysed by an enzyme, and the steps in turn can be organised into pathways. Catabolic pathways are those that break down molecules and release energy, whereas anabolic pathways are those that form molecules and consume energy. Altogether, these pathways can be represented as a metabolic network or map.

WikiUser Zephyris has uploaded a colourful and simplified diagram of a metabolic network to Wikipedia, as seen below:

There are some very large and detailed metabolic maps available, such as those seen at sites like iPath.

It is obvious that if these networks were street maps, they would contain many one-way streets and dead-ends. This is because evolution is lazy. Well, technically evolution isn’t even able to think, let alone show a lack of motivation, but the point if a process can be omitted without negatively impacting the organism too much, a mutation to the enzyme responsible for that step in the pathway will not be selected against (or may even be selected for). Metabolisms of various organisms, therefore, are imperfect, requiring many nutrients, cofactors and minerals to function correctly.

Humans are not exempt to the ‘laziness’ of evolution. As a well known example, is the inability of humans to produce vitamin C (and thus why it is called a vitamin). Sometime about sixty million years ago, the ancestor of the entire group of haplorrhines (a group that includes humans and other apes, as well as monkeys and tarsiers) had a mutation in the gene GLO, which codes for the enzyme L-gulonolactone oxidase (also known as GULO). This enzyme is responsible for the last step in a pathway that converts L-glucose to L-ascorbic acid, or Vitamin C (Nishikimi and Yagi, 1991). Because of this mutation, the haplorrhines have to eat food containing vitamin C to prevent illnesses like scurvy; this was never really a problem, as most haplorrhines are frugivores (eat a lot of fruit, rich in Vitamin C). Therefore, this enzyme remained lost in haplorrhines, with mutations building up in the gene unchecked and now in humans the last remnants of the gene can be seen as the GULO pseudogene on chromosome 8.

It is therefore the case that each and every human inherited the metabolic disease hypoascorbia. Being the fun sorts that we are, humans have tried to fix this. Using genetic engineering to insert a functional copy of the GULO gene from mice into human cells, researchers had already shown that vitamin C synthesis was restored (Ha et al, 2003). More recently, scientists genetically engineered mice to have both copies of their GULO gene knocked out, then re-inserted the gene to restore ascorbic acid synthesis (Li et al, 2008).

Genetic technology, then, may allow us to restore many similarly lost enzymes to the human metabolic system, and even to take enzymes that evolved in other organisms and put them to use in our body. With appropriate regulation, this would cure the scourge the scourge that is nutrition disorders. Those in poorer nations are often afflicted with hypoalimentation (malnutrion) and those in richer nations have problems with hyperalimentation (especially obesity), both caused by the human metabolism being an innefficient hodgepodge of enzymatic pathways.

For a human enhanced with a plethora of new metabolic pathways these nutrition disorders would be far less of a problem. Enzymes would be available to get from each point on the metabolic map to any other point, as many of the essential nutrients, those required nutrients that normal humans cannot synthesise internally, are produced in other organisms (such as the amino acid tryptophan, produced in plants and microorganisms but not in animals). With proper regulation, the body will do the balancing of your diet for you, so you can healthily live on chocolate and ice cream (though probably still with the need for mineral suplements in pill form, as no enzyme can convert one element to another).

In addition, this could potentially alleviate undernutrition too, by broadening the range of foods available for human consumption to include anything eaten by living organisms. With the genes for cellulysis, cellulosic plants could be digested without the need for a gutfull of cellulase-producing bacteria. With enzymes available to break toxins, contaminated or poisonous food could be consumed. And with novel enzymes, other carbon-based materials like plastics (i.e. rubber, polystyrene, polypropylene) could be digested, though this may make medical applications of those plastics more difficult – you don’t want to digest your pacemaker or cyborg implants (at least, not usually). It may even be possible to add organelles responsible for photosynthetic anabolism, allowing for sunlight, carbon dioxide and water to be used as raw materials for the human metabolism. A human enhanced in this way would be the ultimate survivalist, able to consume a wide range of foods normally inedible to humans (of course, taste receptors may have to be adjusted somehow to make these foods palatable).

