What it takes to achieve world-changing scientific breakthroughs

In science, advances are a daily occurrence, but true breakthroughs are rare. What does it take to achieve world-changing scientific breakthroughs? Some are the result of a lucky accident, combined with curiosity: scientists traveling down one road suddenly find reason to veer onto another road, one they never planned to travel — a road that may well lead nowhere.

Other major breakthroughs stem from scientists pursuing a very specific dream. One day, usually early in their career, they get an idea that they can’t stop thinking about. It’s crazy, they say to themselves, but is it really impossible? They talk to respected colleagues who often remind them of all the reasons their idea might not work, and how damaging this could be for their career. It’s a sobering message, yet the idea won’t die. So, they scramble to find financial support and seek out colleagues willing to risk traveling that road with them — a road that may well lead nowhere. But sometimes the road leads to major breakthroughs like penicillin and mRNA vaccines.

Breakthroughs due to lucky accidents and curiosity

One day in 1928, Dr. Alexander Fleming at St. Mary’s Hospital in London was growing bacteria in a laboratory dish. Fleming was not pursuing a scientific dream. He was a microbiologist, just doing his job.

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Then he noticed something odd: overnight, another kind of microbe, a fungus, had traveled through the air, landed on the laboratory dish, and started to grow and spread on the dish where the bacteria were growing. Fleming soon noticed that the growing fungus seemed to be killing the bacteria. He surmised that it was making some substance that killed the bacteria. Because the name of the fungus was Penicillium rubens, he called the substance the fungus was making “penicillin.”

When Fleming published a paper about his discovery, few were interested. It took another 10 years before other scientists tried to generate large amounts of penicillin to see if it might be able to cure bacterial infections and save lives. We all know how that worked out.

Fleming’s scientific breakthrough, like some others, occurred not because Fleming had a brilliant idea and exclaimed “Eureka!” Instead, it occurred because he noticed something and said, “That’s odd,” and then tried to figure it out.

Protect yourself from the damage of chronic inflammation.

Science has proven that chronic, low-grade inflammation can turn into a silent killer that contributes to cardiovas­cular disease, cancer, type 2 diabetes and other conditions. Get simple tips to fight inflammation and stay healthy — from Harvard Medical School experts.

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Breakthroughs due to persistence and resilience in pursuit of a dream

The story of mRNA vaccines, like the Pfizer/BioNTech and Moderna vaccines for COVID-19, is very different from the story of penicillin. For 30 years, a small group of scientists believed that mRNA vaccines would have great advantages over traditional vaccines — if only several obstacles could be overcome. Many of these scientists gave up as they encountered those obstacles, but a few persisted and, ultimately, succeeded. (I described what mRNA vaccines are, how they work, and how obstacles were overcome in a previous blog post.)

One scientist, Dr. Katalin Karikó, joined the faculty of the University of Pennsylvania in the early 1990s with the dream of creating an mRNA vaccine. She applied for grants to support her work, but was repeatedly rejected: the reviewers stated that it was so unlikely that she or anyone could overcome the obstacles that supporting her research would be a wasted investment. Her university only agreed to continue supporting her work if she accepted a demotion and a pay cut. She accepted both, and doggedly pursued her dream.

One major obstacle to mRNA vaccines particularly fascinated her: the violent reaction of the immune system when it encounters mRNA from a virus. Ten years of dogged work helped Karikó and her colleague Drew Weissman figure out how to make a small change in mRNA that prevented that violent immune response — a major step in making all mRNA vaccines possible. Without this, the world wouldn’t have mRNA COVID vaccines today.

Two other scientists who created the Pfizer/BioNTech COVID v

A common virus may be one contributing cause of multiple sclerosis

Discovering the cause of a disease is not easy. One reason is that the vast majority of diseases do not have a single cause. Instead, most diseases occur because multiple factors combine to cause the disease.

One factor is genes. Some people are born with one or more genes that make them vulnerable to a disease. Other factors come from your environment and behavior: what you eat, the air you breathe, the amount of physical activity you engage in, and habits such as smoking. Recent research finds that certain viruses may also be important contributing factors in causing multiple sclerosis (MS).

Multiple sclerosis harms cells in the brain and spinal cord — but why?

