Medicine

Yesterday I outlined why genetically engineered children are not imminent. The Chinese CRISPR gene editing of embryos experiment was lethal to around 20% of embryos, inserted off-target errors into roughly 10% of embryos (with some debate there), and only produced the desired genetic change in around 5% of embryos, and even then only in a subset of cells in those embryos.

Over time, the technology will become more efficient and the combined error and lethality rates will drop, though likely never to zero.

Human genome editing should be regulated. But it should be regulated primarily to assure safety and informed consent, rather than being banned as it is most developed countries (see figure 3). It’s implausible that human genome editing will lead to a Gattaca scenario, as I’ll show below. And bans only make the societal outcomes worse.

1. Enhancing Human Traits is Hard (And Gattaca is Science Fiction)

The primary fear of human germline engineering, beyond safety, appears to be a Gattaca-like scenario, where the rich are able to enhance the intelligence, looks, and other traits of their children, and the poor aren’t.

But boosting desirable traits such as intelligence and height to any significant degree is implausible, even with a very low error rate.

The largest ever survey of genes associated with IQ found 69 separate genes, which together accounted for less than 8% of the variance in IQ scores, implying that at least hundreds of genes, if not thousands, involved in IQ. (See paper, here.) As Nature reported, even the three genes with the largest individual impact added up to less than two points of IQ:

The three variants the researchers identified were each responsible for an average of 0.3 points on an IQ test. … That means that a person with two copies of each variant would score 1.8 points higher on an intelligence test than a person with none of them.

Height is similarly controlled by hundreds of gene. 697 genes together account for just one fifth of the heritability of adult height. (Paper at Nature Genetics here).

For major personality traits, identified genes account for less than 2% of variation, and it’s likely that hundreds or thousands of genes are involved.

Manipulating IQ, height, or personality is thus likely to involve making a very large number of genetic changes. Even then, genetic changes are likely to produce a moderate rather than overwhelming impact.

Conversely, for those unlucky enough to be conceived with the wrong genes, a single genetic change could prevent Cystic Fibrosis, or dramatically reduce the odds of Alzheimer’s disease, breast cancer or ovarian cancer, or cut the risk of heart disease by 30-40%.

Reducing disease is orders of magnitude easier and safer than augmenting abilities.

2. Parents are risk averse

We already trust parents to make hundreds of impactful decisions on behalf of their children: Schooling, diet and nutrition, neighborhood, screen time, media exposure, and religious upbringing are just a few.  Each of these has a larger impact on the average child – positive or negative – than one is likely to see from a realistic gene editing scenario any time in the next few decades.

And in general, parents are risk averse when their children are involved. Using gene editing to reduce the risk of disease is quite different than taking on new risks in an effort to boost a trait like height or IQ. That’s even more true when it takes dozens or hundreds of genetic tweaks to make even a relatively small change in those traits – and when every genetic tweak adds to the risk of an error.

(Parents could go for a more radical approach: Inserting extra copies of human genes, or transgenic variants not found in humans at all. It seems likely that parents will be even more averse to venturing into such uncharted waters with their children.)

If a trait like IQ could be safely increased to a marked degree, that would constitute a benefit to both the child and society. And while it would pose issues for inequality, the best solution might be to try to rectify inequality of access, rather than ban the technique. (Consider that IVF is subsidized in places as different as Singapore and Sweden.) But significant enhancements don’t appear to be likely any time on the horizon.

Razib Khan points out one other thing we trust parents to do, which has a larger impact on the genes of a child than any plausible technology of the next few decades:

 “the best bet for having a smart child is picking a spouse with a deviated phenotype. Look for smart people to marry.”

3. Bans make safety and inequality worse

A ban on human germline gene editing would cut off medical applications that could reduce the risk of disease in an effort to control the far less likely and far less impactful enhancement and parental control scenarios.

A ban is also unlikely to be global. Attitudes towards genetic engineering vary substantially by country. In the US, surveys find 4% to 14% of the population supports genetic engineering for enhancement purposes. Only around 40% support its use to prevent disease. Yet, As David Macer pointed out, as early as 1994:

in India and Thailand, more than 50% of the 900+ respondents in each country supported enhancement of physical characters, intelligence, or making people more ethical.

