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Showing posts with label Medical Science. Show all posts
Showing posts with label Medical Science. Show all posts
Why does immunotherapy achieve dramatic results in some cancer patients but fail in others?
Scientists have elucidated the mechanism behind some tumor's ability to escape immunotherapy drugs.
Image: iStock
Why does immunotherapy achieve dramatic results in some cancer patients but doesn’t help others? It is an urgent and vexing question for many cancer specialists.
Now, two research groups from Harvard Medical School based at Dana-Farber Cancer Institute have independently discovered a genetic mechanism in cancer cells that influences whether they resist or respond to immunotherapy drugs known as checkpoint inhibitors.
The findings, the researchers say, reveal potential new drug targets and could aid efforts to extend the benefits of immunotherapy treatment to more patients and target additional types of cancer.
The two groups converged on a discovery that resistance to immune checkpoint blockade is critically controlled by changes in a group of proteins that regulate how DNA is packaged in cells. The collection of proteins, called a chromatin remodeling complex, is known as SWI/SNF. Its components are encoded by different genes, among them ARID2, PBRM1 and BRD7. SWI/SNF’s job is to open up stretches of tightly wound DNA so that its blueprints can be read by the cell to activate certain genes to make proteins.
Researchers led by Van Allen and Choueiri sought an explanation for why some patients with a form of metastatic kidney cancer called clear cell renal cell carcinoma (ccRCC) gain clinical benefit—sometimes durable—from treatment with immune checkpoint inhibitors that block the PD-1 checkpoint, while other patients don’t.
The scientists’ curiosity was piqued by the fact that ccRCC differs from other types of cancer that respond well to immunotherapy, such as melanoma, non-small cell lung cancer and a specific type of colorectal cancer. Cells of the latter cancer types contain many DNA mutations, which are thought to make distinctive tumor antigens called, neoantigens, which help the patient’s immune system recognize and attack tumors and make the cancer cells’ microenvironment hospitable to tumor-fighting T cells. By contrast, ccRCC kidney cancer cells contain few mutations, yet some patients even with advanced, metastatic disease respond well to immunotherapy.
To search for other characteristics of ccRCC tumors that influence immunotherapy response or resistance, the researchers used whole exome DNA sequencing to analyze tumor samples from 35 patients treated in a clinical trial with the checkpoint blocker nivolumab (Opdivo). They also analyzed samples from another group of 63 patients with metastatic ccRCC treated with similar drugs.
When the data were sorted and refined, the scientists discovered that patients who benefited from the immunotherapy treatment with longer survival and progression-free survival were those whose tumors lacked a functioning PRBM1 gene. About 41 percent of patients with ccRCC kidney cancer have a nonfunctioning PBRM1 gene. That gene encodes a protein called BAF180, which is a subunit of the PBAF subtype of the SWI/SNF chromatin remodeling complex.
Loss of the PBRM1 gene function caused the cancer cells to have increased expression of other genes, including those in the gene pathway known as IL6/JAK-STAT3, which are involved in immune system stimulation.
The finding does not directly lead to a test for immunotherapy response yet, the scientists caution, but they carry a clear therapeutic promise.
“We intend to look at these specific genomic alterations in larger, randomized controlled trials, and we hope that one day these findings will be the impetus for prospective clinical trials based on these alterations,” Choueiri said.
In the second report, the scientists led by Wucherpfennig came at the issue from a different angle. They used the gene-editing CRISPR/Cas9 tool to sift the genomes of melanoma cells for changes that made tumors resistant to being killed by immune T cells, which are the main actors in the immune system response against infections and cancer cells.
The search turned up about 100 genes which appeared to govern melanoma cells’ resistance to being killed by T cells. Inactivating those genes rendered the cancer cells sensitive to T-cell killing. Narrowing down their search, the Wucherpfennig team identified the PBAF subtype of the SWI/SNF chromatin remodeling complex—the same group of proteins implicated by the Van Allen and Choueiri team in kidney cancer cells—as being involved in resistance to immune T cells.
When the PBRM1 gene was knocked out in experiments, the melanoma cells became more sensitive to interferon gamma produced by T cells and, in response, produced signaling molecules that recruited more tumor-fighting T cells into the tumor. The two other genes in the PBAF complex—ARID2 and BRD7—are also found mutated in some cancers, according to the researchers, and those cancers, like the melanoma lacking ARID2 function, may also respond better to checkpoint blockade. The protein products of these genes, the authors noted, “represent targets for immunotherapy, because inactivating mutations sensitize tumor cells to T-cell mediated attack.” Finding ways to alter those target molecules, they added, “will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy.”