Multiple sclerosis is a disease of the brain and spinal cord that can cause many neurological symptoms, including arm and leg weakness, loss of vision, and difficulty thinking, as well as severe fatigue. Over the past 50 years we’ve learned that MS is an autoimmune disease: in various ways, the immune system attacks the brain and/or the spinal cord, leading to the symptoms of the illness.

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However, we haven’t figured out why: what causes the immune system to go on the attack? Over the years, several viruses have been proposed as causes of MS, only to have subsequent research show that they were not. That led some MS doctors and scientists to discount viruses as possible causes.

Yet growing evidence in recent years points to several viruses that may be triggers of MS. The strongest evidence is for Epstein-Barr virus (EBV). This virus infects most people in developed nations like the US in their teen or young adult years.

Once a person is infected, the virus quietly remains alive in the body for the rest of a person’s life. In most people, it causes no health problems. But, rarely, it can cause certain cancers. Now, it has been linked to multiple sclerosis.

Protect yourself from the damage of chronic inflammation.

Science has proven that chronic, low-grade inflammation can turn into a silent killer that contributes to cardiovas­cular disease, cancer, type 2 diabetes and other conditions. Get simple tips to fight inflammation and stay healthy — from Harvard Medical School experts.

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View Protect yourself from the damage of chronic inflammation.

Delving deeper into a link between Epstein-Barr virus and MS

A large, long-term study from Harvard, published in the prestigious journal Science, attracted a lot of attention. Blood samples were repeatedly collected from 10 million US military personnel over 20 years. The samples were tested for evidence of infection with EBV.

Over the 20 years, some people in the study developed MS. The researchers compared two groups: people who were not infected with EBV when they entered military service, but then became infected later on; and people who remained uninfected by the virus. Those in the first group were 32 times more likely to develop MS than those in the second group. On average, symptoms of MS began about five years after a person became infected with EBV.

What do these findings tell us? The study provides strong evidence that a new infection with EBV is one important factor — maybe even a necessary factor — in causing MS. But the story is more complicated than that. Think about this: About 95% of all humans become permanently infected with EBV by early adulthood, but fewer than 1% of people develop MS. So, just being infected with EBV doesn’t mean a person will get MS — far from it. Indeed, other factors besides EBV infection also must be involved in causing MS.

Those other factors almost certainly include being born with certain genes that make you vulnerable to getting MS. Being infected with other viruses, as well as EBV, also may be important factors.

But which viruses? In my opinion, growing evidence indicates that a “cousin” of EBV, called human herpesvirus-6A, also may be important in triggering MS. And the genes of endogenous retroviruses also may be factors.

What are endogenous retroviruses?

About 8% of the genes that we are born with come from ancient viruses called retroviruses. These viral organisms successfully inserted their genes into the genes of the animals that preceded, and led to, humans. Some of those genes can be turned on to make proteins that affect our immune systems. Finally, there is evidence that each of these viruses — EBV, human herpesvirus-6A, and endogenous retroviruses — can activate one another, and gang up to cause a disease.

Going forward: New research may offer new leads for prevention

If the Epstein-Barr virus is one important factor in causing multiple sclerosis, then it is possible that vaccines against EBV might lead to fewer cases of MS. Indeed, several scientific groups around the world are working on such vaccines.

One company that made the mRNA vaccine for COVID-19 is working on an mRNA EBV vaccine. The National Institutes of Health also is developing a vaccine. However, it is unlikely we will know if they are effective against EBV, or against the development of MS, for at least a decade. Still, the linkage with this virus may prove to be an important milestone in ultimately conquering multiple sclerosis.

The case of the bad placebo

When it comes to clinical research, the most powerful type of study is a randomized, double-blind, placebo-controlled trial.

But even a well-designed trial can arrive at questionable conclusions. Recent follow-up on a 2019 cardiovascular study dubbed REDUCE-IT is one example that offers a great lesson. While innovative treatments are the focus of many clinical trials like this one, the choice of placebo is critical as well.

What made this a powerful study?

In this type of study, subjects are randomly assigned to two groups: one group receives the treatment being evaluated (such as a new drug) while the other group gets a fake treatment called a placebo.

Neither study subjects nor researchers know who is receiving active treatment and who is receiving placebo. That is, they are both blind to group assignment — that’s why it’s called double-blind. Treatment assignment is coded and kept secret until the end of the study, or decoded at earlier, planned intervals to monitor effectiveness or safety.

