Posts Tagged ‘Genetic Modification’

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Some scientists make no sense to me

Saturday, 21 March, 2015

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.

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Patent on human cancer gene struck down

Wednesday, 31 March, 2010

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.

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Super-strong genetically-engineered monkeys

Thursday, 19 November, 2009

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.

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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).

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‘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.

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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).

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Gene doping is more fair, not unfair

Friday, 1 August, 2008

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).