Information

How much of the genotype-phenotype map do we understand in HIV?

How much of the genotype-phenotype map do we understand in HIV?


We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

From what I understand, viruses have very small genomes relative to those of standard model organisms used in biological research. For example, according to Wikipedia, "the HIV genome contains nine genes that encode fifteen viral proteins". This is several orders of magnitude below the complexity of the mouse genome for example, with over 20,000 genes encoding over 50,000 proteins.

As a bioinformatics student (from a non-biological background) working with mammalian genomes, I often find the link between genotype and phenotype quite abstract and I'm unable to fully get an intuition for concretely how genomes can encode the instructions (or recipe using Dawkins' analogy) for creating complex phenotypes.

With this in mind, I wondered whether viruses, in particular HIV, which I know has been well studied, provide the simplest models for understanding the principles of how genes can encode the complete phenotypes of a functioning biological entity. Having such a small number of genes, I assume it is feasible to follow the transcription, translation and interaction of all genes and proteins? If so, is it the case that we understand how all of the genes and proteins work in HIV? If not, what is the main barrier in our understanding?

Apologies for this poorly-defined question. I am having a hard time getting my head around how molecular/cellular biology fits in with the complex phenotypes I've been studying in developmental biology/physiology and hoped that a simpler species/biological system could help to illuminate how it all comes together! Any pointers to further resources would be much appreciated.


I'm sure HIV is well studied since as you know it has a small genome and is highly relevent to therapeutic research, but virus regulation can be complicated and not representative of what happens in normal cells. This is why model organisms exist. The yeast Saccharomyces cerevisiae has about 6,000 genes and researchers have systematically deleted nearly every gene and looked at what happens to the cell. This information is available on the saccharomyces genome database. For example if you search SNF1 (which has a human homolog) on SGD (https://www.yeastgenome.org/locus/S000002885). You can see the phenotypes associated with deletion, overexpression, as well as a summary of what it does and how it's regulated (with original references). I don't think it gets any better than that. A lot of what is known about genetics and molecular biology comes from studies in yeast so I think it is worthwhile learning about yeast genetics to get a better understanding of what goes on in cells.


Evidence-Based Patient-Centered Concept Map

Concept maps are an important tool in patient–centered care planning. A concept map helps to synthesize facts about a patient’s health needs and personal circumstances with available evidence and analysis. Such a tool becomes more useful when a patient has complex health, economic, and cultural needs.

In this simulation, you will be choosing a patient (KEITH ROGERS), conducting a short interview, and then assembling a concept map for use in that patient’s care plan.


It'll Take an Army to Kill the Emperor

This story was originally published in May 2017. It's been updated for World Cancer Day for a look behind the scenes at the ongoing battle against cancer.

I. Precision Medicine: What Is Cancer, Really?

When you visit St. Jude Children's Research Hospital in Memphis, Tennessee, you expect to feel devastated. It starts in the waiting room. Oh, here we go with the little red wagons, you think, observing the cattle herd of them rounded up by the entrance to the Patient Care Center. Oh, here we go with the crayon drawings of needles. The itch begins at the back of your throat, and you start blinking very fast and mentally researching how much money you could donate without starving. Near a row of arcade games, a preteen curls his face into his mother's shoulder while she strokes his head. Oh, here we go.

But the more time you spend at St. Jude, the more that feeling is replaced with wonder. In a cruel world you've found a free hospital for children, started by a Hollywood entertainer as a shrine to the patron saint of lost causes. There is no other place like this. Corporations that have nothing to do with cancer&mdashnothing to do with medicine, even&mdashhave donated vast sums of money just to be a part of it. There's a Chili's Care Center. The cafeteria is named for Kay Jewelers.

Scott Newman's office is in the Brooks Brothers Computational Biology Center, where a team of researchers is applying computer science and mathematics to the question of why cancer happens to children. Like many computer people, Newman is very smart and a little quiet and doesn't always exactly meet your eyes when he speaks to you. He works on St. Jude's Genomes for Kids project, which invites newly diagnosed patients to have both their healthy and tumor cells genetically sequenced so researchers can poke around.

"Have you seen a circle plot before?" Newman asks, pulling out a diagram of the genes in a child's cancer. "If I got a tattoo, it would be one of these." Around the outside of the circle plot is something that looks like a colorful bar code. Inside, a series of city skylines. Through the center are colored arcs like those nail-and-string art projects students make in high school geometry class. The diagram represents everything that has gone wrong within a child's cells to cause cancer. It's beautiful.

"These are the genes in this particular tumor that have been hit," Newman says in a Yorkshire accent that emphasizes the t at the end of the word hit in a quietly violent way. "And that's just one type of thing that's going on. Chromosomes get gained or lost in cancer. This one has gained that one, that one, that one, that one," he taps the page over and over. "And then there are structural rearrangements where little bits of genome get switched around." He points to the arcs sweeping across the page. "There are no clearly defined rules."

It's not like you don't have cancer and then one day you just do. Cancer&mdashor, really, cancers, because cancer is not a single disease&mdashhappens when glitches in genes cause cells to grow out of control until they overtake the body, like a kudzu plant. Genes develop glitches all the time: There are roughly twenty thousand genes in the human body, any of which can get misspelled or chopped up. Bits can be inserted or deleted. Whole copies of genes can appear and disappear, or combine to form mutants. The circle plot Newman has shown me is not even the worst the body can do. He whips out another one, a snarl of lines and blocks and colors. This one would not make a good tattoo.

"As a tumor becomes cancerous and grows, it can accumulate many thousands of genetic mutations. When we do whole genome sequencing, we see all of them," Newman says. To whittle down the complexity, he applies algorithms that pop out gene mutations most likely to be cancer-related, based on a database of all the mutations researchers have already found. Then, a genome analyst manually determines whether each specific change the algorithm found seems likely to cause problems. Finally, the department brings its list of potentially important changes to a committee of St. Jude's top scientists to discuss and assign a triage score. The mutations that seem most likely to be important get investigated first.

It took thirteen years and cost $2.7 billion to sequence the first genome, which was completed in 2003. Today, it costs $1,000 and takes less than a week. Over the last two decades, as researchers like Newman have uncovered more and more of the individual genetic malfunctions that cause cancer, teams of researchers have begun to tinker with those mutations, trying to reverse the chaos they cause. (The first big success in precision medicine was Gleevec, a drug that treats leukemias that are positive for a common structural rearrangement called the Philadelphia chromosome. Its launch in 2001 was revolutionary.) Today, there are eleven genes that can be targeted with hyperspecific cancer therapies, and at least thirty more being studied. At Memorial Sloan Kettering Cancer Center in New York City, 30 to 40 percent of incoming patients now qualify for precision medicine studies.

Charles Mullighan,a tall, serious Australian who also works at St. Jude, is perhaps the ideal person to illustrate how difficult it will be to cure cancer using precision medicine. After patients' cancer cells are sequenced, and the wonky mutations identified, Mullighan's lab replicates those mutations in mice, then calls St. Jude's chemical library to track down molecules&mdashsome of them approved medicines from all over the world, others compounds that can illuminate the biology of tumors&mdashto see if any might help.

If Mullighan is lucky, one of the compounds he finds will benefit the mice, and he'll have the opportunity to test it in humans. Then he'll hope there are no unexpected side effects, and that the cancer won't develop resistance, which it often does when you futz with genetics. There are about twenty subtypes of the leukemia Mullighan studies, and that leukemia is one of a hundred different subtypes of cancer. This is the kind of precision required in precision cancer treatment&mdasheven if Mullighan succeeds in identifying a treatment that works as well as Gleevec, with the help of an entire, well-funded hospital, it still will work for only a tiny proportion of patients.

Cancer is not an ordinary disease. Cancer is the disease&mdasha phenomenon that contains the whole of genetics and biology and human life in a single cell. It will take an army of researchers to defeat it.

Interlude

"I used to do this job out in L.A.," says the attendant at the Hertz counter at Houston's George Bush Intercontinental Airport. "There, everyone is going on vacation. They're going to the beaach or Disneyland or Hollywood or wherever.

"Because of MD Anderson, I see more cancer patients here. They're so skinny. When they come through this counter, they're leaning on someone's arm. They can't drive themselves. You think, there is no way this person will survive. And then they're back in three weeks, and in six months, and a year. I'm sure I miss some, who don't come through anymore because they've died. But the rest? They come back."

II. Checkpoint Inhibitor Therapy: You Have the Power Within You!

On a bookshelf in Jim Allison's office at MD Anderson Cancer Center in Houston (and on the floor surrounding it) are so many awards that some still sit in the boxes they came in. The Lasker-DeBakey Clinical Medical Research Award looks like the Winged Victory statue in the Louvre. The Breakthrough Prize in Life Sciences, whose benefactors include Sergey Brin, Anne Wojcicki, and Mark Zuckerberg, came with $3 million.

"I gotta tidy that up sometime," Allison says.

Allison has just returned to the office from back surgery that fused his L3, L4, and L5 vertebrae, which has slightly diminished his Texas rambunctiousness. Even on painkillers, though, he can explain the work that many of his contemporaries believe will earn him the Nobel Prize: He figured out how to turn the immune system against tumors.

"One day, the miracles won't be miracles at all. They'll just be what happens."

Allison is a basic scientist. He has a Ph.D., rather than an M.D., and works primarily with cells and molecules rather than patients. When T-cells, the most powerful "killer cells" in the immune system, became better understood in the late 1960s, Allison became fascinated with them. He wanted to know how it was possible that a cell roaming around your body knew to kill infected cells but not healthy ones. In the mid-1990s, both Allison's lab and the lab of Jeffrey Bluestone at the University of Chicago noticed that a molecule called CTLA-4 acted as a brake on T-cells, preventing them from wildly attacking the body's own cells, as they do in autoimmune diseases.

Allison's mother died of lymphoma when he was a child and he has since lost two uncles and a brother to the disease. "Every time I found something new about how the immune system works, I would think, I wonder how this works on cancer?" he says. When the scientific world discovered that CTLA-4 was a brake, Allison alone wondered if it might be important in cancer treatment. He launched an experiment to see if blocking CTLA-4 would allow the immune system to attack cancer tumors in mice. Not only did the mice's tumors disappear, the mice were thereafter immune to cancer of the same type.

Ipilimumab ("ipi" for short) was the name a small drug company called Medarex gave the compound it created to shut off CTLA-4 in humans. Early trials of the drug, designed just to show whether ipi was safe, succeeded so wildly that Bristol Myers Squibb bought Medarex for $2.4 billion. Ipilimumab (now marketed as Yervoy) became the first "checkpoint inhibitor": It blocks one of the brakes, or checkpoints, the immune system has in place to prevent it from attacking healthy cells. Without the brakes the immune system can suddenly, incredibly, recognize cancer as the enemy.

"You see the picture of that woman over there?" Allison points over at his desk. Past his lumbar-support chair, the desk is covered in papers and awards and knickknacks and frames, including one containing a black card with the words "Never never never give up" printed on it. Finally, the photo reveals itself, on a little piece of blue card stock.

