Posts Tagged ‘genetic engineering’

h1

UK approves experimental genetic engineering of human embryos

Saturday, 6 February, 2016

Good news from the United Kingdom, with the UK Human Fertilisation and Embryology Authority (HFEA) being the world’s first regulatory authority to explicitly approve genetic engineering of human embryos. There are other countries who haven’t banned the technology, but this is the first one to purposefully allow it.

Of course, these won’t be designer babies, as the experiment must cease after the embryos are about 256 cells (about two weeks old). But this is necessary to study the effects of the technology so that maybe one day it will actually be safe enough to use for therapeutic or reproductive purposes. See more about the story in Nature News, Wired and The Guardian.

You can also read some opposition to the decision, with Craig Venter writing in Time and Donna Dickenson in The Telegraph. Both pretty much argue that we don’t yet know enough and should be cautious, and with this I agree. But unless we take the few cautious steps forward by doing the research, we’ll never know enough to be able to edit human genomes. Somehow I think that’s precisely the outcome the opponents want.

h1

TED Talk on CRISPR/Cas9 system of genetic engineering

Sunday, 15 November, 2015

Jennifer Doudna talks on the currently mainstream method of genetic engineering, using the site-specific CRISPR/Cas system.

In addition to the brief summary of how CRISPR works, she also talks about how genetic engineering is currently being used and predicts the first applications of gene therapy will be mostly for immune system diseases, as white blood cells can be removed from the body and modified ex vivo, or outside the body. I totally agree with this, with our current level of technology it’s far easier to engineer a cell outside the body rather than risk any of the adverse reactions to gene therapy in humans.

Most importantly for this blog, she talks about whether this technology could be used for genetic enhancement. She lists simple things that many of us might even consider no different to vaccines, like enhancing our resistance to cardiovascular disease, before quickly moving into the ‘designer humans’ idea of specifying or changing height or eye colour.

She backs up the moratorium on human germline genetic engineering that I have mentioned on this blog before. I have my objections to this idea (see my previous post for those details), but I have just thought of another problem. As mentioned, cells that can be removed from the body and modified in a dish are most likely the first ones we will be able to modify. In addition to blood cells, and perhaps therapies based on stem cells, our gametes (sperm and eggs) are cells that can be removed from the body (especially so with sperm) and modified outside the body, used to create embryos that can be re-implanted. Thus, it’s likely to be relatively easy to prevent certain genetic diseases before embryos with those disease genes are even created.

I suspect the pressure to cure diseases will be much greater than the pressures to create a clone, so a moratorium on human germline engineering is probably going to be more difficult to defend than the one on cloning.

h1

Making a real-world Pandora

Thursday, 14 January, 2010

While many movie-goers were saddened as they left the world of Pandora and came back to Earth, I was not. Instead, as I left the cinema after seeing James Cameron’s Avatar, I was instead happily musing about how the beautiful flora and fauna of Pandora could be created. For real. Here, on Earth.

For me, I was most amazed by the prevalence of bioluminescence among the plants, and even animals, of Pandora. The bioluminescence is especially obvious with the Trees of Souls and Tree of Voices, but nearly all plants and fungi seem to have bioluminescent properties. Bioluminescence is obvious in some Pandoran insects and lizards, and the sentient Na’vi also have lines of blue photophores on their skin.

A tank of firefly squid (Watasenia scintillans) caught off the coast of Namerikawa, Japan.

Fortunately, bioluminescence is not something entirely alien. Many organisms on our own planet are also bioluminescent, though most bioluminescent animals live in the deep ocean (though exceptions, such as glowworms and fireflies, are well-known). Bioluminescence has evolved in insects, molluscs (especially squid), fish, jellyfish, fungi, plankton and bacteria, but to my knowledge no naturally bioluminescent plant species exist on Earth.

I had to say ‘naturally’  in the last sentence of the above paragraph because in recent times, many animals and plants have been genetically engineered to express the firefly (Photinus pyralis) enzyme called luciferase. This enzyme, in the presence of its substrate (luciferin) produces a yellow-green bioluminescence. There are also many other natural and mutated enzymes, allowing for bioluminescence with colours of red , orange, yellow, green, blue and even violet.

Bioluminescence of the bitter oyster fungus (Panellus stipticus) found near Springdale, Wisconsin, USA.

With advances in the knowledge of the chemistry and biology of bioluminescence, genetically-engineered bioluminescent plants and animals may become as commonplace on Earth as on Pandora. As very efficient solar-powered lights (in addition to being very attractive), gardens might be lit by the very plants that inhabit them. We might make animals that can use bioluminescence as a signal, like pets that literally light up when they see their owner. The bioluminescent magic seen in Avatar is entirely feasible!

