First Human Embryos Edited in U.S.

[Lord Crc]

We fix things all the time. Most of the medical sector is about fixing things. Do you want to get rid of modern medicine? If not, where exactly do you see the difference?

That the recipient of the "fix" cannot consent on any level. Consider gender "fixing" done on babies, gender (re)assignment, and how many of those persons suffer later in life due to the choice the doctors made for them.

 

[mfb]

That the recipient of the "fix" cannot consent on any level.

That applies to babies as well, and parents have some responsibility until the child is an adult. Okay: Do you want to get rid of modern medicine applied to anyone who is not an adult yet?

Consider gender "fixing" done on babies, gender (re)assignment

I don't see the relation to life-threatening diseases.

 

[Lord Crc]

That applies to babies as well, and parents have some responsibility until the child is an adult. Okay: Do you want to get rid of modern medicine applied to anyone who is not an adult yet?

Of course not, that would be throwing the baby out with the bath water.

I don't see the relation to life-threatening diseases.

Are you implying this technology will only ever be used for life-threatening diseases? If so, I think history has shown that's a very naive view.

 

[Lord Crc]

I guess my point is, GATTACA was hypothetical. Now it is a possible future we can chose.

Before there was no line to draw. Now we have to draw it somewhere.

Some of you seem to want to reserve it for life-threatening issues. Why not for say meromelia or similar?

 

[Isaac0427]

Are you implying this technology will only ever be used for life-threatening diseases? If so, I think history has shown that's a very naive view.

That is my point precisely.

As Ygggdrasil mentioned already, it is not. It is one step such a technology would need, but that also applies to computers, for example.

But it is a huge step towards such technology. The comparison to computers doesn't make sense at all, though. There is a clear difference between how computers would contribute to a world like GATTACA and how genetic engineering would.

 

[Buzz Bloom]

Sure, this isn't GATTACA... but it certainly opens that door.

While there are a lot of life-saving things this technology can provide, we must ask ourselves if the possible consequences (i.e. something like GATTACA or an international race on who can breed the best hyperintellegent super-strong human army to fight in wars) are worth it.

That doesn't stop a rogue government from using them. Knowing the world as it is, if one country did what I mentioned above, then other countries would follow suit in order to compete. How long after that does GATTACA start happening?

I personally do not think Gattaca is a good example of bad effects from genetic manipulation. I have started a thread in the SciFi forum to discuss this.

https://www.physicsforums.com/threads/bad-society-from-human-genetic-manipulation.922106/​

 

[Ygggdrasil]

There is a clear difference between how computers would contribute to a world like GATTACA and how genetic engineering would.

Can I ask for clarification? You reference GATTACA as an example of the threats of genetic engineering, yet all your examples have to do with the danger of armies of super-human soldiers (not the subject of GATTACA). Along the lines of @Buzz Bloom's comments, can you clarify what aspects of the society portrayed by GATTACA you see as most threatening to society? It seems to me that many of the issues brought up by GATTACA could have policy and regulatory solutions that do not involve completely banning the technology. (Following your arguments, a ban would not actually work since some rouge countries or scientists that do not agree with the ban will continue the research anyway).

With regard to the comment about computers vs genetic engineering, if you are worried about super-intelligent beings causing widespread disruptions to society, I see the threat from artificial intelligence as more imminent than the threat from genetic engineering. (I do support continuing AI research, however).

 

[jim mcnamara]

Can we leave the realm of Science Fiction in fiction? Yes, there can be moral lessons in Uncle Tom's Cabin or Gattaca. Simply regarding stuff like that as THE model for this issue is way less than scientifically illuminating, to be polite.

Once you understand what @Ygggdrasil is trying to say, you get the idea that using a simple map to find your way in an extremely complex and potentially dangerous endeavor is not trivial. And it involves Biomedical Ethics. Gattaca does NOT explain it, nor do superhuman powers. This is not a comic strip endeavor. To continue do comic book analysis is, well, very devoid of good sense.

In literature it is okay, even encouraged, to use fictive models based partially on sets of assumptions outside of Science. Science Fiction and Fantasy (note the equivalence) has had a really great run in fiction and entertainment. But. We do not do that here on PF. Entertainment is not a good model, particularly for this issue. And the argument that you have to rely on this kind of model because it is 'what I understand' is pure baloney. Scientists who get the whole picture are able to carry on good discussions on this topic without basing discussions on TV shows and movies. DiracPool tried. If you cannot participate on a reasonable level, that's okay. There are discussions on PF for which the best I can ever hope to be is in readonly mode, too. Just lurk and maybe learn, too.

Can we please stop with the hoo-ha? This thread has wonderful potential, IMO.

