CRISPR gene editing controversy - does it cause unexpected mutations?

Just over a month ago, a short paper appeared in Nature Methods saying that the gene editing technique known as CRISPR-Cas9 has a big problem: it creates unexpected mutations all over the genome. This was startling news for a technique that has been hailed worldwide as a dramatic breakthrough, not only because it is the easiest gene-editing method yet invented, but also because it is (supposedly) very precise.

This new paper, by Kellie Schaefer and colleagues, found hundreds of mutations (in experimental mice) that weren't supposed to be there. The results contradicted earlier studies that showed CRISPR caused very few of these "off-target" mutations. One of the authors, Stephen Tsang, commented that
"We feel it's critical that the scientific community consider the potential hazards of all off-target mutations caused by CRISPR."
Not surprising, the resulting news headlines were gloomy. The stock in three companies trying to commercialize gene editing–Editas Medicine, Intellia Therapeutics, and CRISPR Therapeutics–all fell sharply.  (Interestingly, the stocks started falling on May 24, and bottomed out on May 31. The paper appeared online on May 30.) Scientists involved with these companies quickly responded, arguing that the study was flawed, but of course those scientists have a lot of money at stake.

Who was right? Well, a new paper by Caleb Lareau and colleagues, just released in the bioRxiv preprint repository, re-examines the same data and concludes that CRISPR is just fine. I've read both papers so you don't have to. Here's what seems to be going on.

The study by Schaefer et al. used CRISPR-Cas9 to create mutations in two mice (called F03 and F05), and then sequenced their genomes. They also sequenced the genome of a third mouse, called FVB. All three mice were supposed to be genetically identical.

Then they compared all three genomes to a "reference" mouse to find mutations. (Aside: this is something my own lab does all the time, so I know the techniques well.) They found over 1,500 mutations in each mouse (which wasn't surprising, because the reference mouse differs from their 3 lab animals), but they found hundreds more mutations in the two CRISPR-edited mice. That was the main surprise from Schaefer's paper, and it's the basis for their claim that CRISPR causes numerous off-target mutations.

I had a big problem with this claim even before reading Lareau's paper. Just TWO mice? That's a ridiculously tiny sample. But I digress.

Lareau et al. pointed out, correctly, that Schaefer's conclusion depends on the mice being genetically identical. But what if the two CRISPR mice (F03 and F05) were closer to each other than to the third mouse, FVB? (It's analogous to comparing two siblings with a first cousin, although these mice are much more inbred than any humans.) In that case, the result falls apart.

Fortunately, Schaefer et al. made all their data available (props to them for doing that), so Lareau could answer this question quite precisely.

It turns out that F03 and F05 are much closer to each other than either one is to FVB.  Lareau discovered that the two CRISPR mice share thousands of mutations that FVB doesn't have.

What does this mean? Lareau and colleagues conclude that the "unexpected" mutations in the CRISPR-edited mice were already there before the experiment began, and were not caused by gene editing. As they put it,
"the CRISPR-treated embryos most likely already harbored these private SNPs and indels prior to nuclease treatment whereas the control mouse did not."
In other words, it seems highly unlikely that CRISPR gene editing caused hundreds of unexpected mutations in these mice.

Even though CRISPR is being over-hyped right now, it is nonetheless genuinely exciting technology. Nature Methods was probably too eager to publish a controversial result, an all-too-common problem with big-name journals, and they seem to have done a poor job managing peer review. (Aside: I'd love to see what the reviewers said. Did they miss the obvious problems, or did the journal editors ignore the reviewers? I doubt we'll ever know.)

A final note: this kerfuffle illustrates the tremendous value of rapid publication through pre-print archives. Lareau et al.'s paper appeared a few days ago (July 5) on bioRxiv, along with all the data they used to support their arguments. We'll probably see a journal version too, but that will take months. Getting this paper out faster was a win for science.

(Postscript: two of the authors on the bioRxiv paper have financial interests in CRISPR technology companies, which they disclosed in the paper. I have no financial interests in any of these companies.)

Gwyneth! How did you learn so much about health?

