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Tag: mutations

  • How a Common Stomach Bug Causes Cancer

    How a Common Stomach Bug Causes Cancer

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    At first, doctors didn’t believe that bacteria could live in the stomach at all. Too acidic, they thought. But in 1984, a young Australian physician named Barry Marshall gulped down an infamous concoction of beef broth laced with Helicobacter pylori bacteria. On day eight, he started vomiting. On day 10, an endoscopy revealed that H. pylori had colonized his stomach, their characteristic spiral shape unmistakeable under the microscope.

    Left untreated, H. pylori usually establishes infections that persist for an entire lifetime, and they’re common: Half of the world’s population harbors H. pylori inside their stomach, as do more than one in three Americans. In most cases, the microbe settles into an asymptomatic chronic infection, but in some, it becomes far more troublesome. It can, for example, cause enough damage to the stomach lining to create ulcers. Worse still, H. pylori can lead to cancer. This single bacterium is by far the No. 1 risk factor in stomach cancers worldwide. By one estimate, some 70 percent can be attributed to H. pylori.

    But what still puzzles doctors years later is why H. pylori has such different consequences for different people. Why is it asymptomatic in most but carcinogenic in others? Although the full answer is complex, one key factor seems to be mutations in H. pylori itself. Not every strain is created equal. The presence of select genes intensifies H. pylori’s pathogenicity, and even a single mutation in a single gene, scientists recently found, enhances the link to cancer. A small genetic tweak in a common stomach bug could have profound consequences for us, its unwitting hosts.

    H. pylori has lived inside of us for a long time. Our ancestors who left Africa likely carried it inside them as they crossed continents and oceans, built and felled civilizations. And over the course of what some scientists hypothesize to be more than 100,000 years of co-evolution, H. pylori has exquisitely adapted to the harsh, acidic conditions of the human stomach.

    It survives, for example, by producing “copious amounts” of an enzyme that neutralizes stomach acid, Richard Peek, a gastroenterologist at Vanderbilt, told me. H. pylori can also burrow into the mucus-gel lining of the stomach using powerful, whiplike flagella. The mucus lining offers a relative haven from stomach acid, but another prize lies underneath too: stomach cells, rich in nutrients that the bacteria needs to survive.

    The way that H. pylori steals nutrients could be the key to how it ends up causing cancer. The bacterium isn’t necessarily out to hurt its human host. “H. pylori doesn’t want you to get an ulcer or to get cancer, but it needs to replicate to high enough levels in the stomach that it can be transmitted to another person,” Nina Salama, a biologist at Fred Hutchinson Cancer Center, told me. (The bacteria seem to spread through an infected person’s saliva, vomit, or feces.) But to replicate, it needs nutrients, in particular iron, which our cells probably hoard to starve pathogens.

    In response, certain strains of H. pylori have evolved genetic changes that might make its iron-mining more efficient. But this also causes more collateral damage to the host’s stomach, enough damage, perhaps, to eventually trigger cancer. First, the bacteria uses a protein called HtrA—essentially “a pair of molecular scissors,” Peek said—to cut the bonds that hold stomach cells together, so the microbes can slip between. A single mutation in this scissor protein makes it better at cutting, a group based in Germany found in a recent study, and this mutation is disproportionately found in H. pylori strains isolated from people who developed stomach cancer.

    Once H. pylori has wedged itself in between cells, it also has clever ways of accessing the nutrients inside. Certain strains carry a set of about 18 genes that collectively encode a molecular needle through which H. pylori injects bacterial proteins, triggering a cascade of changes to the cell. These hijacked cells end up giving up their iron more easily, but they also become worse at essential functions such as fixing damaged DNA. This set of approximately 18 genes, collectively called the “cag pathogenicity island,” are in fact disproportionately found in strains from cancer patients. Stomach cancer thus might be a secondary consequence of the microbe’s aggressive search for nutrients. For the H. pylori, “there’s no selective pressure to cause cancer in 80 years. The selective pressure is to acquire iron now,” Karen Guillemin, a microbiologist at the University of Oregon, said.

    But not everyone infected with one of these cancer-linked strains will develop cancer. Other factors likely play a role too: diet, environment, and genetics of the individual patient  Stomach-cancer rates vary quite widely around the world, with the highest prevalence in East Asia. In Japan, doctors routinely test for H. pylori in people with no symptoms, and prescribe antibiotics if the tests come back positive. But some scientists have argued against aggressive treatment, pointing at hints that humans derive some benefits from living with H. pylori too. Those infected, for example, tend to have lower rates of asthma and allergy. Genetic signatures associated with more pathogenic H. pylori strains, Peek told me, would help identify those at highest risk, who could most benefit from antibiotics.

