Archive for April, 2008

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Wednesday’s Words of Wisdom

Wednesday, 30 April, 2008

Today’s Words are in Latin, truly the wisest-sounding language of them all. These words are attributed to the the Roman philosopher Seneca (the Younger)

“Nemo liber est qui corpori servit” (No one is free who is a slave to his body)

Although it is likely Seneca was using these words to admonish those hedonists who let their bodily urges control them, these words are nonetheless a strong statement for bodily autonomy/morphological freedom.

Our rights to freedom and autonomy should extend to our own bodies and DNA. If a person wants to go for a run, we let them because they have the right to freely do that. So, if a person wants to have cyborg legs in order to allow them to run faster or wants to insert a few genes into their muscles so that they can run faster, they should be allowed to do that too.

It’s my body, my brain and my genome. To forbid me from changing those characteristics is violating my right to liberty.

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GINA + effective genetic predictions = no health insurance

Tuesday, 29 April, 2008

The United States Senate has recently passed the Genetic Information Non-discrimination Act. This bans insurance agencies, and workplaces, from using information obtained from predictive genetic tests to discriminate against their clients (or workers). They can still use existing symptoms to adjust their premiums, but tests that suggest you might get cancer or a similar condition in the future will be off limits to insurers.

But this could provide some very serious problems if genetic tests become very good at predicting disease risks (and they will). If people know they will likely get a genetically-influenced disease in the future, they will take out comprehensive private health insurance. And if people know they very likely won’t get that disease, they will opt for a basic private health insurance plan to cover accidents and contagious diseases. (Those who don’t know their genetic disposition will probably stick with their moderate, employer-provided health plan – and most people say they won’t want to test their genome if GINA wasn’t there).

The effect of this is that insurance becomes less viable, because insurees are now cherry-picking their insurers rather than the reverse. Why would an insurance agency offer cancer cover, if the only people who opt for that will be people likely to get cancer? Offering such cover would be a net drain on the insurer! Therefore, private health insurance, though very profitable in the short term (before the diseases present themselves and claims start being made), will not be able to survive in the long run. No more private health insurance.

There are ways to avoid this. The obvious ways are to allow genetic discrimination (so premiums could be raised for the genetically at-risk), or to ban good genetic testing (not nice). A more likely prospect would be for insurers to be legally required to cover all genetically-determined or influenced conditions under all plans. This would, however, result in many people paying money for health care they will never need, but is arguably better than people going without.

The best (in my opinion), though also unlikely, would be for the United States to accept the death of private health insurance and move to a totally public health system, where all medical expenses are paid for by taxpayers. Taxes not used for health care each budget would be a surplus to cover previous/future deficits or create more facilities (instead of into the pockets of insurance company executives). Plus, genetic discrimination (typical or ‘reverse’) would be impossible.

Although I figured this out on my own, what I have said here has been, of course, said by many others. Here is the best one:

Personal genomics and the end of insurance

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Gene therapy fixes (night) blindness

Monday, 28 April, 2008

Those bionic eyes I blogged about have some competition – from genetic engineering. A form of blindness known as Leber’s congenital amaurosis is caused by a lack of a key gene, RPE65, in cells of the pigment epithelium cells. These are the cells just behind the photoreceptors, and they produce a key pigment molecule called 11-cis-retinal. This pigment is used primarily in rod photoreceptors, because the cones can make a similar molecule known 11-cis-retinaldehyde without relying on the pigment epithelium cells. However, the cones degenerate, meaning that Leber’s congenital amaurosis can cause blindness by middle-age.

Gene therapy was trialled on young adults (17-23), who still have reasonable colour vision thanks to functional cones. However, cone cells require more light to be stimulated, so the rod cells (which only show light and dark, or shades of gray) are used primarily in low-light conditions (and in peripheral vision).

The researchers used the common viral vector AAV (adeno-associated virus) plus an adeno 5 helper virus. This vector contained the DNA of the human RPE65 gene, including its promoter sequence (the terminator sequence was different though – bovine growth hormone polyadenylation sequence was used). They injected these into the subretinal space of one eye.

