Ricochet is the best place on the internet to discuss the issues of the day, either through commenting on posts or writing your own for our active and dynamic community in a fully moderated environment. In addition, the Ricochet Audio Network offers over 50 original podcasts with new episodes released every day.
The Future Is (Almost) Here
Since the first discovery that our physical traits are determined by a four-letter DNA code, and since our first attempts to manipulate that code, the idea of genetically-designed humans has been a staple in the science fiction realm. But among biomedical researchers, the notion of engineering DNA in actual humans remained strictly hypothetical: while all agreed it was theoretically possible, the methods available were too cumbersome, inefficient, and limited to too few species (such as mice) to imagine a realistic path forward.
Until now.
A revolution in the nascent field of nuclease-based genome editing is currently taking place, and even the most skeptical researchers are now proclaiming that we will be regularly manipulating DNA in adults within a few years, and that the first genetically-engineered babies may be a reality within the decade. And unlike previous claims of world-altering advances which promised we would soon be flying in autonomously-guided solar-powered cars while receiving a massage from our personal robot, nuclease-based genome editing has already passed several previously-insurmountable hurdles: genetically-altered monkeys were generated last year, demonstrating feasibility in our closest biological relative. And astonishingly, just three weeks ago a group in China reported successful genome editing in human embryos.
Liu et al. (2014), Cell
This rapid progress owes its success to an ingenious new paradigm. As so often in molecular biology, the most elegant and efficient way to carry out a nearly impossible task is to find a way for nature to do it for you. These new methods take that truism one step further by combining two completely unrelated natural phenomena: a bacterial “immune system,” and the ability of cells to “heal” their DNA when it is injured.
Instead of the antibodies, T-cells, and macrophages used as weapons by our human immune systems, many bacteria have a much more rudimentary defense: identify foreign invading DNA and cut it up using enzymes known as nucleases. Meanwhile, in a complementary but biologically unrelated phenomenon, the cells of all higher organisms have intrinsic methods to repair cut DNA. And like a cut on the skin, when cut DNA heals, it leaves a scar – except that the genetic code is so sensitive that this scar usually inactivates the gene being healed. Moreover, just like a skin wound, it is possible to artificially “graft” a new sequence of DNA into the wound, thereby allowing a new gene to be inserted into the genome.
Thus, a genome is edited by artificially introducing the components of this bacterial immune system into human/primate/mouse/etc. cells and targeting them to the gene of interest – and then letting the nature do the rest. This is the general principle underlying several different methods which have made news since 2010, including ZFNs, TALENs, and CRISPR/Cas9. While each of these methods is slightly different, they are all orders of magnitude simpler, cheaper, safer, more efficient, and more versatile than previous techniques. CRISPR, the newest and most promising of the methods, allows any site in the genome to be targeted, and only requires several days of preparation using simple molecular biological methods. Its basic framework also allows it to be delivered to nearly any type of cell from nearly any species.
There are still several kinks in the methods. Currently, only cells in a Petri dish can be manipulated, not in the organism itself. Off-target mutations may also occur, and the extent and mechanism of this problem remain unclear (off-target mutations were an issue in the experiments on human embryos). However, given the incredibly fast speed at which these methods have been developed, it is reasonable to expect that these issues will also be cleared up in time.
But regardless of any technical road bumps ahead, the success with genetically-manipulated monkeys and human embryos clearly demonstrate that the impossible is now possible: we now have a technology that we can use to change our own DNA.
This brings us to the ethical questions of genome editing. The implications of being able to rewrite any section of DNA and to produce “designer babies” are obvious even without an understanding of the underlying science. In a promising development, all of the leading US and European researchers have agreed to a moratorium on experiments in human embryos. Even the Chinese group at least minimized the ethical ramifications of their human experiments by only using leftover embryos from IVF which had been fertilized by 2 sperm each – meaning they were incapable of sustaining human life even before the experiment.
