Transgenic stem cells lead to a miraculous cure

Sometimes I read a science paper and I just say "Holy cow, this is amazing." I don't have that reaction very often, but I did last week.

Amidst all the hype, the hope, and the controversy about gene therapy and stem cell research, some very real progress is being made. Scientists can create working versions of human genes, package them into a virus, and then use the virus to deliver the genes to a real person. This approach creates "transgenic" cells that have bits of virus DNA within them, but the virus can be engineered to be harmless.

Last week, scientists reported in the journal Nature how they saved the life of a 7-year-old boy using transgenic stem cells. Twenty years ago, this would have been science fiction. Even today it is nothing short of astonishing.

Here's the story, summarized from the paper by Tobias Hirsch, Michele de Luca, and their colleagues. In June 2015, a 7-year-old boy was admitted to the Burn Unit of Children’s Hospital of Ruhr University, in Bochum, Germany, where Hirsch and his colleagues (Tobias Rothoeft, Norbert Teig, and others) work. The child wasn't suffering from burns: he had a devastating genetic disease, junctional epidermolysis bullosa (JEB), that had caused him to lose 80% of his skin.

Figure 1b from Hirsch et al. Schematic
representation of the clinical picture.
The denuded skin is indicated in red;
blistering areas are indicated in green.
Flesh-colored areas indicate currently
non- blistering skin. Transgenic grafts
were applied on both red and green areas.
Children with JEB suffer from constant blistering, wounds, and scarring. The disease is uncurable and children often die before reaching their teens. The 7-year-old boy was near death when he was admitted to the hospital–his weight had dropped to 17 kilograms (38 pounds) and he had severe skin infections from streptococcus and pseudomonas bacteria.

Dr. Hirsch and his team were struggling to keep the boy alive, and they had no treatments to offer. In desperation, they searched the scientific literature and found a possible treatment using gene therapy, developed by Michele De Luca, of the Center for Regenerative Medicine at the University of Modena and Reggio Emilia in Italy. Dr. De Luca had only tried this treatment twice before, and even then only on tiny patches of skin. He had never tried it on such a severe case.

The boy and his parents had no other options to save his life. They agreed to let Dr. De Luca try.

In September of 2015, De Luca took a small patch of undamaged skin (4 square centimeters) back to his lab in Italy. There, he used a retrovirus containing a functioning copy of the LAMB3 gene–the gene that was mutated in the boy–to infect the skin cells. The retrovirus integrated itself into the genome of many of the skin cells, giving them the ability to function normally. Then De Luca grew the repaired cells into new skin grafts, enough to cover 80% of the child's body.

In a series of surgeries starting in October 2015, Hirsch and his colleagues applied the skin grafts to the young boy. The results were amazing.

As reported in the paper itself:
"Virtually complete epidermal regeneration was observed after 1 month.... Over the following weeks, the regenerated epidermis surrounding the open lesions and the epidermal islands spread and covered most of the denuded areas."
In other words, it worked. The new skin completely replaced the missing or damaged skin on 80% of the boy's body. What's even more remarkable is that two years later, his skin remains normal. The new skin is functioning perfectly and the young boy has returned to school.

The science behind this treatment represents the culmination of decades of research into gene therapy, stem cells, retroviruses, and genomics. To make it all work, we had to know: the identity of the gene that caused the disease (LAMB3); the DNA sequence of a normal LAMB3 gene; how to insert the human gene into a retrovirus; how to create a modified retrovirus that wouldn't harm humans; and much more.

The success of the therapy also revealed new insights into stem cells in human skin: the small patch of undamaged skin from the boy contained many cells, a few of which were stem cells (holoclones) that could replenish the skin indefinitely. It was these stem cells that allowed the skin grafts to take hold and continue to function, hopefully for the rest of the boy's life.

Sometimes science and medicine converge, and miracles happen.

(Note: the paper is "Regeneration of the entire human epidermis using transgenic stem cells" by T. Hirsch et al.)

The new Star Trek series gets biology terribly, terribly wrong.

The new Star Trek: Discovery series is based on a massive scientific error. Can it survive?

It didn't have to be this way. Those of us who have followed Star Trek through its many TV series and movies, including the excellent trio of recent moves (2016's Star Trek Beyond is the latest) were eager to jump on board the newest show, Star Trek: Discovery.