Na’vi are human-like in appearance, but are much taller (almost 3m tall) and have some alien characteristics – blue striped skin, pointy and mobile pinna (external part of the ear), catlike tails and (with the exception of the avatars) only four digits on their hands and feet. They also have larger (and yellow) eyes compared to human proportions, flatter noses and slimmer physiques. It’s also mentioned in the film that the Na’vi are stronger and have hardier bones. Each of these characteristics is at least biologically plausible, and so it might be possible to turn a human into something resembling very closely a Na’vi.

Some humans have traits that make them more Na’vi-like than others, and with research the genetic reasons for this difference could yield ways to make a human into a Na’vi. Pituitary gigantism (causing greatly increased growth hormone) can produce humans with heights of up to 2.7m, and it’s possible that a similar pathway can be used for genetic enhancement of skeletal height without the associated health issues of gigantism. Enhancement of bone strength might also solve some of these health problems, and I foresee that stronger bones and muscles will be a desirable trait for future human enhancement (and therefore will be well-researched). Finally, the fact that some humans naturally have very slender physiques suggest the trait might be able to be genetically engineered, and narrow waists, though historically achieved through the use of corsets, should also prove amenable to genetic modification.

An okopipi, or blue poison dart frog (Dendrobates azureus), native to Suriname and Brazil (by ucumari on flickr.com)

Inspiration for more alien features of the Na’vi was found in the animals of Earth, and perhaps we might be able to borrow from these animals genomes. As the very distant ancestors of humans had a tail, restoring one should prove relatively simple also. Animals with mobile pointed pinna exist and are well known (such as the common cat), so with some research, humans could be engineered to have similar. Reducing the number of digits might be more difficult, as five digits is the normal for most, but fortunately not all, limbed vertebrates (and, as the avatars still had five digits, reducing digits to four might not be desirable). Blue skin should be possible, though blue pigment molecules are rare, but one could perhaps be engineered and human skin engineered to produce it instead of the red and brown pigment molecules pheomelanin and eumelanin). Similarly for yellow iris pigmentation (either that, or contact lenses).

Creating the other animals of Pandora, however, might prove more difficult. The other animals seem to mostly be hexapods; Direhorses, Ikran, Thanator and Titanothere all have six legs. The base body plan for limbed vertebrates on Earth is four limbs, and there are no six-limbed vertebrates from which any inspiration can be drawn. Nonetheless, there is nothing biologically implausible about hexapodal mammals and reptiles, so one day such creatures could be created.

The Ikran (also known as Mountain Banshee) could prove the most problematic to engineer. Earth’s gravity is greater than that of Pandora, and the musculature required for powered flight is therefore much greater (and heavier). Because of this, flying creatures on Earth are seldom very large, with the largest ever to exist (Argentavis) weighing only around 100kg (certainly less than the mass of a Na’vi) and a wingspan of 6-8m (the Ikran wingspan is 14m). Though with great re-engineering of muscle tissue, strong but light muscles could circumvent this issue. But don’t even get me started on a Toruk.

So, finally I want to mention perhaps the most imaginative aspect of Pandoran biology – the entire ecosystem of Pandora is seemingly connected into one super-consciousness, termed Eywa. The roots of plants carry signals from one tree to another, and animals (including the Na’vi) have a ‘queue’ (or many queues) extending from the back of their neck, which they can use to connect to other animals (allowing sensory and motor systems to merge) or to certain plants, like the Tree of Souls and Tree of Voices, allowing memories to be accessed and other functions.

A weeping willow (Salix × sepulcralis) photographed with an infra-red filter in Washington D.C, USA (by zachstern on flickr.com)

An analogy is drawn by Dr Augustine between the network of plants on Pandora and a network of neurons in a brain. While this might be valid in terms of numbers of connections, the electrochemical signals used by neurons only travel at a maximum velocity of 120m/s. If the network of Pandora uses similar mechanisms, it would take many minutes for signals to propagate across even a small section of forest and perhaps hours to reach the entire landmass. This is far too slow to produce any coherent or conscious thought. I’m sure there’s some sort of fantastical explanation, as I’ve heard talk of psionic energy or something similarly unreal, allowing for light-speed communication. That might also explain how the animals of Pandora were connected to this network at all times without being tethered to a tree (but simultaneously makes the queue rather redundant as a form of communication).

Anyway, the biological plausibility of interfacing two animals with a queue together is much higher. The queue seems to extend from the base of the head, near the brainstem, which makes it another extension to the central nervous system, secondary to the spinal cord (it occurs to me that extending the spinal cord into the tail, and using that as a queue, might be easier to engineer). This could feasibly allow any motor signals to be sent via either the spinal cord or the queue depending on what is being controlled (e.g. the Na’vi’s hands or the Ikran’s wings), and for any sensory information to be relayed from the brain to the other organism (e.g. the Ikran’s wings to the Na’vi’s brain). A very strong Tsahaylu (connection) between two Na’vi is said to occur during mating. While I’m sure feeling what your mate does and influencing their actions would, as a reciprocal form of communication, lead to totally awesome lovemaking, I doubt that this would lead to any merging of consciousness, as this distances between the brains would be too great for coherent thoughts. Nonetheless, perhaps sharing of memories and feelings could occur, though perhaps not complete thoughts.

