Science TGIF: useful, fun sciency videos & stuff

  • The Myth of Beer Goggles? from Neuroskeptic. No drinking doesn’t necessarily make people seem more attractive…research from the field (bars).
  • Critters take a dip in our world in the videos below. The bear video is awesome.

And these guys trying to catch the pool-crashing gator are not doing too well at first…

Conversation with Kelly Hills: human genetic modification & bioethics

Below is a conversation with bioethics commentator Kelly Hills (who BTW has a great blog), tackling some of the key issues surrounding the potential use of CRISPR-Cas9 technology to make heritable genetic modifications in humans.

I really appreciate her clear and insightful answers to some tough questions that many are grappling with today on this topic.
Kelly Hills

Part of the possible power of some forms of human genetic modification procedures being considered for potential future use is that they are heritable. This means, for example, that embryonic correction of a disease-associated mutation such as in BRCA1 or of a disease-causing mutation such as that in cystic fibrosis, would not only prevent the future individual from having these mutations (and associated risks or disease), but also all of their future descendants as well. So there is at least hypothetical strong, transgenerational benefit. At the same time, this means that any associated risks with these genetic modifications (e.g. off-target effects where other genes are mistakenly edited leading to negative health outcomes or other unintended consequences) would also be inherited down this family tree as well, potentially forever. From a bioethical perspective, what considerations if any should be given to heritability of these kinds of interventions?

KH: First, the general caveat: unlike some fields, bioethics isn’t homogenized and if you ask five folks involved in ethics the same question, you’ll get at least 12 different answers.

So, that said: modifying the germ line is definitely a big issue–I’d like to say big enough that I actually don’t think anyone will seriously try to bring a modified human embryo to term for a while. (Unfortunately, I think we all consume enough science fiction to go “yeah but what about [favourite sci-fi/horror story about genetic superhumans]?”) So far as considerations towards the future, I think that looking back towards IVF, ICSI and other reproductive technologies (since ultimately that’s what this is) is necessary. In particular, there was never any systematized following of babies born from various reproductive interventions–so we actually don’t know about potential harms. From the surface, it certainly seems like everything has been okay, but I think it would be an excellent idea to actually do longitudinal studies once we do get to the point of human use of CRISPR/Cas9. I might even go so far as to say that’s an ethical imperative.

With that, I’m actually less concerned about the viability of the science and more concerned about the dialog we have about what we do or do not fix–which is more in line with how I try to approach bioethics (as a conversation between stakeholders vs a bright line of not crossing).

For example, I’m not sure anyone would say “nope, we shouldn’t eradicate Huntington’s Disease,” if the science of CRISPR/Cas9 editing proves viable in animal models, if 3PN zygote experiments that Zhou, Huang, et al were doing show that we’ve fixed off-target effects, etc.

But should we eliminate hearing loss?

Someone who views hearing loss as a crushing disability, something being taken away, might say YES very quickly to that question–but someone who was born deaf and considers themselves part of the Deaf community could very well be offended by the idea that people want to eradicate not only something that defines them as an individual, but a rich culture with its own language.

So what, then, is normal? How do we decide what should be fixed and what shouldn’t be fixed? Again, this might seem like a simple question–if it’s not one that you’ve thought about. But “normal” is a lot of assumptions, and some of those assumptions are pretty offensive to folks who don’t fit into the definition–and thus find themselves being talked about as if they’re an error that shouldn’t exist.

And what is abnormal? What sort of modifications shouldn’t be made…and why? Should not, as much as should, is a normative statement.

It can be very tempting, when “doing science,” to merely think about the pieces in front of you: I’m swapping out broken DNA for something better! But within that very sentence, we escape from science and in to philosophy, language, culture: how do we define broken? How do we define better? And so we need to very seriously discuss how we define these terms and the others that frame the debate around germline modification-because no matter how hard we try, some genetic variation, including some genetic disease, crops up spontaneously. At this moment in time, we haven’t really managed to create a society that is open and welcoming for everyone, regardless of ability, and I can’t see that we would have a better society waiting for someone who has a spontaneous mutation that cropped up in utero if we eliminated all imperfection and deviation from a norm wherever possible.

