A slow-brewing epidemic of a little-known, potentially fatal bacterial infection appears to be building among cardiac-surgery patients. The physicians who write the blog Controversies in Hospital Infection Prevention—all three of whom work at the University of Iowa—are so concerned about it that they are publicizing one of their own patients (within the bounds of medical privacy) to alert the rest of medicine.
The infection is Mycobacterium chimaera, which does not normally cause disease in humans, but is found in water and soil. The source is troubling and odd: spray from the fan of a heater-cooler device used to control the temperature of blood during a cardiac bypass, which contaminates both the otherwise-sterile operating field, and also any implants—a new valve, a vascular graft—being placed in or around the heart.
The Food and Drug Administration revealed last October that since 2010, it has been told of 32 cases of infection occurring in this manner, eight in the United States and 24 in Europe. The Centers for Disease Control and Prevention followed up with an alert shortly afterward. Papers in two medical journals last year described clusters of cases in cardiac patients in Europe, in hospitals in Switzerland, Germany and the Netherlands. There has been one publicly acknowledged cluster in the US as well, in a hospital in York, Penn., which triggered an alert from the Pennsylvania Department of Health.
But, Mike Edmond told me: “We believe that, given what we know of how many patients are affected, this is probably just the tip of the iceberg.”
Given what we know of how many patients are affected, this is probably just the tip of the iceberg.
Edmond is an infectious disease physician and the chief quality officer at the University of Iowa Hospitals and Clinics, and a colleague of physicians Eli Perencevich and Dan Diekema; the three of them write the blog together. He told me they were aware of the FDA and CDC alerts and had checked and cleaned their hospitals’ devices; but they became more concerned when a patient from their hospital—who had had cardiac surgery in 2012—returned with an unexplained fever. After prolonged examinations that included a bone-marrow biopsy, the patient was found to be infected with M. chimaera that no doubt came from the device used during surgery.
Because of privacy, Edmond couldn’t reveal this patient’s fate. In the European and Pennsylvania case clusters, up to half of the victims died.
He told me it was likely this patient could have slipped through the cracks, for several reasons—reasons which might well exist in other areas of the US too. Iowa is rural, and the medical center where the three physicians work is both the apex of the pyramid medically and not necessarily accessible geographically. “A lot of patients don’t receive their follow-up post-operative care in our hospital,” he said. “They go back to their local doctor, so we don’t see them.”
After the access issue, there’s the problem of recognition. “There are many unusual and problematic features of trying to work this up,” Edmond said. “One is the long duration of time from surgery to diagnosis. This is a very slow growing organism; it takes quite a while for symptoms to even develop in an infected patient. And the other problem is that we don’t normally order Mycobacterium blood cultures on patients unless they are immunosuppressed. In an AIDS patient who has ongoing fevers that we cannot explain, we’ll order them, and you might you order them in a transplant patient. But not in someone who is immunologically competent.”
If this is diagnosed—which means, if physicians think to order a test to look for it— patients face a hard road ahead. “Mycobacterium infections are really tough,” he said. “They require more than one drug, the drugs are toxic, and in the case of people who have implants, a heart valve, a graft—and from the literature, most of these patients do—that implant has to be removed. The actual implant has the organism growing on it.”
Just at Iowa—not the largest cardiac program in the US—this has triggered a re-examination of 1,500 patients.
“Even though we have only found one case, we know there could be other patients like this out there,” Edmond said. “And there may be physicians out there trying to work that up and not coming up with an answer. We felt it is important to try to raise awareness, because who knows how many of these might be out there, lingering without a diagnosis.”
Iowa has sent a letter to every heart surgery patient from the past four years, which refers them to an explanatory webpage and a 24-hour 800-number (866-514-0863) staffed by nurses who walk callers through a list of symptoms: “fever lasting more than one week; pain, redness, heat, or pus around a surgical incision; night sweats; joint pain; muscle pain; loss of energy; and failure to gain weight or grow (in infants).” Depending on the answers, patients are referred for follow-up care.
Since the three physicians put up their post on Tuesday, they have heard from physicians in other locations also struggling with this. (A few have commented on the blog.) But Edmond said the point is not only to alert doctors.
“We also need patients to be aware of this,” he said. “Say your surgery was last December; based on the known cases, there is a 4-year timeline in which you could develop symptoms. And most infectious disease physicians at this point are not aware this is even going on.”
If you are a physician who would like to know more or share your experience, head to the HAI Controversies blog to comment or to email the authors.
Fibrodysplasia ossificans progressiva is an incredibly rare disease, striking just one out of every two million people. It’s also an incredibly astonishing disease. A single mutation to a single gene causes muscles to spontaneously turn into new bones. Over time, people with fibrodysplasia ossificans progressiva (FOP for short) grow a second skeleton–one that can cut their lives short.
I wrote about FOP in “The Girl Who Turned to Bone” in the Atlantic in 2013. At the time, FOP served as a microcosm for the struggles of people with rare diseases. (In the United States, almost 30 million people have rare diseases of one kind or another.) Rare diseases have historically attracted little interest from scientists or pharmaceutical companies. Working on common diseases like cancer or diabetes seemed more likely to lead to rewards, both academic and financial. As I wrote in my article, Fred Kaplan of the University of Pennsylvania got a lot of puzzled looks from his colleagues when he decided in the late 1980s to dedicate his career to figuring out FOP. It seemed like professional suicide. And he has certainly traveled a hard road since then. It took many years for him and his colleagues to find the gene behind FOP. And then they spent many more years trying to understand how a mutation to that gene actually leads to the disease. In the meantime, Kaplan has not had any effective treatment to offer his patients with FOP.
I ended my Atlantic story on a hopeful note, observing how rare diseases like FOP were starting to gain more attention–thanks in part to the efforts of patients themselves, as well as new initiatives from the National Institutes of Health. But in the two years since the story came out, things have changed a lot faster than I would have predicted. Rare diseases are attracting a huge amount of attention, which is leading to some potential treatments. One sign of this progress is a study on FOP that’s being published today in the journal Science Translational Medicine. A team of scientists has found a molecule that appears to block the second skeleton.
The gene behind the disease, called ACVR1, encodes a molecule that sits on the surface of cells. There it can grab signaling molecules and relay messages to the interior of the cell. A team of scientists at Regeneron Pharmaceuticals engineered human cells so that they carried the mutation to ACVR1 that is found in people with FOP. Then they hurled a barrage of molecules at the cells, to see if the mutant ACVR1 responded in a peculiar way to any of them. They discovered one that triggered just such an odd response.
The molecule is called activin A. It is released by cells to help with many different tasks in the body, from the development of organs in embryos to healing wounds. The fact that activin A helps heal wounds is especially intriguing when you consider one of the most striking features of FOP: people with the disease often abruptly grow new bones after injuries–even slight ones like bumping into a table corner. Kaplan and other researchers have long wondered if the mutation that causes FOP alters the body’s ability to heal wounds. Instead of causing stem cells to rebuild muscle and other damaged tissue, the body might signal them to become bones. And activin A might carry that faulty signal. In normal cells, it silences ACVR1, but in mutant cells, it excites the receptor.
To test that possibility, the scientists developed mice that carry the FOP-causing mutation. The mice formed new bones in much the same way people with FOP do. The scientists found that if they inserted a sponge soaked in activin A into the mice, the sponge turned to bone.