Research included in the report by Van Allen and Choueiri was supported by Bristol-Myers Squibb, American Association for Cancer Research Kure It Research Grant for Immunotherapy in Kidney Cancer, Kidney SPORE, and Cancer Immunologic Data Commons (National Institutes of Health grant U24CA224316).
The American College of Cardiology and the American Heart Association certainly grabbed the attention of us busy primary care physicians with the recent release of their updated blood pressure guidelines. These organizations had piqued interest by declaring the release date and labeling it as “highly anticipated.” I pooh-poohed all that drama, but upon reading through the 114-page executive summary PDF with 21 authors and almost a thousand references, I have to say, I am duly impressed.
The definition of the diagnosis of high blood pressure and the decision-making process surrounding treatment have traditionally been quite individualized (read: all over the place). Personally, I invite these stricter measures, because they are accompanied by solid research, logistical guidance, and useful management strategies.
However, a whole heck of a lot of people just got pulled into a significant medical diagnosis.
Let’s review what’s new.
A new definition of high blood pressure (hypertension)
(Please note that all numbers refer to mm Hg, or, millimeters of mercury.) The guidelines, in a nutshell, state that normal blood pressure is under 120/80, whereas up until Monday, normal was under 140/90.
Now, elevated blood pressure (without a diagnosis of hypertension) is systolic blood pressure (the top number) between 120 and 129. That used to be a vague category called “prehypertension.”
Stage 1 high blood pressure (a diagnosis of hypertension) is now between 130 and 139 systolic or between 80 and 89 diastolic (the bottom number).
Stage 2 high blood pressure is now over 140 systolic or 90 diastolic.
The measurements must have been obtained from at least two careful readings on at least two different occasions. What does careful mean? The guidelines provide a six-step tutorial on how, exactly, to correctly measure a blood pressure, which, admittedly, is sorely needed. My patients often have their first blood pressure taken immediately after they have rushed in through downtown traffic, as they’re sipping a large caffeinated beverage. While we always knew this could result in a falsely elevated measurement, it is now officially poor clinical technique resulting in an invalid reading.
New recommendations on monitoring blood pressure
The new guidelines also encourage additional monitoring, using a wearable digital monitor that continually takes blood pressure readings as you go about your life, or checked with your own cuff at home. This additional monitoring can help to tease out masked hypertension (when the blood pressure is normal in our office, but high the rest of the time) or white coat hypertension (when the blood pressure is high in our office, but normal the rest of the time).
There are clear, helpful directions for setting patients up with a home blood pressure monitor, including a recommendation to give people specific instructions on when not to check blood pressure (within 30 minutes of smoking, drinking coffee, or exercising) and how to take a measurement correctly (seated comfortably, using the correct size cuff). The home blood pressure cuff should first be validated (checked in the office, for accuracy).
If you now have high blood pressure, you may not need meds… yet
The guidelines also outline very clearly when a diet-and-lifestyle approach is the recommended, first-line treatment, and when medications are simply just what you have to do. Thankfully, the decision is largely based on facts and statistics. For the elevated blood pressure category, medications are actually not recommended; rather, a long list of evidence-based, non-drug interventions are. What are these interventions? Things that really work: a diet high in fruits and vegetables (such as the DASH diet, which is naturally high in potassium); decreased salt and bad fats; more activity; weight loss if one is overweight or obese; and no more than two alcoholic drinks per day for men, and one for women. Simply changing what you eat can bring down systolic blood pressure by as much as 11 points, and each additional healthy habit you adopt can bring it down another four to five points.
For people with stage 1 hypertension who don’t have cardiovascular disease and are at low risk for developing it (less than 10% risk of an event within 10 years), lifestyle changes are still the way to go.
However, if a patient has any kind of cardiovascular disease and stage 1 hypertension (a blood pressure over 130 systolic or 80 diastolic), or no existing cardiovascular disease but a significant risk of developing it (over 10% risk within the next 10 years), then lifestyle changes plus medications are recommended. And, even if someone has less than a 10% risk, if their blood pressure is over 140 systolic or 90 diastolic, which is now stage 2 high blood pressure, they ought to be treated with medication as well.
Optimizing treatment of high blood pressure
The authors bring several evidence-based yet progressive concepts into the guidelines, the first of which is that high blood pressure should be treated using a team approach. This makes sense, as science supports more and better patient education around self-monitoring, nutrition, and lifestyle changes, as well as stress management. Tele-health is emphasized as a cost-effective method of ongoing monitoring that is more convenient for patients than frequent office visits.
And why should this all matter to you?