Now, all that said, I think it’s also important to move away from the idea of “one gene one disorder”–something admittedly scary like Huntington’s, an autosomal dominant disease tied to a very specific loci, is pretty rare. Much more common are diseases spread across the genome that aren’t going to be easily fixed for swapping one part for another, and if we can move away from having that “swap RED LEGO A for RED LEGO B” mentality when discussing genome editing, we’ll probably have healthier (and less frustrating) conversations for everyone.

What about the issue of consent both of the genetically modified (GM) child and other possible future descendants, none of whom would have given consent to be part of an experimental procedure changing their DNA since they don’t exist at the time of starting the experiment?

Well, the snappy and fast answer here is: if you don’t exist, you can’t consent. That might seem sort of silly, but the question as stated is kind of loaded, because consent is something that we grant to beings we consider autonomous agents–children, for example, may be able to assent to treatment, but they cannot consent, because they’re not considered fully autonomous agents. A zygote cannot assent, let alone consent (and the debate about the agency and autonomy of a zygote through fetal development is at the heart of much of the abortion debate in America).

Now, what I think you’re actually asking is: is it okay to let parents make momentous and life-changing decisions for their children? As you note in your next question, we already allow for parents to make all sorts of medical decisions about children, whether or not those decisions are medically advised; we give parents the ability to consent for their kids because we have a general belief that parents will do what is best for the child. Which goes back to your last question: surely eradicating mitochondrial disorders forever is a worthwhile goal. But is eliminating autism? A lot of this is about values, not science.

Following up, some have argued against the consent issue being important or uniquely relevant here. For example, they point out that parents make these kinds of decisions all the time with respect to lifestyle or medical choices that also affect their children, grandchildren, etc. For instance, some have argued that parental choices about prenatal nutrition, smoking, drinking, and such can impact future children in substantial ways and without the children’s consent. In some cases such as with smoking, it could even hypothetically lead to random, but heritable genomic changes via mutagens in the smoke. Yet we as a society for parents do not prohibit certain behaviors perceived to be risky for future descendant or mandate other behaviors perceived to be positive. In other words, that line of reasoning goes that the lack of consent of future children/descendants is not a serious consideration related to heritable human genetic modification because of how we as a culture have handled other parental behavior issues. What are your thoughts on this one of reasoning?

KH: “We” as which society? American society definitely values autonomy over just about everything else, and parents are certainly allowed to do things that many of us disagree with, like smoking around children. But it would be a mistake to assume that’s the same for all societies! And, even within the USA, it’s not absolute: consider the parents who are convicted of child abuse for allowing children to die instead of taking them to the doctor, or laws that allow prosecutors to charge women with assault if there are complications in pregnancy or delivery after using illegal drugs.

That line of pedantry aside, I think it’s silly to say “we don’t address epigenetic changes so we shouldn’t bother discussing intentional germline manipulation!” It’s sort of a weird variation on appealing to a bigger or more pressing problem (technically, the informal fallacy of relative privation); how can we discuss germline edits when there are children starving in Africa?

Perhaps a better question would be: if we’re considering preventing a constellation of inherited diseases via germline editing, should we also consider trying to prevent negative epigenetic changes and/or other negative parenting choices? If, after all, certain classes of mutation should be prevented, wouldn’t that hold true regardless of how the mutation is caused?

Another argument made contrary to potential concerns over heritable human genetic modification has been that human choices regarding mate selection and societal influences on breeding choices are already commonplace and accepted forms of what can arguably be called “heritable human genetic modification” amongst humans. In this line of thinking, the editing of a genetic mutation in an embryo such as by CRISPR-Cas9 would not be so different than these other everyday, acceptable human sexual/breeding practices that also result in new genomes in children. What do you think of this kind of equivalency argument?

KH: In general, I think we have to be careful with X=Y arguments. Just because something is “of a kind” doesn’t mean it’s necessarily the same, and it can encourage sloppy thinking to lump “of kind” things together. Humans have been doing “genetic modifications” to food crops for thousands of years, but we’ve still been very careful with GMO crops. They’re “of kind” in that they’re both modifying the food we eat, but careful breeding to reduce large seeds in a watermelon is still different than inserting fish genes in a tomato to boost cold-hardiness, and we recognize that in the scientific evidence we require for safety claims.

As you note, we do already have quite a few everyday acceptable attitudes towards human genetic modification: for example, some Jewish populations utilize PGD and IVF in order to avoid heritable diseases. So again, going back to the last question, the answer here might not be “does it matter since we already do” and “we already do, should we think about this some more?”

