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Yesterday CBS had a segment on hyperbolically titled Breeding out Disease. First, we will never “breed out” disease. Part of the reason is that a large fraction of disease is due to non-genetic factors. Perhaps in the future with nanotech we might get at all the biological misfires due to developmental problems which emerge out of the “environmental” (a word for stuff we basically can’t understand in any causal sense) effects. But genes aren’t everything.

Second, the CBS piece had two segments, which differ a lot in terms of their implications. The first involves preimplantation genetic diagnosis (PGD). This is already happening, so what you will see in the future is a matter of scale or magnitude, not a paradigm shift. I do think it is possible that in the next generation we will see the diminishing of recessive diseases due to highly penetrant deleterious alleles. Every birth of a child who is diagnosed with such a disease will allow us to predict future births, because presumably their parents will have rare variants which can then be put in the database. I don’t think this is controversial or scary in any way. It’s classic “science makes the world better.” Your child having a recessive disease or a karyotype abnormality is not part of some grand plan.

But the next element of the segment dealt with the firm GenePeeks. I saw the founder speak at the Consumer Genetics Conference in 2013, and it seemed to be a reasonable idea. Basically right now the play is to simulate the outcome of genotypes for combinations of sperm (donors) and eggs (the founder herself has a child with a recessive disease due to herself and her sperm donor being carriers for a rare disease). Enter Lee Silver, a famous geneticist before genetics was even quite so big. He makes many claims, some entirely reasonable, and some which I view to be a stretch. It seems that in concert with PGD simulating genotypes and looking to avoid highly penetrant alleles is very smart. In fact this is just carrier screening on steroids. But then Silver begins to imply that genetic methods are going allow to predict complex traits. On the face of it this seems likely to be true. The work on height is just a trial run for all sorts of complex traits, in particular diseases. In the next 10 years it is entirely likely that genomic techniques will allow us to capture most of the heritable variation which we now classify as “missing heritability”. Making a prediction which is actionable is a different thing altogether.

If you have a trait whose genetics is distributed across thousands of loci then simulating the gentoypes is going to be a brute force affair. I trust computation to catch up to this problem, but then it is making predictions on the individual level. It is one thing to capture the heritable variation on the population scale, but predicting in an individual case is going to be harder. Then, once you have the prediction you have to screen an enormous number of genetic combinations. If you want more than one complex trait, and they are independent, then the problem becomes exponentially more difficult.

There are two things which I think can get around this. One, which I’ve already mentioned, is to skew the embryos which are enriched for a grandparent whose quantitative trait you value (intelligence, height, or agreeability). Second, as I have said, the 2010s are the decade of reading the genome. The 2020s are going to be the decade of writing the genome. That seems a more viable and probable solution than screening for variants which are “in house.”

Finally, there is the standard question about selecting for non-disease traits like eye color. Silver doesn’t blink, and admits that this might happen. Norah O’Donnell is unsurprisingly concerned. I would reassure that we already select for non-disease traits in our children by selecting our spouses. It’s not that big of a deal. I’m rather sure that O’Donnell’s husband didn’t marry just because she’s a great journalist.

In the end Gattaca is a great movie with contemporary relevance. And thanks to the statistical shenanigans which went on in fMRI research it seems that genetics is unchallenged today as the queen of the biological sciences in our age.* But a movie is not reality, and geneticists have not bit into the apple of knowledge and are not as the gods. Relax, though expect a better future.

* Neuroscience made a play, but I think that’s done.

• Category: Science • Tags: Genetic Engineering 
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Emily Anthes has a new book out, Frankenstein’s Cat. It looks quite interesting, but I’ll be honest and admit I doubt I’ll get to it, mostly because I am relatively sanguine about genetic modification. I don’t think it’s a qualitative difference from what’s been going on for 10,000 years. To me all genuine concerns about this area don’t fundamentally have anything to do with the core idea of genetic modification (e.g., rather, it is about control of the means of production, etc.). If you are wondering if you might like the content of Frankenstein’s Cat, I would recommend this 40 minute interview of Anthes on NPR. It strikes me that she’s presenting a rather “balanced” perspective, acknowledging the concerns of some, while attempting to highlight the genuine benefits of genetic modification.