Mountains of research over time have shown a very clear link between high blood pressure and cardiovascular disease. A 20-point higher systolic blood pressure or a 10-point higher diastolic blood pressure is associated with double your risk of death from a heart attack, stroke, or other cardiovascular complication (like abdominal aortic aneurysm or heart failure). What many people don’t realize is that those who survive these events find their lives permanently altered by disability and medical complications.
Much is being made of the fact that the new definitions of high blood pressure will mean roughly half of all US citizens will be considered to have high blood pressure, but when you really look at the numbers, as cardiologists already have, not that many more people will actually be advised to take medications. Although the public has good reason to be suspicious of “big pharma,” that’s not what this is about.
Diet and lifestyle changes are powerful medicine. Even if your blood pressure is normal now, you can help to prevent it from becoming elevated starting today. Eat more fruits, veggies, and whole grains, and limit foods high in sodium and unhealthy fats. Be as physically active as possible.
There is a lot more in the very long, detailed executive summary, including specific guidance for various populations, myriad diseases, and special circumstances, but this is the gist of it.
Over the next few months, millions of people will receive vaccinations in the hope of staving off the flu — and the fever, pain, and congestion that come with it.
But how can one injection trigger an immune response that protects someone from head to toe?
Part of the answer, says Nicolas Chevrier, a former Bauer Fellow at the Harvard FAS Center for Systems Biology and now an assistant professor in molecular engineering at the University of Chicago, appears to lie in the way antiviral signals spread through the body within hours of a vaccination, seeding immune cells in various tissues. Chevrier’s findings are described in an Oct. 5 paper published in Cell.
“The starting point for this study was the question of how do we study the immune system at the scale of the whole organism?” Chevrier said. “Immune cells are in every organ of the body — in the lungs, the heart, the skin — making it incredibly challenging to study how the immune system can operate across the entire organism. Current studies are siloed. For example, people only looked at the lungs or only looked at the blood.”
To find answers, Chevrier and colleagues turned to a pair of Vaccinia viruses — one a pathogenic version of the disease and the other an inactive strain deployed for formulating vaccines similar to those used to eradicate smallpox in the early 20th century.
“To test our idea, we wanted something to trigger and compare various types of immune responses from vaccination alone, to infection alone, and to a protective one [infection of vaccinated individuals],” he said. “Using this comparative approach allowed us to ask: When you immunize at the skin, does the response stay localized, or does it become systemic? And if so, how far and how fast does it spread? These are fundamental questions about the inner working of the immune system at a scale that we didn’t have any way to look at.”
Researchers first immunized mice against the disease to study how their immune systems responded to the vaccine, and later exposed the same mice to the pathogenic version of the virus to study how it triggered their immune defenses.
“We were very excited to see that our approach worked,” Chevrier said. “We could observe and track immune processes at the whole-body scale for the first time. Based on these findings, we uncovered two new mechanisms of immune protection critical for the host. First, we found that within hours of being vaccinated, a whole-body antiviral is created — as if the body’s defenses were anticipating its virus opponent’s next moves to win the battle.”
That process, he explained, involves a molecule known as interferon, which is secreted at the point of immunization, and quickly propagates through most tissues via the bloodstream.
For years, Chevrier said, scientists believed interferon was merely a local response to an immune trigger, but the new study suggests that it may actually play an important role in activating antiviral genes across many tissues, helping them fight off infection.
What Chevrier dubbed the protective response, on the contrary, seems far more localized to a few organs.
“It seems to be more restrained to where the virus goes,” he said. “In our tests, the infection came in through the lungs, and very quickly progressed to the liver and the spleen. But the immune defenses set by vaccination stopped the virus right there, and very efficiently. We found that memory cells are instructed to reside in those tissues and are set up to counter a potential reinfection.”
That finding contradicts accepted wisdom, which had been that those cells could most effectively fight infection by circulating through the body. In recent years, however, evidence has emerged suggesting that the resident cells might be more potent and widespread than first thought.
“They were seen as local protectors,” Chevrier said. “People thought that when you got immunized at the skin, for example, those cells would reside in the skin, but what we’ve found is that they’re seeded much more broadly across the body to serve as systemic protectors. So as soon as the virus arrives in the liver or the spleen, those cells are ideally placed to fight off the infection as it unfolds.”
He added: “Our study is a proof of principle that the immune system can be observed and studied at the whole-body scale in mammals — as opposed to one or few tissues at a time. That being said, much effort is now needed to test this idea in other immune processes linked to health and disease.”
Harvard study shows how intermittent fasting and manipulating mitochondrial networks may increase lifespan.
Manipulating mitochondrial networks inside cells — either by dietary restriction or by genetic manipulation that mimics it — may increase lifespan and promote health, according to new research from Harvard T.H. Chan School of Public Health.