Despite some rather uneven acting in the pilot, I was willing to give it a chance. So were millions of other Star Trek fans.

But alas, the writers have stumbled into a scientific error so egregious, and so entangled in the entire plot line, that I fear the new Star Trek cannot recover. (Note: a few mild spoilers ahead.)

Episodes 4 and 5, released on October 8 and 15, revealed that the USS Discovery, the ship that the series revolves around, has an advanced form of transport that allows it to travel anywhere in the universe instantaneously. Unlike all previous Star Trek transport tech, this one uses a biological mechanism, based on mushrooms.

Yes, you read that right. The DASH (Displacement Activated Spore Hub) drive uses mushroom spores as its power source. They've discovered a special fungus whose root system extends "throughout subspace" all over the galaxy. Using spores from this fungus, the ship can jump into subspace (or something like that) and jump out somewhere else in real space, light years away, in a matter of seconds. As bizarre and this sounds, the worst is yet to come.

To power its DASH drive, the Discovery maintains a large greenhouse full of spore-producing mushrooms. (Mycologists might love this, but how big a fan base can they be?) The problem for the Discovery, in the first few episodes, is that the experimental drive will only let them jump short distances.

Then they discover the tardigrade. Tardigrades are a real thing: they are microscopic animals, only 0.5 millimeters long, that live all over the planet. Here's a picture of one:
Electron microscope image of Milnesium tardigradum,
from E. Schokraie et al., PLoS ONE 7(9): e45682.

They are also surprisingly cute for a microscopic animal, and they are colloquially known as water bears, moss piglets, or space bears. "Space bears" comes from their ability to survive in extreme environments, possibly including interplanetary space.

Star Trek Discovery's tardigrade is, shall we say, rather different. It looks a bit like the picture shown here, but it's the size of a large grizzly bear, incredibly strong, and extremely fierce. On the show they call it a "giant space tardigrade."

But that's not all. Thanks to a unique biological property that the show's writers apparently misunderstood, the space tardigrade can access the mushroom network to travel throughout the universe, wherever and whenever it chooses.

Here's how the space tardigrade accomplishes this remarkable feat of interstellar travel, as explained by Michael Burnham, the show's central character (in Episode 5, "Choose your pain"):
"Like its microscopic cousins on Earth, the tardigrade is able to incorporate foreign DNA into its own genome via horizontal gene transfer. When Ripper [the space tardigrade] borrows DNA from the mycelium [the mushroom], he's granted an all-access travel pass."
And just like that, not only the tardigrade but the entire spaceship jump across the galaxy. Is this sounding a bit crazy? It should.

Horizontal gene transfer (HGT) is a real thing. It's a process through which bacteria sometimes take up DNA from the environment and integrate it into their own genomes. Animals can't do HGT, but rather infamously, a paper was published in December 2015 that made the bold claim that tardigrades had a unique ability to absorb all kinds of DNA. That paper was instantly controversial in the scientific community, and not surprisingly its findings were being disputed in the Twittersphere within days of its appearance. Surprisingly, the same journal (PNAS) that published the bogus HGT claim published a second paper just a few months later showing that tardigrades do not absorb foreign DNA into their genome. That plus a third paper showed that the original paper had mistakenly identified contaminating DNA as part of the tardigrade's own genome. This rapid correction of the record was a win for science; I've used this example to demonstrate to my undergraduate class how sloppy science (the first paper) can lead one astray.

So: a minor scientific controversy, quickly debunked.

Until, that is, one of the Star Trek writers got their hands on it. Apparently one of them heard the tardigrade story, perhaps someone who'd had a bit of biology in college (I'm guessing here), and got so excited that they turned it into a wildly implausible premise for an intergalactic space drive.

The idea of using horizontally transferred DNA for space travel is so nutty, so bad, that it's not even wrong. Even if tardigrades could absorb foreign DNA (they can't), how the heck is this supposed to give them the ability to tap into the (wildly implausible) intergalactic spore network? DNA that's been taken up through HGT isn't connected to the source any longer. This is no more plausible than asserting that people could connect to the mushroom network by eating a plate of mushrooms. And how would the space-traveling tardigrade take the entire ship with it? Are we supposed to assume it's creating some kind of mushroom-DNA field?