If they could block activin A, the scientists reasoned, they might be able to stop the chain reaction that creates new bones. In another line of research, Regeneron scientists had developed antibodies that latched onto activin A–and only activin A. When the scientists injected these antibodies into FOP-model mice, they prevented the animals from forming any new bones. Full stop.
The fact that researchers at a company like Regeneron made this discovery is telling. Pharmaceutical companies have increasingly turned their attention to rare diseases in recent years, because, paradoxically, the rare disease market may turn out to be very profitable.
Companies are rolling out drugs with sky-high price tags. Even if they’re used by relatively few people, the companies can make a lot of money. In one demonstration of how times have changed, the rare-disease company called Baxaltra is going to be bought soon for a reported $30 billion. Whether the expensive price for rare-disease drugs are really justified, however, is becoming a matter of intense debate.
For one thing, researchers have to see if it works as well in people as it does in mice. But because people with FOP are so sensitive to injuries (even a muscle injection can trigger a new bone), regular human trials won’t work. Fortunately, Kaplan and his colleagues have discovered that they can harvest bone-generating stem cells out of baby teeth from children with FOP. So they’re now trying to replicate the activin A studies with these cells.
Setting aside the possible medical potential of this research, it drives home just how mysterious rare diseases can be. FOP might seem like it should be a simple disease to treat. After all, it’s caused by a single mutation to a single gene. But it’s actually fiendishly complex, because it disturbs an intricate web of chemical reactions that our bodies use to grow muscles and bones. The search for a cure for FOP has been going on for over a quarter of a century, and yet no one thought to consider activin A. A normal version of ACVR1 doesn’t relay activin A’s messages. And so no one even guessed that a mutant version would.
“As Alfred Hitchcock demonstrated with clarity,” Kaplan and his colleagues write, “the best way to conceal reality is to hide critical clues in broad daylight.”
ANNAPOLIS, Md.—Valery Spiridonov looks impossibly small. He is dressed in all white, from his white button-down shirt to the white socks on his feet, which dangle at the ends of white pants and a white blanket. Breaking up the look is a black strap, which holds him to a motorized wheelchair.
He uses his left hand, which he can still move, a little bit, to steer the wheelchair into a hotel meeting room. There, he confirms that he would like to be the first person ever to have his head transplanted onto a new body.
Spiridonov flew from Russia to be at this conference, the American Academy of Neurological and Orthopaedic Surgeons (AANOS). He joined the surgeon proposing to do the transplant, Sergio Canavero of Turin, Italy. Canavero had built up his talk, a keynote address, for months, promising a big reveal of his plans to transplant Spiridonov’s head onto a donor body. (For background, see my earlier blog post and a good overview at New Scientist.)
The meeting is small, maybe 100 or fewer surgeons, and held in a very normal-looking Westin hotel in Annapolis, Md. Conference organizer Maggie Kearney spent much of the day turning away reporters in anticipation of a packed room. She says that in 15 years, she can’t remember a reporter ever attending the surgical conference before.
By the end of Canavero’s three-hour-long presentation (it was supposed to be an hour and a half, Maggie tells me), most of the reporters in the room seem worn out, and a bit confused about what the fuss was all about.
Canavero reviewed, at length, the scientific literature on spinal cord injury and recovery, regrowth of various parts of the central nervous system, and why some of the basic assumptions of neurosurgery are wrong. Throughout the lecture, he would occasionally point to Valery Spiridonov, his wheelchair parked near the stage, and make a declaration (“Propriospinal tract neurons are the key that will make him walk again!”).
Answering detractors’ comments that the transplant could be “worse than death” or could drive Spiridonov insane, Canavero asked Spiridonov directly, “Don’t you agree that your [current] condition could drive you to madness?”
Spiridonov answered quietly in the affirmative.
His condition is grave: a degenerative motor neuron disease that is slowly killing him. “I am sure that one day gene therapy and stem cells will fulfill their future,” Canavero said, “but for this man it will come too late.”
Finally, near the end of the talk, Canavero roughly outlined the surgery. He plans to sever the spinal cord very cleanly, using a special scalpel honed nano-sharp. (I could not see Spiridonov’s reaction to the special scalpel, but wondered.)
To minimize any die-off of cells at the severed ends during the transfer, Canavero says he will cut Spiridonov’s spinal cord a bit lower on the spine than needed, and the body’s a bit higher, and then at the last minute slice them again for a fresh cut. Then, add some polyethylene glycol (shown to stimulate nerve regrowth in animals), join the two ends together with a special connector, and voila. Electrical stimulation would then be applied to further encourage regrowth.
Of course, there’s a bit more to it, like reconnecting all the blood vessels and so forth, but Canavero is a neurosurgeon and the spinal cord was his focus.
Other neurosurgeons at the meeting responded cautiously to the proposal. The surgery might be possible “someday, but it is really a delicate situation,” said Kazem Fathie, a former chair of the board of AANOS.
Craig Clark, a general neurosurgeon in Greenwood, Mississippi, calls Canavero’s idea “very provocative.”
“There have been many papers over the years that have shown regeneration, but for one reason or another they didn’t pan out when applied clinically,” he said.
“There’s a lot of ethical questions about it,” said neurosurgeon Quirico Torres of Abilene, Texas. But Torres thinks it could be ethical to allow volunteers to do the surgery, and one day we might consider it normal. “Remember, years ago people were questioning Bill Gates: why do you need a computer? And now we can’t live without it.”
Apart from the rundown of previous work on spinal cord injury, much of what Canavero said about the surgery was pretty much what he has said before. He supported his arguments for individual elements of a head transplant (or body transplant, if you prefer) but did not reveal any new demonstration of the entire procedure working in a person or an animal.
But Canavero has no shortage of confidence. He says he wants to do the surgery in America (implying Italy doesn’t have its act together enough to host a cutting-edge project like this).
“I have a detailed plan to do it,” he said, adding that he is asking Bill Gates and other billionaires to donate. He invited surgeons at the meeting to join his team, which could be enormous—more than 100 surgeons, he has said—and he wants team leaders in orthopedics, vascular surgery, and so on. These surgeons should work on the project full time for the next two years, he said, “and you will be paid through the nose, because I think doctors involved in this should be paid more than football players.”
After the talk, Spiridonov disappeared into a room to rest. When he came back out, he answered questions for the TV crews that had descended, sounding a bit weary of answering the same questions he’s been asked before. “What will happen to you if you don’t get this surgery?” a reporter called out. “My life will be pretty dark,” he said. “My muscles are growing weaker. It’s pretty scary.”
He looked tired.
During his interviews, I stepped aside to talk with his hosts in Annapolis, who are friends of a friend of the Spiridonov family. “He’s brilliant, he’s happy, he’s funny,” said Briana Alessi. “If this surgery were to go through and if it works, it’s going to give him a life. It’s life-changing. He’ll be able to do the things he could only dream of.”
And if not? “He’s taking a chance either way,” she said.
The final question he takes from the press: What do you say to people who say this surgery should not be done?
Spiridonov’s reply: “Maybe they should imagine themselves in my place.”
Earlier this week, Chinese researchers reported that they edited the genes of human embryos using a new technique called CRISPR. While these embryos will not be growing up into genetically modified people, I suspect this week will go down as a pivotal moment in the history of medicine. David Cyranoski and Sara Reardon broke the news today at Nature News. Here I’ve put together a quick guide to the history behind this research, what the Chinese scientists did, and what it may signify.