Here in the US, human research is focusing on genome editing in (non-embryonic) induced pluripotent stem cells. In this situation, cells (usually skin or blood) are harvested from a patient with a genetic disease, converted to stem cells, the DNA defect is corrected in these cells Petri dish, and then the cells are induced to differentiate to the specific type of cell affected by the disease (say, a neuron or a lung fibroblast) and re-introduced into the body. This is an ethically impeccable approach and will likely work well for certain cell types and diseases (such as leukemias), and phase II have already begun to test genome editing as an approach to counter HIV infection. However, for other diseases the last two steps of the process – converting the stem cells into specific cell types and placing them in the correct context back into the body – remains incredibly difficult. For that reason, altering the DNA in the embryonic stage (or of the sperm and egg which create it) will always remain an incredibly tempting approach.
And even many of the scientists currently calling for a moratorium believe that manipulation of human embryos (and thus permanently changing our genetic lineage) is inevitable. Indeed, given human nature, it is naive to think that such advances can be stopped – and the incredible efficiency of these methods (which thereby require fewer embryos to be destroyed) will only lower any ethical thresholds. Given the breathtaking pace of these technologies, it is incumbent on us to discuss their ramifications now, and not later.
What do you think? Should we impose any restrictions on genome editing? Should the medical profession try to voluntary restrict itself to only performing certain genetic interventions?
Published in General
It should go without saying that this is great news. As the genes responsible for various diseases are identified and fixes proposed, previously impossible to treat diseases and may become relics from textbooks. Even the ability to control inflammatory responses which are the primary culprit in a variety of debilitating diseases might immeasurably improve the quality of life of people the world over.
What a time to be alive – we’ll be growing replacement organs for ourselves in pigs within 20 years.
There’s a big gap between having the technical ability to edit DNA and knowing enough about the code to make useful edits.
Knowing the alphabet and owning some liquid paper isn’t enough to improve upon Shakespeare.
There are even more benefits from this technology than I mentioned in the post.
For instance, previously it was nearly impossible to generate any type of transgenic animal save for mice, which are not always the best representatives of human disease. It now seems likely that we can generate transgenic versions of almost any mammalian species, which would allow researchers to make much more accurate models of human diseases for research.
The same applies to plants, although in that area the technology is not yet as advanced. But the types of transgenic plants which previously took years and millions of dollars to generate will likely soon be feasible within a year and for several tens of thousands.
We have enough knowledge of “the code” that we could likely eliminate several hundred diseases right now (affecting millions of people in the US alone) if we had the ability to edit our genome, and another several hundred or even thousand within a decade or so. In other words, we have been gathering a great deal of information about the genetic bases of diseases for decades, but have had no way of leveraging those insights. So “shovel-ready” projects abound.
Nonetheless, there is still a great deal we don’t know about what our genome encodes. This search will also be greatly facilitated by CRISPR et al., by making it much easier to modify/disrupt those genes in experimental models and thereby elucidate their functions.
I am, in the larger scheme of things, a pretty lucky person. I was born at a time when modern medicine allowed someone with my several now-“minor” medical problems to survive into adulthood and lead something resembling a functional life.
I’m not retarded, I have no major neurological malfunctions, I have all my appendages and they usually have full range of motion (once I’m well enough to have knee surgery, it’s likely only a matter of weeks before I’ll pass the sit test again). Given enough time and a willingness to endure somewhat-more-than-average discomfort, I could probably do anything! (OK, not literally anything – a few things are definitely out. But plenty of stuff.)
This is awesome, right?
But anyone who would call my mother evil for editing me so I didn’t have to live with these “minor” medical problems: sorry, I kind of have a hard time taking you seriously unless your ongoing problems are at least as bad as mine.