Gene doping is more fair, not unfair

Gene doping – the enhancement of athletic ability by genetic manipulation – is a big issue around the upcoming Olympic games in Beijing. The hippies at Friends of the Earth have decried the practice of gene doping in a recent press release. Gillian Madill, a genetic technology campaigner, said this:

“Altering one’s genetic makeup to impact athletic performance is unacceptable. Gene doping is cheating, and it’s dangerous. Professional sports organizations should ban it. All athletes deserve to compete on an even playing field. Gene doping undermines that right.”

“Friends of the Earth opposes all genetic modification of life, including human life. It is important to protect the gene pool, our most basic common natural good, from genetic pollution caused by genetic engineering. It is impossible for humans to comprehend the implications of manipulating the genetic makeup of nature.”

It should be obvious to anyone who has read this blog for more than five seconds that I completely disagree with almost everything she said.

I fully acknowledge that gene doping is unaccepted, but not that it is unacceptable. Gene doping is cheating only because it is against the rules, not because it is inherently unfair. It is dangerous though, I will agree with that (and with a ban against it, it can only get more dangerous).

But that’s not the worst part (by worst, I mean most obviously wrong). Madill says that gene doping undermines the athletes right to compete on a level playing field. Unbelievable. I’ve already talked of this argument before, so now I can do no more than quote Julian Savalescu:

“Sport discriminates against the genetically unfit. Sport is the province of the genetic elite (or freak). […] By allowing everyone to take performance enhancing drugs, we level the playing field. We remove the effects of genetic inequality. Far from being unfair, allowing performance enhancement promotes equality.”

The most level playing field possible would occur when all athletes have a standard body and a standard genome, much like motor racing does with standards on their cars. If it’s a level playing field you want, then how can you justify keeping the natural inequality that pervades athletic competition?

As for the last part on genetic technology in general, I am reminded that one man’s ‘pollution’ is another man’s enhancement. I’ll keep my genes out of the human gene pool if necessary, but I reserve the right to ‘pollute’ my own body. And everyone else can do the same.

I also don’t think it is “impossible for humans to comprehend the implications of manipulating the genetic makeup of nature”, but I will admit that we don’t know everything about the implications. That is a reason to use caution, but not at all a reason to stop genetic technologies altogether. After all, we don’t know the implications of banning genetic technologies, so maybe Madill should follow her own advice and ban the ban (then again, she doesn’t know the full implications of doing that either).

Nature News on the near future of reproduction

A couple of weeks ago, Nature News published an article titled ‘Making babies: the next 30 years‘. It interviews a number of specialists in human reproductive technologies and outlines the predictions that they think are likely to arise in the next few decades. I’ve been waiting until I have some spare time to go through it, and now I have. This gives me the opportunity to also comment on other blogs who picked up this story.

The article

First up is Dave Solter, developmental biologist, who predicts that induced pluripotent stem cells (iPSCs) with be cultured into human gametes (sperm and ova). This would mean that anybody who has skin will be able to be a genetic parent, whether they are just an embryo, a corpse or any stage in between. Given that the harvesting of eggs is a major issue in research and reproductive technology, this would be a major boon to the field. No need for women nor men – just grow the eggs and sperm yourself. It would also mean (Dave doesn’t mention this, but I think it is important) you could test that stability of genetic modifications over many generations in vitro within just a few years by ‘breeding’ human embryos. Dave also mentions that an artificial placenta, allowing for the culture of embryos past the blastocyst stage, may be likely.

Next is Alan Trounson, Australian IVF pioneer and now the director of California Institute for Reproductive Medicine. He seconds Dave Solter’s predictions (adding the possibility using embryonic stem cells derived from somatic cell nuclear transfer instead of iPSCs), but raises some cautionary issues. His other predictions include better gene therapy using genetic cassettes and low-cost IVF for the developing nation. Nothing special here.

Following him is Susannah Baruch, director of reproductive genetics at the Genetics and Public Policy Center at Johns Hopkins University. Her predictions mostly concern preimplantation genetic diagnosis (PGD), which she sees as not being a tool to make designer babies but just for gaining full genetic information about a child’s future. She also states that “The old-fashioned way [of reproducing] is cheaper and more fun and that won’t change in 30 years.” I agree, but the end result (the child) will be less reliable.

I’m not going to talk about what Alastair Sutcliffe, a paediatrician, said because it is just about long-term health of children conceived by this technology. Not really any predictions.