"That's the first patient I met," Allison says. "She was about twenty-four years old. She had metastatic melanoma. It was in her brain, her lungs, her liver. She had failed everything. She had just graduated from college, just gotten married. They gave her a month."

The woman, Sharon Belvin, enrolled in a phase-two trial of ipilimumab at Memorial Sloan Kettering, where Allison worked at the time. Today, Belvin is thirty-five, cancer- free, and the mother of two children. When Allison won the Lasker prize, in 2015, the committee flew Belvin to New York City with her husband and her parents to see him receive it. "She picked me up and started squeezing me," Allison says. "I walked back to my lab and thought, Wow, I cure mice of tumors and all they do is bite me." He adds, dryly, "Of course, we gave them the tumors in the first place."

After ipi, Allison could have taken a break and waited for his Nobel, driving his Porsche Boxster with the license plate CTLA-4 around Houston and playing the occasional harmonica gig. (Allison, who grew up in rural Texas, has played since he was a teenager and once performed "Blue Eyes Crying in the Rain" onstage with Willie Nelson.) Instead, his focus has become one of two serious problems with immunotherapy: It only works for some people.

So far, the beneficiaries of immune checkpoint therapy appear to be those with cancer that develops after repeated genetic mutations&mdashmetastatic melanoma, non-small-cell lung cancer, and bladder cancer, for example. These are cancers that often result from bad habits like smoking and sun exposure. But even within these types of cancer, immune checkpoint therapies improve long-term survival in only about 20 to 25 percent of patients. In the rest the treatment fails, and researchers have no idea why.

Lately, Allison considers immune checkpoint therapy a "platform"&mdasha menu of treatments that can be amended and combined to increase the percentage of people for whom it works. A newer drug called Keytruda that acts on a different immune checkpoint, PD-1, knocked former president Jimmy Carter's metastatic melanoma into remission in 2015. Recent trials that blocked both PD-1 and CTLA-4 in combination improved long-term survival in 60 percent of melanoma patients. Now, doctors are combining checkpoint therapies with precision cancer drugs, or with radiation, or with chemotherapy. Allison refers to this as "one from column A, and one from column B."

The thing about checkpoint inhibitor therapy that is so exciting&mdashdespite the circumscribed group of patients for whom it works, and despite sometimes mortal side effects from the immune system going buck-wild once the brakes come off&mdashis the length of time it can potentially give people. Before therapies that exploited the immune system, response rates were measured in a few extra months of life. Checkpoint inhibitor therapy helps extremely sick people live for years. So what if it doesn't work for everyone? Every cancer patient you can add to the success pile is essentially cured.

Jennifer Wargo is another researcher at MD Anderson who is trying to predict who will respond to checkpoint inhibitor therapy and who will not. Originally a nurse, Wargo got so interested in biology that she went back to school for a bachelor's degree, then a medical degree, and then a surgical residency at Harvard. It was during her first faculty position, also at Harvard, around 2008, that she started to wonder how the microbiome&mdashthe bacteria that live in the human body, of which there are roughly 40 trillion in the average 155-pound man&mdashmight affect cancer treatment. Wargo was investigating the bacteria that lived near the site of pancreatic cancer&mdashin and around the tumor. Could you target those bacteria with drugs and make the cancer recede more quickly?

In the early 2010s, research about the microbiome in the human gut&mdashthe bacteria in humans' stomachs and intestines that appear to affect immune function, gene expression, and mood, among other things&mdashgained traction in journals. Before long, two separate researchers had shown that you could change a mouse's response to immune checkpoint inhibitor therapy by giving him certain kinds of bacteria. Wargo added the microbiome to her slate of experiments. Along with her team, she collected gut microbiome samples from more than three hundred cancer patients who then went on to receive checkpoint inhibitors as treatment. The results were, Wargo says, "night and day." People who had a higher diversity of gut bacteria had a stronger response to checkpoint inhibitor therapy.

Now, Wargo is transplanting stool samples from patients into germ-free mice with melanoma, to see if she can predict whether the mice will mimic the treatment responses of the people whose bacteria they received. "Can we change the gut microbiome to enhance responses to therapy&thinsp.&thinsp.&thinsp.&thinspor even prevent cancer altogether?" she says. "Ah god, that would be the holy grail, wouldn't it?" she whispers, as if not to invite bad luck. "It's gonna take a lot of work to get there, but I think the answer is gonna be yes."

Immunotherapies do have one other problem worth worrying about, one that underlies the most frustrating experience of having cancer. When a patient is diagnosed, the first therapy is still one of the standards: surgery, radiation, or chemotherapy. Cut, burn, or poison, as the doctors say. Doctors can't use promising immunotherapies as first-line treatments yet because immunotherapies are still dangerous: No one knows what will happen long-term if you shut off the immune system's brakes. Does a patient survive cancer just to develop another terrible disease, like amyotrophic lateral sclerosis (ALS), in fifteen years?

Interlude

"Just to play devil's advocate," says a woman at a margarita bar and restaurant in Santa Fe, New Mexico. "Don't you think the cure exists somewhere already and the medical industrial complex is hiding it? People stand to lose billions of dollars. Don't you think they want to keep that money?"

I have been talking to this woman for twenty minutes. She is familiar with cancer. She works with natural cures, is a big fan of neuroscience, and knows some of the prominent names in medical research. I tell her that the conspiracy theory she is referencing&mdashthat the government or pharmaceutical industry is hiding the cure for cancer&mdashcan't be true. Of course it's hard to believe that Richard Nixon initiated the war on cancer in 1971 and the disease still kills 595,690 people a year. And that the most brilliant minds of our time have turned HIV into a chronic disease but cancer continues relatively unchecked. And yet I've talked to thirty-five researchers and policymakers and visited seven cancer centers and I haven't seen a shred of evidence that doctors who treat very sick people&mdashand whose job it is, sometimes, to tell people that they will die&mdasharen't trying with their very souls to succeed at their jobs.

"It's just that it's hard," I say.

The woman huffs. Someone more interesting is sitting on the other side of her. And that's the end of that.

The Magic Isotope

The appeal of actinium-225 as a cancer drug is in the alpha particles it releases. Alpha particles have such low tissue penetration that they can't even pass through a sheet of paper, so in theory they could kill cancer cells without causing many side effects. If a drug company could attach a targeting mechanism to the actinium-225, the isotope would attack cancer cells with alpha particles as it decays into francium-221, astatine-217, and bismuth-213. The fourth decay can occur by two different routes, with each path releasing one alpha particle and one beta particle before reaching lead-209. The small amount of stable bismuth-209 that remains at the end is excreted in the urine.

III. CAR-T Cells: Tiny Machines

On a shelf in Crystal Mackall's office at Stanford University in Palo Alto, California, catty-corner to a window that looks out on a lovely California scrub scape, is a teddy bear that once belonged to a boy named Sam.* Sam, who Mackall treated at the National Cancer Institute more than ten years ago, had Ewing's sarcoma, a rare cancer that usually affects children and grows in or around bones.

Mackall is a pediatric oncologist with a dark blond bob and a wry, take-no-prisoners sense of humor. She has worked on cancer since the 1980s, so she has met a lot of very, very sick children. The way Mackall tells the story of Sam, like she's taking a shot of foul-tasting medicine, you can see the distance she's had to put between her emotions and her work. "We lost Sam. He was ten," she says. "We gave him immunotherapy and it didn't work."

With that, Mackall moves on to the story of a girl named Lisa, who is pictured in a photo not far from the bear. Lisa had the same illness as Sam around the same time, but her therapy did work. Lisa's story lasts more than a minute, with Mackall practically cheering at the end. "So she remained fertile and that's her little boy!" she yells, gesturing toward Lisa's photo. Mackall smiles the pained, confused smile of someone who has inexplicably survived a car crash. "You have your ups and your downs," she says.

Overall, children's cancer has been one of the great success stories in cancer treatment. In the 1970s, dramatic advances in chemotherapy put most patients with certain types of leukemia (particularly acute lymphoblastic leukemia in B-cells, otherwise known as B-ALL) into remission. Today, 84 percent of children who get ALL can be cured. But then treatment stalled. "We have made steady progress, by all accounts," says Mackall. "But it's been largely incremental. And there've been these plateaus that have just driven us crazy."

In those unfortunate few children who relapsed or didn't respond to the chemo, or who got a different variety of cancer, like Ewing's sarcoma, there were few treatments left to try. Mackall's patients came to her after having had surgery and then chemotherapy once, twice, three times. "You can just see, they're beat up. They're making it, but all they do is get their treatments," she says. "They didn't have enough energy to do anything else." And then, if they lasted long enough, they got into a trial.

There are several ways to turn the immune system against cancer. Checkpoint inhibitor therapy is one of them. But it doesn't work in all patients, especially children, whose cancers generally do not have the vast numbers of mutations needed to attract the attention of a newly brake-free immune system. For a long, dark time, immunotherapists would try other sorts of techniques to get the immune system to respond in these patients, and the patients would die anyway, like Sam did. The treatments were toxic or they damaged the brain or they just didn't work. The doctors would recommend hospice. Hospice. Hospice. Hospice.

And then all the research began to pay off. In August 2010, a retired correctional officer named Bill Ludwig walked into the Hospital of the University of Pennsylvania to try a new therapy developed by a researcher named Carl June. Ludwig had chronic lymphocytic leukemia (CLL), another cancer that affects B-cells. Multiple rounds of chemotherapy had failed to cure it, and he didn't qualify for a bone marrow transplant. June's idea, which was so risky that the National Institutes of Health had turned down several grant applications to fund it, was the only option Ludwig had. June had only enough money to try it in three patients. Ludwig went first.

To understand how June's therapy works, consider the T-cells that Jim Allison found fascinating. They're cells that kill other cells, but they don't kill you because they have a built-in targeting mechanism. Each person has millions of T-cells, and each one of those T-cells matches a single virus, like a lock and a key. If a virus enters the body, its own personal T-cell key will find and destroy it, then copy and copy and copy itself until the virus succumbs. "I liken it to a bloodhound," says Mackall. "What the marker says to the T-cell is: Anything that has this thing on it, kill it."

Previously, researchers had created a fake key called a chimeric antigen receptor, or CAR, that matched a particular lock, CD19, on B-cells, which is where Ludwig's leukemia was. During the trial, Ludwig's doctors removed as many of Ludwig's T-cells as they could, and June's team inserted the CAR using a modified form of HIV, which can edit genes. Then they returned the T-cells to Ludwig.

Ten days later, Ludwig started to have chills and fever, like he had the flu. He was so ill that doctors moved him to the intensive care unit. But then, less than a month later, he was in remission. The T-cells had located and demolished the cancer, the same way they would a virus.

When case studies of the first three patients were published in scientific journals, mainstream media went crazy: "Cancer treated with HIV!" they shouted. But it was a later study that showed that the furor was warranted: When the Penn team partnered with the Children's Hospital of Pennsylvania to try CAR-T cell therapy against B-ALL in children, the cancer disappeared in twenty-four out of twenty-seven patients.