There’s not only a typical mind fallacy, but I’m becoming increasingly convinced, more specifically a typical body fallacy. Those lucky enough to be born “naturals” can rave about the wonders of respecting the natural order all your life, but if you were born an “unnatural” like me, the fact that you’re alive already slaps Mother Nature in the face. The only question remains: do you slap her well or poorly?
Long ago I did a post on Gattaca the movie and the ethical issues surrounding our inevitable future. I’m hopeful for these advances, really hopeful, but on a different note just imagine millions of Boba Fetts. What could go wrong.
Midge, I fully expect edited kids this next few decades. We will hopefully pass on the best in our species value wise in addition to the health related designs. I’d wish I’d had some health issues edited from me too:-)
We don’t know yet.
People have done things hoping to help that hurt people.
My fear is that with the legal climate parents will be encouraged to abort and start again because they will “know” the future of the baby.
Fire is a good thing when it brings warmth but when it burns the house down it kinda got out of control. Can we control the result or are we playing with matches? What happens to the “Oopsies” of progress?
With genome editing, this scenario is actually less of a danger: instead of the uncertainty of “natural” conception with the ability to abort when the fetus’ genetics turn out to be below expectations, the fetus can be engineered from the beginning to meet those expectations. And thanks to the efficiency of the CRISPR method, it may even be possible without needing to create (and subsequently destroy) extra in vitro fertilized-embryos in order to obtain a successful fetus.
Of course, it is precisely that precision and efficiency which may soon allow us to play God without any overt negative consequences – which will likely usher in a world of “covert” consequences in its stead.
I say let’s do it. At the age of twelve, every day after school, I started giving my then-seven year old sister one of four daily insulin injections. Doing away with that for her, and for thousands of others, is exactly what science is for.
It opens up a world of possibilities.
Thinking out loud. I wonder what the interplay is. In Japan, they talk about how children have grown up in ultra clean environments which have hurt them because their immune systems have not had enough dirt to overcome. This definitely was an unattended consequence. In technology it happens often where you fix one thing to break another. Whatever the purpose or reason the risks are high. The power will soon be there. Will we “break” things or “fix” things? Will we even know till twenty years out?
where do I sign up?
[edit] seriously, where? I’m guessing https://clinicaltrials.gov/ ?
Is this another one of those perpetually 5-10 years away technologies?
I’m still waiting on holographic media.
http://arstechnica.com/uncategorized/2005/11/5631-2/
http://arstechnica.com/gadgets/2008/04/holographic-storage-150gb-discs-finally-coming-to-market/
“when the fetus’ genetics turn out to be below expectations, the fetus can be engineered from the beginning to meet those expectations. ”
Those expectations will increase. It won’t be enough to have a child without [x] condition. The history of affluence suggests that the more people have the more they want, demand, and cry over. These innovations will indeed discourage some abortions… and be used to justify others.
I don’t categorically object to genetic manipulation. I do think there will be both good and bad consequences. And I don’t know what the limiting principles should be.
Freedom is the limiting principle.
I disagree. Editing is going to need to wait for a lot more research into epigenetics and “duons.”
I think we are going to see some brave new gene splicing experiments get hushed up to hide the horrifying consequences when they go wrong.
OTOH, medicine already has a long history of having horrifying consequences when it goes wrong. This goes not only for ethically-controversial procedures, but treatments that even the most socially-conservative among us accept as right and good.
Take a look at the side-effects for the wonder-drug that revolutionized – and saved – countless lives of people who otherwise would have perished, not because of any infection they had caught, but because of the derangements innate to their very own uninfected, uninjured bodies.
I myself owe my very life to carefully-controlled brushes with this drug – fortunately, I was born late enough that they had already learned how bad too much of it is! Flannery O’Connor, was less lucky. Naive overuse of this “medical miracle” contributed to her demise.
This podcast talks a bit about that (not in Japan though).
http://www.econtalk.org/archives/2014/03/velasquez-manof.html
Better living through chemistry.