Scott Gelfand, director of the Ethics Center at Oklahoma State University, makes the sensible (in my view) prediction that medical technology will allow for the viability of foetuses born even up to 12 weeks of age, or even complete ectogenesis (artificial wombs, no human woman needed). Scott is on the ball, because he sees that this could dramatically affect the abortion debate. A conservative government could require all unwanted pregnancies be transfered into an artificial womb. This would essentially become the dividing line between pro-choice (woman’s control over her body) reasoning and “pro-abortion” (lack of rights for the foetus) reasoning. As I fall into the latter category, I should hope that these artificial wombs are not a tool for outlawing abortion.

Miodrag Stojkovic, stem-cell biologist, predicts that clones will become much easier to make if Dave’s predictions come true. With the requirements for cloning being up to hundreds of eggs, an excess derived from stem cells could allowing reproductive cloning to go ahead. Of course, she points out that reproductive cloning will not be very popular, as (almost) all incentives to clone could be satisfied by artificial gametes. And we won’t make clones for organs either, because we can probably just skip the clone and go straight to the organ (i.e. grow the whole organ from stem cells).

A cure for infertility is the core prediction of Zev Rosenwaks, director of the Center for Reproductive Medicine and Infertility in New York, who also seconds Dave’s predictions about making sperm and ova. This is good, because it puts choice as the core component of reproduction. No more God or Mother Nature choosing whether some people can have children or not.

Finally, Régine Sitruk-Ware, reproductive endocrinologist, looks at the flip side of the previous prediction – contraceptives. She points out that more reproductive research is on people’s choice to have a child and not people’s choice not to have children. She hopes for more effective contraceptives and non-hormonal versions (such as one that prevents sperm from entering the ovum), allowing yet more choice into the realm of reproduction.

The comments

“If a few power crazy experts decide to monopolize the special skills and determine to create thousands of children on their own terms and conditions, the world could be in trouble. I would not want to imagine the consequences. Would you?” -Tan Boon Tee

Given the cost (in time and money) of this idea, it would be easier for said crazy experts to just recruit young people to do whatever they wanted. Which is already what happens.

” It is scary. And i do not want to have a mother who is a hundred years old. Or a father. This is not the earth i want to live in.” – Michael Hoffmann

Get over it. These centenarians only be genetic parents, not gestational or social parents. And if they are healthy enough to be social parents, that will be thanks to life-extension research that will keep these centenarians as healthy as sexagenarians. And already grandparents raise children, but maybe Michael doesn’t like that either.

“I think this has gone too far. We are so keen on improving science investigation that we have lost sense of reality: we can improve nature but not oppose it. Nature is wise and it knows 60-year-old person shouldn’t have baby children, it knows that a mother is important for a baby during pregnacy and it knows is better for evolution genetic variability. I think most of these experiments make people less free because, why do not young partners have children? becase if a woman gets pregnant she’ll probably loose her job. Why do they want to experiment with embrios stem cells? becase they want some profit for all the frozen embrios of IVF. I would recommend to read “Brave New World” from Aldous Huxley so that you would understand my opinion.” – Marina Garci­a

Total bovine excrement here. Nature is not wise (how can it be? it has no brain). Women don’t lose their job for being pregnant (I think that’s illegal). And Brave New World, well that’s a new one? Go read Huxley’s Island – it has reproductive technology done right.

“However there must be some limit for this which I couldn’t found in some of the articles. Who will decide if someone can or can’t be born without mother? Who will claim such wrigth [sic]? Next, think about desingning a persons genome, as Susannah pointed in her article. While pointing there are no data to support the idea, the “genome designer” idea itself is capable to be understood by someone reading the article. Again, this is scary. Some ideas on the articles are beyond the scary, bordering de-humanization. To mention are human clonning and tissue donation. As if the human parts market in some places in this world didn’t required our attentions. Finally, what are we looking for when presenting this idea? Perfection? I can use Susannahs’ comments again: there are no perfection on us. And exactly this is what makes the human existence perfect giving us a path to follow. Why do we not search perfection in eliminating hungher on Earth, or counteracting the global warming?” – Nelson Jacomel Junior

There is nothing scary about designer genomes, and cloning is no more dehumanizing than IVF. The end result will be a human person, no different – no less human (not that this is important) – than any of us. Nelson’s only good point was his first part about whether governments will interfere with reproductive rights by mandating who can be born. They should never be allowed to. Undoubtedly some parent will need to request a child, and that parent could be male or female (we already allow single females to have children by sperm donation in most sensible parts of the world, so why not single males?).