Novartis was the drug company that partnered with the University of Pennsylvania to turn June's treatment into a drug for the general public, and the company submitted results of all three required levels of tests to the Food and Drug Administration early this year. If the FDA approves the drug, any child who has B-ALL and has failed her first therapy can have her white blood cells removed, frozen, and shipped to Novartis's processing facility in Morris Plains, New Jersey, where molecular engineers will insert the new "key" and send the T-cells back. The patient gets a one-time infusion, and there's an 83 percent chance she will be cured.

"We also do a second measure of remissions where we look to see if there's any measurable disease at all," says David Lebwohl, Novartis's global program head for CAR-T treatments. "A more sensitive test than just looking in the blood. And that was also negative for 83 percent of the patients."

An 83 percent cure rate in children who would otherwise die is a monumental achievement. If there is a moment where a culture hits on an idea that can cure a disease&mdashvaccines, for example, or penicillin&mdashwe are in it. It is difficult to overstate this: Humans have been trying to create a cell therapy for cancer patients for generations. "People said: That can't be done, You can't make them from cancer patients, You can't make them, You can't get them, It's too complicated," says Crystal Mackall. "But it's happening." Though Novartis couldn't confirm an official release date, Mackall suspects the drug will become widely available this year.

Cancer being cancer, of course, there are limitations: Until it clears further FDA hurdles, Novartis's drug will be available only for children with B-ALL and not for any of the dozens of other types of cancers that affect children and adults. In solid tumors, the CAR-T cells aren't strong enough to kill the whole thing, or they die before they finish the job. Worse, once attacked, some leukemia cells will remove their CD19 proteins and go back into hiding. "The thing about cancer is, it's quite a foe," Mackall says. "The minute you think you've got the one thing for it, it'll outsmart you."

Slowly, though, the successes are mounting. At City of Hope National Medical Center just outside Los Angeles, Behnam Badie, an Iranian-born brain surgeon who has the kind of bedside manner you'd dream of if you ever required a brain surgeon, is developing a surgical device that can continuously infuse CAR-T cells into the brain tumors of cancer patients while he operates. For a while, he was working with the California Institute of Technology to build a magnetic helmet that could move the cells to the correct places, but the project ran out of money.

Meanwhile, Crystal Mackall is working on a backup target for the CAR-T cells, CD22, in case a child's cancer resists the ones targeted to CD19. She is also trying to make the cells live longer. Working with similar but slightly different engineered cells, she has managed to get her therapy to stay alive and working for up to two years in patients with solid sarcomas. One of her patients has since gotten married and bought a farm. Another went on a volunteer trip to Africa.

Mackall likens genetically engineered cells to rudimentary machines. Over the next decade, she says, scientists will refine them until they can control where they go and what they do and when. "We're going to be in a situation," she says, "where a doctor can tell a patient to take pills to activate his cells one week and then rest them the next." In fact, a biotech company based in San Diego called BioAtla has already developed conditionally active markers that could tell a T-cell to kill or not kill based on where it is in the body.

Eventually, programmable cell machines could fight autoimmune diseases, or arthritis. They could be used to rebuild collagen in athletes' knees. But, because such powerful new technology requires a ton of risk to attempt, none of this would have been developed without an adversary as vile as cancer to require it. "We treated forty-nine kids at the National Cancer Institute with refractory leukemia. Every single one of those kids had exhausted every other therapy available. If it weren't for the CAR-T cells, they were gonna die," Mackall says. Sixty percent of those children went into remission, and a sizable fraction of those appear to be cured. "You're able to take the chance only in that situation, when people don't have other options."

People will die waiting for CAR-T therapy to really, truly happen. In the United States, doctors aren't permitted to experiment on patients who have other options, and it will take a long time for CAR-T to prove itself better than the treatments already available. But someone has to choose to take the first walk down the path to the future. In a final act that is equal parts self-preservation and sacrifice, that person is usually a cancer patient. And soon, more of them will be able to make the decision for themselves.

Interlude

"What're ya down here for?" asks an older gentleman at the bar of a tourist barbecue joint near my hotel in Memphis. I'm halfway through a plate of pickles and dry-rubbed ribs. I explain that I've spent all day at St. Jude.

"God bless you," he says. "I couldn't do it." The man is from Texas&mdashhe works in shipping or packing or something or other.

The bartender, a bubbly twenty-three-year-old, offers the gentleman another beer. "You know, I was treated at St. Jude. Diagnosed at ten. Cured at thirteen," he says, beaming.

"Was it awful?" I ask. "Getting cancer as a kid?"

"Naw, I loved going to St. Jude. I remember I looked forward to school being over so I could go over to the hospital and get chemo. Your doctors are so happy to see you."

The bartender is studying to be a truck driver so he can visit California. He's not sure if he'll settle down there, but it seems nice.

The man from Texas looks at the bartender hard for a good minute, says, "You're a lucky man, son."

IV. Postmodern Radiation: Any Other Ideas?

To get to the Los Alamos National Laboratory in New Mexico, you drive from Santa Fe through peach-parfait mesas and off into the sunset. Even on the public roads, there are checkpoints where security officers will ask to see your driver's license. The deeper you go, the more intense the screening gets, until finally you end up in a place employees just call "behind the fence."

After the public roads but before "behind the fence," are the hot cells: four-foot by three-and-a-half-foot boxes where employees use robot hands controlled by joysticks to process non-weapons-grade isotopes. The isotopes are made on another mesa, by a linear particle accelerator that shoots rare metals with proton beams.

Just outside the hot cells, Eva Birnbaum, the isotope production facility's program manager, asks me if I know what a decay chain is. She points in the direction of an expanded periodic table that, despite a year of college chemistry, means about as much to me as a list of shipbuilding supplies from the 1600s. Birnbaum launches into a primer on radiochemistry: Isotopes are chemical elements with too many or too few neutrons in their centers. Some of these are unstable and therefore release energy by shooting out various types of particles. Unstable isotopes are radioactive, and the particles they shoot out are known as ionizing radiation.

As for what a decay chain is: When radioactive isotopes release radiation, they usually turn into another radioactive isotope, which releases radiation until it turns into another radioactive isotope, and so on, until it hits on something stable. The pattern by which a particular isotope morphs is its decay chain. Today, in addition to whatever goes on behind the fence, Los Alamos National Laboratory is the primary producer of certain isotopes whose decay chains make them useful for medical scans, such as PET scans and heart-imaging techniques. Scientists at Los Alamos deliver the parent isotope in a container called a cow. As the parent decays, doctors "milk" the daughter isotope off to image patients' hearts.

Decay chains present both an opportunity and a responsibility for the U.S. government. You can't just throw decaying radioactive isotopes into a landfill, so after the nuclear age and a half-century Cold War with the U.S.S.R., there are caches of radioactive uranium and plutonium isotopes sitting around gradually turning into other stuff. One of these caches is uranium-233, which was originally created for a reactor program and is currently stored at the Oak Ridge National Laboratory in Tennessee. Over the last forty-some years, it has been slowly turning into thorium-229.

Thorium-229's decay chain leads to actinium-225, which is of interest to cancer researchers for several reasons. For one thing, actinium-225's decay chain goes on for several generations. It turns into francium-221, then astatine-217, then bismuth-213, then mostly polonium-213, then lead-209 before finally hitting a hard stop at bismuth-209, which is stable. In most of these generations, the radiation released consists of alpha particles, which can destroy cancer cells but have low tissue penetration&mdashthey leave the surrounding healthy cells mostly alone. Currently, all but one of the radioactive isotopes used in cancer treatment release beta radiation, which causes considerably more collateral damage.

If a drug company could attach an atom of actinium-225 to a targeting system&mdashlike, say, the kind in CAR-T cells&mdashthe actinium-225 could continuously attack cancer for days at a time, like an artificial, radioactive version of the immune system. Newer chemotherapy drugs called antibody-drug conjugates already use this technique, directing chemotherapy agents that are too strong to give intravenously precisely where they are needed. At least two of these, Kadcyla and Adcetris, have already been approved by the FDA (for HER2-positive breast cancer and Hodgkin's lymphoma, respectively).

The U.S. system of national laboratories is already in talks with drug companies about making antibody-based radioactive drugs a reality. They seem promising: In a paper released last July in the Journal of Nuclear Medicine, one late-stage prostate cancer patient treated with three cycles of targeted actinium-225 at the University Hospital Heidelberg in Germany went into complete remission and another's tumors disappeared from scans.

But of course, there's a problem: Now that the reactor program and the Cold War are both over, no one is making uranium-233 in the U.S. (or anywhere). And because it takes more than forty years for uranium-233 to turn into enough thorium-229 to be useful, it wouldn't matter much even if they did. There are currently only about fifteen hundred to seventeen hundred millicuries of actinium-225 anywhere in the world, which would just treat one hundred to two hundred patients a year.

Which brings us to the reason Los Alamos has gotten deeply involved in actinium-225 at all: They're going to figure out how to make more from scratch.

Interlude

A roughshod man with bloodshot eyes rolls a cigarette outside a coffee shop in Taos, New Mexico. I can't be sure if he is the backpacker who was playing a flute at this table earlier or a new person. "You a reporter?" he asks.

"Er, yeah. Just got off the phone with a drug company that thinks they can cure cancer."

"A drug for cancer already exists," the man says. "More people need to be looking at marijuana. It can cure all kinds of sicknesses, but the thing is, the government doesn't want people knowing about it."

A light breeze rustles the wind chimes. We are hiding from the sun under a pergola on the shop's back porch. Another man attempts to come to my rescue: "But wasn't Obama trying to change the rules about experimenting&mdash"

"Obama doesn't want to change the rules because he's not like us," says the first man. "He's got pharaoh DNA that they blend with lizard blood up in the mountains." He inclines his chin toward Los Alamos.

"So he's like a monster?" asks the second man.

"Nah, they're physical, like us, but they only have three chakras, so they're not as balanced." He nods, sagely. "Highly carnivorous."

V. Policy Reform: Divided We Fall

Imagine cancer researchers as thousands of ships attempting to cross the Pacific, all with skills and tools that they have perfected in their home countries. Some have expert navigators. Others build the most watertight ships. If someone could combine the skills of the entire group, they could build a supership the likes of which has never been seen. Instead, they seem to communicate mostly by throwing paper airplanes at each other.

"All you could do with government-funded academic research, in the age of paper, was share information in person, so you had these huge cancer meetings once a year where everybody holds their research until they get there," says Greg Simon, the executive director of former vice president Joseph Biden's Cancer Moonshot, an initiative launched by the Obama administration in 2016. "We haven't changed it since."

The system of medical journals, subscriptions to which can cost thousands of dollars, are hardly the only baked-in obstacle to progress in cancer research. Clinical trials are still designed the same way they were fifty years ago. Funding, applied for and received in crazed round-robins of grant-writing, tends to reward low-risk experiments. There's secrecy and competition and slowness and inherent bureaucracy. The system wasn't created to be inefficient, but now that it is, it is intractably so.