Thanks
(The cranky old guy who can and will lock this thread)

 

[thejosh]

One of the main problem with genetic engineering is even if we were able to insert and correctly apply a different base, chromosome or some other part of DNA, if we were able to successfully accomplish this feat and come up with the desired phenotype, one of the biggest problems is the fact that we cannot control mutations, which would result in the "normal" genes effectively -lets say- swapping over with the newly introduced gene, now if this were to happen the effect would be unpredictable.
Consider that we improved -lets say- a rodent to have stronger bones , yes.
Now the rodent seems to be okay but we cannot see what's happening to its genetic make-up. If this rodent reproduces with a normal rat and produces a baby with a degenerative disease, let's say haemophilia , chances are that we would be unable to pinpoint exactly where the error in its genetic makeup occurred. We would not be able to tell whether the error occurred due to natural causes or as a result of our "tampering."
Worse still if the degenerative disease occurs further down the rat's bloodline.This could then be an autosomal recessive mutation or-again- it could be a natural reason (this is purely just an example so excuse the use of haemophilia and the rodents etc.)
As you can see from my example- genetic engineering is a very touchy and difficult to understand concept.We do not even know what most genes do or how they affect an animal, whether or not the gene affects the immediate or future phenotype of a species.
If your still not convinced that genetic engineering is a touchy topic listen to this:
The more complex an organism the more chromosomes it has right?
eg a human has 23 pairs of chromosomes whilst a fruitfly has 4
But guess which animal has the largest amount of chromosomes.
You didn't guess it- a SNAIL!
Weird isn't it?Why you ask.We simply do not know, so how can we engineer something we do not understand, it's like building a house with dark matter- simply unattainable until we get the understanding behind the works.

 

[Ygggdrasil]

One of the main problem with genetic engineering is even if we were able to insert and correctly apply a different base, chromosome or some other part of DNA, if we were able to successfully accomplish this feat and come up with the desired phenotype, one of the biggest problems is the fact that we cannot control mutations, which would result in the "normal" genes effectively -lets say- swapping over with the newly introduced gene, now if this were to happen the effect would be unpredictable.

I have not heard of this concern. Do you have a reference discussing this possibility?

Consider that we improved -lets say- a rodent to have stronger bones , yes.
Now the rodent seems to be okay but we cannot see what's happening to its genetic make-up. If this rodent reproduces with a normal rat and produces a baby with a degenerative disease, let's say haemophilia , chances are that we would be unable to pinpoint exactly where the error in its genetic makeup occurred. We would not be able to tell whether the error occurred due to natural causes or as a result of our "tampering."
Worse still if the degenerative disease occurs further down the rat's bloodline.This could then be an autosomal recessive mutation or-again- it could be a natural reason (this is purely just an example so excuse the use of haemophilia and the rodents etc.)

This is why one performs controlled studies with large numbers of animals. One can compare the rate at which bad outcomes occur in the group of animals that underwent gene editing to the rate at which these outcomes happen in a control group which received no treatment or a placebo treatment. The FDA and other regulatory bodies would require these types of controlled trial in both animals and humans to be performed before any medical treatment is approved for use.

As you can see from my example- genetic engineering is a very touchy and difficult to understand concept.We do not even know what most genes do or how they affect an animal, whether or not the gene affects the immediate or future phenotype of a species.

The functions of many genes are not well understood, but that does not mean it is impossible to engineer them. As stated previously, current guidelines limit gene editing to replacing rare, disease alleles with alleles that are prevalent in the population. Because we are changing DNA sequences to sequences that exist in ~7 billion healthy people with varying genetic backgrounds, we can be reasonably sure that the edit will not have any harmful side effects (as long as no "off-target" mutations occur). Furthermore, these technologies will undergo extensive testing to make sure that no unanticipated side effects accompany the treatment (see above).

If your still not convinced that genetic engineering is a touchy topic listen to this:
The more complex an organism the more chromosomes it has right?
eg a human has 23 pairs of chromosomes whilst a fruitfly has 4
But guess which animal has the largest amount of chromosomes.
You didn't guess it- a SNAIL!
Weird isn't it?Why you ask.We simply do not know, so how can we engineer something we do not understand, it's like building a house with dark matter- simply unattainable until we get the understanding behind the works.

It is well known that the size of a genome does not correlate with the complexity of the species. This seeming inconsistency, termed the C-value paradox, is due to the fact that most animal genomes contain a lot of non-coding DNA (only 2% of the human genome encodes protein), most of which is "junk DNA" (e.g. repetitive DNA derived from transposons or endogenous retroviruses). There is a lot of functional non-coding DNA, and there are still many unanswered questions about the functions of non-coding DNA sequences, but only about 10% of the non-coding DNA appears to be evolutionary conserved.

