How much brain damage is too much? NFL players head for the exits.

The smartest player in the NFL just quit.

Not because he was unable to play, and certainly not because of his age–he's only 26. No, Baltimore Ravens' player John Urschel decided to quit because the risk of permanent, irreversible brain damage is just not worth it.

Urschel is a very smart guy. He's currently pursuing a Ph.D. in mathematics at MIT, one of the best and most demanding science universities in the world. Until this summer, he was (impressively) balancing his studies with being a full-time NFL player.

But when Dr. Ann McKee and colleagues published a new study showing that 110 out of 111 former NFL players had suffered serious brain damage, Urschel could no longer pretend he wasn't putting his future at grave risk. McKee's study, the largest study yet of chronic traumatic encephalopathy (CTE), showed alarmingly high rates of CTE in college and high school players as well (91% of former college players).

Let's get one point out of the way: everyone involved with the study, including Dr. McKee, knows that it was biased. The scientists examined brains of deceased players that had been donated to the study because family members–or the players themselves, before they died–suspected something was wrong. So perhaps the true risk of brain damage is lower than 99%. Maybe it's only 50%, or 20%. Do young men playing football want to take that risk?

John Urschel isn't the first player to quit because of the growing realization that football may cause irreversible brain damage. In 2015, San Francisco 49ers player Chris Borland retired at the age of 24, and in 2016 Kansas City Chiefs player Hussain Abdullah retired at 30, both over concerns about concussions and brain damage.

The NFL has been denying or downplaying the risk for years. A few years ago, after the suicide of former player Junior Seau, they announced a $30 million partnership with the NIH to study the risks of football on the brain. As results started coming in, showing that the risk was far more serious than most people knew, the NFL backed out of the deal with $16 million still unspent.

Meanwhile, the chorus of warnings has been growing steadily louder from the medical community. Last year, a former team doctor and a former football player and coach wrote in JAMA that
"unless there is a way to reduce the number of TBIs [traumatic brain injuries] caused by the sport, football will remain a threat to the brains and health futures of the players, including impaired cognitive function and reasoning, memory loss, emotional depression, and other sequelae that profoundly erode quality of life."
Earlier this year, a study out of the CDC reported that "3 high school or college football players die each year from traumatic brain and spinal cord injuries that occur on the field," most them as a result of being tackled during games.

Over the years, football players have grown ever larger (the average NFL lineman today weighs over 300 pounds) and the intensity of the violence on the field has grown with them. It's not just in the NFL, either: last year, three high school teams in the state of Washington forfeited their games against a local team out of a legitimate fear that players would be badly injured by the opposing team's 300-plus pound linemen. Their fears were justified: the human head simply wasn't built to withstand the repeated blows that players endure.

All players might do themselves a favor by listening to John Urschel. He explained his decision–and his abiding love for the game of football–in a lengthy interview on the Freakonomics podcast a couple of weeks ago. That interview should be required listening for young players, and even more so for parents who might be dreaming that their sons have a future career in football.


Houston, we have a problem. It's called global warming, whether you admit it or not.

Hurricane Harvey poured more rain on Texas and Louisiana last week than this country has ever seen from a single storm. The city of Houston is now suffering from historic flooding, with many calling this a "1000-year flood." Congress is likely to pass a huge bailout bill in the coming days, starting with a $14.5 billion "down payment," suggesting much more is to come.

The storm's eventual costs could rise even higher than the costs of 2005's Hurricane Katrina, which cost $160 billion according to NOAA.

Let's not dance around the issue: Hurricane Harvey was a direct consequence of global warming, which in turn is a direct consequence of human activities.

It's ironic that Texas (and Houston in particular) has an economy that is dominated by on oil and fossil fuels. Burning these fuels is what got us in this mess.

It's also ironic that Texas Senator Ted Cruz, who is now at the front of the line asking for a federal government rescue package, is a scientifically illiterate climate change denier. As I wrote shortly after he announced his candidacy for President in 2015, Cruz not only denied that global warming was happening, but he then went on to compare himself to Galileo, as if he were taking a brave and bold scientific position. Right.

A few facts: the Gulf of Mexico is 4 degrees warmer than normal this year, and it has been getting worse. Back in March of this year, the Washington Post's Jason Samenow reported that the Gulf was "freakishly warm, which could mean explosive springtime storms." Warm water feeds hurricanes, and Harvey feasted on it, sucking up energy and using it to dump ridiculous amounts of water onto south Texas.

Noted climate scientist Michael Mann, writing in The Guardian, took the slightly more nuanced position that "climate change made Hurricane Harvey more deadly." True enough: if you want to be strictly accurate, we can't prove that warming temperatures are the sole cause of Harvey. Maybe with cooler temperatures, we'd have had a hurricane anyway–but it would have been a far smaller one, and the damage would have been far less severe.