Just this week, Simon has flown all over the country trying to bring bullheaded institutions with impossibly huge data troves into a single kumbaya circle of progress. This morning, he gave a speech at the 28th Annual Cancer Progress Conference. Now he is entertaining a journalist at a sushi lunch in the lobby of a Manhattan hotel. By rights, he should be asleep at the table with his face on a plate. Instead, he orders plain fish, no rice, in a disarming Southern accent. (Simon is from Arkansas.)

When Simon was twenty-eight, he played drums in a rock band called the Great Zambini Brothers Band. Then he decided to do something with his life, "quit the band, waited tables, went to law school, got a job, and hated it," he says. A friend found him work in Washington and by forty-one, Simon was working in the White House as an aide to then vice president Al Gore. Then he cofounded a Washington think tank called FasterCures. Then he worked as senior vice president for patient engagement at Pfizer. If anyone on earth knows how to get from here to there, Simon is the guy.

"Future." A tricky word for a cancer patient.

Since he left the White House (again) in January, Simon and his team have begun developing, out of a WeWork space, a spin-off of the Cancer Moonshot they're calling the Biden Cancer Initiative. It will be its own separate nonprofit, apart from government or charity. Its goal: Fix policy and make connections so that those with the expertise to cure cancer have a clear path to the finish line.

To achieve such a feat, Simon will work against a scientific version of the tragedy of the commons&mdashan economic theory in which each person, acting in his own best interest, screws up the whole for everyone else. Convincing people and institutions to act against their own best interest will be much like governing, which is to say, slow and impossible. And yet it's hard not to believe in Biden, a man who helped run the most powerful country in the world at the same time he lost his own son to brain cancer.

"We won't be funding research. The world doesn't need another foundation with money," says Simon. "What it needs is someone like Biden, who's willing to knock heads together&thinsp.&thinsp.&thinsp." He pauses. "Or cajole heads together, to make the changes that everyone has an excuse not to do: I wanna make money, I want tenure, I wanna get published, I want this, I want that."

The fragmentation in medical research&mdashthe lone ships out on the ocean&mdashdoesn't exist as much in other sciences, says Simon, because scientists in other disciplines have no choice but to share equipment: telescopes or seismology sensors or space shuttles. Industries that have managed to work together have sent humans to the moon. "We don't even know how much progress we could make in our cancer enterprise because we've never had it up and running at a level that would be optimal," he says.

Simon himself had cancer. Three years ago. It was CLL. "I found it through a physical," he says. "I never had any of the raging symptoms, like bleeding. During the chemo I didn't notice it at all. Zero side effects. I thought I'd lose my hair so I grew a beard. But I didn't."

Interlude

"You are writing. Are you writer?" asks the flight attendant on Delta Flight 3866 from LaGuardia to Memphis in a thick Eastern European accent. It's a late flight&mdashpost-work&mdashand many of the passengers are asleep. My reading light is one of just three that are illuminated.

"I had cancer," she says. "Breast cancer. I still have no boobs. After my surgery, they put in a balloon that they inflate step by step. After a few weeks I say to the doctor, 'I am still as flat as pancake!' And he says, 'Ah, there must be a hole.'&thinsp"

The flight is turbulent, so the flight attendant perches on the arm of the seat in front of me. "I go home after surgery and I have a chill, so I take my medication&mdashthey give you such powerful medication&mdashand I sleep. Thank god my friend came over and said I had to take a shower, because I took off the bandages and it was as red as this!" She points to the crimson bit of her Delta pin.

The flight attendant, diagnosed with stage 3a breast cancer, had developed a blood infection, and had to go to the hospital for intravenous antibiotics. After that, she had eight rounds of chemotherapy and thirty-three of radiation.

"There was so much pain, but I had to walk through the pain. I made myself," she says. "I wrote 'I love you' on my mirror in lipstick. When you're single and you have cancer and you look at yourself, you need to read that. What else is there to do?"

CAR-T Cells Explained

To make a CAR-T cell, doctors remove some of a patient's T-cells using a process similar to dialysis. In a lab, they use a gene-editing technique, such as infecting the T-cells with a modified virus, to add in a new receptor (left). This new receptor, called a chimeric antigen receptor, or CAR, is like a key that matches a very specific lock on the surface of cancer cells.

When doctors return the mutant T-cells to the patient, they flow through the body, attach to the cancer's lock, and start trying to kill it the same way they would a cell infected by a virus. First, the T-cells release a chemical called perforin, which makes a little hole in the cancer cell. Then the T-cells release cytotoxins, which flow in through the hole until the cancer cell dies.

VI. Silicon Valley: The Brain

Through the floor-to-ceiling windows of the Parker Institute for Cancer Immunotherapyin San Francisco are the windswept headlands of the Golden Gate Bridge, the Pacific Ocean, and a frothy coral rotunda called the Palace of Fine Arts.

"Would you like a water?" asks the center's publicist when I visit. "Still or sparkling?"

Of all the cancer centers I visited, the Parker Institute seemed the most like the future of medicine. The office, a few doors from Lucasfilm, has one of those pristine, snack-filled tech startup kitchens with glass jars and a microwave that pulls out like an oven. On a table in the reception area sits a set of glittery silver pamphlets the size of small yearbooks explaining the mission.

The man behind the Parker Institute is serial entrepreneur Sean Parker, the cofounder of Napster and intermittent recipient of richly deserved tabloid jabs. Parker doesn't have the most sterling humanitarian reputation: In the movie The Social Network, Justin Timberlake portrayed him as a narcissistic party boy who screws over one of Facebook's cofounders and is arrested for cocaine possession. Parker was fined $2.5 million by the California Coastal Commission for building the set of his $10 million Lord of the Rings&ndashthemed wedding (complete with fake ruins, waterfalls, and a cottage) in an ecologically sensitive area. And yet, a little over a year ago, the same man donated $250 million to fund the study of immunotherapy at a lavish backyard gala featuring performances by John Legend, Lady Gaga, and the Red Hot Chili Peppers.

The public story about Parker's philanthropic effort is that it stemmed from the death of his close friend, film producer Laura Ziskin, to recurrent breast cancer. According to Jeff Bluestone, the Parker Institute's president and CEO (and, incidentally, the researcher who characterized CTLA-4 around the same time as Jim Allison), Parker was interested in cancer long before he met Ziskin. "Sean's been interested in the immune system for much of his life, because he's got asthma, and he's had a serious immunological imbalance," he says, sitting at a polished raw-wood conference table half again as long as a normal conference table. (Parker is extremely allergic to peanuts.) "As long ago as 2004, before Laura got sick again, he thought the immune system was going to be the answer. He deeply understands a lot of the science. We joke, is he a second-year graduate student? A third-year postdoc? Should he just go get a Ph.D.?"

Parker is not the first very wealthy person who has used his money to combat disease. Several people at the Institute took care to explain how they were different from the Howard Hughes Medical Institute, a science-funding organization founded by the reclusive airman in 1953. A more influential predecessor might be Michael Milken, the Wall Street financier who founded a charity dedicated to family medicine with his brother Lowell in 1982 that supported, among other things, the research that led to Gleevec, the precision-medicine drug. Milken's funds also supported Jim Allison during an important time in his pre-checkpoint-inhibitor-therapy research when his National Institutes of Health grant had briefly lapsed. In 2003, Milken cofounded FasterCures with Greg Simon with the goal of increasing the pace of cures to "all serious diseases."

Some would argue that technology entrepreneurs are exactly the people who should be constructing the immaculate future of cancer research conceived by people like Joe Biden and Greg Simon. For one thing, tech entrepreneurs have already disrupted everything else. They understand the fast-moving, coin-chasing world of biotech development. Parker himself has already succeeded at convincing hardheaded institutions to work together. While he was an early investor and board member in the music streaming service Spotify, he negotiated with Universal and Warner to convince them to participate.

The Parker Institute's fundamental accomplishment thus far has been to do exactly this in cancer research. From the beginning, six academic research institutions signed on to work together under the Parker Institute's umbrella: Memorial Sloan Kettering MD Anderson Penn Medicine Stanford Medicine University of California, Los Angeles and University of California, San Francisco. The six, along with independent investigators at a few other research institutions, agree to share research data and work together on goals and projects without getting hung up on institutional constraints, such as intellectual property. In return, they get two things: money, which every cancer researcher needs and guidance, which is equally pressing but not necessarily as obvious.

"To become a leader in this field, to be a Carl June or a Jim Allison, you usually have to be a bit&mdashnot myopic, but a little blind," says Fred Ramsdell, the Parker Institute's vice president of research. This is common in science. To understand and work on a complicated concept, a researcher has to shut out the noise of everything except his exact area of expertise. Someone who works on checkpoint inhibitor therapies in melanoma, for example, might not see much use in reading about ovarian cancer detectors made out of nanocarbon&mdashuntil suddenly it's the exact bridge to his own next level of progress.

Microsoft believes A.I. will do a better job of parsing papers for insights than people can.

"If a person knows nothing about nanoparticles, I can step in and say, Hey, this nanoparticle thing might be exactly what you need," says Ramsdell. "I spend a lot of time trying to develop relationships between people who might not always do so on their own." Some of those relationships are between researchers themselves. Others are between M.D.'s and Ph.D.'s, or between researchers and drug companies, or engineering companies, or the U.S. Patent Office. It doesn't really matter, so long as the arrangement furthers knowledge.

Up the coast in Seattle, another tech company is attempting to help cancer researchers cross entrenched divides. Microsoft's Project Hanover has already made considerable progress on creating a combined, searchable repository of the scientific news released every month by cancer researchers all over the world. The idea is that artificial intelligence will do a better job of parsing the vast landscape of scientific papers (those paper airplanes flying between ships) for insights. Rather than fallible humans trying to catch every valuable new detail as papers fly out of scientific clearinghouses, the system will do it for them, considering every possible combination of targeted drugs and genetic interactions in less time and more detail than it would take a team of educated humans.

Microsoft calls this the reasoning bottleneck. In a way, they're tackling it the same way the Parker Institute is. The same way the human body does: They're adding a brain.

Interlude

San Francisco. It's late. At the restaurant, there is a man seated at the chef's table when I arrive, drinking a balloon glass of red wine.

"How's the food?" the man asks after a good half hour. It is delicious&mdasha buttery bucatini with lamb ragu and bread crumbs. The man has lived down the street from this restaurant for years. He's a former tech entrepreneur who is now a project manager for a retail company. I tell him what I am writing.

"That's a hell of a coincidence," the man says. "I just flew home from watching my father die of cancer."

"He's still there. With my sister. He told me he was tired of feeling like he was on death watch. He told me I should just go. So I went."

VII. Hope

What you see after a person has been debilitated by cancer and lived are the scars. The missing jaw or breast. The colostomy bag. Hair that has grown back curly or coarse or gray in patches. Tattoos that mark the paths of radiation beams. The disease that contains all of human biology leaves no one unchanged. There is before cancer, and then there is after.

Above Patrick Garvey's desk, on the top shelf of a bookcase, sits a stack of brown resin jawbones&mdashdozens of them, mostly the mandible, or bottom jaw, which is commonly replaced with a bit of lower leg bone when it has to be removed because it is shot through with cancer. Every jawbone above Garvey's desk is a relic from a surgery he has performed at MD Anderson over the course of three years&mdashmore than two hundred patients whose faces are forever altered by their interaction with the disease.