 

[jim mcnamara]

In terms of chromosome number, n, ferns win. What they win I'm not sure. Many fern species have a large n and are polyploid. Ophioglossum reticulata has 1260 chromosomes. I think it wins against all fern contenders. So chromosome number and polyploidy do tell not us much. Except that changing chromosome number is a good way to isolate a newly emerging species from other members of the genus. So it is good evolutionary isolation mechanism to allow a population to differentiate genetic traits without having those changes swamped by genes from cousins.

The fern is small, too.

 

[Buzz Bloom]

but we cannot see what's happening to its genetic make-up

Hi josh:
Part of the technology about genetics is that the research leads to more and more understanding of what the genes do, although we have a long road ahead since this research is only a few decades old. When the eventual gene function database gets large enough then there will be opportunities to "see what is happening to" the genetics of an embryo conceived with a mutated egg or sperm. Today's technology includes the ability to extract a cell from a embryo, and also let this cell multiply sufficiently for a DNA analysis to be performed. The gene function database permits the possibility of detecting a ovum or sperm mutation in an embryo. A mutation to a a non-germ cell in the embryo itself (or later fetus or born child) after fertilization does lead to any inheritance of the mutation.

Regards,
Buzz

 

[thejosh]

immediate or future

even if we were able to insert and correctly apply a different base

Worse still if the degenerative disease occurs further down the rat's bloodline.

how can we engineer something we do not understand

What I was trying to put across is the issue of mutations which would arise in the event that we successfully cracked the problem of how to correctly apply different phenotype traits.This is in the event that we venture into putting relatively foreign genes into an organisms DNA which would effectively increase the risk of mutations coming about and producing maybe even new genetic diseases.(This is where we are trying to go right , since not all genetic diseases are cured by common genes) Ok so let's say we have normal genes W and R. when these mutate together it produces the mutation E but E is recessive and is easily gotten rid of eventually and does not cause much harm.Now let's say we replaced R with S, if W and S mutate together they now produce something quite different T, which has unpredictable effects on the organism. Realising this we must take into account that mutations can occur at any period of an organisms life or not at all so experimental breeding would not solve the issue since mutations are unpredictable. Its like predicting if an organism will get cancer, we can make vague estimates that are often incorrect since cancer can only be risk assessed.this is looking forward past the issue of where to put the correct genes on what chromosomes etc that are the main issues of concern RIGHT NOW, my post was looking a wee bit further than that.

 

[Buzz Bloom]

mutation E

Hi @thejosh:

I think I am finally mostly getting the complicated example you are describing, but it took me a while to decide that your phrase "mutation E" was intended to mean the phenotype E was produced by the combination of mutations to both normal genes W and R. Let us call these mutated versions of W and R: W' and R' respectively. Thus phenotype E is produced by W' and R'.

Now let's say we replaced R with S

As I understand what the genetic repair would be in this example, we do not replace R with S, nor do we replace R' with S. What we do is replace R' with R and also W' with W. With this repair, what is the next mutation in your example?

Regards,
Buzz

 

[mfb]

Ok so let's say we have normal genes W and R. when these mutate together it produces the mutation E

What do you mean by "mutate together"?

What this thread is about: We have variants W and R, where 98% of the world population have WW, 2% have WR and 0.01% have RR. The last one leads to some disease. The method described here changes RR to WW.

Assuming the edit changes nothing else: What exactly could be harmful?

 

[thejosh]

In a nutshell(i have to rush to classes) what i am implying is that genes often cross over during cell division, we call this mutation and it often happens in an organism to produce variation naturally, if we venture into introducing new genes (which is what we will eventually do) new mutations might occur which could potentially disrupt the path of nature, if and when this happens we could cause our own downfall rather than fix the issue, that is one of the main issues with impeding genetic engineering.I will post more later.

 

[Ygggdrasil]

what i am implying is that genes often cross over during cell division, we call this mutation and it often happens in an organism to produce variation naturally

Crossover events during cell division, which lead to a process known as recombination, is usually considered separately from the processes that create mutations. Recombination often helps the cell to repair mutations that occur when DNA is damaged during cell division. During normal cell division, recombination will usually not create genetic variation. Recombination that occurs during meiosis in the process of creating gametes leads to genetic variation by shuffling alleles between the two parental chromosomes, but usually does not introduce mutations.

 

[BillTre]

I can see how you might think of crossing over as being a mutation since it involves DNA breaks and changing the overall sequence, but as @Ygggdrasil, the term is not used that way.

