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.
Here’s some more information on the saga:
[Apologies for a few typos, now fixed–I hit “publish” instead of “save draft”!]
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.
Pfaff and his colleagues propose that the domestication of these virus promoters was a key step in the evolution of mammals with placentas. The idea that viruses made us who were are today may sound bizarre, except that Pfaff is hardly the first person to find evidence for it. Last year, for example, I wrote about how placental mammals stole a virus protein to build the placenta.
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.
(For more on these inner passengers, see my book A Planet of Viruses.)
[Image: Courtesy Salk Institute.]
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.
I wrote about some of Michor’s work in my 2007 Scientific American article, “Evolved for Cancer?” (carlzimmer.com, sciam.com) I’ve also explored cancer evolution here on the Loom: “Inside Darwin’s Tumor” and “The Mere Existence of Whales.” And you can find lots of Michor’s papers as free pdf’s on her publication page.
Yesterday my Fresh Air interview was broadcast. You can listen to it here. I’ve been lots of emails with follow-up questions, and it occurred to me that I really ought to gather up some links to more information about the topics I discussed.
If I haven’t addressed a question you had listening to the show, leave a comment to this post and I’ll add a link.
The “virome”–the viruses that live in our body:
A Loom post about the swarms of viruses in the mouth, where they kill off bacteria
An article in Nature about a study of the viruses in identical twins
My article in the New York Times
My essay on the Loom about medical ecology
My Wired atlas of the human ecosystem
An example of microbiome research: extreme navel gazing
Maryn McKenna’s story in Scientific American on the struggle to mainstream fecal transplants to treat deadly infections
Ed Yong’s oeuvre on the microbiome at Not Exactly Rocket Science
Mayrn McKenna on her blog at Wired writing on the link between beneficial bacteria and protection from asthma, obesity, and other ills.
I think one of the biggest struggles a science writer faces is how to accurately describe the promise of new research. If we start promising that a preliminary experiment is going to lead to a cure for cancer, we are treating our readers cruelly–especially the readers who have cancer. On the other hand, scoffing at everything is not a sensible alternative, because sometimes preliminary experiments really do lead to great advances. In the 1950s, scientists discovered that bacteria can slice up virus DNA to avoid getting sick. That discovery led, some 30 years later, to biotechnology–to an industry that enabled, among other things, bacteria to produce human insulin.
This challenge was very much on my mind as I recently read two books, which I review in tomorrow’s Wall Street Journal. One is on gene therapy–a treatment that inspired wild expectations in the 1990s, then crashed, and now is coming back. The other is epigenetics, which seems to me to be in the early stages of the hype cycle. You can read the essay in full here.
Cancer evolves. Those two words may sound strange together. Sure, birds evolve. Bacteria evolve. But cancer? The trouble arises from the fact that cancers, unlike birds and bacteria, are not free-living organisms. They start out as cells inside a person’s body and stay there, until they’re either wiped out or the person dies.*
Yet the same forces that drive the evolution of free-living organisms can also drive cancer cells to become more aggressive and dangerous. Evolution becomes our inner foe if mutations disable a cell’s self-restraint. The cell multiplies. Sometimes a new mutation arises in its descendants. If the mutations allow the cancer to grow faster, the cells carrying it will take over the population of cancerous cells. Natural selection and other processes that drive evolution on the outside start driving it on the inside.
Like so many other scientists, researchers who study cancer evolution have jumped on new technology for sequencing genomes on the cheap. They’re now starting to publish fine-grained histories of the disease, tracking individual mutations as they arise and spread. Nature has just published a fine example of this new research. I particularly appreciated the informative pictures they came up with to accompany the paper, one of which I’ve included here. You can click on the picture for a bigger version. And below the picture, I’ll explain what it means.
In the new paper, Li Ding and colleagues at Washington University describe a study they carried out on eight people suffering from acute myeloid leukemia (AML), a disease of the immune system. In people with AML, stem cells in the bone marrow that would normally turn into white blood cells instead become cancerous. Treatments include bone marrow transplants and chemotherapy. Unfortunately, AML has a nasty way of bouncing back from chemotherapy, and the drugs become useless to stop it. As a result, a lot of people who seem at first to be in remission eventually die of the cancer.
The Washington University scientists reconstructed the history of the cancer in each patients by sequencing genomes from a number of cells. To determine the normal, original genome, they sequenced DNA from a healthy skin cell. They then sequenced genomes from cancer cells taken from the patients when they were first diagnosed. And then they looked at genomes of cancer cells that emerged after the patients relapsed. From this survey, they came up with a catalog of new mutations that emerged over the course of the cancer. They could then go back into the blood samples and estimate what fraction of the cancer cells had a given mutation at a given point in time.
This figure illustrates the sad chronicle of one particular woman they studied. When she was in her late 50s, she suddenly came down with a sore throat and began to bruise easily. A bone marrow biopsy confirmed she has AML. She got chemotherapy, and then a stem cell transplant. Although she seemed to go into complete remission, the cancer returned 11 months after her diagnosis. The chemotherapy drugs that had previously been so effective now could not stop the cancer. Other drugs failed, too. Two years after her diagnosis, she died.
On the left of the figure, the cancer begins. A single stem cell mutated and became the founder of the cancerous lineage. we start with normal cells. (The cell is dark, and the grey dot marks its original mutation. HSC stands for hematopoietic stem cells).
The cancer cells grew in number, and as they did, they accumulated a lot of mutations, some of which are listed in the figure next to the star. All of these mutations, one after the other, took over the entire population of cells–a signature of natural selection. When the woman went to her doctor, however, the cancer had diversified into a number of different lineage, each carrying additional, distinctive mutations. Over half of the cells belonged to a lineage marked here in purple, known as cluster 2. Cluster 3, marked in yellow, was made up cells with a separate set mutations. And from within Cluster 3 emerged yet another lineage–Cluster 4, marked in orange. The dots in each circle show the sets of mutations that accumulated in each cluster.
The chemotherapy knocked down all the clusters of cancer cells to such low numbers that doctors couldn’t find them any more. But they were still there. And when exposed to chemotherapy drugs, the most successful cluster was not the one that had been most successful back when the cancer was diagnosed. It was the relatively rare Cluster 4. Apparently, it had mutations that made it better able to withstand the chemotherapy drugs. Some its descendants later picked up new mutations, which enabled them to reproduce quickly and take over the cancer population, as they resisted new chemotherapy drugs as well.
“The AML genome in an individual patient is clearly a ‘moving target,'” the scientists right conclude. “Eradication of the founding clone and all of its subclones will be required to achieve cures.” Easier said than done, of course. The parallels between this research and studies on antibiotic resistance in bacteria are sobering. But at least now we’re starting to see what kind of evolutionary challenge we’re really up against.