There are thousands of genetic disorders that can occur if a mutation happens to strike an important piece of DNA. Hemophilia, sickle cell anemia, cystic fibrosis– the list goes on and on. As I wrote in the Atlantic in 2013, a particularly cruel genetic disorder, fibrodysplasia ossificans progressiva causes people to grow a second skeleton. It’s caused by a mutation that changes a single “letter” of a single gene, called ACVR1. The protein encoded by the gene doesn’t work properly, triggering a wave of changes in people’s bodies, with the result that when they heal from a bruise, they replace entire chunks of muscle with new bone.
In some cases, people can offset many of the symptoms of genetic disorders with simple changes, like watching what they eat. In other cases, like hemophilia, they have to take regular doses of drugs to remain healthy. In other cases, like fibrodysplasia ossificans progressiva, there’s no effective treatment yet.
For decades, scientists have tried to develop a new way to treat genetic disorders like these: to heal the patient, heal the gene.
This approach came to be known as gene therapy. As I wrote in Wired, gene therapy soared to heady heights of hype in the 1990s. Researchers developed viruses that they could load with working versions of people’s defective genes. They injected the viruses into their subjects, and the viruses delivered the genes to some cells–enough cells, in theory, to start doing the work required to make the people healthy again.
Gene therapy research crashed around 2000 when one volunteer died during a study due to an overwhelming immune response to the viruses he received. Since then, gene therapy researchers have found safer, more efficient viruses, and now gene therapy is starting to emerge in the clinic.
But the revival of gene therapy doesn’t necessarily mean that viruses are the best of all possible tools to fix broken genes. What if, for example, you could just remove the mutant DNA in a gene and replace it with the right sequence?
For a long time, that question was best left to late nights at bars and episodes of Star Trek. Nobody knew how to manipulate DNA with that kind of precision. But in just the past couple years, scientists have created exactly this kind of gene-editing tool, which is known as CRISPR.
As I wrote recently in Quanta, CRISPR didn’t spring fully formed from someone’s mind. It’s actually a collection of molecules that bacteria use to fight viruses. They can create molecules that can latch precisely to certain stretches of DNA and cut them apart. Shortly after scientists figured out how bacteria use CRISPR, they began to wonder if they could use it, too.
It soon became clear they could. They could easily synthesize “probe” molecules that would grab onto a specific stretch of DNA in just about any cell. Enzymes could then chop out that stretch. If the scientists supplied a different version of that stretch of DNA, the cell would incorporate it where the original stretch once was.
Delivering CRISPR into the bodies of people with genetic disorders could conceivably repair their genes. Of course, the success of this kind of treatment would depend on how efficiently the molecules could get inside the cells that needed repairing, and how accurately they cut the DNA. Still, some early experiments on animals suggest that the approach may someday work on people.
But what if you didn’t have to wait until so late in the game to repair a broken gene? If a fertilized egg ended up with a defective gene, you could conceivably use CRISPR to fix the mistake. That single cell could then give rise to an entire healthy human with trillions of cells that all had the correct version of the gene.
Last month, a team of leading scientists–including pioneers in both gene therapy and CRISPR–declared that this would be a bad idea. “At present, the potential safety and efficacy issues arising from the use of this technology must be thoroughly investigated and understood before any attempts at human engineering are sanctioned, if ever, for clinical testing,” they declared in a piece they published in Science.
But meanwhile, a team of researchers led by Junju Huang at Sun Yat-sen University were testing out CRISPR on human embryos. Huang told Nature that both Nature and Science rejected the paper based on ethical objections. So they ended up publishing the results in the journal Protein & Cell (open access, by the way).
The scientists tested out CRISPR as a form of embryonic gene therapy. Imagine an embryo had a mutation in a gene called beta-globin involved in making hemoglobin. It would develop into a person with the blood disorder beta-thalassemia. Would it be possible to cure the embryo by rewriting the gene?
The researchers set out to do the study on human embryos–but they didn’t want to use embryos that might ever actually be able to develop into a fully-formed human being. When fertility doctors fertilize eggs with in vitro fertilization, they sometimes end up with two sperm delivering their DNA into a single egg. These “tripronuclear zygotes” can start dividing as normal embryos do, but their abnormal collection of genes causes them to stop developing when they’re still just tiny clumps of cells. The researchers argue that this failure makes tripronuclear embryos “an ideal model system” for studying CRISPR therapy. (Bioethicists, start your engines!)
All told, the researchers injected 86 embryos, 71 of which survived long enough for them to study. CRISPR only managed to cut DNA in a fraction of the embryos, and in only a fraction of those embryos did cells manage to take up the new version of the target gene (called beta-globin).
Two big problems stick out from the results.
One is the fact that CRISPR sometimes missed its target and inserted DNA in the wrong places. Such a misfire wouldn’t just fail to fix a disease like beta-thalassemia. It could create a disease of its own.
The other big problem is that the embryos that did get edited correctly were actually a mix of edited cells and unedited cells–what’s known as a mosaic. Mosaics can give doctors a lot of headaches, as I’ve written in the New York Times. If fertility doctors used CRISPR to create healthy, hemophilia-free embryos, they’d need to make sure the embryos were repaired by picking off a cell and examining it up close. A cell from a mosaic embryo could give doctors the wrong picture of the embryo as a whole.
The authors conclude their paper by warning that these failures need to be “investigated thoroughly before any clinical application.”
Just because this experiment came out poorly doesn’t mean that future experiments will. There’s nothing in this study that’s a conceptual deal-breaker for CRISPR. It’s worth recalling the early days of cloning research. Cloned embryos often failed to develop, and animals that were born successfully often ended up with serious health problems. Cloning is much better now, and it’s even getting to be a business in the world of livestock and pets. We still don’t clone people, though–not because we can’t, but because we choose not to. We may need to make the same choice about editing embryos before too long.
Postscript 4/23 9:30 am: While I was hammering out this explainer yesterday, I got in touch with Jennifer Doudna, a CRISPR pioneer at Berkeley I wrote about in my Quanta piece, who co-authored the call for putting the brakes on human germline CRISPR research. She got back to me this morning with this to say:
Although it has attracted a lot of attention, the study simply underscores the point that the technology is not ready for clinical application in the human germline. And that application of the technology needs to be on hold pending a broader societal discussion of the scientific and ethical issues surrounding such use.
[Update: fixed the details on the beta-globin gene]
Last month, I wrote in the New York Times about a creepy yet potent way to reverse aging. All you have to do is join an old mouse to a young mouse. As the young mouse’s blood flows through the old mouse’s body, it rejuvenates the heart, skeletal muscle, and even the brain.
When scientists saw just how dramatic this reversal could be, they started investigating how it happens. They suspected that it wasn’t blood as a whole that was responsible for the transformation. Blood is a finely blended consommé of cells and free-floating molecules. It was possible that only certain compounds in young blood are required to counter aging. That would be excellent if true, since it would put a damper on any vampire-like strategies for applying this discovery to people. All old people would need to do was take a pill containing the compounds that bring about the change.
As I wrote in my article last month, scientists identified one protein, called GDF11, may help reverse aging in the young blood experiments. But they suspected that more than one molecule would be involved. And today, a team of scientists at the University of California at Berkeley are publishing evidence in favor of a new molecule. What makes this result especially surprising is that this molecule is already fairly famous for other effects on the body. It’s oxytocin.
You may have heard of oxytocin as a love drug, or as a moral molecule. It is certainly true that this hormone, which is produced in the brain, plays some important roles in the social life of mammals. Monogamous voles, for example, appear to depend on oxytocin to strengthen their bonds with their mates. When scientists prevent their cells from taking up oxytocin, the voles become more promiscuous. Likewise, oxytocin plays a part in the mother-child bond. Its concentration rises in women during pregnancy and nursing. If ewes are blocked from taking up oxytocin, they neglect their newborn lambs.