The study, published Oct. 26 online in Cell Metabolism, sheds light on the basic biology involved in cells’ declining ability to process energy over time, which leads to aging and age-related disease, and how interventions such as periods of fasting might promote healthy aging.
Mitochondria — the energy-producing structures in cells — exist in networks that dynamically change shape according to energy demand. Their capacity to do so declines with age, but the impact this has on metabolism and cellular function was previously unclear. In this study, the researchers showed a causal link between dynamic changes in the shapes of mitochondrial networks and longevity.
The scientists used C. elegans (nematode worms), which live just two weeks and thus enable the study of aging in real time in the lab. Mitochondrial networks inside cells typically toggle between fused and fragmented states. The researchers found that restricting the worms’ diet, or mimicking dietary restriction through genetic manipulation of an energy-sensing protein called AMP-activated protein kinase (AMPK), maintained the mitochondrial networks in a fused or “youthful” state. In addition, they found that these youthful networks increased lifespan by communicating with organelles called peroxisomes to modulate fat metabolism.
“Low-energy conditions such as dietary restriction and intermittent fasting have previously been shown to promote healthy aging. Understanding why this is the case is a crucial step toward being able to harness the benefits therapeutically,” said Heather Weir, lead author of the study, who conducted the research while at Harvard Chan School and is now a research associate at Astex Pharmaceuticals. “Our findings open up new avenues in the search for therapeutic strategies that will reduce our likelihood of developing age-related diseases as we get older.”
“Although previous work has shown how intermittent fasting can slow aging, we are only beginning to understand the underlying biology,” said William Mair, associate professor of genetics and complex diseases at Harvard Chan School and senior author of the study. “Our work shows how crucial the plasticity of mitochondria networks is for the benefits of fasting. If we lock mitochondria in one state, we completely block the effects of fasting or dietary restriction on longevity.”
Next steps for the researchers including testing the role mitochondrial networks have in the effect of fasting in mammals, and whether defects in mitochondrial flexibility might explain the association between obesity and increased risk for age-related diseases.
It seems like a major part of keeping kids healthy these days is managing their microbial exposure. On the one hand, we’re told that letting our kids get dirty and tempering our use of hand sanitizer can help cultivate a healthy population of good microbes in and on the body, which is associated with lower rates of chronic maladies like asthma and allergies. On the other hand, we know that among all the benign and beneficial bacteria in the world lurk some that are deadly, causing diseases such as whooping cough, pneumonia and meningitis.
To treat these diseases, we need antibiotics, but the downside is that antibiotics indiscriminately kill bacteria in the body, including the ones that contribute to our health. Meanwhile, every course of antibiotics gives bacteria that are resistant to the drugs a chance to grow and thrive. That makes for more antibiotic-resistant infections, all of which are harder to treat and some of which can’t be treated at all.
Ideally, we want to protect our kids from deadly bacteria without disturbing the good ones or worsening the trend of antibiotic resistance. And this is exactly what vaccines do. They give us exposure to the pathogen — be it bacterial or viral — in a weakened, killed or partial form so that we can develop immunity to it without getting the full-blown illness. If we’re exposed to the real thing later, our bodies have antibodies specific to that pathogen ready to fight back. No antibiotics needed, and our friendly microbes can continue to live in peace. But when parents choose not to vaccinate their kids, they’re increasing the kids’ chances of not only becoming seriously ill, but also of needing antibiotic treatment and other medical interventions down the road.
Dr. Joel Amundson, a pediatrician in Portland, Oregon, finds himself frequently talking about vaccines and antibiotics in the same breath. Oregon has one of the lowest immunization rates in the nation, and Amundson said many of the parents he counsels want to keep their kids “all-natural” and see vaccines as an unnecessary medical intervention. But when he explains that vaccines are a tool for decreasing medical interventions, including antibiotic use, that often changes their perspective. “That’s a huge benefit to my families,” he said, “It definitely has them more interested in doing vaccines when they understand that.”
Some parents who are reluctant to vaccinate worry about side effects, and though some kids will experience short-lived, minor reactions such as swelling at the injection site, serious side effects are extremely rare. Side effects from antibiotics, including diarrhea, rashes and allergic reactions, are generally more common and severe, Amundson said. “I see far more harm from antibiotics than I do from vaccines, by a huge margin. It’s not subtle,” he said.
Of course, when a person has a serious bacterial infection, the benefits of antibiotics far outweigh those risks, because these diseases can be deadly. “When we need them, we really need them,” said Janet Gilsdorf, professor emerita of pediatric infectious diseases at the University of Michigan. But in a world where antibiotic-resistant infections are thought to kill 50,000 people each year in the U.S. and Europe alone, a problem that the United Nations has called “the greatest and most urgent global risk,” reducing our use of antibiotics helps preserve their value. “The fewer infections we have, the fewer antibiotics we need to use, and we know that the use of antibiotics is what drives antibiotic resistance,” Gilsdorf said.