This reduces the chance that expectations of the researchers or participants will bias study outcomes. That means any differences in health or side effects can reasonably be attributed to the treatment — or lack of it.

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Protect yourself from the damage of chronic inflammation.

Science has proven that chronic, low-grade inflammation can turn into a silent killer that contributes to cardiovas­cular disease, cancer, type 2 diabetes and other conditions. Get simple tips to fight inflammation and stay healthy — from Harvard Medical School experts.

LEARN MORE

View Protect yourself from the damage of chronic inflammation.

What to know about placebo treatment

Ideally, study participants and researchers cannot tell who is getting an active treatment and who is getting a placebo. But sometimes, participants might be able to tell what they received. For example, the active treatment might have a bitter taste, or a noticeable side effect such as diarrhea.

If that happens, the study is no longer double-blind. This means expectations could affect outcomes. Studies can assess this by asking participants during or after the trial whether they thought they were taking an active treatment or a placebo. If the answers seem random or the subjects answer “I don’t know,” blinding was successful.

While a placebo treatment should have no effect, that’s not always true:

  • The well-known placebo effect is a positive effect related to an expectation of benefit: if you tell someone a pill can relieve pain, some people will experience pain relief, even if that pill was a placebo.
  • A negative side effect due to a placebo is called the nocebo effect: if you tell someone they might develop diarrhea from the placebo pill they’re taking, the expectation may cause some people to experience this. (The very same placebo used in another study may trigger headaches, if that’s the side effect the study subject is warned about.)

Finally, a placebo should not have any direct, biological impact on the person taking it. And that seems to be where REDUCE-IT went wrong.

REDUCE-IT demonstrates the importance of choosing a placebo carefully

The full name of REDUCE-IT is the Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial). It was designed to determine whether the drug icosapent ethyl could lower triglyceride levels as a way to reduce cardiovascular disease, such as heart attack or stroke.

Triglycerides are a type of fat in the blood. High levels may increase cardiovascular risk, but experts aren’t sure whether treatments to lower triglyceride levels result in fewer heart attacks or strokes.

Among participants who received the active drug, triglyceride levels fell. Rates of cardiovascular problems, including heart attack or stroke, were a whopping 25% lower compared with rates in those assigned to take a placebo. There was even a 20% reduction in cardiovascular deaths in the treatment group.

Based on these findings, the FDA approved a drug label claiming that icosapent ethyl benefitted certain people at high risk for cardiovascular disease.

But questions arose soon after the study was published in 2019. True, the treatment group fared better than the placebo group. Yet a careful reading of the results suggested that this may have been because those in the placebo group had more heart attacks and strokes over time, not because the treatment group had fewer.

A follow-up study shows a different result

Responding to these questions, the study’s authors performed additional analyses. This time they looked at substances in the blood called biomarkers associated with cardiovascular risk. They found little change in the biomarker results among participants receiving the active drug. But biomarkers worsened in the placebo group, suggesting that the apparent benefit conferred by the drug may have been due to the negative effects of the placebo!

How can a placebo worsen cardiovascular risk? One possibility is that the mineral oil placebo used in this trial may have reduced absorption of statin drugs participants were taking to lower their cholesterol, which also affect heart and blood vessel health. Regardless, this new analysis suggests that the skepticism about the dramatic results of the original study was appropriate, and additional study is warranted.

The bottom line

For me, this story has three take-home points:

  • There are many ways for research to come to faulty conclusions; an unfortunate placebo choice is an unusual one, but appears to be true here.
  • For medical research to be trusted, researchers must be willing to accept criticism, re-assess findings, and perform additional analyses if necessary.
  • It appears that in the case of REDUCE-IT, this self-correction process worked.

After the initial study in 2019, enthusiasm was high for the drug icosapent ethyl. In the wake of this latest analysis, however, that excitement is likely to wane. But one thing should be clear: this is not science being unable to make up its mind, as is sometimes said. Reassessment and correction, when warranted, is how science is supposed to work.

The rise of computational medicine

Medical research is in the midst of the “big data” revolution. What is it? Until the past 20 years, most laboratory re-search involved simple ideas that could be tested by simple experiments. For example, 70 years ago the biochemist Linus Pauling discovered the cause of sickle cell disease. In this disease, misshapen red blood cells clog up small blood vessels, leading children and young adults to have recurrent bouts of excruciating pain and even strokes and heart attacks.