But, as fellow Phenom Ed Yong explained in this 2012 Slate piece, at this point oxytocin should really be called the “hype hormone.” People are way too eager to leap from the existing evidence about oxytocin’s effects to calls for its use as a therapy for children with depression or autism. And as Ed wrote in April in The Scientist, oxytocin also seems to be involved in negative emotions and even lying. Reckless use of oxytocin could have some unwanted effects.
It may seem strange for one little molecule to influence us in so many ways. But that’s true for many hormones. They are signals, but the message they deliver depends on their context. In that respect, hormones are like the words we use to relay messages to each other. Think of the wildly different messages, depending on the context, that just five words can have: “What are you doing here?”
In fact, the effects of oxytocin range far beyond emotions and behaviors. In recent years, for example, scientists have found evidence that oxytocin can reduce osteoporosis and obesity. Oxytocin can relay important signals to cells throughout the body, not just in the brain.
Recently Irina Conboy and her colleagues became intrigued by a few of these experiments. When scientists remove the ovaries from female mice, for example, their levels of oxytocin drop dramatically. The mice also start to age rapidly. Could there be a cause and effect there?
Another clue came from the receptors on the surfaces of cells that can grab oxytocin. The cells with these receptors include stem cells that can produce new muscle. Was it possible that oxytocin sent these cells a signal to develop and renew old muscle?
Clues like these fostered a hunch in the minds of the scientists. Maybe oxytocin was one of the molecules in young blood that could rejuvenate old animals.
As the scientists report in Natural Communications, they ran a series of experiments that strongly suggest that this is indeed the case. They wondered, for example, if naturally aging mice lost oxytocin, in the same way as mice that have their ovaries removed. They found that as mice get old, their oxytocin level drops to a third of the level in young mice. They also found muscle stem cells produce fewer receptors for oxytocin as mice get older.
The scientists then gave oxytocin to old mice. They found that the mice were able to regenerate more new muscle fibers. And when they blocked oxytocin in young mice, the mice couldn’t renew their muscles. In this respect, they became old.
Conboy and her colleagues got a similar result when they engineered mice that could not produce oxytocin. The mice developed normal muscles, but as adults they lost muscle mass much faster than normal mice.
To get a closer look at what oxytocin was doing, the scientists reared muscle stem cells in a dish and added oxytocin to them. Once the cells grabbed onto the hormone, they multiplied quickly. In other words, oxytocin appears to be directly altering the behavior of stem cells, just as the scientists had suspected.
The new study provides a new hypothesis for how we get old. When people are young, they produce lots of oxytocin. On top of whatever psychological effects it may have, that extra oxytocin also tells stem cells to turn into muscle cells, keeping people strong. Young people might also produce GDF11 and other molecules at high levels, and in combination, they may keep all the organs young. And once those signals start to fade in old age, the body starts to fall apart.
Theoretically, giving old people compounds like oxytocin or GDF11 may cause their cells to act young again. The compounds could be the basis for an all-purpose treatment for the diseases of old age, from osteoporosis to heart disease to Alzheimer’s.
It’s worth bearing in mind that all the studies I’m writing about have only been carried out in mice or rats. We can’t say for sure that the effects would carry over into human trials. We don’t even know if oxytocin is high in children and low in old people–not to mention what the “right” level of oxytocin would be to reverse aging.
It’s also worth bearing in mind that there may very well be a good reason that youth-generating signals fade as we get older. If the signals don’t deliver exactly the right message, in exactly the right context, our cells might misinterpret them in a disastrous way. Instead of just multiplying to restore weakened muscles, for example, stem cells might grow uncontrollably, leading to cancer.
But Conboy and her colleagues respond to that concern by pointing out that we already know a lot about oxytocin as a drug in people. Because its other effects have gained so much attention, it’s already been extensively tested. In its synthetic form, pitocin, it’s approved for use in pregnant women who are past term, in order to speed up their labor. Human clinical trials are already underway to try out oxytocin as treatment for psychological disorders. While it’s not free of side-effects, oxytocin has never been linked to cancer in all the testing that it’s undergone.
Of the many messages oxytocin delivers around our bodies, it’s possible that the message to stay youthful is relatively clear. On the other hand, if there’s one thing oxytocin has taught us so far, it’s that hype can’t replace real research.
Worldwide, women suffer an estimated 2.65 million stillbirths each year. Despite those huge numbers, we only understand some of the factors that are responsible. In low- and middle-income countries (where most of the world’s stillbirths occur), diseases like malaria can put pregnant women at risk of stillbirths. In wealthier countries, the biggest risks include smoking and obesity. But these factors only go partway to explaining why some women have stillbirths, leaving many cases unaccounted for. The benefits that would come from that knowledge could be enormous.
One way to learn about reproductive health is to observe how our primate cousins have babies. And a new study on marmosets offers some hints about the causes of stillbirth. It suggests that a mother’s health during pregnant may not be the whole story. In fact, some of the risk factors may arise before mothers are even born.
The first thing that one notices about the white-tufted ear marmoset (Callithrix jacchus) is its wildly adorable face–a tiny visage framed by shocks of white fur. Marmosets are interesting to scientists not because they’re cute, but because of their intriguing way of having kids. While most primate females have a single offspring at a time, marmoset typically have twins. Some marmoset mothers even have triplets.
This is a tricky strategy for passing on marmoset genes. Marmoset babies can weigh between a fifth and a quarter of their mother’s weight. Imagine a 135-pound woman giving birth to two 16 pound babies–and then nursing them. The strategy only works because marmosets live in groups. A breeding female and male marmoset are attended to by helpers–usually related females that suppress their own ability to have babies while they assist the breeding female. They take turns carrying the babies and getting food. The father even helps out, too.
Despite all the help, however, female marmosets sometimes have stillbirths. Recently, Julienne Rutherford, a biological anthropologist at in Department of Women, Children, and Family Health Science at the University of Illinois at Chicago, went on a search for the factors that put a marmoset at greatest risk of having one.
She and her colleagues studied a marmoset colony at the Southwest National Primate Research Center in San Antonio, Texas. The center keeps detailed records for all the marmosets, from birth to death. Rutherford and her colleagues analyzed the reproductive history of 79 female marmosets since 1994. And when they were done with the analysis, one factor in particular jumped out of the data. Females that were born in sets of triplets are three times more likely to lose a fetus than females born as twins.
The scientists looked at the other data to figure out what was happening. The risk of stillbirth wasn’t just part of an overall problem with fertility. Triplet females were just as likely to get pregnant as twin females. It’s just that they were less likely to carry their pregnancies to a successful term.
Perhaps the result was just a shadow of a much bigger pattern. Scientists have long known that women who were low weight at birth end up at greater risk of stillbirths when they get pregnant. The same goes for other female primates. It was therefore possible that triplet female marmosets were at greater risk of stillbirths simply because triplet marmosets are smaller at birth than twins. Rutherford and her colleagues looked over the records to see if that was the case.
It wasn’t. Triplet females are born at a range of weights, and extra size offer them no protection against stillbirths. The big triplet females are also at risk of having stillbirths when they grow up.