Vaccines have prevented millions of illnesses
Estimated number of infections prevented by vaccines over the lifespan of children born in the U.S. in 2009
INFECTIOUS DISEASE
CAUSED BY
CASES PREVENTED
Varicella
Virus
3,942,546
–
Measles
Virus
3,835,825
–
Pertussis
Bacteria
2,950,836
–
Pneumococcus-related diseases
Bacteria
2,323,952
–
Mumps
Virus
2,312,275
–
Rubella
Virus
1,981,066
–
Rotavirus
Virus
1,582,940
–
Diphtheria
Bacteria
275,028
–
HepB
Virus
239,993
–
HepA
Virus
153,164
–
Polio
Virus
67,463
–
Hib
Bacteria
19,606
–
Congenital rubella syndrome
Virus
632
–
Tetanus
Bacteria
169
–
We don’t yet have research on whether emphasizing this benefit of vaccines might encourage parents to immunize their kids. While the vast majority of parents vaccinate their kids on schedule, the number of parents who are reluctant to do so does seems to be increasing in the U.S., despite a mountain of evidence supporting the efficacy and safety of vaccines. Reasons for parents’ concerns about vaccines are varied, and each type of concern will likely need to be addressed differently to improve vaccination rates. But there’s some evidence that parents are becoming more aware of the problem of antibiotic resistance, and a study of Austrian adults found that those with more knowledge about antibiotics were more likely to get the flu vaccine.
There’s no question that vaccines have dramatically reduced the burden of disease. A study published in 2014 estimated that among U.S. children born in 2009, following the recommended childhood vaccine schedule (not including the flu vaccine) would prevent 20 million cases of disease across their lifespans, and about 30 percent of these are bacterial diseases that would likely require antibiotic treatment. These are diseases like diphtheria and pertussis, both of which were major causes of childhood illness and death before their vaccines were developed in the first half of the 20th century.
More recently, the vaccine for Haemophilus influenzae type b (Hib), which the Food and Drug Administration approved for use in toddlers starting in 1985 and infants in 1990, nearly eliminated the dangerous blood and brain infections caused by this bacteria.
Pneumococcal vaccines have also reduced our dependence on antibiotics. The first was recommended in the U.S. for infants and young children in 2000, followed in 2010 by an updated version covering more strains of the bug. Like Hib, pneumococcus bacteria can cause pneumonia and invasive blood and brain infections, but it’s also a major cause of ear infections, which are one of the biggest reasons that children are prescribed antibiotics. Before the vaccine was added to the infant immunization schedule, up to 40 percent of invasive pneumococcal infections — meaning infections that spread to parts of the body, such as the bloodstream, that are normally germ-free — were resistant to at least one antibiotic, making them more difficult and costly to treat. The first pneumococcus vaccine decreased antibiotic-resistant invasive pneumococcal infections in young children by 81 percent, and the second vaccine caused an additional 61 percent drop. (These studies looked at different age groups, however; the first included only children younger than 2, and the second looked at children up to age 4.)
Pneumococcal vaccines have also reduced our dependence on antibiotics. The first was recommended in the U.S. for infants and young children in 2000, followed in 2010 by an updated version covering more strains of the bug. Like Hib, pneumococcus bacteria can cause pneumonia and invasive blood and brain infections, but it’s also a major cause of ear infections, which are one of the biggest reasons that children are prescribed antibiotics. Before the vaccine was added to the infant immunization schedule, up to 40 percent of invasive pneumococcal infections — meaning infections that spread to parts of the body, such as the bloodstream, that are normally germ-free — were resistant to at least one antibiotic, making them more difficult and costly to treat. The first pneumococcus vaccine decreased antibiotic-resistant invasive pneumococcal infections in young children by 81 percent, and the second vaccine caused an additional 61 percent drop. (These studies looked at different age groups, however; the first included only children younger than 2, and the second looked at children up to age 4.) The U.S., Israel and the U.K. have also observed big drops in kids’ ear infections coinciding with the introduction of pneumococcal vaccines. (Other factors, such as increased breastfeeding and tightened diagnostic criteria for ear infections, have likely contributed to these improvements, but researchers believe that the vaccines have played an important role.) In a paper published last year, researchers estimated that making the pneumococcal vaccine universally available to children in the 75 countries they looked at could not only prevent disease but also avert 11.4 million days of antibiotic treatment each year, a 47 percent drop in current antibiotic use for pneumonia.