Mann also pointed out that global warming has already caused sea levels to rise over half a foot, which made the flooding in Houston significantly worse than it would have been otherwise.

Now it's time to rebuild, which raises a dilemma. The U.S. can't just abandon Houston, one of our country's largest cities, even if most of its residents deny the reality of global warming (and perhaps they don't). But given that global warming is well under way, with rising sea levels and warming oceans, more catastrophic flooding events like Harvey are highly likely. Should we pay to rebuild the city exactly as it was, basically ignoring the problems of floodwater management as Houston has done until now? Or should we use the government bailout funds to reduce the risk from future flooding?

Actually, it might do even more good to impose a simple requirement, before Texas gets any of our bailout funds. Let's require U.S. senators Ted Cruz and John Cornyn, and Texas governor Greg Abbot, to state publicly that global warming is real, that humans are making it worse, and that they will work in the future to mitigate the risks posed by continued climate change. Wouldn't that be something? A simple statement, nothing more, to unlock billions of dollars in aid.

If we just rebuild everything like before, then Houston will continue to have a problem.

(*Note about the title of this article. The original quote was "Houston, we've had a problem," famously utterly by Apollo 13 astronaut Jim Lovell. In the movie Apollo 13, actor Tom Hanks (playing Lovell) instead said, "Houston, we have a problem.")

NIH institute purges climate change references, but not very well

Last week, one of NIH's institutes, the National Institute for Environmental and Health Sciences (NIEHS), did something rather mysterious. The institute purged references to climate change on its website by replacing the phrase "climate change" with "climate."

For example, a page formerly titled "Health Impacts of Climate Change" is now titled "Health Impacts of Climate," a title that obscures the main point of the page's content, which is all about climate change. Another page formerly called "Climate Change and Human Health" is now called "Climate and Human Health." Ironically, the web addresses of both these pages still contains the term 'climatechange':

  •   https://www.niehs.nih.gov/research/programs/geh/climatechange/health_impacts/
  •   https://www.niehs.nih.gov/research/programs/geh/climatechange/

which is something of a smoking gun showing the after-the-fact alterations. The attempted purge was first revealed by the nonprofit group EDGI, a group dedicated to addressing "potential threats to federal environmental and energy policy." The Washington Post revealed that these changes were made by Christine Flowers, the NIEHS Director of Communications. As quoted in the Post, Flowers explained that:
"It’s a minor change to a title page, but the information we provide remains the same. In fact, it’s been expanded."
True, the contents of these pages seem to be unchanged. But in that case, why change the titles and headings? Clearly something more is afoot. Is NIEHS trying to pretend that climate change isn't real, or that it has no effect on human health? If so, this would undermine the very mission of the institute. Are the NIEHS staff fearful that one of Trump's minions will attack them for describing objective scientific facts? If so, perhaps they should get another job.

NIEHS's attempt to re-write its own history has been woefully ineffective. It's easy to find other NIEHS webpages devoted to climate change, such as:
https://www.niehs.nih.gov/health/topics/agents/climate-change
which has the title "Climate Change" right at the top, and which links to a major report called "The Impacts of Climate Change on Human Health in the United States: A Scientific Assessment." There's also the NIEHS Climate Change and Environmental Exposures Challenge, a competition sponsored by NIEHS to create graphical visualizations showing the effect of climate change on health.

The WashPost story did not mention whether the NIEHS director, Dr. Linda Birnbaum or her boss, NIH Director Dr. Francis Collins, had plans to restore the original language to the website. I've written to them both to ask, and I'll post an update here if they do.


Reject this incompetent Trump appointee

Sam Clovis standing next to Trump during the campaign.
Trump has nominated a non-scientist to be chief scientist at the U.S. Department of Agriculture. This is an outrageous slap in the face to science. It's also a slap in the face to Congress.

As I predicted back in May, Trump has nominated Sam Clovis, a former right-wing radio talk show host and failed Senate candidate from Iowa, to be the chief scientist of the USDA. ProPublica was the first to break this story, and they also pointed out that Clovis was a vocal climate change denialist. Clovis has an undergraduate degree in politics and graduate training in business, but he has no formal training in science at all.

Clovis does have one qualification, though. As ProPublica pointed out, he has been a "fiery pro-Trump advocate on television." Sounds like a good candidate for a chief scientist job to me.

Fortunately (perhaps), the Senate has to approve this appointment. The Senate itself stipulated, in a bill that Congress passed in 2008, that the USDA's chief scientist (the Under Secretary for Research, Education, and Economics) must be appointed from
"distinguished scientists with specialized or significant experience in agricultural research, education, and economics."
The law also says, just to make it crystal clear, that the Under Secretary "shall hold the title of Chief Scientist of the Department."