    Marshall, the Australian doctor who infected himself with H. pylori, ultimately recovered just fine. His self-experiment, in addition to other studies with his collaborator Robin Warren, proved that the bacterium does indeed infect the stomach and does indeed cause stomach ulcers, which later spurred the work linking H. pylori to cancer. Understanding exactly how and why H. pylori becomes pathogenic is still key to finding the way to treat it, but in the past 40 years the significance of H. pylori to human health has become indisputable—so much so that in 2005, Marshall and Warren won the Nobel Prize in Medicine.

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    Sarah Zhang

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  • How Bad Could BA.2.86 Get?

    How Bad Could BA.2.86 Get?

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    Since Omicron swept across the globe in 2021, the evolution of SARS-CoV-2 has moved at a slower and more predictable pace. New variants of interest have come and gone, but none have matched Omicron’s 30-odd mutations or its ferocious growth. Then, about two weeks ago, a variant descended from BA.2 popped up with 34 mutations in its spike protein—a leap in viral evolution that sure looked a lot like Omicron. The question became: Could it also spread as quickly and as widely as Omicron?

    This new variant, dubbed BA.2.86, has now been detected in at least 15 cases across six countries, including Israel, Denmark, South Africa, and the United States. This is a trickle of new cases, not a flood, which is somewhat reassuring. But with COVID surveillance no longer a priority, the world’s labs are also sequencing about 1 percent of what they were two years ago, says Thomas Peacock, a virologist at the Pirbright Institute. The less surveillance scientists are doing, the more places a variant could spread out of sight, and the longer it will take to understand BA.2.86’s potential.

    Peacock told me that he will be closely tracking the data from Denmark in the next week or two. The country still has relatively robust SARS-CoV-2 sequencing, and because it has already detected BA.2.86, we can now watch the numbers rise—or not—in real time. Until the future of BA.2.86 becomes clear, three scenarios are still possible.

    The worst but also least likely scenario is another Omicron-like surge around the world. BA.2.86 just doesn’t seem to be growing as explosively. “If it had been very fast, we probably would have known by now,” Peacock said, noting that, in contrast, Omicron’s rapid growth took just three or four days to become obvious.

    Scientists aren’t totally willing to go on record ruling out Omicron redux yet, if only because patchy viral surveillance means no one has a complete global picture. Back in 2021, South Africa noticed that Omicron was driving a big COVID wave, which allowed its scientists to warn the rest of the world. But if BA.2.86 is now causing a wave in a region that isn’t sequencing viruses or even testing very much, no one would know.

    Even in this scenario, though, our collective immunity will be a buffer against the virus. BA.2.86 looks on paper to have Omicron-like abilities to cause reinfection, according to a preliminary analysis of its mutations by Jesse Bloom, a virologist at the Fred Hutchinson Cancer Center, in Washington, but he adds that there’s a big difference between 2021 and now. “At the time of the Omicron wave, there were still a lot of people out there that had never been either vaccinated or infected with SARS-CoV-2, and those people were sort of especially easy targets,” he told me. “Now the vast, vast majority of people in the world have either been infected or vaccinated with SARS-CoV-2—or are often both infected and vaccinated multiple times. So that means I think any variant is going to have a very hard time spreading as well as Omicron.”

    A second and more likely possibility is that BA.2.86 ends up like the other post-Omicron variants: transmissible enough to edge out a previous variant, but not transmissible enough to cause a big new surge. Since the original Omicron variant, or BA.1, took over, the U.S. has successively cycled through BA.2, BA.2.12.1, BA.5, BQ.1, XBB.1.5—and if these jumbles of numbers and letters seem only faintly familiar, it’s because they never reached the same levels of notoriety as the original. Vaccine makers track them to keep COVID shots up to date, but the World Health Organization hasn’t deemed any worthy of a new Greek letter.

    If BA.2.86 continues to circulate, though, it could pick up mutations that give it new advantages. In fact, XBB.1.5, which rose to dominance earlier this year, leveled up this way. When XBB.1.5’s predecessor was first identified in Singapore, Peacock said, it wasn’t a very successful variant: Its spike protein bound weakly to receptors in human cells. Then it acquired an additional mutation in its spike protein that compensated for the loss of binding, and it turned into the later-dominant XBB.1.5. Descendents of BA.2.86 could eventually become more transmissible than the variant looks right now.

    A third scenario is that BA.2.86 just fizzles out and goes away. Scientists now believe that highly mutated variants such as BA.2.86 are probably products of chronic infections in immunocompromised patients. In these infections, the virus remains in the body for a long time, trying out new ways to evade the immune system. It might end up with mutations that make its spike protein less recognizable to antibodies, but those same mutations could also render the spike protein less functional and therefore the virus less good at transmitting from person to person.