While most of Europe has banned genetic engineering, and the US looks likely to follow suit, it’s likely to go forward in at least some parts of Asia. (That is, indeed, one of the premises of Nexus and its sequels.)

If the US and Europe do ban the technology, while other countries don’t, then genetic engineering will be accessible to a smaller set of people: Those who can afford to travel overseas and pay for it out-of-pocket. Access will become more unequal. And, in all likelihood, genetic engineering in Thailand, India, or China is likely to be less well regulated for safety than it would be in the US or Europe, increasing the risk of mishap.

The fear of genetic engineering is based on unrealistic views of the genome, the technology, and how parents would use it. If we let that fear drive us towards a ban on genetic engineering – rather than legalization and regulation – we’ll reduce safety and create more inequality of access.

I’ll give the penultimate word to Jennifer Doudna, the inventor of the technique (this is taken from a truly interesting set of responses to Nature Biotechnology’s questions, which they posed to a large number of leaders in the field):

Doudna, Carroll, Martin & Botchan: We don’t think an international ban would be effective by itself; it is likely some people would ignore it. Regulation is essential to ensure that dangerous, trivial or cosmetic uses are not pursued.

Legalize and regulate genetic engineering. That’s the way to boost safety and equality, and to guide the science and ethics.

A large study in the New England Journal of Medicine verifies that financial rewards for quitting smoking are effective. Participants were randomly offered one of a variety of incentive schemes that paid participants who successfully quit smoking (verified with saliva and urine tests). Participants were free to decline the offer.

The most interesting variation of the study was to compare a carrot model which paid up to $800 for success with a carrot-stick model in which participants lost $150 if they failed to stop smoking but gained $800 if they succeeded (i.e. $650 of reward plus refund of $150). In theory, the carrot-stick model should work better because it harnesses loss-aversion. And statistical analysis suggested that for those who would accept either the carrot or the carrot-stick model, the carrot-stick model did work better. The problem is that far fewer people who were offered the carrot-stick model chose it compared to those offered the carrot model. Overall, therefore, the carrot model was far more successful.

Smokers are costly so even a pure carrot model of $800 paid by employers would more than pay for itself:

…Finally, the finding that individual rewards of $800, as compared with usual care, nearly tripled the rate of smoking cessation among CVS Caremark employees and their friends and family confirms and extends the generalizability of our finding from a previous trial involving General Electric employees. In addition to the public health effects of such smoking reductions, these findings are important for employers. Because employing a smoker is estimated to cost $5,816 more each year than employing a nonsmoker, even an $800 payment borne entirely by employers and paid only to those who quit would be highly cost-saving.

Don’t Fear the CRISPR

by on May 18, 2015 at 7:00 am in Medicine, Science | Permalink

I’m honored to be here guest-blogging for the week. Thanks, Alex, for the warm welcome.

I want to start with a topic recently in the news, and that I’ve written about in both fiction and non-fiction.

In April, Chinese scientists announced that they’d used the CRISPR gene editing technique to modify non-viable human embryos. The experiment focused on modifying the gene that causes the quite serious hereditary blood disease Beta-thalassemia.

You can read the paper here. Carl Zimmer has an excellent write-up here. Tyler has blogged about it here. And Alex here.

Marginal Revolution aside, the response to this experiment has been largely negative. Science and Nature, the two most prestigious scientific journals in the world, reportedly rejected the paper on ethical grounds. Francis Collins, director of the NIH, announced that NIH will not fund any CRISPR experiments that involve human embryos.

NIH will not fund any use of gene-editing technologies in human embryos. The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed.

This is a mistake, for several reasons.

  1. The technology isn’t as mature as reported. Most responses to it are over-reactions.
  2. Parents are likely to use genetic technologies in the best interests of their children.
  3. Using gene editing to create ‘superhumans’ will be tremendously harder, riskier, and less likely to be embraced by parents than using it to prevent disease.
  4. A ban on research funding or clinical application will only worsen safety, inequality, and other concerns expressed about the research.

Today I’ll talk about the maturity of the technology. Tomorrow I’ll be back to discuss the other points. (You can read that now in Part 2: Don’t Fear Genetically Engineered Babies.)