The first published paper to report germline editing of human embryos came out a few months ago and it used CRISPR-Cas9 technology. It reported a number of problems with the technology including mosaicism, off-target effects in the genome, and more. In the publication the authors indicated that they had approval from an institutional ethical oversight committee. Is that sufficient to demonstrate that this work was ethical? From a distance and not knowing specifics of a particular oversight committee’s mission, institutional guidance, membership, etc., from a bioethics perspective how can one evaluate whether such work was given a rigorous review?

KH: You can’t–this is a problem in academic science publishing regardless of the subject. Last year, two researchers assured PNAS they had IRB approval for their Facebook emotional manipulation research–oops, they didn’t, and two universities and PNAS played “not me hot potato!” denying responsibility for confirming ethical oversight.

Earlier this year, a paper on how to change people’s minds regarding gay rights was retracted by Science when it came out that the researcher, LaCour, had falsified data…but hidden in all of the information that came out about how he falsified data was that he also lied about having IRB approval. (And this I confirmed with the Science EIC; he told them he had IRB approval, and never contacted them to “clarify” the mistake, as he was ordered to do by his IRB when they found the error.)

The majority of academic journals request that authors give a confirmation (via a check box, signature, etc) that they followed the human subjects research rules of the Declaration of Helsinki; you’ll see this somewhere in the first few paragraphs of any paper: “The authors confirm that this paper meets the requirements of the Declaration of Helsinki and has been approved by University IRB.”

But it would be naïve to pretend that this is an issue only with ethics in scientific research. Most scientific papers don’t provide the raw data from their experiments, or lab notebooks, or anything else that can be verified externally. No one actually ran Obokata’s stem cell stresser experiment; we take researchers at their word because we extend trust–and you might say that the existence of sites like Retraction Watch should encourage us to rethink how we approach all of the data submitted with research papers, from IRB approval and ethical research declarations to raw data and so on.

Until there is a radical adjustment in the process of publication, the ethics of each paper has to be judged just as the rest of the data and information in a paper: with skepticism until the author supports their work.

Following up, in the media it has been mentioned numerous times that a version of the same manuscript was rejected by “elite” journals such as Nature and Science due to ethical concerns. Without factual confirmation of such alleged “ethical concerns”, should the community disregard such reports as simply rumor?

KH: Well, if a paper was rejected several times by “elite” journals for scientific concerns before finally being published, should the science community disregard further scientific concerns without factual confirmation–or should they go look for those scientific concerns and see what they come up with?

As I recall, that’s precisely the situation of the Obokata/RIKEN stem cell issue, which led to–well, a lot of chaos, and ultimately retractions and ruined careers, as your readers are well aware. If folks have ethical concerns, they should by all means chase them–but they should be sure their concerns are actually ethical concerns, rather than unconscious racism, race bias, or other issues that have certainly come up to cloud the discussion since the Huang et al paper was published.

I think that for some people, they may have ethical worries but not be trained in bio/research ethics, and be unsure how to vocalize those concerns. In this case, I’d say to that person: contact your friendly local bioethics specialist, ideally someone who specializes in research ethics, and talk to them. Go get a beer or a coffee or whatever the socially acceptable academic drink is where you are, and be honest about your concerns, and let your friend/colleague/expert help you figure out where your unease sits. You might come across something new and exciting and get a paper out of it! Or you might learn more about ethics and research and have your fears assuaged at the same time–a win any which way, right?

(And for the record, something akin to this with ethics did happen last year: a study was published about Facebook doing some emotional manipulation studies, social scientists and ethicists had concerns, started talking to one another, and in addition to getting everyone involved to admit that oops, no ethical oversight, quite a few people got papers out of it.)

Healthy skepticism needed on claim of stem cell-derived human fetal brain

human fetal brain IPSCOne of the biggest claims related to stem cells and in particular to induced pluripotent stem cells (IPSC or IPS cells) of 2015 came just yesterday.

A press release from Ohio State University reports that two of its researchers had grown a nearly full-formed human fetal brain.

My initial reaction was, “Wow”, but a very skeptical “wow”.

A few past stem cell claims that turned out to be too good to be true have made me even more cautious and skeptical about what I read, especially if it is a sexy claim without much data.

In this case, the work has not been published. We need to learn more before we can be sure about this fetal brain claim so it’s no time for hype.