Speaking of which, one thing which came out in the NPR interview is that some animal geneticists are actually moving to places like Brazil to do their work because of disquiet about the nature of their research. In this specific case it had to do with replicating the anti-bacterial properties of human milk for goats using trans-genic methods (I presume). The host naturally expressed difficult to suppress revulsion at the idea of “human genes” in “animals.” To be pedantic of course we are ourselves animals, and what is a “human gene” supposed to even mean? A substantial portion of the human genome does not derive from humans.

On the one hand it’s sad when American researchers have to go abroad when their work really isn’t that objectionable. If, for example, they were modifying goat milk with cow genes that would not arouse as much concern, even though fundamentally the process is the same. Intuitive folk biology and a moral sense of the special character of humanity which is somehow ineffably tied up into our form and genetic character bubble up unbidden. But in nations like Brazil where diarrhea is major public health concerns these wisdom-of-repugnance intuition lack as much relevance. There is often the presumption that genetic engineering will be accessible only to the rich. And yet I wonder perhaps if being “wholly organic” might become a sort of signal of affluence and conspicuous consumption, with those closer to the margin of poverty engaging in various transformations which are ethically, morally, or aesthetically disquieting.

Addendum: Organisms which have been modified to have human genes have been around for a while obviously. What seems new on the horizon is the industrial scale, and likely real world (as opposed to basic science) application.

• Category: Science • Tags: Genetic Engineering, Genetics 
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With the election coming up, California Proposition 37, Mandatory Labeling of Genetically Engineered Food, is on my mind. From Ballotpedia:

If Proposition 37 is approved by voters, it will:

* Require labeling on raw or processed food offered for sale to consumers if the food is made from plants or animals with genetic material changed in specified ways.

* Prohibit labeling or advertising such food as “natural.”

* Exempt from this requirement foods that are “certified organic; unintentionally produced with genetically engineered material; made from animals fed or injected with genetically engineered material but not genetically engineered themselves; processed with or containing only small amounts of genetically engineered ingredients; administered for treatment of medical conditions; sold for immediate consumption such as in a restaurant; or alcoholic beverages.”

James Wheaton, who filed the ballot language for the initiative, refers to it as “The California Right to Know Genetically Engineered Food Act.”

Michael Eisen has two posts up on this which get the meat of the issue for me. I disagree with Prop 37, though on first blush I think the idea of transparency is radically empowering. Before I get to my reasoning, I want to set aside some ancillary considerations. Some are voting for the measure because they oppose agribusiness in general, or have a particular bone to pick with the way that some firms enforce their intellectual property on seed lines. These are fine critiques, but I’m not going to address them, because I think they’re separate from the science.

Why don’t people have the right to know? The primary objection from me is that the government is enforcing the right to know by force. I don’t think this is illegitimate per se. But the force of the law should only be brought to bear in cases where the benefit is clear. We have a “right to know” that a product was “Made in China.” Why? Honestly, because a level of economic nationalism is widely popular. But we don’t have a “right to know” every single step of the production of a good. The bureaucratic hassle would be prohibitive, and the reality is that most people don’t care about most things, and we can’t let the curiosity of a minority motivate labeling and food and drug regulation. Additionally, we need to keep the government out of adjudicating in matters of fashion, taste, and prejudice. That’s one reason why state governments in the United States have gotten into trouble when they put the force of law behind a particular kosher certification. There’s a clear interest, in that a significant number of citizens are Jews for whom this certification is important. But the state isn’t in the business of enforcing Jewish law and preference.