Star Trek has had faster-than-light warp drives for 50 years. Although physically implausible, warp drive isn't laughably ridiculous. The DASH drive is.

And now the entire series seems to be based on a combination of magic (an intergalactic mushroom network in subspace) and scientific errors (horizontal gene transfer by tardigrades).

I can't watch this nonsense. I'm willing to suspend disbelief for the sake of a good story (warp drive!), but I can't accept obviously bogus claims. I don't know how the Star Trek writers can get themselves out of this one, but if they don't, then Star Trek Discovery is finished. If they're reading this, here's my plea: ditch the DASH drive and find something to replace it–and for god's sake, hire a competent science consultant.

Should we all be on statins? (reprise)

Should you be on statins? New guidelines and an online calculator may allow you to answer this question yourself.

Back in 2011, I asked whether we should all be on statins. At the time, it was clear that statins offered benefits for people who had already suffered heart attacks or other serious cardiovascular problems. But for the rest of us, it wasn't clear at all. A number of studies had been published suggesting that millions more people (in the U.S. alone) might benefit from statin therapy, but most of those studies were published by drug companies that made statins. As I wrote at the time, "we need more data from completely unbiased studies."

So has anything changed? Actually, it has. Last year, the U.S. Preventative Services Task Force (USPSTF) reviewed all of the evidence and updated its former (from 2008) recommendations. The evidence now suggests that some people–even those who have never suffered a heart attack–would benefit from statins.

Here's what the current USPSTF recommendations suggest. If you've never had a heart attack and have no history of heart disease, you still might benefit from statins if:

  • you're 40-75 years old,
  • you have one or more "risk factors" for cardiovascular disease (more about this below), AND
  • you have a 10-year risk of cardiovascular disease (CVD) of 7.5%-10%, using a "risk calculator" that I'll link to below.

Now let's look at those risk factors for CVD. There are four of these, and any one of them puts you in the category of people who might benefit from statins: diabetes, high blood pressure (hypertension), smoking, or dyslipidemia.

Most people already know their status for the first 3, but "dyslipidemia" needs a bit more explanation. This is simply an unhealthy level of blood cholesterol, defined by USPSTF as either "an LDL-C level greater than 130 mg/dL or a high-density lipoprotein cholesterol (HDL-C) level less than 40 mg/dL." You can ask your doctor about these numbers, or just look at your cholesterol tests yourself, where they should be clearly marked.

For that last item, how do you calculate you 10-year risk of CVD? Most people should ask their doctor, but if you want to see how it's done, the calculator is at the American College of Cardiology site here. It's quite simple and you can fill it in yourself to see your risk.

A big caveat here, as the USPSTF explains, is that the "risk calculator has been the source of some controversy, as several investigators not involved with its development have found that it overestimates risk when applied to more contemporary US cohorts."

Another problem that I noticed with the risk calculator is that using it for the statin recommendation involves some serious double counting. That's because the risk calculator relies in part on your cholesterol levels and blood pressure, but those same measurements are considered to be separate risk factors for CVD. This puts a lot of weight on cholesterol levels–but on the other hand, statins' biggest effect is to reduce those levels.

The USPSTF is a much more honest broker of statin recommendations than industry-funded drug studies, so we can probably trust these new guidelines. Note that if the risk calculator puts you in the 7.5%-10% range, you will only get a very small benefit from statins–as the USPSTF puts it, "Fewer persons in this population will benefit from the intervention."

Don't rush to go on statins without giving it some serious thought. As Dr. Malcolm Kendrik put it last year (quoted by Dr. Luisa Dillner in The Guardian),
“If I was taking a tablet every day for the rest of my life, I would want to know how long I would have extra to live. If you take statins for five years and you are at higher risk, then you reduce the risk of a heart attack by 36%. But if you rephrase the data, this means on average you will have an extra 4.1 days of life.” 
So no, we shouldn't all be on statins. But until something better comes along (and I hope it will), they are worth considering for anyone who is in a higher-risk group for cardiovascular disease.

Clever food hacks from Cornell Food Lab might all be fake

Have you heard that serving your food on smaller plates will make you eat less? I know I have. I even bought smaller plates for our kitchen when I first heard about that study, which was published in 2011.