Something must be happening in the marmoset womb that is leaving an invisible mark on triplet females for their entire life. As a female primate embryo develops, it grows the ovaries and uterus it will eventually use to bear its own young. The development of those organs is normally choreographed by the hormones that swirl around the embryo’s body. Sharing a uterus with two other embryos may disrupt that choreography. Most triplet females are born along with at least one brother, for example. It’s possible that the male hormones produced by their brothers interfered with their own development.
Since women typically only have one baby at a time, there isn’t a simple lesson in Rutherford’s research for medicine. But it may encourage scientists to to widen their search for the cause of stillbirths. Yes, the health of a woman while she’s pregnant is enormously important to a successful pregnancy. But her reproductive health may be altered before she’s even born.
Scientists have done very little research on this possibility in humans. One of the few studies looked at the legacy of the so-called “Dutch Hunger.” In the winter of 1944/45, the Netherlands suffered a famine. Many women who were pregnant at the time suffered from malnutrition. Scientists have followed their children ever since to see what effect the famine had on them before they were born. In 1997, researchers found that the women were just as fertile as women from well-fed mothers. But their children were at greater risk of stillbirth or of dying just after birth [pdf].
Given how long people live, tracing the effects of pregnancy on stillbirths is going to be slow work. Female marmosets, on the other hand, can start having babies before they’re two years old. Rutherford and her colleagues are taking advantage of the fast life of marmosets by following a number of females from birth to first pregnancy. The scientists are using ultrasound to take pictures of the marmosets’ developing reproductive systems, and measuring their hormone levels along the way.
This new research may allow Rutherford to pinpoint the reason that it’s so risky to be a triplet mother. And it may let her offer some ideas about how to make human childbirth healthier, too.
The idea of personalized medicine is very simple. Your doctor peruses your genome to tailor your medical treatment. If you get cancer, she compares the genome of your tumor cells to your ordinary genome.
But in between idea and practice are rough waters yet to be crossed. That’s because the genome doesn’t speak for itself. Instead, we will probably need the help of computers with a human-like power to learn.
For my new “Matter” column in the New York Times, I take a look at this challenge, on the occasion of a new study being launched on brain cancer patients. Helping out the oncologists will be the most famous supercomputer on Earth, Watson, the machine that beat humans on Jeopardy. Check it out.
A number of studies have shown that bilateral risk-reducing mastectomies (the official term) do indeed reduce the risk of breast cancer in women with the BRCA1 mutation. In a study published last month in Annals of Oncology, a team of Dutch medical researchers tracked 570 women with BRCA1 (or a mutation in the related gene BRCA2). At the start of the study, all the women were healthy; 212 of them later chose to get risk-reducing mastectomies. Over the next few years, the researchers followed their progress. Sixteen percent of the women who didn’t get risk-reducing mastectomies developed breast cancer; of the women who went Jolie’s route, none did.
The initials in BRCA1 stand for breast cancer. Its name reflects how it was discovered: scientists found it as they were searching for the cause of the disease. But such names are really misnomers. After all, genes don’t simply sit in our DNA so that they can mutate in some people and make them sick. Normally, they have a job to do. In the case of BRCA1, there are many jobs. For one thing, it protects DNA from harmful mutations that can arise as it’s getting replicated. And if DNA does get damaged, the BRCA1 protein helps fix it. It joins together with several teams of other proteins, and each team carries out a different part of the complex task of DNA repair.
BRCA1, in other words, normally keeps our cells in good shape. If it mutates, though, it can’t do its jobs properly. Cells with a mutant copy of BRCA1 let mistakes slip by. Mutations in other genes can accumulate in a line of dividing cells. Some of those mutations will cause cells to die, but sometimes they have the opposite effect: the mutant cells grow and divide rapidly. As they proliferate, they accumulate even more mutations, eventually becoming full-blown cancer. As a result, women who carry BRCA mutations have a 40 to 85 percent risk of developing breast cancer during their lifetime. (They also run a 16 to 64 percent risk of ovarian cancer.)
Last year, a team of scientists at the University of Utah discovered an unexpected side effect of BRCA mutations. They looked at medical records of women who carried BRCA mutations and compared them to women with a normal version of the genes. The scientists found that women with the mutations weren’t just more likely to develop cancer. They also had more children. The effect was particularly strong among women born before 1930: they had, on average, two additional children (6.22 compared to 4.19).
The Utah scientists couldn’t say from their study how the mutations could lead to more children. But they offered one suggestion. A woman’s fertility depends on the viability of her eggs. Like other cells, eggs have caps called telomeres on the ends of their chromosomes that keep them from getting damaged. The longer the telomeres, the better shape an egg is in. Among its many jobs, BRCA1 helps control the length of telomeres. The Utah scientists suggest that mutant BRCA1 proteins may lengthen the telomeres in eggs, keeping them more viable.
BRCA mutations are so good for fertility that Jack da Silva, a biologist at the University of Adelaide, has pointed out that they should be a lot more common. Only a few percent of women carry them, but they enable women to have so many more children, you’d expect the mutation to become more common with each generation. Within a few centuries of the mutation first appearing, everyone should have it.
Da Silva proposes that the mutations hang in an evolutionary balance. Before the age of 40, a woman with a BRCA mutation only has a 20% chance of developing breast cancer. That risk rises to 37 percent by the age of 50 and continues going up; by the age of 70, it’s 70 percent. In other words, these women have good odds of surviving to the point at which they can give birth to children, but they’re less likely to be alive to see their own children become parents.
A number of biologists have argued that grandmothers have played an important part in the survival of their grandchildren. In fact, some maintain that their help is so valuable that menopause evolved as a result. Women who stop raising their own children can better channel their efforts into helping to raise their grandchildren. Women with BRCA mutations are less likely to be able to provide that help. As a result, Da Silva suggests, the odds of their grandchildren surviving may have been somewhat lower than for grandmothers without the mutations.
This balance could account for the puzzling nature of BRCA mutations. They’re more common than other potentially fatal disorders like cystic fibrosis, and they’re unable to spread to more than a few percent of the population. It is this ancient legacy of BRCA’s many effects that women like Jolie are grappling with today.
[Update 5/14: I corrected the cause of Angelina Jolie’s mother’s death from breast to ovarian cancer.]
Albert Alexander, a 43-year-old policeman in Oxford, England, was pruning his roses one fall day when a thorn scratched him at the corner of his mouth. The slight crevice it opened allowed harmless skin bacteria to slip into his body. At first, the scratch grew pink and tender. Over the course of several weeks, it slowly swelled. The bacteria turned from harmless to vicious, proliferating through his flesh. Alexander eventually had to be admitted to Radcliffe Hospital, the bacteria spreading across his face and into his lungs.
Alexander’s doctors tried treating him with sulfa drugs, the only treatment available at the time. The medicine failed, and as the infection worsened, they had to cut out one of his eyes. The bacteria started to infiltrate his bones. Death seemed inevitable.
But then, on February 12, 1941, Alexander was injected with an experimental drug: a molecule produced by mold.
The molecule was, of course, penicillin. It had been discovered thirteen years earlier but soon abandoned because there didn’t seem to be any way to turn it into an effective drug. In the late 1930s, Howard Florey and his colleagues at the University of Oxford revived the drug and began testing it on mice. They found the penicillin could cure them of infections by killing their bacteria. Florey then gave a dose of penicillin to a woman dying of cancer and found that it wasn’t toxic to her.
Now Florey and his colleagues wanted to see if it could stop an infection in a human being. Alexander, with nothing left between him and death, was their first subject.
“Striking improvement” was how Florey described what happened next. Within a day, Alexander’s infections were subsiding. After a few more days, his fever broke and much of his face cleared up.