CRISPR Babies Aren’t Near

Despite the public reaction (and the very real progress with CRISPR in other domains) we are not near a world of CRISPR gene-edited children.

First, the technique was focused on very early stage embryos made up of just a few cells. Genetically engineering an embryo at that very early stage is the only realistic way to ensure that the genetic changes reach all or most cells in the body. That limits the possible parents to those willing to go through in-vitro fertilization (IVF). It takes an average of roughly 3 IVF cycles, with numerous hormone injections and a painful egg extraction at each cycle, to produce a live birth. In some cases, it takes as many as 6 cycles. Even after 6 cycles, perhaps a third of women going through IVF will not have become pregnant (see table 3, here). IVF itself is a non-trivial deterrent to genetically engineering children.

Second, the Chinese experiment resulted in more dead embryos than successfully gene edited embryos. Of 86 original embryos, only 71 survived the process. 54 of those were tested to see if the gene had successfully inserted. Press reports have mentioned that 28 of those 54 tested embryos showed signs of CRISPR/Cas9 activity.

Yet only 4 embryos showed the intended genetic change. And even those 4 showed the new gene in only some of their cells, becoming ‘mosaics’ of multiple different genomes.

From the paper:

~80% of the embryos remained viable 48 h after injection (Fig. 2A), in agreement with low toxicity of Cas9 injection in mouse embryos  […]

ssDNA-mediated editing occurred only in 4 embryos… and the edited embryos were mosaic, similar to findings in other model systems.

So the risk of destroying an embryo (~20%) was substantially higher than the likelihood of successfully inserting a gene into the embryo (~5%) and much higher than the chance of inserting the gene into all of the embryo’s cells (0%).

There were also off-target mutations. Doug Mortlock believes the off-target mutation rate was actually much lower than the scientists believed, but in general CRISPR has a significantly non-zero chance of inducing an unintended genetic change.

CRISPR is a remarkable breakthrough in gene editing, with applications to agriculture, gene therapy, pharmaceutical production, basic science, and more. But in many of those scenarios, error can be tolerated. Cells with off-target mutations can be weeded out to find the few perfectly edited ones. Getting one complete success out of tens, hundreds, or even thousands of modified cells can suffice, when that one cell can then be replicated to create a new cell line or seed line.

In human fertility, where embryos are created in single digit quantities rather than hundreds or thousands – and where we hope at least one of those embryos comes to term as a child – our tolerance for error is dramatically lower. The efficiency, survivability, and precision of CRISPR all need to rise substantially before many parents are likely to consider using it for an unborn embryo, even to prevent disease.

That is, indeed, the conclusion of the Chinese researchers, who wrote, “Our study underscores the challenges facing clinical applications of CRISPR/Cas9.”

More in part two of this post on the ethics of allowing genetic editing of the unborn, and why a ban in this area is counterproductive.

Declan Butler reports:

Giving some of the world’s poorest people a two-year aid package — including cash, food, health-care services, skills training and advice — improves their livelihoods for at least a year after the support is cut off, according to the results of an experiment involving more than 10,000 households in six countries.

The poverty intervention had already been trialled successfully in Bangladesh, and the study’s researchers say it shows the approach works in other cultures too. “We finally have truly credible evidence that a programme for the poorest of the poor can really help them meaningfully reduce their poverty,” says Dean Karlan, an economist at Yale University in New Haven, Connecticut, and a co-author of the study, reported today in Science. “Until now, we haven’t really been able to go to a government outside Bangladesh and say, we’re confident this works.”

Ethiopia, one of the countries that was in the trial, is planning to continue and scale up the intervention to cover around 3 million people, says Karlan, and Pakistan and India are considering scaling up interventions, too.

Banerjee and Duflo are involved in the work as well, and this is sometimes called the “graduation model,” because the aim is to graduate people out of poverty.  Note this:

The intervention is not cheap. Costs per household ranged from $1,455 in India to $5,962 in Pakistan, although they were offset by positive returns on investment ranging from 133% in Ghana to 433% in India. The researchers hope to cut costs in future by scaling back the experiment’s more expensive components, such as training.