Unfortunately, though three patients underwent the surgery (at least, three were included in the study – I think it has been trialled on others), only one showed improvement. It was a dramatic improvement though – improved visual mobility, as measured by a navigation in a simulated street scene in low-light conditions – from 77seconds to 14 seconds, without bumping into the wall eight times like he did before the surgery. The researchers believe this lack of improvement in the other patients was due to their retinal degeneration being more severe, which if true would mean that this therapy should be targeted at children with the condition.

View full article in the New England Journal of Medicine.

Now the race is on. I wonder which will end up curing blindness first – bionics or genetics. This race is going to be in many areas aside from vision research, such as in giving mobility back to amputees (can we regrow limbs before we get fully functional prosthetics?). Personally, I’m willing to let both fields work, so that those who want it can be enhanced from both directions.

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I’ve bought Bill McKibben’s book

Saturday, 26 April, 2008

For some reason, I’ve actually bought a book by one of the crazy people in this arena of human enhancement – Bill McKibben’s Enough: Staying Human in an Engineered Age. If you don’t see any blog posts from me this week, it’s because I’m outside screaming at the sky or possibly burning the book in a fit of rage against the status quo bias present throughout the book.

I’m not looking forward to reading this one, but as Francis Bacon said: Knowledge is power.

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Bionics eyes are everywhere!

Friday, 25 April, 2008

Everywhere I look, I see some mentions of bionic eyes. Well, ok not everywhere, but there are stories this week about visual bionics coming from the US, the UK and from here in Australia.

A US company, Second Sight, working through the University of Southern California, has a nice bionic eye called the ‘Argus II’. Two blind patients in the UK have received the implants, which sends information from a camera worn on the head to a retinal implant featuring 60 electrodes on a 1mm2 chip. Now 60 electrodes isn’t much, considering that the retina contains about 160 million photoreceptor cells. Each of those electrodes is likely to be stimulating large portions of those. So it’s only rudimentary sight at the moment – only able to distinguish between large objects. But it’s only a matter of time.

The Prime Minister of Australia, at his 2020 Summit this week, thought that research into further bionics was a good plan for Australia, seeing as the University of Melbourne were the leaders in developing bionic ears (cochlear implants). The cochlear implant has a similar problem as the bionic eye – it uses a mere 22 electrodes to stimulate a few thousand receptors. One other Australian design, a bionic eye developed at the Sydney Eye Hospital, has a cost-effective design featuring only 30 electrodes, but differs from the Argus II in that it is fitted on the extra-ocular surface of the eyeball, rather than on the internal surface of the eye.

The Australian researchers at The Bionic Ear Institute in Melbourne have learned from this, and their bionic eye design features a total of 1000 electrodes. It also stimulates the optic nerve, rather than the retina itself. I’d imagine this would have the advantage of allowing more of the visual field to be stimulated at once, rather than just the part of the retina where the chip is.

Only a matter of time now before we have bionic eyes like Steve Austin (Six Million Dollar Man) or Jaime Sommers (Bionic Woman – the 2007 one). Or Batou from Ghost in the Shell. And if you really want to stretch for it – John Silver from Disney’s Treasure Planet.

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Wednesday’s Words

Wednesday, 23 April, 2008

I’m unsure as to whether these words are wise or not. They are not words of worry in that they were not written in fear or anxiety, but they have certainly caused enough worry by others. These are pretty much guaranteed to be quoted in some form in a book critical of human enhancement (and published after 1997). Some of these words are those of molecular geneticist Lee M. Silver, in his book Remaking Eden (first published in 1997, but I only have the 2007 reprint):

  • [A]ll people [belong] to one of two classes. The people of one class are referred to as Naturals, while those in the second class are called the Gene-enriched, or simply GenRich.
  • The GenRich – who account for ten percent of the American population – all carry synthetic genes.
  • The GenRich are a modern-day hereditary class of genetic aristocrats.
  • The GenRich class are anything but homogeneous. There are many types of GenRich families, and many subtypes within each type.
  • All aspects of the economy, the media, the entertainment industry, and the knowledge industry are controlled by members of the GenRich class
  • Naturals work as low-paid service providers or as laborers.
  • [B]y the end of the third millennium, the GenRich class and the Natural class will become the GenRich humans and the Natural humans – entirely separate species with no ability to crossbreed, and with as much romantic interest in each other as a current human would have for a chimpanzee.