Your comments just highlight how quickly our knowledge has advanced. Nobody wants to allow us to fully digest the information we have gained; careers and fortunes await the impatient who restlessly seek the next advance. I am glad that we have a Food and Drug Administration with a scientifically derived protocol for experiments on new treatments both before and during the initial experiments with people. Yet we have all sorts of folk clamoring for quicker processing and less government interference.
I am amazed at the rapid pace of advances. Just last year they released a cure (not a treatment, a cure!) for Hepatitis C. It is too late to save my Mama, whose veins and liver are shot after 44 years of the progress of her disease, but I am glad for the advance. Yet I think the rapid pace is going to yield casualties.
There are trade-offs both ways, and people have differing ideas on where the optimum lies.
Centralized monitoring (as opposed to decentralized monitoring – there’d be monitoring either way for something we value as much as health) has benefits but also costs. Delaying a drug that actually works costs lives, as does distributing one that is harmful. Moreover there are diseconomies of scale as well as economies of scale to monitoring organizations. If a monopolistic monitor gets something wrong, it can stay wrong for much longer, since there aren’t alternate monitors available to produce the correct alternative.
Two thoughts. 1) the SNP for sickle cell may provide a protective advantage against malaria when only one copy is present, but causes diseases when homozygous. Do we only correct this genetic defect in first world countries? 2). I get nervous that magic bullet cures are a license for poor decision making.
No. You apply this science to anopheles so they can’t harbor the parasite any more, and make it dominant, and then inroduce these modified mosquitos into the African population.
In the vast majority of cases there will be less casualties than the ones which would be avoided by earlier approval.
The person who dies because the treatment isn’t approved yet is just as dead as the one who died advancing the knowledge.
As long as there is reasonably informed consent, that’s how we minimize casualties without violating anyone’s rights.
Whenever I think of the great possibilities of gene therapy, several cautionary thoughts come to mind: The First Commandment, the ancient Greek admonitions regarding hubris/nemesis, and the often overwhelming unintended consequences of social policy enacted through legislation/regulation (societal DNA modification, if you will).
As one who is not a geneticist, my knowledge of the specifics is limited. Epigenetics – the regulation of gene expression by DNA sequences which are not transcribed into proteins -mentioned by others, is not, as yet, well understood. As well, many sequences of base pairs are highly repetitive, appearing in many areas, both transcribed and non-transcribed. Is it thus possible (even likely?) that an intended point correction may occur at numerous sites on numerous chromosomes? If so, the likelihood of unintended consequences seems significant, until we fully understand gene regulation and can change only one specific, intended, codon to the exclusion of others. I do not know whether the methods described here accomplish that.
When I was in medical school, untranscribed DNA was referred to as “junk DNA.” There was much speculation as to its function and content. One concern was that it might contain viral DNA, incorporated in our ancient past, which could become activated so as to reconstitute viral particles with which we no longer have immunological defense.
As conservatives – at least in the sense that we generally honor much ancient wisdom as to our human and fallible nature – I think we are more likely than utilitarians to attend to such cautions.
When it’s known that a recessive genetic disorder confers an advantage to the heterozygous carriers, wouldn’t people weigh that into their decisonmaking?
For example, my husband is a CF carrier. Since I am not, why would we edit our babies against CF even if we could?
Now, if both of us were CF carriers (and especially considering that asthma and other autoimmune derangements whose genes aren’t so easily edited out run on both sides of the family) we would have a better reason to be worried about conceiving a child whose relationship to the very air we breathe would be… rather fraught (to say the least). But if genetic editing were available, wouldn’t we have the luxury of editing our child’s CF genes only if he were homozygous for CF?
I work in the world of behavioral cancer research. I’m excited by the lives that will be saved by these advances in technology. But I have multiple concerns that shouldn’t necessarily be constraints on the development and implementation of these technologies, but actively weighed in the decision-making process.