At first I thought you were talking about two new mutations occurring at the same time which is highly unlikely since the probability of such a combination would be the probability of a mutation in one particular gene times the probability of a mutation in the other gene, which would be very improbably.

Synthetic lethals might be something like the idea you are trying to express.
They occur when two different alleles of two different genes come together in a single organism. This combination of alleles could be lethal (or just deleterious in less extreme cases) while the individual alleles themselves would not be.
These alleles could be either dominant or recessive in their synthetic effect (meaning you need only one or both copies of one of the alleles to be present to result in the synthetic effect).
The is an effect much like enhancers and suppressors have on other genes. Some enhancers can enhance the effects of another gene to the extent that it can cause lethality. These should not be confused with the enhancer sequences of molecular biology which thought to bind proteins and exist fairly near the gene they are affecting. Enhancer and suppressor mutations can be completely different genes.

If the two interacting genes are linked on a chromosome (they are physically linked by both being on the same piece DNA), they can not both be homozygous (both copies of a given gene the same) which is required for expression of recessive traits, unless recombination happens. After recombination, double homozygotes (or a homozygote and a heterozygotes would be possible for linked alleles, in the next generation.
There would be selection against this because lethality or other deleterious effects are non-adaptive.

This is independent of the source of the alleles involved (not particular to human generated genome changes) and can arise in hybrids or just from crossing between populations that have not had a lot of recent genetic interchange.
If new alleles were human introduced and they interacted with already existing genes to have bad effects, they would also be selected against, not just naturally, but also through human regulation since these effects (if significant) would be noticed and then researched. Certain gene constructs would be no longer made because they did not work well (regulatory agencies might get involved) and genetic consultation (which will develop along with the increased capacity to determine an individual's genome sequence) would advise against particular combinations (similar to what is being done already).

 

[Ygggdrasil]

Synthetic lethals might be something like the idea you are trying to express.
They occur when two different alleles of two different genes come together in a single organism. This combination of alleles could be lethal (or just deleterious in less extreme cases) while the individual alleles themselves would not be.
These alleles could be either dominant or recessive in their synthetic effect (meaning you need only one or both copies of one of the alleles to be present to result in the synthetic effect).

Synthetic lethality is a legitimate concern and one reason why guidelines recommend introducing only alleles that are already prevalent in the general population. That these alleles exist in healthy individuals with a wide range of genetic backgrounds ensures that these alleles would be unlikely to have unwanted synthetic genetic interactions with rare variants carried by some individuals in the population.

 

[Evanish]

Interesting thread. It gets into a lot of murky issues. I guess to sum it up I'd say the issue is who gets to choose the genetic makeup of unborn children. In the recent past the people that get to choose are the parents. They choose who they want to reproduce with. In the more distance past maybe the family would more often be the one who choses through arranged marriages. With this new technology maybe in the future other people/groups (governments, corporations, etc.) might in some way be more involved in this choice. Such powerful groups involvement will of course bring controversy as it bears some resemblance to the ideas of eugenics which many people have strong feeling about. I personally am in favor of the parents continuing to be the ones that make the final choice. Whatever genetic services that may be provided in the future they should be able to choose freely from among them with the minimal amount of pressure being applied to them by other people/groups (governments, corporations, etc.). As for what genetic services will be available that will surely be subject to regularity and financial constraints. Personally I think the regulations should be kept to the minimal as I think the individual parents have the right to choose for themselves what they thing is best for their unborn children.

 

[Ygggdrasil]

Researchers have raised doubts about the study by Mitalipov's team, suggesting that there could be alternative explanations for the authors' data. Stem cell biologist Paul Knoepfler describes the concerns on his blog:

An international team of top scientists led by first author Dieter Egli has responded via a preprint on Biorxiv to that Mitalipov team high-profile https://ipscell.com/2017/08/review-mitalipov-paper-Nature paper on CRISPR gene editing of human embryos. Egli, et al. raise the possibility that the CRISPR gene editing as reported in the Nature study may actually not have happened, at least not in every case and perhaps not the way the Ma, et al. paper argued it did (via homology directed repair (HDR)-based CRISPR-Cas9 action specifically depending on interaction between normal maternal and mutant paternal chromosomes).