Later today, Garvey will operate on a man with a more difficult case&mdasha large tumor in the maxilla, or top jaw&mdashas part of two surgical teams. The first team will remove the tumor and most of the bone, including the man's eye, and then Garvey's team will remove a piece of the man's fibula along with its blood supply and use it to reconstruct the man's face. "We'll be here into the night," Garvey says.

This type of surgery is called microvascular reconstruction surgery. It drastically improves life for patients who would otherwise, like late film critic Roger Ebert, no longer be able to eat or talk without support. When it fails, however, it fails impressively: The transferred bone must have the correct blood supply or the body will simply reabsorb it, leaving only the bare metal scaffold the doctor implanted. Human bone is far better suited to the long-term mechanics of chewing and talking than metal is, and a plate without bone to protect it will eventually snap, like a paper clip bent back and forth over and over. Garvey has had to reconstruct jaws that have failed before, leaving patients disfigured and unable to chew properly. For a patient who has already undergone treatment for cancer, the impact of having to have multiple reconstructive face surgeries is harrowing.

To make the surgery simpler, Garvey's team uses 3D-printed cutting guides and robotically milled metal plates to create the most precise reconstruction possible. This is how the brown resin jawbone graveyard above his desk got started. After a patient has a CT scan, a company called Materialise in Plymouth, Michigan, prints the jaw models as well as bolt-on cutting guides that show the surgeons exactly where to saw and reconnect fibula bones to match the person's original bone structure. Another company, in New York, creates a metal scaffold that is meticulously bent so as to re-create the original face angles, so MD Anderson's surgeons don't have to bend an off-the-shelf part into position during the reconstruction.

By all accounts, using 3D-printed guides to reconstruct a human face is an advance at the very edge of cancer medicine, and yet it is still disheartening to look at the statistics. Last year, another 1.7 million Americans were diagnosed with cancer, and almost six hundred thousand died. Since 2004, according to the latest data available, the overall decline in death rates has been just 1.8 percent in men and 1.4 percent in women year over year. The five-year survival rate for pancreatic cancer, which most doctors consider the worst of the worst, sits stubbornly at just 8.2 percent.

Perhaps the cure for cancer seems so elusive because it's a failure of semantics. "Curing cancer" is impossible, and the statistics reflect that: Cancer kills more Americans every two years than those who died in every war we've ever fought. However, helping some cancer patients, the luckiest of the unlucky, live in relative normalcy for years is not just possible. It is happening. The five-year overall cancer survival rate is up from 50 percent in 1975 to 67 percent today. For melanoma, it's 91.7 percent. For prostate cancer, it's 98.6. It will take time for the most promising treatments to trickle down to everyone they might be able to help, but in the meantime, the march continues.

What this has to do with Patrick Garvey is that, even subtly, using 3D-cutting guides to improve plastic surgery shifts the focus of cancer treatment from emergency battlefield triage to matters of aesthetics and psychology that matter months and years down the line. Without saying it, exactly, the field of cancer treatment is acknowledging that cancer could one day become a survivable disease&mdashthat even a stage four metastatic cancer patient could survive long enough for normalcy to matter.

There are others on the front lines: At hospitals across the country, women with breast cancer can wear a scalp-cooling system called DigniCap during chemotherapy treatments to reduce the likelihood of hair loss. At MD Anderson, a neuroscientist retrains patients' brains to improve altered nerve sensation caused by chemotherapy. St. Jude hired a psychologist to help teen cancer patients plan to save their eggs or sperm, in case their treatments render them infertile and they want to have a family in the future.

Future. A tricky word for a cancer patient. Who gets to have one is still a function of blind fortune. But all these ideas are starting to come together, and progress is suddenly accelerating. We are at what Crystal Mackall calls "the end of the beginning," and the hope is that one day soon, the miracles will no longer be miracles. They will just be what happens. Until then, we pin our hopes on the incremental or unpredictable improvements&mdashthe half measures, the better outcomes. It will always be true that once a person has had that most frightening of conversations with chance, life will be split into two parts&mdashthe time before cancer, and the time after it. But for a fortunate few, perhaps the second part can be as good, and even as rich and wonderful and as great as the first.

This article first appeared in the June 2017 issue of Popular Mechanics.


Development of Cancer Cell Line Panels

An important paradigm shift occurred in the late 1980s in response to the limited success in the clinic of compounds identified through screens using transplantable murine neoplasms for solid tumors (14). Consequently, development of an in vitro human-based tool for drug discovery to increase the translational success of newly identified anticancer compounds was sought. So the idea arose to develop a panel of cell lines that would recapitulate the variability of the chemotherapy response observed in the clinic for a particular tumor type. At that time, the observed response rate of many tumors to conventional chemotherapy ranged from 25% to 70%. Therefore, it was assumed that six to nine cell lines per tumor type would be sufficient to capture this variability. In the United States, the National Cancer Institute 60 (NCI-60) panel of cancer cell lines, which included 60 cancer cell lines representing nine different cancer types, was launched in 1990 (15). A few years later, the Japanese Foundation for Cancer Research developed its own panel of 39 cancer cell lines, which also represented nine cancer types (16). Although that panel included 30 cell lines in common with the NCI-60, it also provided a subpanel of six gastric cancer cell lines owing to the prevalence of stomach cancer in the Japanese population. Those platforms led to the generation of a wealth of information but also led to further confusion as to the origin of some cell lines and to the development of new analytical methodologies to integrate high-throughput data (15,17). Nonetheless, recent efforts have been carried out by the American Type Culture Collection Standards Development Organization Workgroup ASN-0002 to develop a standardized protocol and a publicly searchable database for the authentication of human cell lines using short tandem repeat profiling (18�). This is an important step to minimize, if not to eradicate, cell line misidentification.


Contents

Although the term "mind map" was first popularized by British popular psychology author and television personality Tony Buzan, the use of diagrams that visually "map" information using branching and radial maps traces back centuries. These pictorial methods record knowledge and model systems, and have a long history in learning, brainstorming, memory, visual thinking, and problem solving by educators, engineers, psychologists, and others. Some of the earliest examples of such graphical records were developed by Porphyry of Tyros, a noted thinker of the 3rd century, as he graphically visualized the concept categories of Aristotle. Philosopher Ramon Llull (1235–1315) also used such techniques.

The semantic network was developed in the late 1950s as a theory to understand human learning and developed further by Allan M. Collins and M. Ross Quillian during the early 1960s. Mind maps are similar in structure to concept maps, developed by learning experts in the 1970s, but differ in that mind maps are simplified by focusing around a single central key concept.

Popularization Edit

Buzan's specific approach, and the introduction of the term "mind map", arose during a 1974 BBC TV series he hosted, called Use Your Head. [4] [5] In this show, and companion book series, Buzan promoted his conception of radial tree, diagramming key words in a colorful, radiant, tree-like structure. [6]

Buzan says the idea was inspired by Alfred Korzybski's general semantics as popularized in science fiction novels, such as those of Robert A. Heinlein and A. E. van Vogt. He argues that while "traditional" outlines force readers to scan left to right and top to bottom, readers actually tend to scan the entire page in a non-linear fashion. Buzan's treatment also uses then-popular assumptions about the functions of cerebral hemispheres in order to explain the claimed increased effectiveness of mind mapping over other forms of note making.

  • Concept maps: Mind maps differ from concept maps in that mind maps focus on only one word or idea, whereas concept maps connect multiple words or ideas. Also, concept maps typically have text labels on their connecting lines/arms. Mind maps are based on radial hierarchies and tree structures denoting relationships with a central governing concept, whereas concept maps are based on connections between concepts in more diverse patterns. However, either can be part of a larger personal knowledge base system.
  • Modelling graphs: There is no rigorous right or wrong with mind maps, relying on the arbitrariness of mnemonic systems. A UML diagram or a semantic network has structured elements modelling relationships, with lines connecting objects to indicate relationship. This is generally done in black and white with a clear and agreed iconography. Mind maps serve a different purpose: they help with memory and organization. Mind maps are collections of words structured by the mental context of the author with visual mnemonics, and, through the use of colour, icons and visual links, are informal and necessary to the proper functioning of the mind map.

Effectiveness Edit

Cunningham (2005) conducted a user study in which 80% of the students thought "mindmapping helped them understand concepts and ideas in science". [7] Other studies also report some subjective positive effects on the use of mind maps. [8] [9] Positive opinions on their effectiveness, however, were much more prominent among students of art and design than in students of computer and information technology, with 62.5% vs 34% (respectively) agreeing that they were able to understand concepts better with mind mapping software. [8] Farrand, Hussain, and Hennessy (2002) found that spider diagrams (similar to concept maps) had limited, but significant, impact on memory recall in undergraduate students (a 10% increase over baseline for a 600-word text only) as compared to preferred study methods (a 6% increase over baseline). [10] This improvement was only robust after a week for those in the diagram group and there was a significant decrease in motivation compared to the subjects' preferred methods of note taking. A meta study about concept mapping concluded that concept mapping is more effective than "reading text passages, attending lectures, and participating in class discussions". [11] The same study also concluded that concept mapping is slightly more effective "than other constructive activities such as writing summaries and outlines". However, results were inconsistent, with the authors noting "significant heterogeneity was found in most subsets". In addition, they concluded that low-ability students may benefit more from mind mapping than high-ability students.

Features Edit

Joeran Beel and Stefan Langer conducted a comprehensive analysis of the content of mind maps. [12] They analysed 19,379 mind maps from 11,179 users of the mind mapping applications SciPlore MindMapping (now Docear) and MindMeister. Results include that average users create only a few mind maps (mean=2.7), average mind maps are rather small (31 nodes) with each node containing about three words (median). However, there were exceptions. One user created more than 200 mind maps, the largest mind map consisted of more than 50,000 nodes and the largest node contained

7,500 words. The study also showed that between different mind mapping applications (Docear vs MindMeister) significant differences exist related to how users create mind maps.

Automatic creation Edit

There have been some attempts to create mind maps automatically. Brucks & Schommer created mind maps automatically from full-text streams. [13] Rothenberger et al. extracted the main story of a text and presented it as mind map. [14] And there is a patent about automatically creating sub-topics in mind maps. [15]

Mind-mapping software can be used to organize large amounts of information, combining spatial organization, dynamic hierarchical structuring and node folding. Software packages can extend the concept of mind-mapping by allowing individuals to map more than thoughts and ideas with information on their computers and the Internet, like spreadsheets, documents, Internet sites and images. [16] It has been suggested that mind-mapping can improve learning/study efficiency up to 15% over conventional note-taking. [10]

The following dozen examples of mind maps show the range of styles that a mind map may take, from hand-drawn to computer-generated and from mostly text to highly illustrated. Despite their stylistic differences, all of the examples share a tree structure that hierarchically connects sub-topics to a main topic.