Pauling bet that the children had inherited a defect in a specific protein, globin, that caused the protein, and then the red blood cell, to become misshapen. The simple idea led to a simple experiment. He put globin from people with and without the disease into a gel. Then, he turned on an electric current that caused the globin to move through the gel. Diseased globin moved differently from healthy globin. Anyone could see the difference, just looking at the gel. No fancy analysis was necessary.

For a few years it seemed possible that most diseases might be caused by a defect in a single protein or other type of molecule. If so, perhaps simple cures would follow. Unfortunately, by the 1970s it had become clear that inside every cell are thousands of molecules of different types, including proteins and nucleic acids, and that the cause of most diseases involved the interaction of many of these different molecules. That meant that, with most diseases, one would have to analyze thousands of molecules to figure out what was wrong. However, in the 1970s, such analyses were not possible. Scientists could not identify which molecules were the abnormal ones: they could only guess, like Linus Pauling did. And the guesses were often wrong — clever, but wrong.

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Protect yourself from the damage of chronic inflammation.

Science has proven that chronic, low-grade inflammation can turn into a silent killer that contributes to cardiovas­cular disease, cancer, type 2 diabetes and other conditions. Get simple tips to fight inflammation and stay healthy — from Harvard Medical School experts.

LEARN MORE

View Protect yourself from the damage of chronic inflammation.

Fortunately, the effort to identify every one of our roughly 20,000 genes accomplished not only that remarkable feat but also led to the development of technologies that simultaneously analyze thousands of molecules of different types. Even 30 years ago, few scientists imagined that this could be possible in their lifetimes.

However, unlike Pauling’s experiment, these experiments involving thousands of molecules require very fancy analysis — new mathematical techniques to make sense out of the thousands of numbers (the “big data”) that are generated with each experiment. A whole new field, computational medicine, emerged. At Harvard Medical School we have created a large department dedicated to developing such computational medicine techniques and to training young scientists to use and teach them.

The new world of “big data” in biomedical research has brought about another change, as well. Today, we don’t always need a bright idea to advance science. We now have the tools to compare tissue from people with and without a disease and ask what molecules are different. Guessing what might be different is no longer essential. Now, we can just let nature speak for itself.

Prostate cancer: Zapping metastatic tumors with radiation improves survival

Oligometastatic cancer is an early form of stage 4 prostate cancer that has spread to other organs in the body, but only to a limited degree — generally defined as no more than three to five areas outside the prostate gland, most commonly the lymph nodes or bones.

Barely a decade ago it was considered universally fatal, and treatment was limited to systemic hormonal therapies that shut down testosterone, a hormone that drives the tumors to grow. But now, exciting developments in the field are leading to new treatment strategies that are improving patient survival in clinical trials.

These strategies are enabled by advances in medical imaging, revealing metastatic tumors that were previously too small to see. Doctors can now treat the tumors directly with radiation or surgery. This is called metastasis-directed therapy (MDT), and it is allowing some men with oligometastatic prostate cancer to delay or even completely avoid hormonal therapy, along with its challenging side effects.

Now, results from an important new study show that beneficial responses to MDT hold up with long-term follow-up.

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The researchers’ methodology

To generate the findings, researchers combined results from two prior studies that randomized men to MDT or observation: one called STOMP and another called ORIOLE. The men in the studies were treated with a technique called stereotactic ablative radiotherapy, which focuses intense beams of radiation on tumors from multiple directions, while sparing healthy tissues. Taken together, the studies showed that MDT delays cancer progression and the subsequent need for hormonal therapy. After they were published, MDT started becoming more widely adopted.

For this new study, the STOMP and ORIOLE subjects were combined into a single group of 116 men with a median follow-up of 52.5 months. The research’s aim was to compare differences in progression-free survival (the amount of time it takes for the cancer to worsen) between men who were treated with MDT and those who were not.

Results showed a clear benefit from radiation: progression-free survival lasted 11.9 months, on average, among the MDT-treated men, compared to 5.9 months among the untreated controls.

But the researchers also went a step further: they analyzed archived samples of the subjects’ blood and tumor tissues for cancer-associated mutations in five different genes: ATM, BRCA1, BRCA2, Rb1, and TP53. Again, the data revealed a stark discrepancy: among men with at least one mutation, progression-free survival lasted an average of 7.5 months, compared to 13.4 months on average among those who had none.