Why is this appointment so wrong? I'll repeat what I wrote back in May:
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, a 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.
If the Senate has any backbone at all–if Republicans are willing to show that they are capable of doing something other than rubber-stamping every action, no matter how damaging, of our self-absorbed, ignorant President–then they will turn down this nomination. Sam Clovis is so obviously unqualified that this should be easy to do.

Actually, if Mr. Clovis cared about the USDA's mission, he would recognize that he's the wrong man for the job and refuse the nomination. Even Dan Glickman, the former Secretary of Agriculture, said "I wouldn't be qualified for that job" (about himself–he's a lawyer) in a recent interview about Clovis' appointment. The current and previous Chief Scientists at the USDA have Ph.D.s and extensive scientific publication records. Mr. Clovis does not. (Note that when I wrote to Mr. Clovis in May to ask about his pending appointment, he declined to respond on the record.)

The Senate's Republicans have confirmed all of Trump's nominees so far, and I fear they will rubber-stamp this one as well. Let's hope that a few of them (and only 3 have to object, assuming all 48 Democrats vote no) realize that appointing a non-scientist to be Chief Scientist of the USDA is a slap in the face not only to science, but to Congress itself, because the appointment scoffs at Congress's own law, passed during the George W. Bush administration.

Trump can find another political appointment for Sam Clovis, as he has for other Trump loyalists. But appointing a former talk radio host, a non-scientist who has never published a single scientific paper, as the Chief Scientist of the USDA is a gross insult to the thousands of hard-working real scientists at the USDA, and to millions more who depend on, and benefit from, the USDA's research programs. Senators: do the right thing and tell Trump to appoint a real scientist to this job.

Will this be the end of college football? The risk of brain damage is startlingly high.

Parents send their kids off to college with high hopes and great expectations. Universities, in turn, have a responsibility to provide an education in an environment that supports and also challenges the students.

Universities are not supposed to encourage activities that may result in permanent brain damage.

And yet, they do. As revealed in a new report by Jesse Mez and colleagues from Boston University, just published in the Journal of the American Medical Association, a shockingly high number of former football players, from both college and professional teams, suffered chronic traumatic encephalopathy (CTE) later in life, likely as a result of their years playing football.

The study authors looked at 202 deceased former football players whose brains had been donated for research, and found that 87% of them had some degree of CTE. The highest rates of CTE were among former NFL players, which affected 110 out of 111 players. CTE was nearly as bad in college football players, though, with 91% of them (48 out of 53) suffering from CTE.

Over half of the high school players (27) had "severe pathology." The authors noted that in deceased players with severe CTE, the most common cause of death was neurodegenerative disease. As they also explain:
"There is substantial evidence that CTE is a progressive, neurodegenerative disease."
In other words, CTE is a death sentence.

The authors of the study stated their conclusions carefully, noting that the study was not randomized, and that players and their families may have been motivated to participate because they were concerned about a possible link between football and CTE. Nonetheless, even if the risk of CTE is much lower than found in this study, universities should be taking a very hard look at the risks that they are exposing their students to.

Or to put it another way, is it okay to ask young men to play football if the risk of permanent brain damage is only 50%? What if it's just 10 or 20%? Is that okay? Is football that important?

Readers of this column know my answer: no. College is not about football, and if it disappears completely, universities will be just fine. The University of Chicago eliminated its football program in 1939, and brought it back in decades later as much-reduced program, now in NCAA Division III. The university itself has remained a powerhouse, routinely ranked in the top universities in the country academically.

As I've written before, football is corrupting our universities, blinding them to their true mission (education and research) in the pursuit of a profitable entertainment business. University presidents seem helpless to stop or even slow down the enormous machine that is big-time college football. For example, in 2015 the University of Maryland (where I used to be a professor) paid millions of dollars to buy out the football coach, so that he could quit a year early and the university could pay millions more to a new coach. Ironically, Maryland had done exactly the same thing in 2011 to buy out the previous coach, at a time when the entire state had hiring and salary freezes in place. None of these actions benefitted the university or its students.

All the while, universities pretend that they are educating the players. Here's a quote from Bleacher Report's interview with star UCLA quarterback Josh Rosen:
"Look, football and school don't go together. They just don't.... No one in their right mind should have a football player's schedule, and go to school."
This from one of the top college football players in the country. (On this topic, Taylor Branch's 2011 exposé in The Atlantic is particularly worth reading. Or this article by a disillusioned former Michigan fan.)