On one level it isn’t so unusual to see a scientific critique of and technical questions raised about a published paper that made splashy news. However, I see this particular case as a striking turn of events because although the new Egli, et al. piece is very collegial and diplomatic, they convincingly lay out a number of rather compelling reasons why the main conclusions of the Ma paper might be incorrect and the reasons why there may not have been CRISPR gene editing in many of the embryos. To be clear, Egli and colleagues don’t seem to be saying the Ma, et al. paper is definitely wrong, but they describe some quite reasonable ways in which the Ma paper could hypothetically have inadvertently reached incorrect central conclusions. To me these possible alternative explanations just simply make a lot of sense and are things that should have been ruled out as alternative explanations.

https://ipscell.com/2017/08/doubts-...chnologies-wont-lead-designer-babies/']crispr-gene-editing-of-human-embryos/[/URL]

See also coverage at Science news: http://www.sciencemag.org/news/2017...chnologies-wont-lead-designer-babies/']crispr-human-embryo-editing-claims[/URL]

The critique of the study is available on bioRxiv: http://www.biorxiv.org/content/early/2017/08/28/181255

 

[stefan r]

Genetic engineering is a whole different ballgame. In fact, I don't really like the idea of genetic engineering on any animal species, much less humans. If you're going to experiment with it, keep it out of Kingdom Animalia.

Genetically engineered fungi could be scary too.

 

[lavinia]

Transgenic technology in mammals has existed for many years. Gene constructs originally were inserted into 1 cell embryos - in mice I think - and these constructs integrated into the genome and were expressed in the offspring.

A biologist told me that if one could insert genetic constructs into one cell human embryos then one could possibly cure various diseases. The example he gave was a cure for liver cancer. One would splice the promoter for alphafetal protein - a gene that is expressed in liver cancer cells but not in normal adult cells - with the gene for a Herpes protein that is fatal to the cell in the presence of a certain drug. If a liver cell becomes malignant then the promoter for alphafetal protein is turned on and the Herpes protein is produced in the cell. If one gives the drug, then the cell dies. Only the cancer cells will be killed and the normal cells will be unaffected. So in effect, liver cancer would be cured. Further this trait would be inherited.

The technological problem with this sort of therapy might be that the gene construct integrates somewhat randomly and might disrupt the genome - with unpredictable effects. If I understand it right, this current paper on CrispPR seems to say that this problem can be solved by restricting the genetic modification to a specific known site. This would remove the randomness and hopefully would not damage the chromosome. This might actually make genetic therapy feasible. It seems though that this is a technique that applies to single mutations and not multiple gene abnormalities.

 

[Ygggdrasil]

The technological problem with this sort of therapy might be that the gene construct integrates somewhat randomly and might disrupt the genome - with unpredictable effects. If I understand it right, this current paper on CrispPR seems to say that this problem can be solved by restricting the genetic modification to a specific known site. This would remove the randomness and hopefully would not damage the chromosome. This might actually make genetic therapy feasible. It seems though that this is a technique that applies to single mutations and not multiple gene abnormalities.

Correct. CRISPR shows promise in enabling scientists to make precise edits to the human genome. There is concern, however, that CRISPR could still make unintended, "off-target" mutations elsewhere in the genome and these off-target mutations have the potential to cause problems like cancer. More work needs to be done to assess the frequency of these off-target mutations and figure out how to minimize their occurrence. Still, when compared to other techniques that cause random integration of a transgene into the genome, CRISPR is a big step forward.

 

[stefan r]

...integrates somewhat randomly and might disrupt the genome - with unpredictable effects...

Does the meaning change if I quote just that part of a sentence? It looks like something a protester would say.

 

[lavinia]

In a nutshell(i have to rush to classes) what i am implying is that genes often cross over during cell division, we call this mutation and it often happens in an organism to produce variation naturally, if we venture into introducing new genes (which is what we will eventually do) new mutations might occur which could potentially disrupt the path of nature, if and when this happens we could cause our own downfall rather than fix the issue, that is one of the main issues with impeding genetic engineering.I will post more later.

Biologists that I know do not believe in a "path of Nature". Can you explain what you mean by this?

 

[jim mcnamara]

No. thejosh made several errors. There is no 'path of nature'. And single mutations alone will not wipe out a species - they are not a time bomb.
What I think he means is: If a mutation that is fatal homozygously (means just one allele of the the pair is required to have the effect) is common in a population, all people with it will die. But. How did it get into enough people long enough to be "common" in the first place.
Without killing them first?

What kills species is usually major environmental change, which usually occurs over periods longer than one lifetime. Sometimes a catastrophic event can cause a so-called population bottleneck (Founder Effect) . A few hundred individuals survive a major population die out. Modern cheetahs are an example of this.
See:

As a species, cheetahs have famously low levels of genetic variation. This can probably be attributed to a population bottleneck they experienced around 10,000 years ago, barely avoiding extinction at the end of the last ice age. However, the situation has worsened in modern times.

evolution.berkeley.edu/evolibrary/news/070701_cheetah