And while the model worked in many places, it failed in rural southern India and Honduras, in part due to…problems with chickens.  Nonetheless this is big, big news.  The link to the original research is here.

For pointers I thank Kevin Lewis and Michelle Dawson.

The Vangardist, a German men’s magazine, is printing an entire issue using HIV-infected blood in a quest to educate the public and eliminate misconceptions about HIV and AIDS.

Of course, there’s also the issue of taking this approach to raise the magazine’s literary and commercial value. The Vangardist‘s May issue is already being considered a collector’s item since just 3,000 copies featuring the HIV-positive ink blood have been printed.

There is further information here.

Bart Madden and James Pinkerton suggest a new “free to choose” track for pharmaceuticals. Pharmaceuticals which showed initial effectiveness would be available for early sale but all treatment information under the early-sale program would have to be reported to an open-access database.

After a drug successfully passes safety trials and shows initial effectiveness in clinical trials—that is, the early steps—a drug developer could request that their drug be available for sale on a “free to choose” track (the developer could elect also to continue on the FDA clinical trial track). As a result, patients such as Matt Bellina would be able to access innovative new drugs up to seven years earlier than waiting for a final FDA decision. For patients given only a few years—or months—to live, seven years sooner could spell life, not death.

Under our proposal, a patient’s doctor would be required to submit treatment results and medical information such as a patient’s genetic data to the open-access database. Doctors and patients would get real-time updates about the benefits and side effects of any “free to choose” drug and be able to make informed decisions about an early use of these new drugs versus approved drugs.

We might bear in mind that clinical trials involve patients who are mostly similar. On the other hand, because the “free to choose” option would be available to everyone, new insights would be obtained about how a drug performs for a far broader range of patients. These insights would better inform the biopharmaceutical industry, leading, in turn, to better allocation of research funds and faster innovation.

Bart’s excellent book Free to Choose Medicine has more on the proposal, which I think would speed drugs to patients and increase pharmaceutical research and development. Do note that I hold the Bartley J. Madden chair in economics at Mercatus at GMU and I have my biases.

Chad writes me:

What jobs (particularly ones we think of as being inherently beneficial to society) might America have too many of? Political journalism comes to mind this particular month, since we apparently have enough to carefully monitor the Chipotle orders of presidential candidates 19 months before the election. Writers might be another, particularly in a world of self-publishing.

One can imagine lots of reasons for a greater-than-optimal number of people in a particular profession, from government subsidies to cultural biases, but I’m curious if you have a gut feeling about any professions in particular.

A good question, in my view the answer is not so simple.  Writers and artists are indeed a possible nomination, but some of the demand for these professions is likely for consumption, which makes the overinvestment difficult to judge.  And what about lawyers?  Relative to the number of laws and regulations (too many in my view, but take them as given), it is not obvious to me that we have too many lawyers.  Someone has to tell companies when it is safe to proceed, or not.

How about too many people selling medical devices and other high margin items?  Too many people making alcohol?  Too many people raising and selling animal meat?  Those would be my picks.

The finance sector is another obvious culprit, but as a fraction of wealth I do not think it is larger than in the past.  Admittedly people in the finance sector may be engaging in the wrong activities, but I am not sure the case for fewer employees per se is so obvious.  Still, it is another candidate, if only because it (often) involves people selling high-margin items.

David Cyranoski and Sarah Reardon report:

In a world first, Chinese scientists have reported editing the genomes of human embryos. The results are published1 in the online journal Protein & Cell and confirm widespread rumours that such experiments had been conducted—rumours that sparked a high-profile debate last month about the ethical implications of such work.

In the paper, researchers led by Junjiu Huang, a gene-function researcher at Sun Yat-sen University in Guangzhou, tried to head off such concerns by using ‘non-viable’ embryos, which cannot result in a live birth, that were obtained from local fertility clinics. The team attempted to modify the gene responsible for β-thalassaemia, a potentially fatal blood disorder, using a gene-editing technique known as CRISPR/Cas9. The researchers say that their results reveal serious obstacles to using the method in medical applications.