Claim: COVID-19 was made in a lab kind of like Nuclear Man in Superman IV, if you saw that

Truth: COVID-19 evolved from nature.

While Mikovits does not say the virus was created on purpose, she does say &ldquothis family of viruses was manipulated and studied in a laboratory, where the animals were taken into the laboratory, and this is what was released, whether deliberate or not.&rdquo

But back in March, researchers who studied the genetics of the novel coronavirus published otherwise in Nature. The scientists checked COVID-19 against features of other coronaviruses that occur in nature. &ldquoOur analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus,&rdquo they concluded.

The conspiracy theory is easier to believe, though, since we are more likely to be familiar with action movie plots than functional polybasic cleavage sites. &ldquoThe elements of conspiracy theories are also elements of other genres like mysteries and thrillers or soap opera,&rdquo said Mark Fenster, professor of law at UF and author of Conspiracy Theories: Secrecy and Power in American Culture.

The conspiracy theory is also easier to stomach than accepting the cold indifference of nature. &ldquoI think that for some people it is more comforting to believe that there&rsquos a human agent responsible for chaos and suffering than the alternative explanation: bad things happen randomly in life, and we'll never be able to change that,&rdquo said Joshua Hart, associate professor of psychology at Union College.


How to Make a Mind Map

This article was co-authored by Paul Chernyak, LPC. Paul Chernyak is a Licensed Professional Counselor in Chicago. He graduated from the American School of Professional Psychology in 2011.

There are 17 references cited in this article, which can be found at the bottom of the page.

wikiHow marks an article as reader-approved once it receives enough positive feedback. This article received 23 testimonials and 85% of readers who voted found it helpful, earning it our reader-approved status.

This article has been viewed 935,897 times.

People have been using visual methods of representing, organizing and understanding information since ancient times. In the 1970s, researcher and educator Tony Buzan formally developed the mind map. Its colorful, spider- or tree-like shape branches out to show relationships, solve problems creatively, and help you remember what you’ve learned. Mind mapping can help you understand things more easily. This article will walk you through planning a mind map, constructing it by hand, and looking at the pros and cons of many mind mapping software programs now on the market.


Is Anal Sex Safe?

Let's just get right to it: Anal sex can be totally safe&mdashand all taboos about it really need to go away (like, yesterday).

&ldquoAnal sex is a common human sexual behavior for women in hetero and same-sex relationships. This is not a rare activity!&rdquo says Stacy Tessler Lindau, M.D., professor at The University of Chicago Medicine, who also runs the site WomanLab.org.

While she says that research on the whole "is anal sex safe" question is limited, more than 20 percent of women ages 20 to 39 have had anal sex. &ldquoGiven that it&rsquos so common, it seems that most people do find pleasurable and safe ways to have it,&rdquo she says.

That said, there are some factors that may get in the way of safe anal sex. So, whether you're interested in trying it for pleasure, to shake up your sex life, or because a medical reason means you can&rsquot have vaginal sex&mdashhere's what you need to know:

Is it possible to injure your anus?

There's certainly a risk of tearing, especially if you're new to anal sex. But there are some simple things you can do&mdashlike starting with a small butt plug and working your way up to a penis, or using lube&mdashto minimize the chances. (Check out our Ultimate Anal Sex Guide for all the tips.)

Also keep in mind that using something like an enema in preparation can cause inflammation or trauma to the mucosal barrier of the rectum, increasing the risk of injury during anal sex, says Landau. Go ahead and poop before, but don&rsquot feel the need to go crazy flushing out the pipes.

Can you get an infection from anal?

Yep, there's no skirting around it: Poop comes out of your anus, and feces are filled with bacteria that can cause a vaginal infection, should stool travel to your lady parts. (That&rsquos why you wipe front to back.) One infection associated with anal sex is bacterial vaginosis.

To prevent this, if you&rsquore on the receiving end, make sure that your partner wears a condom. If you move from anal to vaginal sex, have him take off the condom and put on a new one, recommends Lindau. &ldquoThis will reduce the transmission of bacteria,&rdquo she says. Even if you&rsquore in an exclusive relationship and don&rsquot typically use condoms, she recommends wearing one for safe anal sex. You can then take it off for vaginal or oral.

And if you're into oral-anal stimulation, you can use a dental damn over the anal area which &ldquostill allows sensation to come through and reduces exposure to bacteria,&rdquo says Landau.

Are there any more serious long-term risks?

Having unprotected anal sex with a man increases your risk of HIV transmission. Abrasions or small tears during anal sex likely make transmission of the virus easier, says Lindau. (Again, condoms are your friend here.)

Another possible problem is fecal incontinence, when stool leaks out unexpectedly. Research from 2016 found that anal sex was associated with a slightly higher chance of fecal incontinence (FI) in women (we're talking 2 percent). According to the study authors, "anal intercourse could dilate and eventually stretch the internal and external anal sphincters leading to damage of these structures."

That said, the study didn't look at how often the subjects had anal sex, so there's really no way of confirming how much it ups your risk of FI. If you're truly concerned, doing kegels can help strengthen your sphincter (who knew?).

Regardless, don&rsquot be afraid to talk to your doctor if you notice this happening&mdashwhether related to anal sex or not.

Are there any signs I shouldn't have anal sex?

To protect yourself from any problems related to anal sex, follow this rule: If it&rsquos painful, stop. It&rsquos as simple as that, says Landau.

She also advises you try anal with a safe partner who you can easily communicate with. When you&rsquore on the same page, you can both have a good, safe anal sex experience.


Can You Be Too Clean?

We lead super clean lives in which hand sanitizers and antibiotics are the answers to everything. But what if our war on germs was backfiring&mdashand making us not only sicker but fatter?

In mid-november, 2010, Alex O. wondered for the first time if he might be dying. For 6 weeks, the 27-year-old had been suffering from a digestive disease as horrific as it was mysterious. Shortly after breaking up with his girlfriend in late September that year, he'd started experiencing bouts of diarrhea, which he initially thought might be due to the stress of heartbreak. After a month, however, his diarrhea hadn't improved and was now flecked with blood. Stabs of gut pain had begun to wake him up at night.

"The persistence of the diarrhea," he recalls, "kind of told me it wasn't due to my mental landscape."

Alex, a freelance graphic designer who works part-time at a food co-op in Minneapolis, had long described himself as "100 percent average"&mdash5'10", 170 pounds, brown hair, brown eyes. But his illness was making him look and feel anything but average. He could see in the mirror how quickly his face was turning gaunt and pale. He could feel his vitality draining too, almost as if someone had tapped a vein with an IV line and forgotten to cap the other end. A passionate, lifelong skateboarder, he no longer had the energy for his favorite recreation. He could barely make it through a day of work.

Alex's family doctor had tried everything he could think of, including diet changes and a weeklong course of antibiotics. Nothing worked. The doctor finally referred Alex to a gastroenterologist, who ordered tests for three potential culprits: cancer, HIV/AIDS, and a gut infection caused by a bacterium called Clostridium difficile, or C. diff, for short. First identified as a cause of intestinal infection in the 1970s, this rod-shaped bacterium inhabits the digestive tracts of up to 8 percent of healthy people without producing symptoms. It can be harmless, provided its population remains under control.

Considering the alternatives, Alex found himself hoping his problem was an overgrowth of C. diff. "When the gastroenterologist explained what he was testing for, he didn't rate one possibility as more likely than the others because he didn't want to give me false hope. I remember waiting for the HIV/ AIDS test, in particular, which he'd ordered because I was so anemic. There was one night when I thought that it probably was HIV and that I might die from it. It's really awful to say, but physically and mentally I was in so much pain I almost wished I were dead."

Eventually the doctors ruled out cancer and HIV. Alex was so relieved when the tests came back positive for an infection that the news struck him as more curious than dire. What he didn't know then was that eliminating this stomach bug is one of the most difficult battles faced by infectious-disease specialists today&mdashand one they often lose.

Each year, C. diff kills more Americans than HIV does.

Take a quick look at yourself in a full-length mirror. What stares back is first and foremost a human being: a massive assortment of human cells organized into human tissues and human organs.

If this conventional description seems reasonable to you, brace yourself for a fundamental shift in self-concept: For every one cell in our bodies, at least 10 microbes&mdashfrom bacteria to fungi to viruses&mdashpiggyback atop and within us. Thanks to powerful new investigative tools such as next-generation gene sequencers, scientists continue to uncover an astonishing diversity of species. To date they've been concentrating on bacteria. This is partly because these are our most common fellow travelers, and partly because technologies for sampling viruses, fungi, and other such organisms are still being refined.

The figures are nothing short of flabbergasting. Up to 100,000,000,000,000 (that's 100 trillion) individual bacterial cells from thousands of different species colonize everything from the mucous membranes of your nostrils to the lining of your urethra&mdashand a myriad of body niches in between. An infinitesimal pittance of these bacteria consists of hostile invaders their numbers, for the most part, are held in check. A slightly larger share is made up of transients&mdashbugs whose populations rise and fall depending on your environmental exposure. The vast majority, however, are permanent residents called "commensals," which are beneficial bugs whose lives have coevolved with ours since ancient times. This collective assortment is known as the human microbiome.

A single square centimeter of skin, for example, hosts 10,000 bacteria perched just on the outside surface. Lightly scrape your fingernail across the same small area and you'll unearth 50,000 more.

Skin, of course, is an ecological dessert compared with your body's truly prime real estate. "Most microbes prefer rich environments where there's a lot of food," says George Weinstock, Ph.D., associate director of the Genome Institute at Washington University in St. Louis. "And the gut is obviously where the nutrients are." Some estimates suggest that up to 9 pounds of microorganisms colonize the food highway that begins at the average guy's mouth and ends at his butt. Revolting, yes, but also crucial.

"The more we learn, the more we recognize how many vital contributions our commensals provide," says Lita Proctor, Ph.D., project director of the $175 million Human Microbiome Project, which was launched in 2007 by the National Institutes of Health.

Start with the role they play in activating, training, and maintaining our immune systems. For example, when skin commensals detect harmful bacteria, they trigger their human host to recruit inflammatory and immune cells to aid in the defense. Likewise, new research on mice suggests that when commensals in the gut detect flu viruses, they may use white blood cells to send warning signals to the lungs, sparking a counterattack from respiratory immune cells.

Our microbiome also helps us digest components of plant-based foods, such as dietary fiber and polysaccharides (the long-chain carbohydrates in starch), that we can't break down on our own. Researchers have even discovered that the intestines of Japanese people carry bacteria that help digest seaweed.

In the ultimate example of human-bacterial symbiosis, each cell in our bodies contains mitochondria, organelles that take energy stored in simple sugars, fatty acids, and amino acids and release it in a form that powers everything we do. Our mitochondria are so essential that you might think they've always been absolutely, 100 percent human. But in fact, ancestors of today's mitochondria were once bacterial that were living independent lives. Serendipitous infection of the ancestors of humans led eventually to the merger of invader and host. We've remained inseparable ever since.