I don’t think it will be possible to recreate every aspect of Pandora in the near future. Floating mountains would likely be a significant geoengineering problem for many years to come. And low gravity

I think the sadness and even weltschmerz experienced by those fans of Avatar is entirely justified, but being dissatisfied with reality is nothing new to transhumanists. But I just want to say this: if you want to live in a world like Pandora, then why not go ahead and make this world (or a small section of it) just like it! If you want to be a Na’vi, then why not engineer yourself to be just like one! Go study biology: plant and animal genetic engineering, bioluminescence, biomechanics, neuroscience and so on. Are you prepared to work toward making a better planet, a better ecosystem, and better people?

h1

Enhancing memory and learning in mice

Monday, 23 March, 2009

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 discussion170,171.

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).

h1

‘Genetic engineering’ implies an act of engineering

Friday, 6 February, 2009

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.

h1

Genetic enhancement of the human metabolism

Thursday, 4 December, 2008

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).

h1

Anti-ageing telomerase with cancer resistance too

Saturday, 15 November, 2008

Telomerase is the enzyme that elongates the ends of chromosomes, and because these telomeres become shorter every time a cell divides, this enzyme is essential to making a cell, and an organism made of cells, become immortal. Despite this, I neglected putting telomerase on my list of eight genetic modifications to live forever, because increased telomerase activity also increases the risk of cancer. For a cancer cell to proliferate into a tumour it will have to divide almost limitlessly, so cancer cells usually mutated to over-express telomerase. But if a cell is already expressing loads of telomerase, that is one less mutation that needs to occur before a cell becomes cancerous.

But, on that list I did include a study that showed mice with extra copies of the tumour supressor genes p53, p16 and Arf (so called Sp53/Sp16/SArf mice, where the S is short for ‘super’) are largely cancer-resistant (Matheu et al, 2007). This occurs because a cell must acquire mutations in all copies of these genes before it can become a tumour, and with extra copies, this requires more specific mutations.

Now, the same lab has reported, in yesterday’s edition of the journal Cell, that if they crossed transgenic mice that expressed telomerase reverse transcriptase gene Tert in many of their epithelial tissues, with those transgenic cancer-resistant mice, they end up with Tert-transgenic mice with cancer resistance (Tomas-Loba et al, 2008). The resulting mice are named Sp53/Sp16/SArf/TgTert mice. The cancer-resistance should offset the increased risk of cancer due to telomerase, leaving the telomerase to keep the telomeres on the chromosomes from getting too short, preventing at least one of the causes of ageing.

So, while the Sp53/Sp16/SArf mice lived 16% longer than wild-type (i.e. normal) mice, these Sp53/Sp16/SArf/TgTert mice lived 26% longer again. While they didn’t look at normal mice in this study, they did look at Sp53 mice (which don’t really age too differently to normal mice), and found that the Sp53/Sp16/SArf/TgTert mice lived 40.2% longer than the Sp53 mice. And, if they looked at mice lucky enough not to get cancers in these two groups (which are presumed to have died from age-related decay along, not cancer), the Sp53/Sp16/SArf/TgTert mice lived over 50% longer than the Sp53 mice. In addition to this, the older Sp53/Sp16/SArf/TgTert mice were still able to balance on a tightrope just as well as they were when they were young.

And to top it off, even the young Sp53/Sp16/SArf/TgTert mice had better glucose tolerance and gastro-intestinal tract barrier function, which suggests that telomerase can even improve regenerative capacity in young tissues. Yet these additional regulatory genes seem to slow down stem cell proliferation, but it is suggested that this may be beneficial in ensuring stem cells are still around later in life. So each stem cell is dividing less quickly, but there are more of them, even at young ages.

It is worth noting that these mice only expressed more telomerase in their epithelial cells, not their entire body. Although the telomerase seemed to have some effects on the entire body, the researchers hint strongly at their next step:

It will be of great interest to study the impact of ubiquitous TgTert expression on mouse fitness and longevity.

Given that the researchers also note that the increased lifespan of their Sp53/Sp16/SArf/TgTert mice is of similar magnitude to mice with a calorie-restricted (CR) diet, and that it may well be through a different anti-ageing pathway, these two may be combinable. If you want to win the Methuselah Mouse Prize, I suggest genetically modifying some mice with Sp53/Sp16/SArf genes as well as TgTert, and either switch them to a CR diet (or with engineered genes that mimic such a diet). And if you want to live forever, I suggest you get what these mice are having.