    “Variants like that have been identified over the last few years,” Bloom said. “Often there’s one sample found, and that’s it. Or multiple samples all found in the same place.” BA.2.86 is transmissible enough to be found multiple times in multiple places, but whether it can overtake existing variants is unclear. To do so, BA.2.86 needs to escape antibodies while also preserving its inherent transmissibility. Otherwise, Bloom said, cases might crop up here and there, but the variant never really takes off. In other words, the BA.2.86 situation basically stays where it is right now.

    The next few weeks will reveal which of these futures we’re living in. If the number of BA.2.86 cases starts to go up, in a way that requires more attention, we’ll know soon. But each week that the variant’s spread does not jump dramatically, the less likely BA.2.86 is to end up a variant of actual concern.

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    Sarah Zhang

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  • Early Diagnosis and Why It Matters

    Early Diagnosis and Why It Matters

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    From the minute we wake up until we go to sleep, our eyes help us navigate the world. Like a finely tuned camera, each part of our eyes has a very specific job to do.

    What Is Inherited Retinal Dystrophy (IRD)

    Our dome-shaped cornea, the front layer of the eye, allows light to pass through and bends it to help us focus. Some light enters though the small opening of the pupil. How much light the pupil can let in is controlled by the iris, the colored part of the eye. That light then travels through the lens of the eye, which works together with the cornea to focus light on the retina. The retina, located at the back of our eye, is light sensitive. It contains special cells called photoreceptors that turn light into electrical signals that go to your brain and changes those signals into the images you see.

    Sometimes things can go wrong with one of the parts of our eyes. A rare group of disorders affecting the retina are called inherited retinal dystrophies (IRDs.) These groups of diseases are hereditary, meaning they are passed down through families. The cause is mutations, or malfunctions, in at least one gene that is not working properly. There are around 300 known to play a role in these diseases.

    Some IRDs may progress slowly, while another may change vision much more quickly. Some may lead to vision loss.

    Why Is Earlier Diagnosis of IRDs Helpful?

    “It’s important to understand these diseases are rare, relatively speaking. But for the people who have an IRD, it can be life-changing,” says Shree Kurup, MD, FACP, a retinal specialist at  University Hospitals Cleveland Medical Center. “But what’s important to know is that early diagnosis of any one of these diseases can absolutely improve lives. We may not be able to cure every IRD, but we are making significant progress in learning more about the several hundred genes that can cause them.”

    There are more than 260 genes that can cause IRDs. But getting a diagnosis is more involved than a routine eye exam. “There can be a lot of reasons for blurry vision, and an IRD is not going to be the first thought of any eye doctor,” says Matthew MacCumber, MD, PhD, a retinal specialist at Rush University Medical Center. There is a great amount of variety among all IRDs, so it can be tough to make an accurate diagnosis. “Sometimes patients may be misdiagnosed for years and when they finally get a firm, accurate diagnosis it’s almost a relief because they can finally put a name to their problem,” MacCumber says.

    To make a diagnosis, doctors rely on a battery of specialized tests that give them information on many aspects of your vision. A genetic test will tell you exactly what genetic mutation you have and can help your doctor confirm your diagnosis. It will also give you and your family important information about your disease, how you may need to plan for your own future, and how it may affect other family members and future generations.

    “It’s important to spend a lot of time with people to explain how an IRD may change their lives,” MacCumber says. “An early diagnosis also gives patients access early on to a team of experts that can help them.” That team is made up of ophthalmologists, optometrists, retinal specialists, genetic counselors, and other experts in low vision.

    Early Diagnosis and Clinical Trials

    An early and accurate diagnosis also can help you enroll in a clinical trial. This will give you the chance to try new therapies before they’re available to the general public. Although almost no IRDs have treatments right now, doctors are hopeful about the future of gene therapies. In clinical trials of one such therapy, patients reported that they were able to get rid of some devices designed to help those with vision loss see faces and read.

    “Gene therapy is the future of IRDs, and we’ve come a long way in genetic testing, We are learning more and more about these diseases. I absolutely, 100% recommend that patients participate in a clinical trial if they are eligible. This is the way we will find cures,” MacCumber says.

    The most important thing for the majority of people with IRDs right now is to not lose hope. “Imagine how hard it can be for a parent to hear their child may lose their sight or how hard it is for an active adult to hear they may have to change things in their life,” Kurup says. “IRDs are very complex, but each patient is an individual. For these people, knowledge really is power, and the earlier they get that power the better.”

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