Less obviously, vaccines that protect against illnesses caused by viruses rather than bacteria can also help cut antibiotic use. For example, influenza is viral, but flu season always brings an uptick in antibiotic prescriptions. In many cases, the antibiotics are being inappropriately prescribed, but some are necessary treatments for secondary bacterial infections, like pneumonia and ear infections, that can move in when a person’s immune system is busy fighting the virus. When Ontario, Canada, started offering free flu vaccines, the province’s rate of antibiotic prescriptions associated with the flu dropped by 64 percent.
The vaccine against measles, another viral infection, also probably decreases antibiotic use. A 2015 paper showed that a measles infection weakens a person’s immune system for two to three years, which explains why the measles vaccine reduces childhood mortality by 30 percent to 50 percent in poor countries, which can’t be explained by measles prevention alone. “Not having measles is a really good thing for your immune system in terms of preventing other infections,” said Marc Lipsitch, professor of epidemiology at Harvard T.H. Chan School of Public Health.
In a paper published last year, Lipsitch argued that development of new vaccines should be considered an important strategy in the fight against antibiotic-resistant bacteria. He believes that it would be most useful to have vaccines against certain bacterial strains that patients tend to pick up in hospitals — those strains are often resistant to multiple antibiotics. A more effective flu vaccine and a vaccine for respiratory syncytial virus, known as RSV, which sends more than 57,000 young children and 177,000 elderly people in the U.S. to the hospital each year, could also reduce antibiotic use. Potential vaccines for a number of these diseases are in various stages of clinical trials.
Lipsitch envisions vaccines that go even further. “I actually think one of the most interesting ideas I’ve had is the idea of using vaccines directly to target [antibiotic] resistant bacteria, not just all bacteria, but directly aiming at the targets that are the resistant genes.” This type of vaccine would be especially helpful for bacteria like pneumococcus and Staphylococcus aureus, which are so ubiquitous that they’re unlikely to be eliminated; keeping drug resistance at bay would help us coexist with them more peacefully. “The idea of these resistance-targeted vaccines is to try to make life extra hard for the resistant organisms,” Lipsitch said.
But would it be tough to sell people on more vaccines for both kids and adults when some people are refusing to get the vaccines we already have? “I think it ought to be a pretty easy sell, actually,” said David Salisbury, associate fellow at the Chatham House Centre on Global Health Security in London and former director of immunization at the U.K. Department of Health. “Imagine if an ear infection, which happens so commonly in children, became untreatable. You can fantasize about false risks of the vaccines, but they turn to nothing when you compare them with untreatable infections. Would you seriously prefer your child not to have a vaccine and risk an infection to which there was no treatment?”
A global challenge as big as antibiotic resistance will require multiple solutions, including reducing the use of antibiotics in agriculture and developing new antibiotics, but Salisbury says that vaccines deserve more attention and investment. Gilsdorf is on board with that. “What we need is more good science, which means we need more funding for the National Institutes of Health, the National Science Foundation, and these federal agencies that support scientists to learn the nitty-gritty of these bacteria,” she said.
Initial results reveal more than 760 genetic dependencies across multiple cancers
Graphic: The Broad Institute of MIT and Harvard
In one of the largest efforts to build a comprehensive catalog of genetic vulnerabilities in cancer, researchers from the Broad Institute of MIT and Harvard and Dana-Farber Cancer Institute have identified more than 760 genes upon which multiple types of cancer cells are strongly dependent for their growth and survival.
Many of these “dependencies,” the researchers report today in the journal Cell, are specific to certain cancer types. However, about 10 percent of them are common across multiple cancers, suggesting that a relatively small number of therapies targeting these core dependencies might each hold promise for combating several tumors.
To generate these findings, the research team conducted genome-wide RNA interference (RNAi) screens on 501 cell lines representing more than 20 types of cancer, silencing more than 17,000 genes individually in each line to identify genetic dependencies unique to cancerous cells.
Cancer cells can harbor a broad variety of genetic errors, from small mutations to wholesale swaps of DNA between chromosomes. If an error shuts down a critical gene, a cancerous cell will compensate by adjusting other genes’ activity, frequently developing a dependence on such adaptations in order to persist.
Identifying these dependencies provides opportunities for scientists to gain deeper insight into cancer biology and determine new therapeutic targets.
“Much of what has been and continues to be done to characterize cancer has been based on genetics and sequencing. That’s given us the parts list,” said study co-senior author William Hahn, an institute member in the Broad Cancer Program, chief of the Division of Molecular and Cellular Oncology at Dana-Farber, and a leader in the Cancer Dependency Map initiative, a joint effort spanning the Broad Institute and Dana-Farber. “Mapping dependencies ascribes function to the parts and shows you how to reverse-engineer the processes that underlie cancer.”