“I believe this is the first report of CRISPR/Cas9 applied to human pre-implantation embryos and as such the study is a landmark, as well as a cautionary tale,” says George Daley, a stem-cell biologist at Harvard Medical School in Boston. “Their study should be a stern warning to any practitioner who thinks the technology is ready for testing to eradicate disease genes.”

There were too many off-target mutations, but the Chinese attitude seems to be if at first you don’t succeed…

…there are reports that other groups in China are also experimenting on human embryos.

The article is interesting throughout, for instance:

Huang says that the paper was rejected by Nature and Science, in part because of ethical objections; both journals declined to comment on the claim (Nature’s news team is editorially independent of its research editorial team.)

There is more here.  And Carl Zimmer wrote an explainer on it.

A conglomerate on the order of the old Gulf + Western, China National runs more than 160 cigarette brands, manufactured in about 100 factories across the country, and uses its earnings to invest in banks, luxury hotels, a hydroelectric plant, a golf course, and even drugmakers. Most of its money goes to its owner, the Chinese government; the tobacco industry accounts for about 7 percent of the state’s revenue each year [emphasis added], and China National controls as much as 98 percent of the market. All told, the industry in China employs more than 500,000 Chinese. They are among roughly 20 million people who get some income from tobacco, including members of 1.3 million farming households and workers at 5 million retailers, according to government figures. The extent to which the government is interlocked with the fortunes of China National might best be described by the company’s presence in schools. Slogans over the entrances to sponsored elementary schools read, “Genius comes from hard work. Tobacco helps you become talented.”

From Andrew Martin, there is more here.  Of course this helps explain why the Chinese government has such mixed feelings about conducting a successful anti-tobacco campaign.  By the way, do any of you know of a source on the 7 percent figure?

This sprawling comic novel cum history is likely to go down as one of the books of the year.  I thought Lawrence D. Mass’s review was excellent, here is one excerpt:

Conversely, is The American People the War and Peace or Gone With The Wind of LGBT history? The American People is so many disparate things that comparisons will inevitably fall short. It’s a Swiftian journey through an America we never knew; a Voltairean satire of American life and ways; a literary offspring of Gore Vidal’s Lincoln and Myra Brenckenridge; a pornographic American history through the eyes of a Henry Miller; a Robin Cook medical mystery. It’s a Sinclairean expose of American industrial and corporate skulduggery, and otherwise breathtakingly testimonial to the art of muckraking. It’s a treasure trove of historical findings, especially of the history of sex in America — of prostitution, communal living, of STD ‘s, of medicine and infectious diseases, of sanitation and health care, of medical and historical institutions, research, opinion, publications, figureheads and testimony. It’s an ultimate coming together (pun intended) of the personal with the political. And it’s the grandest telling yet of Kramer’s own story.

But as you can see from the above description, a significant chunk of readers will reject the book’s premise, language, and topics altogether.  I think it is very, very good, you can order it here.

In my TED talk I said that if India and China were as rich as the United States is today then the market for cancer drugs would be eight times larger than it is now. Larger markets, both in size and wealth, increase the incentive to invest in R&D. Larger markets save lives. As India and China become richer, they are investing more in R&D and investing more in educating the scientists and engineers who produce new ideas, new ideas that benefit everyone.

The WSJ reports on this trend:

Chipscreen’s drug, called chidamide, or Epidaza, was developed from start to finish in China. The medicine is the first of its kind approved for sale in China, and just the fourth in a new class globally. Dr. Lu estimates the research cost of chidamide was about $70 million, or about one-tenth what it would have cost to develop in the U.S.

…China’s spending on pharmaceuticals is expected to top $107 billion in 2015, up from $26 billion in 2007, according to Deloitte China. It will become the world’s second-largest drug market, after the U.S., by 2020, according to an analysis published last year in the Journal of Pharmaceutical Policy and Practice.

China has on-the-ground infrastructure labs, a critical mass of leading scientists and interested investors, according to Franck Le Deu, head of consultancy McKinsey & Co.’s pharmaceuticals and medical-products practice in China. “There’re all the elements for the recipe for potential in China,” he said.

We have much to gain from increased wealth in the developing world.

How many robot alarms are there anyway?