Gwyneth Paltrow has invented stickers that promote healing. Yes, stickers. Little circular stick-on thingies that you might give to your 1st-grader as a reward for doing her homework.

Gwyneth, though, has discovered something much deeper about stickers. If you make them with just the right materials, and then stick them on your body in the right places, they "rebalance the energy frequency in our bodies."

(A quick warning: if you follow the links in this article, put down your coffee first. You might laugh so hard that you'll spill it all over yourself.)

Until a day or two ago, Gwyneth Paltrow's Goop website–a "lifestyle" business that sells all things Gwyneth–advertised these stickers as using "NASA space suit material," which presumably was the source of their magic healing properties. Then Gizmodo called someone at NASA to check out this claim, and got a very clear answer.

Nope. Goop's stickers are not made of space suit material. (Not that space suit material has healing properties in the first place–it doesn't.) Gizmodo's quote from a former NASA scientist, Mark Shelhamer, sums it up nicely:
“Wow,” Shelhamer told Gizmodo. “What a load of BS this is.”   
Goop quickly updated their site, and now they don't claim anything about NASA space suits in their stickers. But they didn't dial back any of their magical healing claims. Here's what Goop says now, in an article called "Wearable Stickers that Promote Healing (Really!)":
"Human bodies operate at an ideal energetic frequency, but everyday stresses and anxiety can throw off our internal balance, depleting our energy reserves and weakening our immune systems. Body Vibes stickers come pre-programmed to an ideal frequency, allowing them to target imbalances."
Wow. What gobbledygook. I see what that NASA scientist meant. But wait, there's more! Goop tells us:
"Studies have shown that when your frequency slips, your immune system is compromised, which opens the door to getting sick."
Studies? No such studies exist. People don't have a "frequency," and there's nothing to "slip." I think it's fair to say that the Goop claims about these stickers are so ridiculous that they're not even wrong.

These stickers are powerful, though, so you must be careful. Goop warns that
"We recommend starting with 1 or 2 for sensitive people. Wearing more than 4 may cause some dilution of the individual frequencies."
Oh boy.

Paltrow sells these magic stickers (and all of her products) using pictures of beautiful models doing healthy activities while wearing stickers. This is part of Goop's appeal: Paltrow is suggesting, in essence, "I'm beautiful and healthy and I'm in my forties, so I know the medical secrets that will keep you beautiful too."

Of course, the special Goop stickers aren't cheap: they cost $60 for a 10-pack.

Not surprisingly, Goop sells lots of overpriced dietary supplements too, such as a bottle of multivitamins with fish oil for $90, which comes with claims about keeping the immune system strong. Almost no one needs these supplements, and they don't do anything for your immune system, as I've explained before.

It took me just a few seconds to find that you can get a sheet with about 50 "dreams come true" stickers at for less than $2. These don't come with any wild health claims, but they do make kids happy. I recommend trying these before you get the Goop stickers.

Goop's (and Gwyneth's) claims about their stickers are so ridiculous, so laughably nutty, that I can't really feel sorry for the people who fall for them. Anyone who can afford to waste $60 for a pack of stickers probably has too much money and not enough sense. It's just too bad that they're giving their money to a wealthy actress rather than donating it to some worthy cause.

Finally, I should note that I've always liked Paltrow as an actress, in movies such as Emma and Shakespeare in Love from the 1990s through the recent Iron Man franchise. But why would her acting skills make her an expert on human health? They don't.

Apple's next iPhone iOS will save lives

There's no way that we can convince people to stop texting while driving. It's incredibly dangerous, selfish, and reckless. According to the National Highway Traffic Safety Administration, distracted driving killed at least 3,477 people in 2015 alone. Many states have outlawed texting while driving, including my own state of Maryland, but every day I pass people on busy roads who are looking at their phones.

The only solution is technological. The phone itself needs to stop distracting you while you're driving. People aren't going to put their phones down voluntarily.

Apple's iOS 11, coming this fall, finally offers a solution. It may not solve the problem entirely, but it will likely save lives.
Apple's IOS 11, coming in the fall of 2017,
will offer Do Not Disturb while driving
The solution is very simple, technically speaking. Your phone already knows when it's on a roadway, and it knows that it's moving. So the phone's software–iOS, if it's an Apple phone–can simply disable any apps that might cause distractions.