1. Cancer involves multiple genetic and cell mutations (over-simplified). However, as we change these cells DNA, what are the downstream effects on cell processes over the lifespan?
2. Several people have mentioned informed consent. Actually, this is decision-making in the context of uncertainty. We have new important information; life-saving, life-changing information. Yet we can’t pretend to know the long-term effects in humans. However, we can assume the stakes are high, because we’re intervening in our governing genetic code.
3. Our excitement can cause us to overstate and overvalue the good, and undervalue the possible negative effects. One example is the developmental effects of cancer treatment during pregnancy. The guidelines say “don’t give chemo during the first 3 months.” Yet, there is no cohort study examining these kids beyond age 3. Maybe it is ok, and the kids don’t suffer any or significant neurodevelopmental problems…I don’t know. But the informed consent process for these women typically overstates the confidence in which we can say “by following the guidelines, your baby won’t be affected”
The failure of a lot of supposedly “utilitarian” thinking lies in utility calculations that fail to take how little we know into account. That not only makes them un-conservative calculations, it also makes them defective as utility calculations. In other words, making a decision in the face of incomplete knowledge without properly taking the incompleteness of your knowledge into account is bad utilitarianism, too.
The biggest problem, frankly, with many self-styled utilitarians is that they are doing bad utilitarianism – they too often assume that what they already know is all there is to know, and so don’t properly hedge for their own ignorance in their utility calculations (which a good utility calculation should do). I ran into a doctor like this yesterday – it was unpleasant :-)
Now, my pointing out that the trouble with a lot of utilitarian arguments is that they fail at even being good utilitarian arguments needn’t be read as an endorsement of utilitarianism. I tend to side with Mike H – our moral intuitions are supplying us some of that information which current utilitarian computational ability is so lousy at dealing with.
The term Epigenetics has come up at least twice in this thread.
As a layperson, here is my understanding:
Epigenetics deals with the idea that some genes in our DNA interact with our environment to decide whether to switch on or off. We don’t understand all the various environmental interactions that cause switches to get flipped.
So for example, clones don’t look the same as their original.Hollywood science fiction lied to us!
Another example is the disease Ankylosing Spondylitis that affects the spine, which has a genetic component and an environmental component that is not understood. The vast majority of people with genetic markers for the disease don’t have it, but some do, causing doctors to speculate that there is an environmental component or trigger.
Other areas of Epigenetics relate to genetic inheritance. As a layperson, for years my understanding was that only certain things get passed down to children from their parents, like potential height, eye color, skin color, etc. But now there is a big question mark around things we were told didn’t pass down through genes, like intelligence, work ethic, fitness level, etc.
I THINK I first heard about epigenetics on the econtalk podcast, but I’m not sure.
Here is a source or two that came up while googling:
Not necessarily. When it comes to “fixing” a gene with a single deleterious mutation – think CFTR in the case of cystic fibrosis – epigenetics are fairly irrelevant. The problem in these cases is that a defective gene is being expressed. If we fix the gene and it remains expressed (i.e., no epigenetic change), problem solved. If we fix the gene but it becomes repressed at that locus (i.e., there is a change at the epigenetic level), also no problem – the other healthy locus on the other chromosome remains untouched.
At the moment there are very few clinical trials taking place – one of the few is a phase II trial on HIV which I mentioned in my post.
There will likely be a flurry of new clinical trials within the next 2-3 years as companies which jumped onto the first-generation technology bring it to fruition, and some projects using CRISPR get fast-tracked. However, the first round of clinical trials will not simply be tests of “genome editing” as a principle, but will be focused a small number of diseases with genetic etiology which are already very well-characterized.
Furthermore, since the method is currently only feasible in cells outside of the body, the first generation of treatments will likely be limited to blood disorders (since blood can easily be removed, manipulated, and returned to the body) or to disorders for which stem cell therapies already exist.
In other words, don’t look for clinical trials for diabetes utilizing genome editing any time soon.