I don’t really know why Silver wrote about a seperate human species. I don’t think it is likely to ever happen. Silver refers to the evolutionary process of speciation occurring as the two classes become less genetically compatible due to reduced breeding. But I suspect that enough GenRich will fall in love with the “lower” tiers of society (who will probably have some genetic enhancements, as they become cheap enough to afford) to keep the gene flow going, and thus prevent sympatric speciation.

And besides, Silver is talking about the third millennium here! Did he not think that by that stage, geneticists would have worked out how to overcome any genetic incompatibilities between two closely related species? Even if this reproductive incompatibly is caused by differing chromosome numbers (the objection often raised to human artificial chromosomes), at the current rate of advancement in the science of ‘reprogenetics’, there will be a way to make them compatible.

As I said at the start of this entry, Silver appears to have worried more people than he comforted with the Prologue of Remaking Eden. And without good reason, in my opinion.

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Positive feedback loops in bioethics

Wednesday, 23 April, 2008

There are some situations in bioethics were people use a prior action has justification for further actions. I like to call these positive feedback loops, as they remind me of the positive feedback mechanisms of the body; an increase in one property (say, the level of a hormone) causes a set of signals to be releases that cause that property to change in the same direction as the initial perturbation. In economics, such loops are called ‘vicious circles’, such as where lack of education leads to a lack of income which leads to a further lack of education leading to a further loss in income and so on.

The most obvious loop is that involved in the debate about human embryonic stem cell research. These were banned or restricted (by limiting funding) in many places around the world, and many researchers no doubt shied away from the field due to the funding or legislative insecurity. Unsurprisingly, there have been far more treatments developed that involve adult stem cells than those using embryonic stem cells. Detractors of embryonic stem cells claim this lack of results is due to the inferiority of embryonic stem cells, and without the push for therapies, the restrictions on embryonic stem cell research are not likely to change, and could even be increased.

Similar examples involve agricultural biotechnology, where harsh restrictions GM crops causes them to be far more expensive and less efficient to grow, which weakens claims about solving the food crisis, which removes the major reason for allowing the research, which causes restrictions to increase.

I’m worried a similar problem of this sort could arise with human enhancement technologies, like genetic modification. They will first be banned for ethical problems or safety concerns. Then a few researchers will begin their research in other nations where there are no safety concerns or clinical trials, leading to horrible experimental disasters unrivaled in sci-fi films. Then those experiments will be exposed to the public, leading to mass panic. This social pressure will leading to even harsher restrictions on the research, driving the research even further underground, thus restarting the cycle again.

We need to watch out for these loops. It is entirely unscientific for people to claim that stem cells are better derived from adults than embryos if both are not on equal footing. It is entirely illogical for people to claim that growing GM food is more expensive if their concerns about GM food are what made it so expensive in the first place. And, it is especially bad to force research underground where it will be carried out in a manner unsafe to both the researchers and the research subjects, and illogical to believe such research would be equally dangerous if carried out in approved facilities under regulatory oversight. These loops can quickly spiral out of control into a land of very, very harsh restrictions on scientific research. And I, for one, would much rather have too much science than too much legislation.

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Eight genetic modifications for dramatically increasing your chances of living forever

Thursday, 17 April, 2008

This is my answer to George Dvorsky’s Eight Tips. His version included boring things like eating good food and getting exercise, which require a lifelong commitment. More my style, however, is just changing my genome so that my cells think I’m living the healthy and calorie-limited lifestyle, whereas I’m actually sitting at my computer all day eating junk food.

1. Decrease your expression of the insulin receptor gene INSR and the insulin-like growth factor receptor gene IGF1R

Instead of eating less and eating healthily, why not just tell your body that you are, but still eat what you want? Mutations of insulin receptors and insulin-like growth factor receptors have been associated with longevity in humans (Suh et al. 2008). Indeed, calorie restriction has been demonstrated to act on insulin and IGF-1 (Breese, Ingram & Sonntag 1991). Mice with one copy of the IGF-1 receptor deleted live 33% longer for females and 13% longer for males (Holzenberger et al. 2003).