The story was picked up like wildfire by the media. That’s the danger with science communication by press release. Maybe it really is a nearly fully formed fetal human brain grown from IPSC in a dish (see image above) or maybe it isn’t.

Update: For some background on solid, organoid, mini-brain stuff, I recommend this.

Professor Rene Anand and colleague Susan McKay reportedly did this newly reported work, and presented it at the 2015 Military Health System Research Symposium in Florida. I was unable to find a copy of the presentation or abstract, which would have been helpful. Without more data, the structure shown in the above image could be just about anything. That’s the thing with organoids; from the outside they don’t look like much.

The Ohio State PR says that Anand is somewhat new to stem cells and yet was able to grow this nearly fully formed fetal human brain.  That would be a rare and impressive accomplishment.

They apparently used an organoid-type approach that is apparently being patented and is proprietary, which also makes it hard to evaluate. An important focus seems to be on commercialization:

“Anand and McKay are co-founders of a Columbus-based start-up company, NeurXstem, to commercialize the brain organoid platform, and have applied for funding from the federal Small Business Technology Transfer program to accelerate its drug discovery applications.”

In addition to analysis by microscopy they reportedly did some kind of gene expression analysis to make the claim that the IPSC fetal brain expresses 99% of the expected genes. I’d like to learn more about that. More from the PR:

“High-resolution imaging of the organoid identifies functioning neurons and their signal-carrying extensions – axons and dendrites – as well as astrocytes, oligodendrocytes and microglia. The model also activates markers for cells that have the classic excitatory and inhibitory functions in the brain, and that enable chemical signals to travel throughout the structure.”

In principle these kinds of analyses would indeed help to identify this tissue as brain-like in nature. Let’s wait and see the data. There is no patent application in the public domain on this that I could find at least, which is too bad as that could have provided more information too.

I also wondered about ethical issues of making a fetal brain. At some point could it start to think? Anand is not concerned according to The Guardian:

“The ethical concerns were non-existent, said Anand. “We don’t have any sensory stimuli entering the brain. This brain is not thinking in any way.”

You sure about that? Have they talked to a bioethicist?

The Guardian reporter Helen Thomson deserves a hat tip on this story. She really did the needed homework on this one unlike the other media stories I found and she reached out to independent scientists who formed a consensus that we can’t be sure of this claim:

Several researchers contacted by the Guardian said it was hard to judge the quality of the work without access to more data, which Anand is keeping under wraps due to a pending patent on the technique. Many were uncomfortable that the team had released information to the press without the science having gone through peer review.

Zameel Cader, a consultant neurologist at the John Radcliffe Hospital, Oxford, said that while the work sounds very exciting, it’s not yet possible to judge its impact. “When someone makes such an extraordinary claim as this, you have to be cautious until they are willing to reveal their data.”

On this and other similar cool science claims made by press release, the best approach is to employ a healthy dose of skepticism. Of course an antidote to skepticism is rigorous peer-reviewed data.

CRISPR off-target effects important, but not severe challenge, says poll

In a poll on CRISPR-Cas9, respondents so far have predominantly viewed potential off-target effects as a moderate (28%) to substantial (25%) problem.CRISPRCas9poll

The poll is still running if you are interested in participating.

As to the more polar answers, only 20% and 4% answered “minor” or “a non-issue”, respectively, while 14% thought that off-target effects would be a “severe” problem.

Respondents from 29 countries participated. Most countries fit with the overall pattern of votes. However, those in the UK, Australia, and Singapore, were relatively more concerned about off-target effects.

If, as is expected based on current trends, CRISPR technology continues to rapidly improve and more data are produced indicating that subsequent next generation versions have substantially improved accuracy (e.g. already the nickase system is proven more accurate), it’ll be interesting to run the poll again.

Where’s the Beef? Why I Disagree with Pinker On CRISPR

Steve PinkerProfessor Steven Pinker of Harvard has been making the case recently that when it comes to novel biotechnologies such as CRISPR-Cas9 that bioethics should just get out of the way. Further, he has argued that we do not need a moratorium on clinical use of CRISPR-Cas9 for human genetic modification. In fact, he says that such a moratorium would be harmful.

I think he’s wrong about that. I’m not a bioethicist so rather than talk primarily about his views on bioethics, I’m going to focus instead on a scientist’s perspective on the key issues.

I respect Pinker’s intellect. In addition, I share his goal of stimulating dialogue on innovative biotechnologies. Sometimes being provocative is the best way to stimulate much-needed discussion.