Every day, the bedside cardiac monitors threw off some 187 audible alerts. No, not 187 audible alerts for all the beds in the five ICUs; 187 alerts were generated by the monitors in each patient’s room, an average of one alarm buzzing or beeping by the bedside every eight minutes. Every day, there were about 15,000 alarms across all the ICU beds. For the entire month, there were 381,560 alarms across the five ICUs. Remember, this is from just one of about a half-dozen systems connected to the patients, each tossing off its own alerts and alarms.

And those are just the audible ones.

If you add the inaudible alerts, those that signal with flashing lights and text-based messages, there were 2,507,822 unique alarms in one month in our ICUs, the overwhelming majority of them false.

That is all from Bob Wachter, an interesting piece.

The YouTube version is here, the podcast version is here.

I was very happy with how it turned out, as I deliberately set out not to copy the content of any of Peter’s other dialogues.  You can learn how he thinks we will leave the “great stagnation,” whether the AI hype is justified, how he would boil his thought down to the smallest number of dimensions, whether NYC is over- or underrated, why globalization is likely to decline and what that means for different regions, the parts of the Bible which have influenced him most, “the Straussian Jesus,” to what age he thinks he will live, why Japan is special, how his German background matters, his favorite opening chess move, how and why company names matter, and even his favorite TV show, which he calls “schlocky.”

And much, much more, with commentary and questions from me throughout.  A transcript is being prepared as well.

musiclife

That is from Dianne Theodora Kenny, via Ted Gioia.  Kenny notes:

For male musicians across all genres, accidental death (including all vehicular incidents and accidental overdose) accounted for almost 20% of all deaths. But accidental death for rock musicians was higher than this (24.4%) and for metal musicians higher still (36.2%).

Suicide accounted for almost 7% of all deaths in the total sample. However, for punk musicians, suicide accounted for 11% of deaths; for metal musicians, a staggering 19.3%. At just 0.9%, gospel musicians had the lowest suicide rate of all the genres studied.

Murder accounted for 6.0% of deaths across the sample, but was the cause of 51% of deaths in rap musicians and 51.5% of deaths for hip hop musicians, to date.

Beware selection, because of course most rap musicians aren’t dead yet.  This problem will be more extreme, the younger is the genre.  Another selection effect may be that getting killed, or dying in an unusual way, contributes to your fame.

You will find a Qanta primer here.  Here is an excerpt:

In the same month, separate teams of scientists at Harvard University and the Broad Institute reported similar success with the gene-editing tool. A scientific stampede commenced, and in just the past two years, researchers have performed hundreds of experiments on CRISPR. Their results hint that the technique may fundamentally change both medicine and agriculture.

Some scientists have repaired defective DNA in mice, for example, curing them of genetic disorders. Plant scientists have used CRISPR to edit genes in crops, raising hopes that they can engineer a better food supply. Some researchers are trying to rewrite the genomes of elephants, with the ultimate goal of re-creating a woolly mammoth. Writing last year in the journal Reproductive Biology and Endocrinology, Motoko Araki and Tetsuya Ishii of Hokkaido University in Japan predicted that doctors will be able to use CRISPR to alter the genes of human embryos “in the immediate future.”

Thanks to the speed of CRISPR research, the accolades have come quickly. Last year MIT Technology Review called CRISPR “the biggest biotech discovery of the century.” The Breakthrough Prize is just one of several prominent awards Doudna has won in recent months for her work on CRISPR; National Public Radio recently reported whispers of a possible Nobel in her future.

Even the pharmaceutical industry, which is often slow to embrace new scientific advances, is rushing to get in on the act. New companies developing CRISPR-based medicine are opening their doors. In January, the pharmaceutical giant Novartis announced that it would be using Doudna’s CRISPR technology for its research into cancer treatments. It plans to edit the genes of immune cells so that they will attack tumors.

How immediately will this come for ordinary use?  Here is the big package of articles from Science.  The Chinese already have done it with monkeys.

Here are my earlier remarks on eugenics.  Here is a group of scientists calling for a moratorium on the technique, at least until rules can be established.  Here are further articles on CRISPR.  There are further comments here.

I believe the implications of all this — and its nearness to actual realization — have not yet hit either economics or the world of ideas more generally.  This is probably big, big news.