Apple's preview of iOS11 says it will do more than that. It will not only silence all incoming calls, text messages, and other notifications, but it will text people back automatically and tell them that you're driving.

You'll still be able to use maps and GPS for directions, which is an extremely useful feature that many people just can't do without (and that doesn't cause traffic accidents).

This is a great idea that is long overdue. Apparently, Apple couldn't resist allowing passengers in the car to override the do-not-disturb mode, which I think is a pretty terrible idea. I doubt that the phone will recognize when a passenger just hands it to the driver, but I'll have to wait and see how Apple implemented this override feature. I hope it's really hard to do.

iOS 11 is coming in the fall. Google hasn't yet said anything about whether Android phones will have a similar feature, but I hope they will. This is desperately needed, and it will save lives.

Google, the ball is in your court.

Germany takes action to stem measles outbreak. Anti-vaxxers to blame–again.

Measles is on the rise in Europe, driven by "vaccine gaps" which in turn are due to misinformation about the benefits of vaccines. Vaccines are possibly the single greatest contribution to human health in the past century. Literally millions of people are alive today who would not be, thanks to vaccines.

And yet: vaccine rates have dropped in recent years in multiple countries. In March, the BBC reported that measles had become endemic (meaning that it is self-sustaining, continuing to spread within the country) in France, Germany, Italy, Poland, Romania, Switzerland and Ukraine. The worst measles outbreak is in Romania, which reported over 3,400 cases and 17 deaths in just the first 3 months of this year.

Now measles is spreading in Germany, which is scrambling to contain it. Germany had 504 cases through mid-April, versus just 33 cases for the same period last year. At least one person, a young mother of three children, has died. The primary reason for the spread of the disease, as reported by the German news outlet RT, is unvaccinated individuals, and the reason their numbers are growing is simple: the anti-vaccine movement.

In the U.S., the anti-vaccine movement caused the worst measles outbreak in 20 years in 2015. The outbreak in Germany appears even worse, despite the fact that parents can be fined as much as €2500 ($2800) for failing to vaccinate their children. In a remarkable effort to try to get this outbreak under control, the German parliament has decided to require kindergartens to report parents who don't vaccinate their kids. Let's hope this works.

Vaccination is safe and remarkably effective, but the anti-vax movement is furiously trying to convince parents not to vaccinate. Their latest gambit is "Vaxxed," a conspiracy-mongering anti-vaccine screen produced by Andrew Wakefield, the notorious ex-doctor who published a fraudulent (and later retracted) study claiming that MMR vaccines caused autism. Nearly 20 years later, despite Wakefield losing his medical license because of his "elaborate fraud," he continues to push his debunked claims.

Fortunately, many people are now pushing back. Just last week, noted New Zealand physician Dr. Lance O'Sullivan jumped up on stage at a screening of "Vaxxed" to warn people in the audience that they were being defrauded. O'Sullivan was named New Zealander of the Year in 2014 for his efforts to bring health care to disadvantaged people in rural areas. I will close with his words from a Radio New Zealand story describing the dangers of vaccine refusal:
"We are trying to save a child's life, we put it on a helicopter, it flies to Starship Hospital. The kidneys are failing, its heart's failing, its lungs are failing. All because we didn't put a bloody $7.50 meningococcal vaccine into that child's thigh."

Trump to appoint non-scientist as chief scientist of USDA

Scientists work here now, but Trump's new overseer
will probably make them all want to flee.
This is how corruption starts.

Donald Trump's expected appointment for under-secretary for research at the USDA will be a right-wing talk radio host with no scientific credentials, according to a new report from ProPublica. The expected appointee, Sam Clovis, worked as a political aide to Trump on his transition team, and was installed at the USDA in a temporary role soon after Trump took office, to be Trump's "eyes and ears" until a permanent USDA director was approved.