Florey could have saved Alexander’s life, if he hadn’t run out of penicillin after a few days. Nobody but Florey knew how to make the stuff, and his recipe only yielded a tiny amount at a time. To stretch out their supply of penicillin, a member of Florey’s lab would visit the hospital each morning to collect Alexander’s urine. He would carry it back by bicycle to the lab, where the scientists extracted the penicillin that Alexander’s body hadn’t absorbed. Alexander’s doctors then injected the recycled antibotic into Alexander’s arm.
But the salvaging operation didn’t recover enough penicillin to keep the bacteria from growing again. The infection returned and grew worse than before. On March 15, Alexander died. In his final report, Florey called Alexander’s death “a forlorn case.”
It is hard to imagine a time when a scratch could so easily lead to death. Albert Alexander died precisely at the dawn of the Antibiotic Era. Shortly after failing to save Alexander’s life, Florey harvested more penicillin and gave it to another patient at the hospital, a 15-year-old boy who had developed an infection during surgery. They cured him in a few days. Within three years of Alexander’s death, Pfizer was manufacturing penicillin on an industrial scale, packing 7500-gallon tanks with mold, fed on corn steep liquor. In that same year, Selman Waksman, a Rutgers microbiologist, and his colleagues discovered antibiotics made by soil bacteria, such as streptomycin and neomycin.
What made antibiotics so wildly successful was the way they attacked bacteria while sparing us. Penicillin, for example, stops many types of bacteria from building their cell walls. Our own cells are built in a fundamentally different way, and so the drug has no effect. While antibiotics can discriminate between us and them, however, they can’t discriminate between them and them–between the bacteria that are making us sick and then ones we carry when we’re healthy. When we take a pill of vancomycin, it’s like swallowing a grenade. It may kill our enemy, but it kills a lot of bystanders, too.
It’s understandable that few scientists gave this fact much thought in the 1940s, when the lives of people like Albert Alexander hung in the balance. Even if they did wonder about the 100 trillion microbes that live in our healthy bodies–known as the microbiome–they were poorly equipped to investigate them. They could only study bacteria that they could rear in their labs. E. coli thrived outside of the body, sucking in oxygen and feeding on just about any sugar on offer. That’s why scientists now understand E. coli better than any other species on Earth.
But in its natural habitat–the human gut– E. coli is a rare bird. Only about one microbe in a thousand in the gut belongs to the species. The rest of the microbes are far too fussy to survive in just any Petri dish. They need a special balance of gases, acidity, and nutrients. In many cases, they can’t survive unless they’re living alongside other species. Their fussiness has slowed down scientists trying to explore the microbiome. But now that they can fish out the DNA of the microbiome, scientists are beginning to get a sense of the staggering diversity of microbes we harbor.
Each of us is home to several thousand species. (I’m only talking about bacteria, by the way–viruses, fungi, and protozoans stack an even higher level of diversity on top of the bacterial biodiversity.) My own belly button, I’ve been reliably informed, contains at least 53 species. Many of the species I harbor are different than the ones you harbor. But if you look at the kinds of genes carried by those species, our microbiomes look very similar. That’s partly because surviving on a human body requires certain skills, so any species that is going to last long in your lungs, say, will need many of the same genes.
But the similarity speaks to something else. The microbiome keeps us healthy. It breaks down some of our food into digestible molecules, it detoxifies poisons, it serves as a shield on our skin and internal linings to keep out pathogens, and it nurtures our immune systems, instructing them in the proper balance between vigilance and tolerance. It’s a dependence we’ve been evolving for 700 million years, ever since our early animal ancestors evolved bodies that bacteria could colonize. (Even jellyfish and spongeshave microbiomes.) If you think of the human genome as all the genes it takes to run a human body, the 20,000 protein-coding genes found in our own DNA are not enough. We are a superorganism that deploys as many as 20 million genes.
It’s not easy to track what happens to this complex organ of ours when we take antibiotics. Monitoring the microbiome of a single person demands a lot of medical, microbiological, and genomic expertise. And it’s hard to generalize, since each case has its own quirks. What happens to the microbiome depends on the particular kind of bacteria infecting people, the kind of antibiotics people take, the state of their microbiome beforehand, their own health, and even their own genes (well, the human genes, at least). And then there’s the question of how long these effects last. If there’s a change to the microbiome for a few weeks, does that change vanish within a few months? Or are there effects only emerge years later?
Scientists are only now beginning to get answers to those questions. In a paper just published online in the journal Gut, Andres Moya of the University of Valencia and his colleagues took an unprecedented look at a microbiome weathering a storm of antibiotics. The microbiome belonged to a 68-year-old man who had developed an infection in his pacemaker. A two-week course of antbiotics cleared it up nicely. Over the course of his treatment, Moya and his colleagues collected stool samples from the man every few days, and then six weeks afterwards. They identified the species in the stool, as well as the genes that the bacteria switched on and off.
What’s most striking about Moya’s study is how the entire microbiome responded to the antibiotics as if it was under a biochemical mortar attack. The bacteria started producing defenses to keep the deadly molecules from getting inside them. To get rid of the drugs that did get inside them, they produced pumps to blast them back out. Meanwhile, the entire microbiome powered down its metabolism. This is probably a good strategy for enduring antibiotics, which typically attack the molecules that bacteria use to grow. As the bacteria shut down, they had a direct effect on their host: they stopped making vitamins and carrying out other metabolic tasks.
In another intriguing response, the microbes dimmed their immune systems. To defend against invading viruses, bacteria deploy a collection of enzymes that recognize foreign genes and chop them up. As the bacteria dialed these enzymes down, they may have allowed viruses to infect them more easily. In some cases, the invasion led to their death. But in other cases, the viruses may have delivered them useful genes, including genes that let them resist the antibiotics.
Moya and his colleagues found that some types of bacteria were able to survive the onslaught of antibiotics, while others failed. As a result, the overall diversity of bacteria in the man’s gut changed from day to day over the course of his treatment. Before he started taking antibiotics, the scientists identified 41 species in a stool sample. By day 11, they only found 13. Six weeks after the antibiotics, the man was back up to 38 species. But the species he carried six weeks after the antibiotics did not represent that same kind of diversity he had before he took them. A number of major groups of bacteria were still missing.
This long-term disturbance was not unusual. Other scientists have tracked the diversity of the microbiome for many months after people get antibiotics. Even after all that time, the microbiome may not return to its original state. By disturbing our inner ecosystem, antibiotics can affect our own health.
In some cases, for example, antibiotics can make it easier for pathogens to invade. Eric Pamer of Memorial Sloan Kettering Cancer Center and his collegues recently provided a striking demonstration of this effect. They gave mice a single dose of the antibiotic clindamycin. Ninety percent of the diversity in the gut of the mice disappeared and was still gone four weeks after the treatment. The scientists then inoculated the mice with the spores of Clostridium difficile, a particularly nasty pathogen that can cause lethal cases of diarrhea. They invariably got an overwhelming infection, and half of them died within a few days. Pamer could wait as long as ten days after giving the mice antibiotics, and they were still felled by C. difficile. Healthy mice, on the other hand, easily kept the invasion in check.
Antibiotics may also exert subtler, longer-term effects on our health. Matthew Kronman of Seattle Children’s Hospital and his colleagues, for example, recently reviewed the medical records of over a million people. They found that children who took antibiotics were at greater risk of developing inflammatory bowel disease later in life. The more antibiotics they took, the greater the risk. Similar studies have found a potential link to asthma as well.