“When we learn to correct and reprogram our DNA then we will have conquered ageing and disease and the problem of infertility would also disappear and all these proposed technologies would become obsolete.” – Richard Dawson

A sensible view, as anti-ageing research may indeed make some reproductive technologies less popular. But in the next few decades, it is still likely that these technologies will be developed and will be utilised.

“While I admit it is in the best interest of the patients involved to have a kid, plainly speaking aren’t we acting against “survival of the fittest”? Further, if nature (mother nature) wanted us to reproduce at the age of 100, it would have made it so. That nature imposed a reproductive age limit of ~45 for women should ring a bell.” – K Sivaraman

Holy FSM, another person who thinks that an inanimate process of evolution is more intelligent than the scientific community. Nature has a poor record of doing good (are there not natural disasters as well as man-made ones?), so I don’t see why we should be respecting what is natural. I think this is just a disguise for fear of change.

The blogosphere

A sensible view given here, at Genetic Future. Here are two key points:

“The point is not that we will never understand the genetic basis of complex traits – we will, at least to a pretty good approximation, given advanced tools and sufficiently large cohorts. The point is that even once we understand the genetics of complex traits perfectly, that won’t be enough to generate a “perfect baby” through embryo screening alone.”

“So it’s safe to say that there will be no perfect baby. Instead, the prospective parents will face a tough choice between embryo A, who will likely be tall, slim, smart and cancer-free but have a higher-than-average chance of bipolar, early-onset dementia, and infertility; embryo B, who will be a little shorter, dark-haired, probably fairly gregarious, resistant to coronary artery disease, susceptible to bowel cancer, hypertension and early deafness; embryo C, who will be of average intelligence, unlikely to suffer premature baldness, prone to mild obesity and diabetes, but not at a high risk of any of the other major common diseases; and embryos D-N, who present a similar panel of competing probabilities”

On the other hand, many blogs have perpetrated the distorted view started by the ignoramuses at FOXNews, that this will lead to pregnancy at 100:

“Solter, writing in the journal Nature, claims that advancements over the next 30 years should make it possible for women at any age to give birth.”

No he didn’t! He claimed that “newborn children could have children and 100-year olds could have children” but he never said they would become pregnant and give birth. He was obviously implying that they would use a surrogate womb or an artificial womb. Having a child is not the same as bearing and birthing a child, but I guess I expect much for the traditionalist readers of FOXNews to realise that.

Conclusion

I’m a little dismayed that nobody predicted that gene therapy will become advanced and reliable enough to be used on embryos, ushering in the era of the designer baby. That would be my prediction.

Anyway, the issues brought up are good to consider, especially the idea of artificial wombs and artificial gametes. More choice, more reproductive freedom – can’t go wrong.

GM Human Embryo? Nope, that doesn’t count!

Those at the London Times are conveniently twisting the truth to claim that scientists have created the first genetically engineered human embryo. What did they do? Insert the gene for green-fluorescent protein. Big deal, that’s not what I want to hear when I see the words ‘GM embryo’!

Lots of hype over nothing. This was done last year, and now we finally hear about it. That alone should have you wondering if it had been a blow-up about nothing. If it was an amazing work, the scientists involved would have been calling press conferences and everything.

The embryo wasn’t even viable (it had ‘abnormal chromosomes’ according to the London Times. I think they mean it was triploid), and wasn’t even going to be implanted into a woman. Just a bunch of fluorescent green cells in a dish, destroyed after five days of growth. BORING! There have been stem cell experiments more exciting than this.

It’s only being brought up because the current HFEA bill in the UK actually expresses permission for this research, though it does ban implantation of such embryos.

Reading the comments on the London Times site, and on the other news sites that picked up the story, is fun at least:

“Read your bible people. We are living and acting out every word of revelation’s. , Next thing you know like one comment was made the rich would have perfect babies and the poor , would get thrown to the side like trash .” – Lola of the United States of America (of course)

“These mad scientists are totally out of control, They will completely destroy life on this Planet but before they do this, monsters will be created as in days of old. Which is why that old technology advanced civilisation were destroyed, you cannot mess with nature without being punished.” – Arthur of England

Oh noes, the sky is falling. A bit more sensible, but still wrong, is the commentary from New Scientist:

No-one is contemplating King’s “nightmare” scenario: the creation of genetically-engineered babies.