Remarkably, progression-free survival lasted four years or longer in up to 20% of the MDT-treated men, regardless of their mutational status. But in general, men lacking in the mutations had the best responses. MDT by itself may be initially sufficient for these men, the researchers concluded, while among those with high-risk mutations, MDT might be more effective if paired with a systemic therapy.

Protect yourself from the damage of chronic inflammation.

Science has proven that chronic, low-grade inflammation can turn into a silent killer that contributes to cardiovas­cular disease, cancer, type 2 diabetes and other conditions. Get simple tips to fight inflammation and stay healthy — from Harvard Medical School experts.

LEARN MORE

View Protect yourself from the damage of chronic inflammation.

An expert’s reaction

“The authors should be applauded for their respectable follow-up of 52 months,” says Dr. Nima Aghdam, a radiation oncologist at Beth Israel Deaconess Medical Center in Boston, and a member of the Harvard Medical SchoolAnnual Report on Prostate Diseases advisory board. In the right setting, Dr. Aghdam added, MDT can be delivered safely, delaying treatments that often lead to a decline in the patient’s quality of life.

Selecting the right patients for treatment is critical, but the mutations identified “may allow us in the future to determine who will benefit most from MDT,” he said. It may be, Dr. Aghdam said, that MDT given by itself offers a pathway for a long-term, disease-free period among patients treated in community settings. “This will require longer studies to clarify,” he said, “but the possibility that a good proportion of patients can defer=”defer” ADT for a long time will be broadly appreciated.”

Motorcycle rallies and organ donation: A curious connection

It’s an old and morbid joke, particularly apt in hospital emergency rooms: What do you call someone on a motorcycle speeding past you on the freeway? An organ donor.

It’s not funny, of course. But that sad, dark humor appears to have a kernel of truth in it, according to a study in JAMA Internal Medicine that suggests large motorcycle rallies modestly increase organ donation.

Why did researchers decide to study this?

Strong evidence shows that motorcycles are riskier than other modes of transportation, especially if the operator is driving recklessly, not wearing a helmet, or under the influence of alcohol or other drugs.

Yet in the past 20 years, the number of motorcycles registered in the US doubled from 4.3 million to 8.6 million. Motorcycle rallies are popular as well: in 2022, more than half a million people attended the largest motorcycle rally in the world in Sturgis, South Dakota. And that’s actually about 200,000 fewer than had attended in some years.

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With so many people on motorcycles converging in one place, researchers wondered whether fatal accidents might rise — and whether that might temporarily increase the rate of organ donation.

Their study threw the net wider than the Sturgis rally. Focusing on towns and cities that hosted major motorcycle rallies in the US between 2005 and 2021, the researchers tallied fatal motor vehicle accidents that led to organ donation and transplantation. Then they compared the numbers to rates four weeks before and after rallies in those places. They also looked at rates in parts of the country where no rallies occurred.

Protect yourself from the damage of chronic inflammation.

Science has proven that chronic, low-grade inflammation can turn into a silent killer that contributes to cardiovas­cular disease, cancer, type 2 diabetes and other conditions. Get simple tips to fight inflammation and stay healthy — from Harvard Medical School experts.

LEARN MORE

View Protect yourself from the damage of chronic inflammation.

What did the study find?

On average, a single organ donor can provide three to four organs for transplantation, including kidneys, liver, and heart. That’s why choosing to be an organ donor can change many lives.

When the researchers analyzed nearly 11,000 organ donations that followed motor vehicle accidents after seven major motorcycle rallies, they found:

  • The organ donors were mostly young (average age 32) and male (71%).
  • On average, during each day of a motorcycle rally, there were 21% more organ donors and 26% more organ recipients compared with the same areas on non-rally dates or in nearby regions that did not host rallies. That sounds substantial, yet it translates to only one additional donor for two major motorcycle rallies.
  • Donor deaths due to causes other than motor vehicle accidents didn’t increase during rally dates.