Having no insulin receptors is fatal, and a dramatic reduction in this signalling can cause pathologies, like Laron-type dwarfism (sufferers of which incidentally tend to live for a long time). However this could be avoided by targeting this genetic modification to adipose (fat) tissue. FIRKO mice (fat-specific insulin receptor knock-outs) are resistant to diabetes and obesity, and live 20% longer than normal mice (Okamoto & Accili 2003).

Also, the regulatory hormone KLOTHO inhibits both IGF-1 and insulin receptor signals. Overexpression of this gene has been shown to make mice live 20-30% longer (Kurosu et al. 2005). Humans with a mutation at the Klotho gene, KL-VS, have low levels of KLOTHO, and as a result have a much higher risk of stroke, atherosclerosis and osteoporosis (Arking et al. 2005).

2. Increase your expression of PEPCK

The phosphoenolpyruvate carboxykinase (PEPCK) enzyme in involved in energy metabolism (specifically gluconeogenesis), and indeed is one of those enzymes inhibited by insulin (so these effects may not be cumulative with the first modification). Mice expressing 100 times more of this enzyme in their muscles are more active in old age (and, in fact, in their prime), have little body fat and can run twice as fast for up to ten times as long! But, just to put the icing on the cake, they also age more slowly and retain their reproductive capacity into old age (Hakimi, Yang et al. 2007)!

However, mice with more PEPKC do tend to be more aggressive and eat far more, but eating more is not usually a problem for humans and we can probably control our aggression (or, we can fix that with some other modification).

3. Decrease your expression of the apolipoprotein E gene APOE, or switch to the ε2 allele

George advocates supplements like omega fatty acids, but you can regulate your fatty acids by altering your lipid-binding proteins called apolipoproteins. High levels of the apoliprotein epsilon (APOE) have been correlated with arthrosclerosis, neurodegenerative diseases and higher mortality. One particular allele, the ε4 form, is rarer in the very elderly than in the general popular, and another allele, the ε2 form, is more common (Rontu et al. 2006). Studies have confirmed that the ε2 form has a protective effect and that the ε4 form has a negative effect. (Corder et al. 1994).

Similar effects may be present for the other apoproteins, such as apolipoprotein B and C, or cholesteryl ester binding proteins (CETP).

4. Increase your expression of AMPK

Who really wants to go through an exercise routine every day for their entire life? Not me. So, how about just mimicking the benefits of exercise on a cellular level? AMP-activated protein kinase (AMPK) is an enzyme that is expressed in muscle, liver and fat cells in response to exercise (when levels of AMP increase). AMPK is also activated by a drug called metformin (Hawley et al. 2002), which is effective in combating the effects of Type II diabetes and has been shown, in trials on overweight insulin-resistant patients, to reduce risk of diabetes-related death by 42% and all causes mortality by 36% (‘Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)’ 1998).

AMPK also seems to be an inhibitor of the kinase target of Rapamycin (TOR) (Kimura et al. 2003). Inhibition of TOR by RNA interference has been shown to more than double the lifespan of the worm C. elegans (Vellai et al. 2003) and overexpression of the tuberous sclerosis complex genes TSC1 and TSC2 – also TOR inhibitors – can extend the lifespan of Drosophila by 20-30% (Kapahi et al. 2004).

5. Increase your expression of Sirtuin genes, especially SIRT-3

Here’s a genetic modification which could give you some of the benefits of caloric restriction without the dedication and starvation. Increased levels of the Sir2 enzyme can extend lifespan in C. elegans (Tissenbaum & Guarente 2001) and Drosophila (Rogina & Helfand 2004). Mammals don’t have this gene, but they have seven homologues called SIRT1-7. These enzymes are involved in wide areas of energy and metabolism, including insulin signalling, mitochondrial activity and adipocyte function. They have also been shown to regulate the fork-head box-O transcription factors, which been shown to be involved in the process of tumour suppression, but are also involved in ageing (Brunet 2007; Kuningas et al. 2007).