Everyone has a right to know by contacting the producer. Everyone does not have a right to know about a particular detail enforced by the law. Therefore, we need to ask: is this is a right to know which is warranted by the concerns that the public has? This is an issue where I’ve had most of my exchanges in “private,” through conversation. I have a reasonable sampling of “lay” opinion on this topic. Only a small minority of people I talk to are genuinely frighted of GMOs in a strident manner. Many more are concerned by the social and economic angles, as opposed to the public health one. But the idea that people have a right to know about the possible dangers crops up again and again.

As I suggest above there’s no abstract and obvious right for the government to enforce a particular categorization regime of products. That’s an outcome of public discussion and political action. The question I have for my friends: do you trust us? But “us,” I mean geneticists. The reality is that GMO simply aren’t that scary to geneticists. The sort of things needed for the production of GMOs are the bread & butter of many laboratories (not to mention the strangeness which is plant breeding and genetics, with hybridization, clonal lineages, and introgression). And the processes are not particularly exotic or amazing. It’s all rather banal. Additionally, most geneticists are conscious of the fact that much of our own genome derives from viruses.

I had a long exchange with a friend on Prop 37 where I basically asserted that the skepticism of many people of the ability of geneticists to give plausible reassurances on this issue rather resembled Creationists who reject the informed wisdom of evolutionary biologists. Ultimately it came down to the fact that I could not guarantee with 100.00000% certainty that nothing devilish was ever going to come out of GMO. There had not been a sufficient number of randomized field trials on GMO vs. non-GMO consuming subjects to satisfy my friend.

We are at this point at somewhat of an impasse I believe. Our civilization rests upon science. But at the end of the day a broad mass of humans would prefer to rely on “horse sense,” rather than the accumulated wisdom of science. In the case of Creationists, they reject the evidence for evolution. In the case of the health skeptics of GMO, they are skeptical of the mastery of the science of genetics by geneticists. Ultimately the only way you can persuade people is by practical fruits. If GMO does transform agriculture in the developing world, then the good may be such that those who worry may overcome their qualms. Until then, I assume Pro 37 will pass.

• Category: Science • Tags: Genetic Engineering, Genetics 
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This story in The New York Times, Flavor Is Price of Scarlet Hue of Tomatoes, Study Finds, is pretty cool:

Yes, they are often picked green and shipped long distances. Often they are refrigerated, which destroys their flavor and texture. But now researchers have discovered a genetic reason that diminishes a tomato’s flavor even if the fruit is picked ripe and coddled.

The unexpected culprit is a gene mutation that occurred by chance and that was discovered by tomato breeders. It was deliberately bred into almost all tomatoes because it conferred an advantage: It made them a uniform luscious scarlet when ripe.

Now, in a paper published in the journal Science, researchers report that the very gene that was inactivated by that mutation plays an important role in producing the sugar and aromas that are the essence of a fragrant, flavorful tomato. And these findings provide a road map for plant breeders to make better-tasting, evenly red tomatoes.

The paper, Uniform ripening Encodes a Golden 2-like Transcription Factor Regulating Tomato Fruit Chloroplast Development:

Modern tomato (Solanum lycopersicum) varieties are bred for uniform ripening (u) light green fruit phenotypes to facilitate harvests of evenly ripened fruit. U encodes a Golden 2-like (GLK) transcription factor, SlGLK2, which determines chlorophyll accumulation and distribution in developing fruit. In tomato, two GLKs—SlGLK1 and SlGLK2—are expressed in leaves, but only SlGLK2 is expressed in fruit. Expressing GLKs increased the chlorophyll content of fruit, whereas SlGLK2 suppression recapitulated the u mutant phenotype. GLK overexpression enhanced fruit photosynthesis gene expression and chloroplast development, leading to elevated carbohydrates and carotenoids in ripe fruit. SlGLK2 influences photosynthesis in developing fruit, contributing to mature fruit characteristics and suggesting that selection of u inadvertently compromised ripe fruit quality in exchange for desirable production traits.

Genetics for better living! But I had no idea that the laws in regards to mutant varieties were so retrograde:

But were the genetically engineered tomatoes more flavorful? Because Department of Agriculture regulations forbid the consumption of experimental produce, no one tasted them.