Universities now face an ethical dilemma far more serious than merely taking advantage of athletes' skills to entertain football fans and pay inflated salaries to coaches. The JAMA study reveals that by running a football program, universities are not just robbing young men of four years that might be better spent getting an education and preparing for life: they might be robbing their students of life itself.

ClinicalTrials.gov, a great resource for patients, is being abused to market bad medicine

This wasn't supposed to happen.

Since 1997, the National Institutes of Health has maintained a database of clinical trials, ClinicalTrials.gov, that lists trials under way in the U.S. and throughout the world. It's an invaluable resource, providing a single source for patients trying to find where to get the newest experimental treatments, and for doctors and scientists looking to enroll patients in their trials.

In recent years, companies offering questionable stem cell therapies got the bright idea that they could describe their treatments as clinical trials, register them on ClinicalTrials.gov, and thereby get some free advertising. Most stem cell treatments are not FDA-approved, and many have little or no data supporting their effectiveness, but clinics can still register their "trials" on the NIH site, making it appear that they are supported and endorsed by the government. A new study by Leigh Turner, published this week in Regenerative Medicine, reveals the growing extent of this problem.

What's especially worrisome is that some stem-cell treatment clinics charge patients very high fees to participate in their "trials." Some patients (perhaps most) don't know that legitimate clinical trials virtually never charge fees.

Consider this example, reported last July by Emily Bazar at Kaiser Health News: California resident Linda Smith has knee osteoarthritis, and was looking for treatments that could restore her knees to health without surgery. She found a stem cell trial at ClinicalTrials.gov that was run by StemGenex, a clinic in La Jolla. The clinic promised it could inject stem cells into her knees to replace lost cartilage. When she inquired about signing onto the trial, Smith was shocked to learn that StemGenex wanted a $14,000 fee for her to participate.

StemGenex claimed that “The actual treatment is not part of the study protocol”: you pay for the treatment, they explained, and the study is merely a followup to see how you did afterwards.

What nonsense. I checked the StemGenex site today (a year after the quotes above), and they proudly boast that they are registered on ClinicalTrials.gov, and that
"Stem cell therapy for Osteoarthritis is being studied for efficacy in improving the complications in patients through the use of their own stem cells."
Hmm. This sure sounds like the study is about the treatment. StemGenex's site strongly suggests that their therapy works wonders:
"The goal of each stem cell treatment is to inject the stem cells into the joint to create cartilage (chondryte cells)."
Sounds good, right? If only it were true.

I've got bad knees myself, so I've been following the research on stem cell treatments for cartilage replacement for years. I would love to be able to get a simple injection that could repair my damaged cartilage. Alas, though, no one has yet developed an effective stem cell treatment for bad knees, although it is plausible, and legitimate trials are under way right now (here's one).

Unfortunately, the lack of evidence hasn't stopped clinics from offering stem cell injections right now, accompanied by all sorts of promises that are not backed by science. It's not just knee injections, either: this past March, Sharon Begley at STAT reported on three women who were blinded by stem cell therapy injected into their eyes.

Most patients think, mistakenly, that if a clinic offers stem cell therapy, it must have been approved by the FDA. That's not true–clinics offering these therapies don't have FDA approval, and they argue that they don't need it (which might be correct, but that's a topic for another day).

Patients also assume that trials listed on ClincialTrials.gov must have been approved by some government agency, but that's not true either. The site is a clearinghouse that uses the honor system, nothing more, to ensure that trials listed there are legitimate. If you read their Disclaimer (but who does?), you find that studies listed on the site are not necessarily funded by NIH or approved by the FDA.

Turner's study found 7 trials that openly state they charge patients to participate. At least they're honest about it. Turner found many more (including several run by StemGenex) that appear to charge patients despite not explaining their policy on ClinicalTrials.gov. For example, a stem cell trial by Cell Surgical Network plans to enroll 3000 patients and will charge each of them $6000 or more to participate. As Turner writes
"Cell Surgical Network uses its registered ClinicalTrials.gov study as a powerful marketing device. Press releases and the websites of the clinics that are part of this network emphasize that the study is registered on ClinicalTrials.gov."
NIH needs to start policing this site before the situation gets worse. Coincidentally, I know just where they can find the resources to do it. NIH just announced that it's about to start regulating all sorts of basic science studies as clinical trials, a move that will cause a "massive amount of dysfunction and paperwork," according to one MIT scientist. Rather than over-regulating basic science, NIH should devote those same resources to cleaning up and then continuously monitoring the ClinicalTrials.gov database.

What these stem cell clinics are doing is not a clinical trial, and advertising their services through ClinicalTrials.gov is reprehensible. For now, if a doctor or clinic tries to charge you to participate in a clinical trial, your best course may be to find another trial–and another doctor.

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.)