Actually, I’m contemplating it. So are many others. It’s not a nightmare, it’s a dream!

However, I think I prefer the words of Annalee Newitz over at io9.com, who said:

[Q]uit your whining and learn some science, bitches. This isn’t a designer baby.

Re-engineering the phototransduction pathway

I’m sure many have looked at the phototransduction pathway and just gone “there has to be a better way!”. If so, then I agree with you. Evolution had to work with what it was given, and it’s no surprise it has made many compromises. But surely, you must agree, we intelligent humans could optimise what blind evolution stumbled upon. And why shouldn’t we – we could enhance our vision!

For those who don’t know, the phototransduction pathway is the process that happens between a photon of light hitting your retinal cells and the change in firing activity of that retinal cell. In a sense, it is the processing time. Now, it takes a long time to occur many milliseconds. Probably not as long as it takes for the signal from that photoreceptor to pass through across the synapse to the bipolar cell, along the bipolar cell, from the bipolar cells to the retinal ganglion cell and along that ganglion to the lateral geniculate nucleus of the brain, but I’m sure it is nonetheless too much time to be wasting on needless reactions.

The phototransduction pathway happening in the eyes of people reading this first involves photons hitting the 11-cis-retinal molecule of opsin molecules, which are G-protein coupled receptors (seven transmembrane domain proteins) sitting in the membranes of your photoreceptor cells. The photon is absorbed by the 11-cis-retinal, causing it to form all-trans-retinal. This structural change causes the opsin molecule to change shape, which bends a G-protein attached to the opsin called transducin. The change in transducin shape causes it to release its attached guanine-diphosphate (GDP) molecule and bind instead to a guanine-triphosphate (GTP). The GTP binding causes the alpha-subunit of the transducin to translocate to an enzyme called phosphodiesterase (PDE) located on the membrane, where it binds to the inhibitory gamma subunit of PDE. The binding event decreases the inhibitory effect of the gamma PDE subunit, causing the PDE to start actively hydrolyse (split open) cyclic guanine-monophosphate (cGMP). There are channels in the membrane that open and let sodium ions (Na⁺) and calcium ions (Ca²⁺) into the cell when cGMP binds to them. The loss of cGMP caused by PDE activity causes closure of these channels. And this causes the whole cell to hyperpolarise (get more negative) to around -70mV, which stops it from releasing glutamate. Essentially, light turns off the photoreceptor, dark turns it on again.

If you didn’t get it, read it again and look at this wonderful diagram by Jason J. Corneveaux over at Wikipedia:

So, the main point is that there is a lot of stuff to happen between light hitting the cell and a response. This isn’t all bad – there is a lot of amplification there. One opsin can activate 100s of transducins, two of which are required to fully activate PDE. So one opsin can activate ~50 PDEs, each of which can hydrolyse thousands of molecules of cGMP (at a rate of ~100,000cGMP/second). This loss of cGDP causes the closure of 100s of cation channels (of the tens of thousands that are open in each cell during darkness). So there is a lot of amplification going on during this waste of time, so it’s not a total waste – one photon can lead to the closure of a hundred channels. Pity it takes so long.

Of course, evolution often finds multiple ways to get to the same solution, some of them effective and some of them not so much. One such molecule is the channelrhodopsin-2 (ChR2), found in a species of green algae called Chlamydomonas reinhardtii. It looks a lot like our opsins, so it likely a distant relative, but while our opsins go like this:

Opsin activation → Transducin activation → PDE activation → cGMP decrease → closed channel

the channelrhodopsin-2, because it actually is a channel itself, goes like this:

channelrhodopsin activation → open channelrhodopsin

Here is a picture, to compare with the above (from Zhang, F. et al. Circuit-breakers: optical technologies for probing neural signals and systems. Nature Reviews Neuroscience 8, 577-581 (August 2007). Used without permission, so reproduce at your own risk):

You may notice the diagram indicates blue light. This is because the ChR2 protein has a peak absorbance at 460nm, which is a bit on the blue side. For comparison, our blue photopsin absorbs maximally at around 420nm, our green photopsin at 534nm, our red photopsin at 564 and our grey rhodopsin at 498nm. So, we’d need to mutate the ChR2 protein for use in humans, if we were to replace our photopsins with similar proteins.