A study carried out by Dennis Kasper at Harvard hints at how antibiotics can send the immune system off the rails. They reared mice in isolated containers so that they never developed a microbiome. The germ-free rodents developed unusually high levels of an aggressive type of immune cell called an invariant natural killer T cell. If Kasper inoculated baby germ-free mice with a normal microbiome, the T cells remained rare. Antibiotics, the scientists propose, allow the T cells to explode and to run amok.
It’s even possible that long-term antibiotic use may influence how people put on fat. Martin Blaser of New York University and his colleagues carried out an experiment on mice in which they fed the animals antibiotics and then tracked their metabolism. The scientists found that the mice fed with antibiotics developed a higher percentage of body fat than mice that didn’t.*
Antibiotics cause this rise in fat, Blaser and his colleagues argue, by creating long-term changes in the microbiome. The species fostered in the mice produce enzymes that change not just how they break down our food, but also send signals to our own hormones to change the way we store energy from our food.
None of these results would ever lead a doctor to give up on antibiotics altogether. Seventy years after Albert Alexander died, they remain the best tool we have to fight off deadly infections. But we shouldn’t be blasé about them. Doctors often prescribe antibiotics to patients simply on the hunch that they have a bacterial infection. It often turns out that viruses are causing the trouble instead. Many parents are all too familiar with the endless cycle of ear infections and antibiotics. That cycle may take a toll.
There are changes that would help fight against that toll–some that we could make right away, and others that will demand a lot more research before becoming practical. We could become less casual about asking doctors for antibiotics. If DNA-sequencing becomes cheap enough, doctors might become able to diagnose bacteria infections quickly and accurately, so as not to prescribe antibiotics when they can’t help. And when it turns out we are infected, there are other ways to fight bacteria. For a century, some scientists have explored using bacteria-infecting viruses as a weapon against infections, for example.
It might even be possible to fight bacteria with bacteria. Instead of blasting both pathogens and harmless microbes alike, we might tend the microbial garden better and keep down the weeds. The most dramatic example of this gardening is the fecal transplant. Half a million people get C. difficile infections a year, many of which can’t be stopped by antibiotics. Doctors have found that a little stool from a healthy donor can crush these invasions. Fecal transplants may also help against inflammatory bowel disease, by restoring the immune system’s essential partners. Transplants might treat infections elsewhere in the body, from cavities in the mouth to rashes on the skin.
These treatments would do more than tamp down the harmful effects of antibiotics. They’d also help keep antibiotics themselves useful. When Florey first tried out penicillin against Alexander and other patients, he worried that the bacteria might adapt to the drug. It eventually did; for many pathogens, penicillin is now useless because they’ve evolved strong resistance against it. C. difficile and many other pathogens have become resistant against many other antibiotics, too. Developing new antibiotics is essential for stopping this decline, but we will need to use them just as sparingly to slow down evolution’s relentless push.
Otherwise, we may return to a time when roses killed policemen.
[This post emerged from the research I did for a talk I gave last week at Rutgers]
[*Upate 12/20 7:20 am: In the original version, I incorrectly stated that the mice’s overall body mass increased. This was only true among female juveniles. By seven weeks, however, there was no increase in body mass–only its composition of fat and lean mass. Thanks to zmil for pointing out my error.]
Yesterday I went to Rutgers University to give a talk about medical ecology. Afterwards, I got a delightful surprise: Amy Chen Vollmer, the president of the Waksman Foundation for Microbiology, got on stage to announce I had won the Byron H. Waksman Award for Excellence in Public Communication of Life Sciences.
Byron Waksman, who passed away this June, was an immunologist who made important discoveries about auto-immune diseases and the signals white blood cells send to each other. Spreading the word about science was another of his passions; after he retired from his scientific work, he became a middle-school science teacher. Waksman was also the director of a foundation set up by his father, Selman Waksman, who won the Nobel prize for discovering many of the antibiotics we depend on today. Byron Waksman used the foundation’s resources to advance the understanding of science. One of the programs he initiated brings journalists to the Marine Biology Lab in Woods Hole to learn how science is done. All the journalists I’ve spoken to who have gone through it have sung its praises. It shows them the real science that lies beyond the press release and the phone call.
I’m hugely honored to get an award in Byron Waksman’s name. And it’s a particular pleasure to get an award decorated not with some non-descript humanoid, but with the Tree of Life. It’s a privilege to get to jump among its branches for a living.
The virus known as XMRV does not cause chronic fatigue syndrome.
Achieving this particular bit of knowledge has taken a pretty spectacular couple of years.
In October 2009, Judy Mikovits, a scientist then at the Whittemore Peterson Institute in Reno, Nevada, and her colleagues published a startling paper. They found that 68 out of 101 people suffering from chronic fatigue syndrome (also known as myalgic encephalomyelitis) carried a virus called XMRV. Only 8 out of 218 healthy people had it. That’s 67% versus 3.7%. Mikovits and her colleagues raised the possibility that the virus played a part in the disorder, which affects an estimated 60 million people. If that were true, then there might be a straightforward way to treat people: wipe out the offending virus.
Very quickly, a number of other scientists replicated the experiment. One team found evdience of a different virus in some of their subjects–not XMRV. The other scientists couldn’t find any virus at all that was present in any significant number of people with chronic fatigue and not in people without it.
With remarkable speed, the study and the follow-up research gave rise to a fierce controversy. Critics dismissed Mikovits’s work as nothing more than contamination (the virus is common in mice). Mikovits dismissed her critics becasue they hadn’t replicated her experiment closely enough to really test it. Many people with chronic fatigue syndrome, embittered by years of suffering (and suggestions that it was all in their head) rallied around Mikovits. (To get a sense of the back story, see the comments many people left on a blog post I wrote about this controversy last year.)
A few months into the controversy, I was at Columbia University to interview a scientist named Ian Lipkin for a profile for the New York Times. I focused mainly on his research linking viruses to new diseases. But Lipkin also does the reverse–what he likes to call “de-discovery.” When someone makes a controversial claim that virus X causes condition Y, Lipkin sometimes puts the claim to the test. Lipkin explained to me how it’s important to get everyone on board with such a replication study–both the original scientists and their critics. And he told me that he had launched a big study on XMRV, in collaboration with a team of scientists that included Mikovits, scientists who failed to find a link, and others. (I wrote more generally about de-discovery last year in the Times.)
The study would take a lot of time. The scientists and doctors would examine 147 people with chronic fatigue and 146 normal people, giving them thorough medical exams and a close inspection of their blood. Several labs would use identical methods to search for XMRV. And in that time a lot happened.
More scientists investigated XMRV on their own and found still more evidence that the viruses had likely contaminated Mikovits’s cell cultures. Mikovits wouldn’t budge, even as Science retracted the paper in December 2011. Meanwhile, Mikovits got into a battle royale with her institute, getting locked out of her office, sneaking in a grad student in to get her notebooks (possibly to work on Lipkin’s study), and spending five days in jail.
Today, nearly three years after the start of the XMRV affair, the big study came out in the journal mBio. The scientists found no evidence of XMRV in people with chronic fatigue. Mikovits fully endorsed the conclusion.
I am curious how people with this condition view this finding. I find it pretty depressing. It’s taken up plenty of money along with the valuable time of lots of talented researchers. It’s raised and then dashed hopes. And all we have to show for it is the lack of a link. What causes chronic fatigue syndrome? Your guess is as good as mine.