I invited Pinker to do an interview on this blog last week, which you can read here. In that conversation he goes into much more depth on his view of human genetic modification via CRISPR, a possible moratorium on such efforts (which again he strongly opposes), and bioethics. It’s a fascinating read even if you disagree with him.

His is a wonderful, bright writing style and I appreciate his inventive neologisms like the new words bioethocrats and moratoristas even if admittedly (we need thick skins to weigh into science politics) they tend toward the pejorative and arguably are divisive.

The real Achilles heel of his argument on human germline modification is the lack of hard science behind it. As a spin on “where’s the beef?” we might ask Pinker, “where’s the data?” In fact, his main assertions are not backed up with data, but rather with assumptions, predictions and clever use of words. Most scientists that I know aren’t convinced by this kind of argument because there’s not much if any data behind it. The arguments are not scientific, but more philosophical and speculative.

For instance, his super cheery vision on biotech and in particular clinical use of CRISPR puts him at odds with leaders in the gene editing field including scholarly scientists such as Jennifer Doudna. Doudna and other prominent scientists have publicly voiced concerns over the potential for misuse of and unintended consequences from CRISPR-Cas9.

Doudna and fellow scientists such as Nobel Laureates David Baltimore and Paul Berg correctly see there being great potential for good in CRISPR-Cas9 and I totally agree on that, but Doudna, even as a discoverer of CRISPR-Cas9, doesn’t view this technology as being free from complications or bioethical issues. Of course she’s right about that too. Even geneticist and CRISPR-Cas9 innovator George Church, who has been relatively more enthusiastic about the possible future role for heritable human modification via CRISPR, has raised some concerns at times about this technology including safety and possible weaponization. Those issues plus many others including commercialization and potential conflicts of interest, are precisely where we scientists need the expertise of bioethicists. But really what the scientists like to focus on is data and that’s one major thing lacking from Pinker’s argument.

Biotechnology is neither as simple nor as positive as over-exuberant technophiles would have us believe. In the real world of science, things are complicated. Experiments are rarely black and white in this arena where grey dominates. We might say, “Data is king” and data are glaringly absent from the writings of those promoting human genetic modification. For instance, Pinker hasn’t presented data to back up his sweeping assertions that (A) we can do a risk-benefit calculation for innovative biotechnologies such as CRISPR-Cas9 and that (B) as a result we can confidently predict that benefits will greatly outweigh risks. He’s engaging largely in wishful thinking. I pressed him on this point in my interview and I don’t believe he answered that question convincingly. In addition, Pinker is far too optimistic about the protections in place for individuals or future individuals who might be genetically modified and harmed in the process.

As a scientist and an admitted datacrat, I have to look skeptically on this kind of breathless optimism in the process of policy formation. The fact that the CRISPR-Cas9 data we have so far is at least somewhat concerning on certain levels is certainly relevant here as well and concretely supports a moratorium. These data include the evidence of substantial off-target activity of CRISPR at times, that CRISPR can also make the “wrong” genetic modification in the “right” place too, the fact that CRISPR technology is new and rapidly improving giving a sound, data-based basis for predicting that even in a few years CRISPR-Cas9 will be a dramatically better tool than it is today, the reality that the first paper reporting CRISPR editing of a human embryo used a suboptimal form of the technology (i.e. human judgment is not perfect even in science), and more.

We can argue about philosophy and debate about future visions. We can battle with words. In the end, our decisions need to be in large part driven by data and even by the absence of data. For example, scientists can say, “we need to know XYZ before we can proceed, but we just don’t know that yet”. More data is definitely needed before we can confidently make predictions about CRISPR’s use in humans.

Further, bioethicists have a key, positive role to play here in community discussion and policy formulation even as we take the appropriate time to accumulate more data. I would hazard to guess that most scientists (and I include myself in that) wouldn’t want bioethicists to completely run the show on this, but at the same time we realize that we need some bioethics expertise around the table. That certainly was the case for the Napa meeting on CRISPR. I’m confident that the organizers of the upcoming NAS meeting on human germline modification share this view too so I’m not going to belabor that point.

The bottom line is that the keys to a constructive path forward on CRISPR-Cas9 and evaluation of potential human genetic modification overall will be more data as well as balance in discussion and policy making. We haven’t had time for that yet so at least a temporary clinical moratorium is the wise way to proceed.