Clovis has no scientific background or credentials. As ProPublica explained, he was a talk radio host in Iowa who ran unsuccessfully for the Senate in 2014. He majored in political science in college and studied business administration in graduate school, and has never published a scientific paper.

Now Trump is appointing Clovis to be Under Secretary for Research, Education, and Economics (REE) at the Department of Agriculture. This administrator is responsible for a large portfolio of research, both internal and external, conducted by and supported by the USDA, including NIFA, the National Institute for Food and Agriculture.

I've had several research grants supported by USDA's NIFA, through which my colleagues and I sequenced the genomes of many agriculturally important animals and plants. I've also collaborated with internal USDA scientists who work for the Agricultural Research Service, another branch of the USDA that will soon report to Sam Clovis. I've met many outstanding scientists, both inside and outside the USDA, through these projects.

Overseeing the USDA's research programs requires strong expertise in biological science. A non-scientist has no basis for deciding which research is going well, or what questions need further study, or which questions present the most promising avenues for research. A non-scientist is simply incompetent to choose among them–and I mean this in the literal sense of the word; i.e., not having the knowledge or training to do the job. (This does not mean that I think Sam Clovis is incompetent at other things; I don't know him and he might be very capable in other areas.) Among other problems, an non-scientist leader of a scientific agency will be incapable of using scientific expertise to set priorities, and instead can make up his own priorities. In the case of Sam Clovis, his history leads me to believe that his priorities will be based on his conservative political agenda.

The previous under secretary, Catherine Woteki, has a Ph.D. in human nutrition and was previously the dean of the school of agriculture at Iowa State University. The current Acting Under Secretary, Ann Bartuska, has a Ph.D. in ecology and has worked in many scientific positions, including high-level positions at the U.S. Forest Service and the Nature Conservancy.

Both Dr. Woteki and Dr. Bartuska could run circles around Sam Clovis on any of the scientific issues under the purview of the USDA's Under Secretary for Research. Nonetheless, Clovis will soon oversee thousands of scientists currently working at the USDA, despite the fact that he has no idea what they do. It is still possible that Trump will appoint someone else, or that the Senate will decline to confirm Clovis, but these possibilities seem unlikely.

When leaders are incompetent, they appoint people under them who are also incompetent. Trump's intention to appoint Sam Clovis as the chief scientist of the USDA isn't the first demonstration of his incompetence, and I don't expect it to be the last. What's most dangerous about this appointment (and others like it) is that incompetence enables and even encourages corruption, because the appointees don't understand or respect the mission of their own agencies. Instead, they follow their own agendas, whatever those might be.

The 2008 Farm Bill stipulated (section 7511) that the Under Secretary for REE must be chosen from
"distinguished scientists with specialized or significant experience in agricultural research, education, and economics."
Sam Clovis is not such a person, but Donald Trump just doesn't seem to care.

Trump's Energy Department just killed jobs in 19 states

ARPA-e's announcement sounded good. But now it turns out
to be just a tease.
It's a lot easier to kill jobs than to create them. It is much easier to kill innovation than to create it. Trump's Department of Energy, led by former Texas governor Rick Perry, seems to be taking the easy route.

As reported in the journal Science this week (and first reported by Politico Pro), DOE has halted its process to award $70 million in new grants that its research agency, ARPA-E, had announced this past December. ARPA-E is the Energy Department's Advanced Research Projects Agency, created to fund high-risk, high-reward new ideas about energy.

Even more alarming is that DOE has imposed a gag order on the program managers, so that scientists have no idea why their funding is being delayed, or it if will ever arrive. According to the Science story,
"The resulting uncertainty is having a devastating impact on research teams, scientists say, and even threatens the viability of small companies for whom these major awards are so important."
The move, which came with no warning, leaves many scientists, including young Ph.D.s just starting new jobs, suddenly without jobs. Bloomberg BNA was able to extract this tiny bit of explanation from an Energy Department spokesman:
"As with any transition from administration to administration, we have undertaken a full review of all department programs, policies and taxpayer-funded grants."
I'm sure that makes the unemployed scientists and struggling energy technology companies feel much better.