Next question you should be asking is – what about the amplification? Well, I think the answer lies in voltage-gated sodium channels (VGSCs) and voltage-dependant calcium channels (VDCCs). If the ChR2 protein lets in some cations, that will make the inside of the cell membrane near that ChR2 more positive. Conveniently, VGSCs and VDCCs will open when the membrane gets more positive! So having these together – ChR2 and VGSCs/VDCCs – should allow for rapid amplification of photon binding into channel activation. (Anyone who knows voltage-gated sodium channels may remember they have a refractory period, but that only lasts for a millisecond and you can probably mutate the beta subunit or site 3 of the alpha subunit to get accelerate that). The upside of this design is that one photon could potentially activate all ion channels on the photoreceptor as the depolarisation spreads, rather than just a few hundred of the nearby ones.

That said, you don’t want it to be too sensitive. Ion channels are known to spontaneously open, and you don’t really want flickers appearing in your vision because one channel accidentally opened and was amplified across the whole receptor. The normal system is resistant to this, because channel activity doesn’t affect the amplification part. But I’m fairly sure there will be enough sensitivity available that once the amplification is turned down to eliminate ‘noise’, perhaps by ensuring that more than one photoreceptor is required to activate (via bipolar cells) a ganglion cell, you will still be able to see better in the dark than before.

An additional issue, however, is the structure of the rod photoreceptor cells. The membrane infoldings of the cones are not closed off, meaning they exposed to the extracellular fluid (creating the membrane potential used by channels). The rods, however, have free-floating membrane discs fully enclosed by cell membrane. So, if ChR2 was placed on these, the light-activated opening would be unlikely to result in a net ionic movement, because neither side of the channel would be exposed to the extracellular environment. So, either this development will be restricted to cones, or that developmental aspect could be changed somehow to prevent the photoreceptor discs from detaching from the cell membrane.

Another question you may have is “hey, our opsins cause hyperpolarisation of receptors in response to light, but ChR2 would cause depolarisation”. There are two options here. We could alter the ChR2 so that it is only permeable to potassium ions (K⁺), which, because K⁺ is more plentiful inside the cell, cause cations to flow out of the cell, causing hyperpolarisation. We’d also have to downregulate the amount of K⁺ leakage channels in the photoreceptor membrane, because those are what normally causes the cell to hyperpolarise once light turns of the cGMP-gated channels, so perhaps this is too difficult. Alternatively, the protein structure of the channelrhodopsin could be altered to close, instead of open, in response to light. Both of these systems could be amplified by voltage-gated potassium channels instead of voltage-gated sodium channels.

Then again, the polarity of the responses might not even matter. By changing the receptors used by the bipolar cells to receive the signal, the signal could be inverted (it’s inverted anyway for cone cells – bipolar cells come in different types, some of which activate when the cone photoreceptor turns on and others when the cone photoreceptors turn off). As long as the cones and rods are both sending signals for ‘light on’ and ‘light off’ at the right times, and not contradicting each other, the system should work regardless of the polarity.

Regardless of these problems, researchers are trying. Yes, researchers have inserted ChR2 into the retinal neurons of a photoreceptor deficient mouse (Bi, Chui et al, 2006). Although it doesn’t look like they were able to restore noticeable sight to the mouse, they were able to get the retina to function (but others have partially restored sight – see Lagali, 2008). Now, they were trying to get the ganglion cells to work as photoreceptors, which isn’t going to be very effecient due to their low membrane area in comparison to photoreceptor cells. They also didn’t use any amplification like I mentioned above, nor could multiple photoreceptors cooperatively activate a single ganglion cell like normal. Unsurprisingly, they found it took 50-100% more photons to elicit a response.

So, why does all this belong on a human enhancement blog? Well, the clunky natural system has a poor temporal resolution. Put simply, it takes too darn long to work (like, tens of milliseconds!). So, if we replaced our foveal cone photoreceptors with a ChR2-based system, we could possibly see things happen slightly earlier, or even see a much greater amount happening every second (though this would depend on deactivation times as well as activation times, and whether the downstream connections could handle the increased frequency stimulation), which could possibly lead to greater reflexes. As most of the problems here relate to amplification and rod architecture, it may make the most sense to apply these modifications to our fast-response, daylight-vision cone cells and leaves the rods alone (at least the phototransduction mechanisms – they’d be my first target for infrared vision).

So, bring on my genetic super-vision! At least until the bionic eyes arrive.