Another contribution comes courtesy of the extraordinary number of metabolic by-products our microbiome produces. Bacteroides in the colon produce vitamin K. One common skin resident, Propionibacterium acnes, breaks down sebum, an oily substance produced by our sebaceous glands, creating a natural skin moisturizer. Other commensals alter the acid levels of their preferred habitat, making these areas less hospitable to destructive microbes.

When pathogens do attempt a hostile takeover, our good bugs release natural antibiotics known as bacteriocins to halt their advance. Lactobacillus salivarius in our mouths, for example, secretes a toxin lethal to Listeria monocytogenes&mdashthe bug behind deadly foodborne infections. Another bodyguard, the skin commensal Staphylococcus epidermidis, produces a peptide that can kill other dangerous staph germs.

Finally, the sheer enormity of friendly bacteria guard us against dangerous bugs by way of a process known as "colonization resistance." It's analogous to an apartment complex that's jam-packed with good tenants who don't ask for much and always pay their rent on time. When microbial thugs&mdashC. diff, for example&mdashcome looking for a place to grow, those tenants help ensure they don't find any vacancies.

At least not usually&mdashand not without help.

On New Year's Day 2011, Alex called his father to ask for a ride to the hospital. A week before, he'd completed his fifth course of antibiotics, this time with a more powerful, broad-spectrum drug. For 10 days he'd religiously swallowed four pills a day, in the process killing virtually everything inside his digestive tract.

Once the pill supply ended, his gastroenterologist prescribed probiotic capsules, which contain several strains of live bacteria common in a healthy gut. The hope was that these bugs might jumpstart the repopulation of a more normal gut microbiome. And this, in turn, could prevent C. diff from running wild again.

Alex realized within a few days that this latest strategy, like all of those preceding it, was failing. By New Year's Day he was in a world of hurt. "As a skateboarder," he says, "I'd developed a pretty high threshold for pain. Over the years, I've broken fingers, an ankle, a wrist, and my arm." But these injuries were nothing compared with the agony now stabbing his core.

The diarrhea was also the worst he'd ever experienced. What his body was producing, Alex recalls, had no resemblance whatsoever to normal human waste. "It was bright red and completely liquefied," he says. "It looked like exorcism blood." By the time his father got him to the hospital, he was so anemic the ER docs debated giving him a full blood transfusion. In 3 months he'd lost 27 pounds. He was gaunt to the point of emaciation, and the pain had kept him awake for days.

The ER docs prescribed oxycodone and administered multiple units of saline. As soon as the gastroenterologist arrived, he immediately started yet another round of antibiotics, this time using vancomycin, the most powerful agent yet. For the next month, Alex rarely left home.

"I could go to work for maybe 3 hours," he says. "I was so sick at many points that I couldn't do much more than immediately return home and lie around. I'd get these occasional survival pangs of hunger, and then I'd eat a little."

Vancomycin in pill form, alas, proved no more effective than the other antibiotics Alex had taken. His doctor next tried liquid vancomycin, which he hoped might work better. This had to be refrigerated, which bound Alex even closer to home. He began despairing that he'd never lead a normal life again.

The liquid drug failed too. His gastroenterologist searched the medical literature, desperate to find something&mdashanything&mdashthat might give his young patient a chance against the relentless enemy ruining him from within. The search led to Alexander Khoruts, M.D., a gastroenterologist who'd reported nearly too-good-to-be-true success at treating recurrent C. diff infection. The intervention sounded both bizarre and, frankly, disgusting. But it had worked for dozens of patients.

What's more, a referral to Dr. Khoruts wouldn't even require Alex to leave Minneapolis. An associate professor of medicine at the University of Minnesota, Dr. Khoruts's office was just blocks away from Alex's apartment.

The only time in our lives when our bodies are thought to be completely sterile is during the 9 months we spend in the womb. Throughout gestation, researchers have found, the composition of microbes in the mother's vagina undergoes dramatic changes in preparation for the newcomer's passage through the birth canal.

"Infants are like microbe magnets," says Proctor, "and we know babies pick up a huge part of their microbiome during vaginal delivery." Researchers refer to this as vertical transmission because it's handed down from one generation to the next.

But birth is only the start. In the first 2 to 3 years of life, we continue to add and subtract new populations in many ways. We pick up some new germs through skin-to-skin contact with parents and siblings. We add others during the transition to solid foods, crawling explorations of the natural world, taste-testing virtually anything we can cram into our infant mouths, encounters with animals and insects, and increased exposure to more and more humans and their microbes.

"Your immune system needs to be educated," says Julia Segre, Ph.D., a skin researcher at the National Human Genome Research Institute, "and the best way to do this is to be exposed to lots of different microbes that can do the teaching."

What's worrisome is that we may be flunking ourselves. Evidence continues to mount that the younger we are when our antibiotic exposure starts, the more serious and lasting are the problems caused to the "good bug" populations in our bodies.

"The average child in the United States has received 10 to 20 courses of antibiotics by the time he or she is 18 years old," says Martin Blaser, M.D., a professor of medicine and microbiology at New York University's Langone Medical Center. Typically the drugs are prescribed for ear infections, bad colds, sore throats, and the like. And antibiotics can sometimes prevent serious escalation of an illness&mdashstopping strep throat, for example, from turning into rheumatic fever. Still, experts believe, the drugs are wildly overprescribed, and may be dispensed more to palliate worried parents than to help their kids.

Patients have long assumed that antibiotics may not always help, but they're unlikely to hurt either&mdashin other words, "better safe than sorry."

But is this true? Of course, one well-known consequence is the emergence of antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), which made its first U.S. appearance in a Boston hospital in 1968. In 2005, the CDC estimated that MRSA caused 278,000 hospitalizations and contributed to 17,000 deaths. Its targets aren't limited to the sick and immune-compromised: News accounts nationwide have documented athletes in peak shape succumbing to MRSA through skin exposure in locker rooms, gyms, and contact sports.

Another deadly germ E. coli O157:H7, has followed an eerily similar trajectory. It was first identified as a foodborne pathogen in 1982, after contaminated hamburger triggered severe bloody diarrhea in dozens of diners. Since then, this virulent cousin of our "normal" E. coli intestinal residents has led to deaths and high-profile recalls of tainted foods&mdashfrom last year's 10-state outbreak linked to lettuce to 2009's 30-state swath of contagion traced to cookie dough.

But even if you eat that cookie dough and don't get sick, there's a good chance you will gain weight&mdashand believe it or not, antibiotics may be one of the culprits here too.

Since at least the early 1950s, low-dose antibiotics have been a routine additive in livestock feed, a practice known by the acronym STAT, for subtherapeutic antibiotic therapy. "Most nonfarmers assume that this is to prevent some disease in the herd," says Dr. Khoruts. "It's not. The real reason is the discovery that antibiotics make animals fatten up more quickly."

By 1954, researchers at the Naval Medical Research Unit had heard about STAT. They also knew of several small human studies that showed that antibiotics helped premature infants and undernourished children gain weight. Very little, however, had been published on weight effects in adults.

Strep infections can quickly spread through military ranks, and Navy researchers had demonstrated that giving antibiotics prophylactically at the first sign of an outbreak could reduce the number of people sickened. Might these drugs also be boosting the weight of robustly healthy young men?

To find out, they randomized six 55-man companies of Navy recruits into three groups. At reveille every morning for the next 7 weeks, each man was given a yellow capsule containing either an antibiotic (penicillin or Aureomycin) or a placebo he didn't know which one he was taking.

By the end of week 7, all three groups had gained weight. But those on antibiotics had gained significantly more&mdashon average, 4.8 pounds from Aureomycin and 4.1 pounds from penicillin, versus only 2.7 pounds from the placebo. This antibiotic-enhanced fattening may not have reached the level seen in antibiotic-fed farm animals, but then again, most men of that era hadn't received their first antibiotic doses as young as weaned calves and piglets had&mdasha distinction that's no longer true today. "Can using antibiotics to treat our kids for ear infections be setting them up for obesity in adulthood?" asks microbiologist Weinstock. "And if so, how?"

One intriguing possibility centers on the gut bacteria Helicobacter pylori. This bug hit the medical radar big time after two Australian doctors proved that it caused most stomach ulcers the doctors won Nobel Prizes for their work. But H. pylori isn't all bad&mdashquite the opposite, actually. When it's present in healthy numbers, H. pylori reduces the stomach's production of ghrelin, the so-called hunger hormone. In so doing, H. pylori may not only dampen appetite signals in the brain but also decrease fat storage in adipose tissue. So H. pylori could be a natural ally against gluttony.

Until the beginning of the 20th century, researchers believe, H. pylori was the single most common bacterial species in the human stomach. But then, suddenly and without warning, it began disappearing. "By the turn of the 21st century," says Dr. Blaser, "fewer than 6 percent of children in the United States, Sweden, and Germany were carrying the organism." Many factors, he concedes, could be playing a role in H. pylori's rapid demise, but antibiotics are his prime suspects. A single course of the antibiotic given for ear infections, for instance, could wipe out the entire H. pylori population in up to half of young patients.

Emerging research suggests that damage to the gut microbiome may be partly to blame for metabolic syndrome, a cluster of conditions including high blood sugar, high triglycerides, and a large waist circumference. Left untreated, the syndrome increases the risk of heart disease, stroke, and type 2 diabetes. In a fascinating study published last fall in the journal Diabetologia, French researchers showed that the blood concentrations of a specific bacte^al gene accurately predicted which of 3,000-plus people would go on to develop diabetes 6 to 9 years later. The same gene concentrations also predicted which normal-weight patients would go on to develop abdominal obesity.

Another component of metabolic syndrome is inflammation in fat cells. For reasons not yet understood, inflammation appears to change the way these cells store and mobilize fat. "This is the basis for one leading hypothesis about a microbiome role in metabolic syndrome," says Weinstock. "Certain bacteria overgrowing in the gut may increase an inflammatory response in adipose tissue, ramping up fat storage and weight gain."

The troubling extinction of H. pylori in so many people has been impossible for scientists to miss. But what about other, less visible members of our microbial ecology? Researchers continue to discover never-before-seen genes with each successive round of sequencing. Could the tag team of modern hygiene and indiscriminate antibiotic use be eradicating critical commensals before we even learn of their existence, let alone what roles they serve?

"The most important factor in modern allergic and metabolic diseases might not be the decreased sampling of microorganisms in the food, air, water, and soil," says Dr. Blaser, "but instead could reflect the loss of our ancestral microorganisms. Antibiotics kill the bacteria we do want as well as those we don't."

Dr. Khoruts did not invent the fecal transplant, which was first described in the medical literature in 1958. But over the past 3 years, he has become one of the most accomplished practitioners and enthusiastic proponents of the procedure. Also known euphemistically as "human probiotic infusion," or HPI, Dr. Khoruts concedes that regardless of nomenclature, most people greet the concept with disgust.

The notable exceptions are those who are too sick to care.

Such was the case with Dr. Khoruts's first fecal transplant patient, a 63-year-old woman infected with C. diff who came to him as her last hope. "By this point," he says, "her life was ruined. She'd lost 60 pounds, and I knew she was going to die. I gave her every antibiotic combination I could think of, and not one of them helped."