It would be nice if there was a simple set of instructions for finding the cause, but that’s probably just a fantasy. Perhaps the best we can hope for is to avoid these expensive, time-consuming wrestling matches in the first place. That’s why I find projects like the Reproducibility Intiative so interesting. When scientists make mistakes, let’s find out as fast as possible.
Two years ago, I wrote in the New York Times about scientists exploring evolution to discover the function of our genes. We share a 1.2 billion-year-old common ancestor with fungi, for example, and it turns out that fungi (yeast in particular) have networks of genes remarkably similar to our own.
Back in 2010, the scientists I interviewed told me they hoped to use this method to find new drugs. In today’s New York Times, I write about how they’ve delivered on that promise. It turns out that a drug that doctors have used for over 40 years to kill fungi can slow the growth of tumors. It’s a striking illustration of how evolution provides a map that allows medical research to find their way to promising new treatments. Check it out.
This month has seen a flood of new studies and reviews on the microbiome, the collection of creatures that call our bodies home. In tomorrow’s New York Times, I look at why scientists are going to so much effort to map out these 100 trillion microbes.
The microbiome is not just an opportunistic film of bugs: it’s an organ that play an important part in our well-being. It starts to form as we’re born, develops as we nurse, and comes to maturity like other parts of the body. It stabilizes our immune system, keeps our skin intact, synthesizes vitamins, and serves many other functions. Yet the microbiome is an organ made up of thousands of species–an ecosystem, really. And so a number of scientists are calling for a more ecological view of our health, rather than simply trying to wage warfare against infections.
We all started out as a fertilized egg: a solitary cell about as wide as a shaft of hair. That primordial sphere produced the ten trillion cells that make up each of our bodies. We are not merely sacs of identical cells, of course. A couple hundred types of cells arise as we develop. We’re encased in skin, inside of which bone cells form a skeleton; inside the skull are neurons woven into a brain.
What made this alchemy possible? The answer, in part, is viruses.
Viruses are constantly swarming into our bodies. Sometimes they make us sick; sometimes our immune systems vanquish them; and sometimes they become a part of ourselves. A type of virus called a retrovirus makes copies of itself by inserting its genes into the DNA of a cell. The cell then uses those instructions to make the parts for new viruses. HIV makes a living this way, as do a number of viruses that can trigger cancer.
On rare occasion, a retrovirus may infect an egg. Now something odd may happen. If the egg becomes fertilized and gives rise to a whole adult individual, all the cells in its body will carry that virus. And if that individual has offspring, the virus gets carried down to the next generation.
At first, these so-called endogenous retroviruses lead a double life. They can still break free of their host and infect new ones. Koalas are suffering from one such epidemic. But over thousands of years, the viruses become imprisoned. Their DNA mutates, robbing them of the ability to infect new hosts. Instead, they can only make copies of their genes that are then inserted back into their host cell. Copy after copy build up the genome. To limit the disruption these viruses can cause, mammals produce proteins that can keep most of them locked down. Eventually, most endogenous retroviruses mutate so much they are reduced to genetic baggage, unable to do anything at all. Yet they still bear all the hallmarks of viruses, and are thus recognizable to scientists who sequence genomes. It turns out that the human genome contains about 100,000 fragments of endogenous retroviruses, making up about eight percent of all our DNA.
Evolution is an endlessly creative process, and it can turn what seems utterly useless into something valuable. All the viral debris scattered in our genomes turns out to be just so much raw material for new adaptations. From time to time, our ancestors harnessed virus DNA and used it for our own purposes. In a new paper in the journal Nature, a scientist named Samuel Pfaff and a group of fellow scientists report that one of those purposes to help transform eggs into adults.
In their study, Pfaff and his colleagues at the Salk Institute for Biological Sciences examined fertilized mouse eggs. As an egg starts to divide, it produces new cells that are capable of becoming any part of the embryo–or even the membrane that surrounds the embryo or the placenta that pipes in nutrients from the animal’s mother. In fact, at this early stage, you can pluck a single cell from the clump and use it to grow an entire organism. These earliest cells are called totipoent.
After a few days, the clump becomes a hollowed out ball. The cells that make the ball up are still quite versatile. Depending on the signals a cell gets at this point, it can become any cell type in the body. But once the embryo reaches this stage, its cells have lost the ability to give rise to an entirely new organism on their own, because they can’t produce all the extra tissue required to keep an embryo alive. Now the cells are called pluripotent. The descendants of pluripotent cells gradually lose their versatility and get locked into being certain types of cells. Some become hematopoetic cells, which can turn into lots of different kinds of blood cells but can no longer become, say, skin cells.
Pfaff and his colleagues examined mouse embryos just after they had divided into two cells, in the prime of their totipotency. They catalogued the genes that were active at that time–genes which give the cells their vastly plastic potential. They found over 100 genes that were active at the two-cell stage, and which then shut down later on, by the time the embryo had become a hollow ball.
One way cells can switch genes on and off is producing proteins that latch onto nearby stretches of DNA called promoters. The match between the protein and the promoter has to be precise; otherwise, genes will be flipping on at all the wrong times, and failing to make proteins when they’re needed. Pfaff and his colleagues found that all the two-cell genes had identical promoters–which would explain how they all managed so become active at the same time.
What was really remarkable about their discover was the origin of those promoters. They came from viruses.
During the earliest stage of the embryo’s development, these virus-controlled genes are active. Then the cells clamp down on them, just as they would clamp down on viruses. Once those genes are silenced, the totipotent cells become pluripotent.
Pfaff and his colleagues also discovered something suprising when they looked at the pluripotent ball of cells. From time to time, the pluripotent cells let the virus-controlled genes switch on again, and then shut them back down. All of the cells, it turns out, cycle in and out of what the scientists call a “magic state,” in which they become temporarily totipotent again. (The pink cells in this photo are temporarily in that magic state.)
Cells in the magic state can give rise to any part of the embryo, as well as the placenta and other tissue outside the embryo. Once the virus-controlled genes get shut down again, they lose that power. This discovery demonstrated that these virus-controlled genes really are crucial for making cells totipotent.
A discovery this strange inevitably raises questions that its discoverers cannot answer. What are the virus-controlled genes doing in those first two cells? Nobody knows. How did the domestication of this viral DNA help give rise to placental mammals 100 million years ago? Who knows? Why are viruses so intimately involved in so many parts of pregnancy? Awesome question. A very, very good question. Um, do we have any other questions?
We don’t have to wait to get all the answers to those questions before scientists can start to investigate one very practical application of these viruses. In recent years, scientists have been reprogramming cells taken either from adults or embryos, trying to goose them back into an early state. By inducing cells to become stem cells, the researchers hope to develop new treatments for Parkinson’s disease and other disorders where defective cells need to be replaced. Pfaff suggests that we should switch on these virus-controlled genes to help push cells back to a magic state.
If Pfaff’s hunch turns out to be right, it would be a delicious triumph for us over viruses. What started out as an epidemic 100 million years ago could become our newest tool in regenerative medicine.
Earlier this year, TEDMED took place in Washington DC, showcasing people doing innovative research in medicine. This year’s talks are now being loaded online, and today I was happy to see that cancer and evolution got their due. Franziska Michor of Harvard explained how the threat of cancer is a legacy of our evolution into multicellular animals, and how every case of cancer is a miniature unfolding of evolution within our own bodies. What makes Michor’s work particular exciting is that she is bringing the mathematical precision of population genetics and other aspects of evolution to the treatment of cancer.