And, Dr. Giovannoni says, do not look for those genetically engineered tomatoes at the grocery store. Producers would not dare to make such a tomato for fear that consumers would reject it.

But, Dr. Powell said, there is a way around the issue. Heirloom tomatoes and many wild species do not have the uniform ripening mutation. “The idea is to get the vegetable seed industry interested,” Dr. Powell said.

Image credit: Fir0002/Flagstaffotos, GFDL v1.2.

• Category: Science • Tags: Anthropology, Genetic Engineering, Genetics 
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Over at Genetic Future Dr. Daniel MacArthur has a measured response to a Nature commentary by David Goldstein, Growth of genome screening needs debate. As Dr. MacArthur notes an excessive portion of Goldstein’s piece is taken up with inferences derived from assuming that the model of rare variants causing most diseases is correct, when that is an issue currently in scientific contention (and this is a debate where Goldstein is a primary player on one side). But the last two paragraphs of the piece is where the real action is, no matter the details of genetic architecture of diseases:

One potential problem with this is that numerous genetic risk factors will have diverse and unexpected effects — sometimes causing disease, sometimes being harmless and sometimes perhaps being associated with behaviours or characteristics that society deems positive. Even for simpler Mendelian diseases, up to 30% of the mutations originally termed pathogenic have turned out to be apparently harmless…Wholesale elimination of variants associated with disease could end up influencing unexpected traits — increasing the vulnerability of populations to infectious diseases, for instance, or depleting people’s creativity.

There are no clear-cut answers to the questions of what should be screened for and to what end, but we must at least begin the debate.

There’s nothing that I can find objectionable at all about the last sentence. We’re really close to the “we have the technology” moment. Seeing as how more and more of the higher socioeconomic strata are delaying having children you are going to have a phenomenon where those with disposable income are going to “want to make it count,” so to speak. Especially since children born to older parents already have a higher likelihood of having medical issues.

The specific point which Dr. MacArthur brings to light is that we need to balance social consequences with individual incentives. Consider something which is more clear-cut than diseases: sex selection. Intuitively we understand that humans flourish best in circumstances when the ratio between the sexes is balanced. Imbalances tend to lead in a skewing of social dynamics. But in many societies there are strong incentives toward having children of one particular sex. Therefore on an individual level the rational calculus is one where you make the choice which is totally irrational when everyone else makes the same choice. I have pointed out before that the reality is that male sex bias in both Japan and Korea have shifted toward a female sex bias (first in Japan, and now in Korea). So just like biological sex ratios cultural pressures tend toward equilibrium. Eventually. But, that equilibration may take a generation, and between now and then the social phenomena which we are confident will eventually fade may not be so positive, whether in the individual happiness of the excess sex, or in the aggregate functioning of a well balanced society. An average stable point can still manifest as uncomfortable swings and transitions for human beings living their lives.

In relation to preimplanation genetic diagnosis the moral and ethical dilemma is somewhat different. Overall there is a boundary condition where most might agree that genetic screening of some sort is preferred. The issue is that when price points decrease it is inevitable that instead of preventing Tay-Sachs, parents will want to prevent the birth of a brown eyed child. The latter is a pretty plausible candidate for selection; readers of this weblog who have brown eyes but one blue eyed parent have expressed the wish to load the die so that their children might be homozyogte for the allele which tends* to produce blue eyes. Or going to an example which is less Eurocentric, there are large effect genes segregating within South Asian populations which are responsible for the great amount of within population and family range in complexion. It is entirely plausible that South Asian parents, who are already major practitioners of sex selection, will be open engaging in diagnostic screening so that biological children are as “fair and lovely” as possible out of the potential range (skin color has huge life implications in India, especially for women, so sex selection and complexion selection may actually have opposite effects in that the latter may diminish the “need” for the former).