And did you know that men eat more when other people are watching? Women, though, behave exactly the opposite: they eat about 1/3 less when spectators are present. Perhaps guys should eat alone if they're trying to lose weight.

Or how about this nifty idea: kids will eat more fruits and vegetables at school if the cafeteria labels them with cool-sounding names, like "x-ray vision carrots." Sounds like a great way to get kids to eat healthier foods.

Or this: you'll eat less if you serve food on plates that are different colors from the food. If the plate is the same color, the food blends in and it looks like you've got less on your plate.

And be sure to keep a bowl of fruit on your counter, because people who do that have lower BMIs.

Hang on a minute. All of the tips I just described might be wrong. The studies that support these clever-sounding food hacks all come from Cornell scientist Brian Wansink, whose research has come under withering criticism over the past year.

Wansink is a professor at Cornell University's College of Business, where he runs the Food and Brand Lab. Wansink has become famous for his "kitchen hacks" and healthy-eating tips, which have been featured on numerous media outlets, including the Rachel Ray show, Buzzfeed, USA Today, Mother Jones, and more.

Last week, Stephanie Lee at Buzzfeed wrote a lengthy exposé of Wansink's work, based on published critiques as well as internal emails that Buzzfeed obtained through a FOIA request. She called his work "bogus food science" and pointed out that
"a $22 million federally funded program that pushes healthy-eating strategies in almost 30,000 schools, is partly based on studies that contained flawed — or even missing — data."
Let's look at some of the clever food hacks I described at the top of this article. That study about labeling food with attractive names like "x-ray vision carrots"? Just last week, it was retracted and replaced by JAMA Pediatrics because of multiple serious problems with the data reporting and the statistical analysis.

The replacement supposedly fixes the problems. But wait a second: just a few days after that appeared, scientist Nick Brown went through it and found even more problems, including data that doesn't match what the (revised) methods describe and duplicated data.

How about the studies that showed people eat more food when others are watching? One of them, which found that men ate more pizza when women were watching, came under scrutiny after Wansink himself wrote a blog post describing his methods. Basically, when the data didn't support his initial hypothesis, he told his student to go back and try another idea, and then another, and another–until something comes up positive.

This is a classic example of p-hacking, or HARKing (hypothesizing after results are known), and it's a big no-no. Statistician Andrew Gelman took notice of this, and after looking at four of Wansink's papers, concluded:
"Brian Wansink refuses to let failure be an option. If he has cool data, he keeps going at it until he finds something, then he publishes, publishes, publishes."
Ouch. That is not a compliment.

Soon after Gelman's piece, scientists Jordan Anaya, Tim van der Zee, and Nick Brown examined four of the Wansink's papers and found 150 inconsistencies, which they published in July, in a paper titled "Statistical Heartburn: An attempt to digest four pizza publications from the Cornell Food and Brand Lab." Anaya subsequently found errors in 6 more of Wansink's papers.

It doesn't stop there. In a new preprint called "Statistical infarction," Anaya, van der Zee and Brown say they've now found problems with 45 papers from Wansink's lab. Their preprint gives all the details.

New York Magazine's Jesse Singal, who called Wansink's work "really shoddy research," concluded that
"Until Wansink can explain exactly what happened, no one should trust anything that comes out of his lab."
In response to these and other stories, Cornell University issued a statement in April about Wansink's work, saying they had investigated and concluded this was "not scientific misconduct," but that Cornell had "established a process in which Professor Wansink would engage external statistical experts" to review many of the papers that appeared to have flaws.

And there's more. Retraction Watch lists 14 papers of Wansink's that were either retracted or had other notices of concern. Most scientists spend their entire careers without a single retraction. One retraction can be explained, and maybe two or even three, but 14? That's a huge credibility problem: I wouldn't trust any paper coming out of a lab with a record like that.

But how about those clever-seeming food ideas I listed at the top of this article? They all sound plausible–and they might all be true. The problem is that the science supporting them is deeply flawed, so we just don't know.

Finally, an important note: Brian Wansink is a Professor of Marketing (not science) in Cornell's College of Business. He is not associated with Cornell's outstanding Food Science Department, and I don't think his sloppy methods should reflect upon their work. I can only imagine what the faculty in that department think about all this.

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.