If anything, her condition worsened, and Dr. Khoruts suspected he knew why. One of the unique traits of C. diff is its ability to hunker down during hard times. It does this by forming seedlike spores that place it in near-suspended animation. Because of this, any antibiotic treatment has an inherent limitation: It effectively kills off active C. diff as well as most of the "good guy" commensal species active in the gut. But C. diff spores aren't doing anything active, so antibiotics have no target to attack. As soon as a patient stops taking the drugs, the spores "hatch" and C. diff returns in overwhelming numbers.

"Our first and best barrier against C. diff is our natural bacteria," says Dr. Khoruts. "As long as that microbial world is balanced and intact, it's very difficult to become infected. But when antibiotics suppress or disrupt our natural bacteria, it creates room for C. diff to proliferate."

Normally, if you need to restore the balance of good bacteria in your gut, you can pop probiotic capsules. This wasn't really an option for Dr. Khoruts's first HPI patient. A single probiotic capsule contains, at most, billions of live bacteria from only a handful of species she needed trillions of individual microbes from hundreds of species.

To date, doctors have found only one way to accomplish this: After approval by the university's institutional review board, Dr. Khoruts secured a 3-ounce sample of feces from the patient's husband, placed it in a blender with saline solution, and created a "special smoothie." After filtering and screening this for transmissible diseases, it was ready for transplant by colonoscope.

Based on the scattered case reports he'd read, Dr. Khoruts was guardedly optimistic that the transplant would help. What he didn't expect was how much it helped&mdashand how quickly. Within a matter of days, the horrible affliction that had tormented the woman for a year was gone.

Not everyone responds that quickly, and sometimes it takes more than one try for the microbial "graft" to take.

Alas, this is exactly what happened with Alex. Dr. Khoruts offered two options. Alex could go back on vancomycin to again exterminate everything in his gut, and then try a second transplant. Or he could opt for a stalemate: to remain on vancomycin "essentially forever." The C. diff would stay dormant, but his natural gut microbiome would be permanently wiped out.

"I told Dr. Khoruts that I absolutely did not want to be on antibiotics for the rest of my life," Alex says. "I said I was willing to have as many transplants as I needed to eliminate this bug."

Luckily, he needed only one more. Within 2 days of the second transplant, Alex sensed that something truly different was happening inside him. By the 10th day, he had his first solid elimination in nearly 9 months, which he now jokingly refers to as his "proud father's stool."

"I wanted to take pictures," he recalls, "and send them to my parents, saying, 'Look what I did!'"

Alex, who feels "insanely lucky" to have received such innovative medical care, has suffered no recurrent symptoms in the half year since the graft "took." If anything, he feels even better than before, in large part because he now takes his health&mdashand that of his microbiome&mdashto heart.

If the only use for fecal transplants was to save the lives of C. diff sufferers, they would still be a boon to medicine. But Dutch researchers think there's even more untapped potential in this unorthodox treatment, which is why they're currently trying to find out whether transplants can help people suffering from metabolic syndrome. Dr. Khoruts thinks it's worth the gamble.

"This is really complex biology," he says, "and we can try to sort through this for the next hundred years, hoping to make sense of it all. Or we can take a shortcut with fecal transplants and see what they can fix and what they can't. Maybe that's just primitive surgeonlike thinking."

Throughout the history of medicine, such "primitive" thinking has led to the discovery of many treatments that we knew were effective long before we knew why. Preliminary data from the Dutch scientists suggest this might prove true here too. "An abstract of early results shows that the transplants are improving insulin sensitivity, the fundamental defect in metabolic syndrome," says Dr. Khoruts.

Proctor has even heard of pioneering medical schools offering fecal banking programs. This way, patients facing chemo, radiation, and similarly harsh interventions that wreak havoc with good bugs can be restore the microbiome once treatment ends.

Dr. Khoruts suspects that it's only a matter of time before specially engineered lozenges, designed to crack open in the lower gut, make fecal transplants as easy as swallowing a pill. Other doctors share his optimism that someday we'll see a host of such interventions.

Segre, for example, imagines different "prebiotic" skin creams that nourish and serve as ideal growth media for the legions of commensals standing guard across our hides. And J. Dennis Forten-berry, M.D., an infectious-disease researcher at Indiana University, thinks that perhaps the condoms of the future will deliver a dose of commensals that hate STDs as much as we do.

Until such changes in medical treatment become mainstream, there's one change we can all make right now&mdashand it involves our attitude.

"We've long been taught to consider microbes our enemies," says Segre. "We talk about them in the language of warfare&mdashhow best can we kill all these adversaries? But the vast maj ority of microbes living on and in us aren't our enemies. Our goal should be not to annihilate them but to maintain a healthy balance. It's time to start having a more kind and loving relationship with our bacteria."

Gut Reaction

Naming the bacteria in your stomach could help doctors heal you

You know your blood type, right? How about your bug type? In 2011, a study in the journal Nature found that your individual microbiome is dominated by one of three bacterial genuses-Bacteroides, Prevotella, or Ruminococcus-swimming around in your stomach. More than a mere scientific curiosity, the finding could lead to a new era of personalized medicine. "The three gut types can explain why the uptake of medicines and nutrients varies from person to person," says study coauthor Jeroen Raes, Ph.D. Knowing your type, in other words, might lead to diets and drug-delivery systems customized for you and your bacteria. That's the best case however, the reality is likely to be much more complicated, says George Weinstock, Ph.D., a microbiologist at Washington University in St. Louis. Still, if such links do emerge, he adds, another recent study gives hope for self-determination: University of Pennsylvania researchers showed that switching from a meat-based diet to a plant-based diet, or vice versa, may alter your type. "Unlike blood type, you are not necessarily locked into your bacteria type forever," says Weinstock.

Living the Life Bacterial

How to stay on good terms with your germs

1. Skip antibacterial soaps
The active ingredient, triclosan, has been linked to hormone disruption in animals and bacterial resistance to antibiotics. A University of Michigan study found that using plain soap prevented infectious illness just as effectively as using triclosan products did.

2. Nix antibiotic ointment for nicks

Overuse of creams containing neomycin, a common antibiotic, may be leading to resistant strains of MRSA, say researchers in Japan. Clean small wounds with soap and water, and use a bandage to prevent contamination by potential pathogens.


Scientists Can Now Radically Expand the Lifespan of Mice&mdashand Humans May Be Next

Medical researchers at Mayo Clinic have made this decade's biggest breakthrough in understanding the complex world of physical aging.

With a bit of clever genetic engineering, a team of scientists has just found an astonishing way to significantly expand the natural lifespan of mice. Now, at least one biotech company hopes to translate this breakthrough to fight aging in humans.

In a study published today in the journal Nature, medical researchers at Mayo Clinic College of Medicine&mdashled by cell biologists Darren Baker and Jan van Deursen&mdashhave made this decade's biggest breakthrough in understanding the complex world of physical aging. The researchers found that systematically removing a category of living, stagnant cells (ones which can no longer reproduce) extends the lives of otherwise normal mice by 25 percent. Better yet, scouring these cells actually pushed back the process of aging, slowing the onset of various age-related illnesses like cataracts, heart and kidney deterioration, and even tumor formation.

"It's not just that we're making these mice live longer they're actually stay healthier longer too. That's important, because if you were going to equate this to people, well, you don't want to just extend the years of life that people are miserable or hospitalized," says Baker.

The cells the scientists eliminated are called senescent cells. A senescent cell is an otherwise normal cell&mdashsay a skin or heart muscle cell&mdashthat has stopped dividing and reproducing. Right now, they're found all over your body. Now, these cells have long been known to be associated with aging, "for example, in mice or people or monkeys, you find an accumulations of these senescent cells over time and with age. And at sites of age-related disease, like osteoporosis, you'll also find these cells," says Baker. One theory behind why these cells exist in the first place is that hyper-stressed cells become senescent to prevent potentially cancerous, unfettered reproduction.

But until now, exactly what effect living senescent cells actually have on the body&mdasheither slowing aging, speeding it up, or not effecting the aging process at all&mdashhas largely been a mystery. But by leveraging modern techniques in genetic engineering, Baker and his colleagues finally set up an experiment that conclusively proved that the presence of senescent cells is largely a negative one. They shorten total lifespan and hasten the onset of age related illnesses, like cardiovascular disease.

Cellular Kill Switch

Although today's paper is the result of many careful experiments painstakingly developed over a 7 year period, "the beauty of this study is that it's actually really quite simple," says Baker. The scientists took advantage of the fact that one hallmark of senescent cells is that they steadily secrete a certain tumor-suppressing protein molecule called "p16Ink4a." We'll call it p16, and you can think of it as basically their calling card.

By rewriting a tiny portion of the mouse genetic code, Baker and van Deursen's team developed a genetic line of mice with cells that could, under the right circumstances, produce a powerful protein called caspase when they start secreting p16. Caspase acts essentially as a self-destruct button when it's manufactured in a cell, that cell rapidly dies.

So what exactly are these circumstances where the p16 secreting cells start to create caspase and self-destruct? Well, only in the presence of a specific medicine the scientists could give the mice. With their highly-specific genetic tweak, the scientists had created a drug-initiated killswitch for senescent cells.

In today's paper, Baker and van Deursen's team reported what happened when the researchers turned on that killswitch in middle-aged mice, effectively scrubbing clean the mice of senescent cells. The medicine was injected into the genetically engineered mice's bellies when they were 12 months old. (Keep in mind, the process isn't perfect. Some senescent cells, including those found in the colon and liver managed to survive&mdashpossibly by avoiding the killswitch drug.)

The big takeaway is that "we saw about a 25 percent expansion of median lifespan of these mice. This held true for two different genetic strains of mice," each engineered with the killswitch tweak, "and was irrespective of sex or the diet," says Baker. These mice also showed delayed cancer onset, fewer cataracts, an increased drive to explore, and various other age-resistant effects in a wide range of body tissues. The body, it seems, is better off without senescent cells.

As far as the researchers could find, there was pretty much just a single downside of eliminating senescent cells: Wounds healed more slowly. That's no big surprise, as senescent cells are known to play a role in healing and scar-tissue formation.

On To Humans?

Jesús Gil and Dominic Withers, two medical researchers at Imperial College London&mdashwho were not involved in today's research&mdashapplaud today's research and concur with the results. "The removal of senescent cells does indeed delay ageing and increase healthy lifespan," they write in an essay accompanied alongside the research paper in the journal Nature.

So what's next? Well, at the same time today's paper was published, a company called Unity Biotechnology launched, with the stated goal to use today's breakthrough understanding of senescent cells to develop medicines that fight the process of aging. (Obviously they're going to have to use a different approach to genetically engineering humans.)



Comments:

  1. Voodookinos

    I think he is wrong. Let us try to discuss this. Write to me in PM, it talks to you.

  2. Audrick

    Excuse me, I have removed this question

  3. Voodoojinn

    Wacker, the ideal answer.

  4. Moogular

    In my opinion you commit an error.

  5. Beowulf

    And where at you logic?

  6. Chait

    What words ... Great



Write a message