Though SIRT1 has been shown to be involved in caloric restriction in mammals (Cohen et al. 2004), lifespan correlations in humans have been found only with respect to mutations in SIRT-3 (Bellizzi et al. 2005). Regardless, as these enzymes are correlated with insulin signalling, these are possible target for genetic interventions into the ageing process.

6. Increase your oestrogen expression or receptor activity

For point 6, George basically advises to avoid taking life-threatening risks. I can go one better, and suggest you increase your oestrogen expression. It’s no coincidence that most partakers in extreme sports and other risky activities are males – females have more oestrogen, and oestrogen-treated mice have a greater fear response to potentially dangerous situations, but increased activity in calming environs (Morgan & Pfaff 2002).

Plus, in addition to the fact that females tend to live longer than males, there is a lot of evidence that oestrogen affects a lot of age-related genes, such as those involved in repair of oxidative stress (Vina et al. 2008).

Don’t worry guys, once you’re fully grown and still expressing the same levels of testosterone, oestrogen won’t shrink your penis. You ‘might’ grow breasts, but what price immortality, right?

7. Decrease expression of IL6 and other interleukins

Studies have shown that overexpression of the inflammatory cytokines, such as interleukin 6 or 10, are associated with increased mortality (Bonafe et al. 2001; Harris et al. 1999). Indeed, there is an age-related increase in plasma IL-6 level, and those with lower levels of IL-6 are likely to live longer and healthier lives, with less severe bone and neural degeneration (Ershler & Keller 2000; Gallucci et al. 2007). It is known that IL-6 is lessened in calorie-restricted mice , and some studies have found an association between mutations in promoter region of the IL-6 gene and longevity in human populations (Christiansen et al. 2004).

Sex steroids are inhibitors of the interleukins like IL-6, so preventing degeneration of the reproductive system would therefore be a promising target for anti-ageing interventions.

8. Have more copies of the Arf/p53 genes

So, if you’ve done the above you’re now a safe person with resistance to cardiovascular disorders and neurodegenerative diseases, but cancer is a leading cause of death among the elderly, so you’ll have to prevent that? Some people have thought that the same mechanism used to destroy cancer cells would also destroy aged cells, leading to degeneration with ageing. But maybe not. Super-Arf/super-p53 (Genetically engineered mice with an extra copy of both Arf and p53) live 16% longer and show less physiological decay with ageing, such as greater motor control and hair regeneration in old age (Matheu et al. 2007).

p53, and its regulator Arf, are integral to stress-responses, and have been shown to cause the expression of antioxidants in response to mild stress (Sablina et al. 2005) and to shut down severely damaged cells by apoptosis (cell suicide). They are also common genes to be mutated in cancer cells, so an extra copies provides a backup for the cell as well as increasing their activity. Provided the regulation is not disturbed (as some other overexpression studies may have done), an extra copy of p53 should increase resistance to cancer and reduce the accumulation of aged/damaged cells. It isn’t known yet whether the longevity is due to increased cancer resistance or to actually preventing the ageing process, but from where I stand, it’s all good.

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By the way, you may be wondering what happened to the mention of the telomerase enzyme. Well, it’s not true that organisms with longer telomeres live much longer (humans have very short telomeres, but live longer than any other mammal) and it seems that increasing it in mammals is more likely to cause a tumour than provide the elixir of life. So, although it is likely to be a solution in the long-term, I can’t see it being a good idea until we can cure cancer. (UPDATE: It appears this is exactly what some researchers have done: see my blog post on that research)

References can be accessed by hitting the ‘read the rest of this entry’ link below.

Read the rest of this entry ?

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Wednesday’s Words of Worry

Wednesday, 16 April, 2008

I know I’m supposed to be giving you some Wisdom to counter last week’s Worry, but I’m afraid I need to point this particular quote out to you all. If I wasn’t so fond of the alliterative title, I would have called this ‘Wednesday’s Words of Utter Tripe’.

It comes from the UK, where if you’ve been following the biopolitical debates, the HFEA bill is causing controversy in the deaf community over a particular clause that rules it illegal to select a disabled embryo over a non-disabled embryo. So, this particular quote comes from Professor Peter Braude, of Guy’s and St Thomas’ Hospital in London, where he is the director of the Assisted Conception Unit.