Cutting funding that has already been awarded–and which used money that was already appropriated by Congress–is especially disruptive. How can anyone hire new scientific staff when the federal agency might yank away a grant that it had already announced? The Science story described a young Ph.D. plant biologist from Penn State, Molly Hanlon, who was due to start work next week on one of the new ARPA-e projects, but now she might not have any job at all.

The 26 projects, all of them now on hold, were originally announced by DOE in December. Here are the states that are homes to the threatened projects:
California, Connecticut, Colorado, Delaware, Florida, Illinois, Iowa, Kansas, Massachusetts, Minnesota, New Mexico, New York, North Carolina, Pennsylvania, South Carolina, Texas, Utah, Washington, West Virginia 
15 of the 26 projects are led by companies, most of them small companies trying to creative innovative new technologies. The other 11 are housed at universities, including Energy Sec. Rick Perry's alma mater, Texas A&M (so at least we can't blame Perry for bias). And 9 of these 19 states voted for Trump last November.

This isn't even the whole story. Eight more projects under a different ARPA-E program, ENLITENED, were told in mid-March that they would be funded, Science reports. Just a week later, though, the press conference to announce the awards was cancelled, and the program now appears to be in danger of cancellation.

I'm sure that all of these project teams invested many months in preparing their winning proposals. Leaders of the projects announced back in December were poised to begin their research until the sudden announcement this week, with no explanation, that everything was on hold.

All that Mr. Trump has to do to save these valuable, high-tech jobs is nothing; just let the DOE's ARPA-E program do its work. Unfortunately, this seems to be too much to ask.

An aspirin a day keeps the grim reaper away

Low-dose aspirin is good for you. Any brand of aspirin 
will do, Bayer or otherwise.
Should you take an aspirin every day to prevent some types of cancer? The evidence is growing, and it all points to the same answer: yes.

In 2016, the US Preventive Services Task Force, a science-guided panel that reviews the evidence for a wide range of treatments, recommended regular low-dose aspirin use for people between the ages of 50 and 69 as a way to prevent heart attacks, strokes, and some types of cancer. For people younger than 50 or older than 69, the USPSTF said that the evidence was inconclusive.

The 2016 recommendations came with a caveat: long-term aspirin use carries a slightly increased risk of bleeding in the stomach and intestinal tract, and a small increase in the risk of a hemorrhagic stroke–although it reduces the risk of ischemic strokes. (Ischemic strokes are caused by blood clots in the brain, while hemorrhagic strokes are caused by bleeding. Aspirins reduces the blood's ability to clot, so this tradeoff makes sense physiologically.)

Later in 2016, a study by Yin Cao and colleagues at Harvard found that aspirin use reduced the risk of cancers, especially colon cancer. To be specific, they found a benefit from taking 0.5 to 1.5 aspirin tablets per week for at least 6 years (a standard tablet is 325 mg). For people who followed this regimen, the risk of colon cancer was about 19% lower.

Now, a new study also led by Yin Cao and others at Harvard, just reported in the annual meeting of the American Association for Cancer Research, shows even clearer benefit. They looked at long-term results in a group of 130,000 women (mostly nurses) and men (doctors and other health professionals) who have been followed since the 1980s. Overall, woman had a 7% reduction in the relative risk of dying from any cause and men had a 11% reduction.

Most of the reduction in mortality was due to the reduced risk in dying from colon cancer, breast cancer, and prostate cancer. Just as with the previous study, the benefit appeared in people who took 0.5 to 1.5 aspirin tablets per week for at least six years.

A decrease in the risk of dying by 7-11% seems like a mighty nice benefit from such a simple treatment. For those (like me) whose stomach is upset by aspirin, a low-dose aspirin tablet taken with food may be easier to tolerate. The low-dose pill contains 81mg, one-fourth of a standard tablet, so 2-6 of these per week is equivalent to the 0.5-1.5 tablets that provided a benefit in the latest study.

It's very encouraging when the evidence for a simple, low-cost treatment consistently shows the same benefit. An important caveat is that that if you have any bleeding problems, you should consult your doctor before taking aspirin.

As for me, I've already stocked up on low-dose aspirin. I'm trying the chewable ones first.