RNAi silences genes using small pieces of RNA called small interfering RNAs (siRNAs). To run a genome-wide RNAi screen, researchers expose cells to pools of siRNAs and track the cells’ behavior.
“The simplest thing one can do with perturbed cells is allow them to keep growing over time and see which ones thrive,” explained study co-senior author David Root, an institute scientist and director of the Genetic Perturbation Platform at the Broad. “If cells with a certain gene silenced disappear, for example, it means that gene is essential for proliferation.”
The data revealed striking patterns in cancer cells’ dependencies. Many dependencies were cancer-specific, in that silencing each affected only a subset of the cell lines. However, more than 90 percent of the cell lines had a strong dependency on at least one of a set of 76 genes, suggesting that many cancers rely on a relatively few genes and pathways.
Using a set of molecular features (e.g., mutations, gene copy numbers, expression patterns) from each cell line, the team also generated biomarker-based models that helped explain the biology behind 426 of the 769 dependencies. Most of those biomarkers fell into four broad categories:
Mutation(s) of a gene;
Loss of a copy or reduced expression of a gene;
Increased expression of a gene;
Reliance on a gene functionally or structurally related to another, lost gene (a.k.a., a paralog dependence).
Surprisingly, more than 80 percent of the dependencies with biomarkers were associated with changes (up or down) in a gene’s expression. Mutations, often used as the grounds for pursuing a gene as a drug target, accounted for merely 16 percent of biomarker-associated dependencies.
Twenty percent of the dependencies the team discovered were associated with genes previously identified as potential drug targets.
“We can’t say we’ve found everything, but we can say that the genes we’re seeing fall into a relatively small number of bins, some of which are familiar, some less so,” Hahn said. “That initial taxonomy is a great starting point for building a full map.”
“Our results provide a starting point for therapeutic projects to decide where to focus their efforts,” said study co-first author Francisca Vazquez, a Cancer Dependency Map project leader. She added that while there was still much to do to validate the list, “It’s becoming increasingly easier to triangulate data and generate hypotheses as more genome-scale systematic data sets, like those from the Cancer Cell Line Encyclopedia, Genotype-Tissue Expression, and the Cancer Genome Atlas projects, become available.
“Bringing of all the data together will help us generate a truly comprehensive cancer dependency map.”
To eliminate false-positive results caused by seed effects — a phenomenon by which siRNAs inadvertently silence irrelevant genes — study co-first author Aviad Tsherniak led the development of a novel computational tool dubbed DEMETER.
“People sometimes take a dim view of RNAi because seed effects make the data so noisy,” said Tsherniak, leader of the Broad Cancer Program’s Data Science group. “DEMETER models gene knockdown and seed effects within the data, and computationally subtracts the seed effects. It cleans up the data and helps you find true dependencies.”
According to Hahn, the data argue that the time is ripe to pay more attention to the broader landscape of functional aspects of cancer, in addition to focusing on protein-coding gene mutations and variations.
“I think we’re close to the end of finding genes that are mutated or focally amplified in cancer,” he said. “To me, that’s a huge opportunity, because it means we have many heretofore untapped avenues for understanding cancer.”
Single-cell breakthroughs let scientists see exactly what we’re all made of In Israel for Broad Institute conference, Eric Lander, pioneer of Human Genome Project, marvels at speed with which ‘new genomics’ opens ways to fight disease
Two years ago, when mathematician and biologist Eric Lander was in Israel for an innovative gathering of researchers and students, he took a break from his conference to describe to The Times of Israel how scientists had completed the sequencing of the human genome — a person’s “parts list” — and were now working on the “wiring diagram,” setting out how those parts work together.