“I have serious concerns about deliberately selecting a embryo for deafness. This is the same as taking a normal child and deliberately making it deaf so that it can fit in with a community. I don’t see how that can be acceptable.” (source: Telegraph)

I really hope that it is obvious to you all that this is not the case. Nobody is modifying any children, nor are there any children in this case to modify. They are embryos, and they are not genetically modified – their genome is exactly what they had since conception. Embryo selection merely chooses which are implanted and which are not. They are choosing to have a deaf baby, not making a baby deaf.

Consider other examples. Choosing not to have children because you want to focus on your career is not the same thing as killing a child because you want more time for work. Choosing to have a child free from Down’s syndrome is not the same thing as curing a child from Down’s syndrome. Choosing to have a boy is not the same thing as performing a sex-change on a girl.

I would have thought a Professor would have the brains to realise this, but obviously I am wrong.

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The Swiss must be crazy!

Tuesday, 15 April, 2008

I know arguments about human genetic modification usually use the theme of ‘dignity’ , but I didn’t expect it to appear in plant biotechnology debates. But, it has!

In Switzerland, the federal Ethics Committee on non-human Gene Technology (ECNH) have a report titled “The dignity of living beings with regard to plants. Moral consideration of plants for their own sake“. The conclusions of this report are:

“[T]he Committee members unanimously consider an arbitrary harmcaused to plants to be morally impermissible. This kind of treatment would include, e.g. decapitation of wild flowers at the roadside without rational reason.”

And, with respect to biotechnology:

“According to the majority position, there is nothing to contradict the idea of dignity of living beings in the genetic modification of plants, as long as their independence, i.e. reproductive ability and adaptive ability are ensured. Social-ethical limits on the genetic modification of plants may exist, but are not the object of this discussion.”

This isn’t really a new conclusion. Apparently, the Swiss constitution gives dignity to all living organisms and discussions in constitutional law use the term “Würde der Kreatur” (dignity of living beings) to apply to both plants and animals.

On page 13, the report summarises the group’s position as follows:

“Answers to the question of whether and to what extent a being itself can be harmed:
Sentientism: Only if a being consciously experiences something as harm is it being harmed.
Non-sentientism: Even if an organism is not able to experience anything consciously, it can be harmed. An intervention may be harmful even if it is not experienced as such.
A clear majority takes the position of non-sentientism. A minority takes a sentientist position.”

Well that’s your problem right there! Most of your members think that you can hurt a tree, despite the clearly obvious fact that they don’t have a brain with which feel pain much less any nociceptors to sense it in the first place. Harm, after all, is only wrong when it causes (a net increase in) pain, suffering or loss of freedom to a sentient being. Harming an anesthetized patient during surgery, for example, is not wrong because is causes no pain (because the pain signals, or the ability for the brain to perceive them, have been stopped) and that harm is a net benefit once the surgery is over.

But wait, there’s more!

“The majority of the committee members at least do not rule out the possibility that plants are sentient, and that this is morally relevant. A minority of these members considers it probable that plants are sentient. Another minority assumes that the necessary conditions for the possibility of sentience are present in plants. The presence of these necessary conditions for sentience is considered to be morally relevant.

Finally, a minority of the members excludes the possibility of plants having sentience, because in their view there are no good grounds for such an assumption.”

Here is another problem – only a minority of members appear to be sentient themselves, because the majority are obviously as thick as a plank of wood. Again, plants do not have a nervous system, and rely entirely on chemical signalling. It is certain (as much as you can be), that without a nervous system (or some other effective information transmission system), sentience cannot exist. You’d have to believe in magic (like the Treant/Ent picture above) to think plants could possibly be sentient.

The report also says that no member took the position of theocentricism – “the idea of a God who is creator, and therefore the creative ground of all living organisms. What counts for its own sake is God. All organisms count because of their relationship to God.” Which is proof that future objections to human biotechnology will not necessarily come from the fundamentalist religions of the right, but also the tree-hugging left.