I jumped straight to cosmetic issues because I’m rather skeptical that governments or cultural elites will be able to prevent a lot of discretionary genetic screening for possible disease alleles. Unless we mandate that the whole society raises children and is responsible for their needs through mass transfer of payments in terms of a cradle-to-grave welfare state I think the demand will be strong enough that any debate of ethical concerns will be rendered moot and pushed to the margins of the anti-biotech movements of the Right and Left. A more interesting issue to me is the implication by Goldstein that we “need” more genetic diversity which might have negative byproducts for creativity.

There are ~7 billion people alive today. In raw absolute terms we’ve got a lot more summed up genetic variation than we did 100 years ago, let alone 1,000 years ago. Is there no point of diminishing marginal returns on absolute variation levels? In other words I suspect that in terms of creativity and the downside risks of removing some of the positive externalities of “oddballs” who are weird and unexpected we’ve got a lot of slack with our huge population. There are always going to be large groups of people who will refuse to manipulate the nature of their offspring, or constrain the parameters excessively. Large perhaps not in a proportional sense, but we’ve got a huge census size now. My own suspicion is that there are limits to how many creative types a society can absorb. Most people are going to be more conventional, or going to have to be more conventional, because much economic and social productivity is driven by workaday behaviors. PGD is going to “perfect” these workaday types. I don’t see a problem with that. There will be huge numbers of Leftist Deep Ecology types and Rightist Roman Catholics who will let nature or god decide for them. These will be the cultural creatives if deviation from the genetic ideal is strongly correlated with creativity.**

* ~75% of the variation in the European population in blue vs. brown eyes is accounted for by a few SNPs around the HERC2-OCA2 locus…but, the prediction algorithm isn’t perfect, so a parent might not get their heart’s desire.

** With widespread whole genome sequencing I’m assuming we’ll actually have time to see if this is true. That is, genetic oddballs are more creative.

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834518 In the 1920s the Soviet Union sponsored a “humanzee” breeding program. From what I recall the ultimate rationale for the funding was that the program might create a race of superior warriors, combing the incredible physical strength on a per pound basis of the chimp, with the greater level of intelligence found in human beings. To our knowledge the experiments were failures, though there have long been rumors of successes in these sorts of programs. I suspect the possibility persists because of the transgressive freak-show aspect.

This was a case where the science of the time was simply not up to the ambitions of the scientists, and this sort of engineering for the good-of-society has been the domain of science fiction. Consider the novel Cyteen. In this future history cloning is normal and acceptable, and the heart of the story involves the attempt to replicate a super-genius. There are broader stellar-political implications, as these sorts of minds are driving engines of innovation, and so strategically valuable. A cruder model of this was also explored in the G. I. Joe universe in the form of the villain Serpentor. He was engineered from the genetic material of ancient conquerors.

One of the issues which naturally cropped up in Cyteen is that genius seems to emerge through an intersection of environmental and genetic inputs. So part of the novel focuses on the environmental inputs which are replicated for the copy-genius, and the tensions which arise from this. But even granting this mitigating factor the underlying model is that the genes of geniuses will increase the odds of producing geniuses. We see this with professional athletes; regression toward the mean explains why the offspring of most professional athletes are not good enough to become professionals themselves. But, the odds of one’s child becoming a professional athlete are far above expectation if a parent is a professional athlete. The Bonds and Griffeys illustrate this.

With all that said, we have long been able to “brute force” the existence of clones in theory (at least since Dolly). Combined with the future reboot of gene therapy procedures, as well as the ability to extract and amplify older DNA samples, there is the possibility that with enough capital inputs you could “re-create” Einstein. I’m talking a classic Boys from Brazil scenario. The humanitarian and ethical obstacles to this are clear and present in any liberal society, but what about a totalitarian one? Stalin was in power for about 25 years.

Addendum: And then there’s the famous case of Duncan Idaho.

• Category: Science • Tags: Genetic Engineering, Genetics 
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Gene Genie hosted by Hsien at Eye on DNA. Mendel’s Garden, over at The Daily Transcript (via evolgen).

• Category: Science • Tags: Genetic Engineering 
Razib Khan
About Razib Khan

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