Back in Israel recently for the third of his Broad Institute’s annual conferences, Lander enthused over the “amazing” pace at which science has moved on since that last visit, most especially in the study of single cells — what he called “the new genomics.” One of the founding fathers of the Human Genome Project, Lander has dedicated his work to understanding what makes us tick, the better to keep us ticking. To underline the significance of this work for all of us, I headlined my 2013 interview with him, “This man’s work will change your life.” What’s unfolded in the last two years, he said, is a growing ability to identify what we humans are made of at the most fundamental level — the level of a single cell — with extraordinary potential benefits for understanding, observing and treating the diseases that afflict us. Lander, 58, is the founding director of the Broad Institute of Harvard and MIT, which is devoted to utilizing human genome research in medicine. He was back in Israel for the “Third Annual Broad-Israel Science Foundation (ISF) Cell Circuits Symposium” — which brought together experts and students from the Broad Institute, from Harvard, and from Israel’s universities, on the cutting edge of human genome research and its applications for medicine. Capitalizing on an Israeli scientific community that is very strong when it comes to combining biology and info-technology skills, the Broad-Israel partnership encourages Israeli and American trailblazing in an increasing number of joint projects, all designed to speed our progress toward thwarting cancers, Alzheimer’s, diabetes and other diseases. Explaining the rapid advances in single-cell research, Lander said that as recently as two years ago, scientists had only what you might consider “a pixelated, low-resolution image” of our cell structure. They really didn’t know how many different types of cells there are in the body, and they couldn’t identify the differences between them. “In the past we had a kind of blended big picture, a ‘smoothie,'” said Lander, finding another metaphor to enlighten this non-expert. “Now, because of new laboratory techniques and maths and advances in DNA sequencing,” he went on, “we have the ability to study single cells. Folks spent 40 years working to identify the cells of the retina, the back of an eye,” he said by way of an example. “Now you can do that in an afternoon.” And why should we care? Because, Lander positively sparkled, “the ability to do single-cell analysis, to get the identities and states of each of the cells, is the final revolution in this field. It’s the equivalent of an amazing new microscope” — a microscope that offers remarkable potential for improving our health. Human cancer cells with nuclei (specifically the DNA) stained blue. The central and rightmost cell are in interphase, so the entire nuclei are labeled. The cell on the left is going through mitosis and its DNA has condensed. (TenOfAllTrades/Wikipedia) Human cancer cells with nuclei (specifically the DNA) stained blue. The central and rightmost cell are in interphase, so the entire nuclei are labeled. The cell on the left is going through mitosis and its DNA has condensed. (TenOfAllTrades/Wikipedia) For instance? In the old days — that is, until a couple of years ago — scientists struggled to understand what constituted a tumor. What common genetic features do tumors have? How might tumors be tackled most effectively? “Now we can see the commonality, the types of cells, the proportions, the logic,” he said. “This has major implications for our health. “You want to kill a tumor? Well, maybe our treatments work on one type of cell. We were blind to that. Now we can test a treatment on the few different types of cells.” The new microscope, in other words, enables an unprecedentedly precise understanding of disease. “It tells us what we need to solve.” ‘The ability to do single cell analysis, to get the identities and states of each of the cells, is the final revolution in this field. It’s the equivalent of an amazing new microscope’ “Imagine medicine before gross anatomy,” Lander suggested, as he sought to put the dramatic recent progress into historical perspective. “Then comes anatomy, and you can describe the organs of the body. You can see something problematic, say, in the lung, or in the heart. Well, this is the ultimate anatomy. It will penetrate every type of medicine. Not bad for two years. This just didn’t exist last time we spoke.” Another area of rapid progress cited by Lander is the ability to “precisely edit” the genome of human cells, which has massive potential to help treat certain diseases. Just two years ago, Feng Zhang, a researcher at the Broad, invented this power gene-editing technology by harnessing by harnessing — called CRISPR-Cas9 — that can cut genomes in any place and thus enable editing. Already an Israeli researcher at Broad has published a paper “editing” each of the 20,000 genes to find those that are essential to particular types of cancer cells – in effect, identifying the Achilles Heels of these cancers. These advances also might open up possibilities of altering the human gene pool, of working to create less-diseased humans, even super-humans. “There’s talk of editing the DNA of embryos to alter our gene pool,” he acknowledged. “It’s being discussed.” Then he added dryly, “I’m not sure it’s a good idea. Eugenics hasn’t worked out too well for society. Moreover, changing DNA for one purpose can have unexpected bad consequences.” Where the advances are clearly positive is in the capacity — as genetic mapping becomes more affordable and more sophisticated — to identify the genes that predispose to Alzheimer’s, early onset cancer and many other diseases. (A personal genome map now costs about $3,000, he said.) In some cases, genetic information can be important to parents. “Today, doctors can check two folks getting married for some mutations that would cause a disease if it was inherited by their children. In the future you would do checks for more.” The partnership between Broad and Israel, Lander stressed, works particularly well because of Israel’s strong information technology and bio-science communities. “Israel is such an intersection of those skill sets,” he said. And Israel’s ever-strained public health system, he added, actually has very good electronic medical records — “a 20-year history,” he said — which makes it well-placed to utilize new advances as they become available. “In the next decade we’ll collect a lot of information, and we’ll figure out the best uses. We’ll assess the risks of disease, the possibility to intervene.” For all of that, you need groundbreaking scientists and good data. Like the United States, said Lander, Israel has both. View at the original source