This study’s findings raise new questions

The study suggests that more accidents — and more organ donations — occur on days when large motorcycle rallies are held. But there’s a lot we don’t learn that might put study findings in a different light. For example:

  • Did fatal accidents occur mostly on major thoroughfares, smaller roads, or off-road?
  • Was there any relationship between fatal accidents and passengers on motorcycles, or certain vehicles — a motorcycle alone, say, or a motorcycle and a truck?
  • How do motorcycle rallies affect rates of injury and death? This study likely underestimated the overall impact because it only included fatalities after motor vehicle accidents that led to organ donation. Nonfatal accidents and fatal accidents that didn’t lead to organ donation were not included.
  • Is the number of fatal accidents during motorcycle rallies higher than would be expected from the dramatic increase in crowds and traffic?

The answers to these questions could help guide rally organizers improve the safety of these events.

The bottom line

In my view, this remarkable study has several take-home messages.

First, motorcycle rallies are associated with an uptick in fatal motor vehicle accidents. Knowing this, rally organizers, local leaders, and health care providers should act to improve safety and prepare for an increased number of crash-related injuries. At a minimum, rally participants should be encouraged to wear helmets, and discouraged from reckless driving or driving while under the influence of drugs or alcohol.

In addition, this study suggests motorcycle rally organizers should incorporate organ donor sign-up programs into these events. Doing so could increase the number of organs available to those in need of organ transplant at a time when there are significant shortages. It might even encourage people to ride more safely.

Does drinking water before meals really help you lose weight?

If you’ve ever tried to lose excess weight, you’ve probably gotten this advice: drink more water. Or perhaps it was more specific: drink a full glass of water before each meal.

The second suggestion seems like a reasonable idea, right? If you fill your stomach with water before eating, you’ll feel fuller and stop eating sooner. But did that work for you? Would drinking more water throughout the day work? Why do people say drinking water can help with weight loss — and what does the evidence show?

Stretching nerves, burning calories, and thirst versus hunger

Three top theories are:

Feel full, eat less. As noted, filling up on water before meals has intuitive appeal. Your stomach has nerves that sense stretch and send signals to the brain that it’s time to stop eating. Presumably, drinking before a meal could send similar signals.

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  • The evidence: Some small, short-term studies support this idea. For example, older study subjects who drank a full glass of water before meals tended to eat less than those who didn’t. Another study found that people following a low-calorie diet who drank extra water before meals had less appetite and more weight loss over 12 weeks than those on a similar diet without the extra water. But neither study assessed the impact of drinking extra water on long-term weight loss.

Burning off calories. The water we drink must be heated up to body temperature, a process requiring the body to expend energy. The energy spent on this — called thermogenesis — could offset calories from meals.

  • The evidence: Though older studies provided some support for this explanation, more recent studies found no evidence that drinking water burned off many calories. That calls the thermogenesis explanation for water-induced weight loss into question.

You’re not hungry, you’re thirsty. This explanation suggests that sometimes we head to the kitchen for something to eat when we’re actually thirsty rather than hungry. If that’s the case, drinking calorie-free water can save us from consuming unnecessary calories — and that could promote weight loss.

  • The evidence: The regulation of thirst and hunger is complex and varies over a person’s lifespan. For example, thirst may be dulled in older adults. But I could find no convincing studies in humans supporting the notion that people who are thirsty misinterpret the sensation for hunger, or that this is why drinking water might help with weight loss.

Protect yourself from the damage of chronic inflammation.

Science has proven that chronic, low-grade inflammation can turn into a silent killer that contributes to cardiovas­cular disease, cancer, type 2 diabetes and other conditions. Get simple tips to fight inflammation and stay healthy — from Harvard Medical School experts.

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View Protect yourself from the damage of chronic inflammation.

Exercise booster, no-cal substitution, and burning fat demands water

Being well-hydrated improves exercise capacity and thus weight loss. Muscle fatigue, cramping, and heat exhaustion can all be brought on by dehydration. That’s why extra hydration before exercise may be recommended, especially for elite athletes exercising in warm environments.

  • The evidence: For most people, hydrating before exercises seems unnecessary, and I could find no studies specifically examining the role of hydration to exercise-related weight loss.

Swapping out high calorie drinks with water. Yes, if you usually drink high-calorie beverages (such as sweetened sodas, fruit juice, or alcohol), consistently replacing them with water can aid weight loss over time.

  • The evidence: A dramatic reduction in calorie intake by substituting water for higher-calorie beverages could certainly lead to long-term weight loss. While it’s hard to design a study to prove this, indirect evidence suggests a link between substituting water for high-cal beverages and weight loss. Even so, just as calorie-restricting diets are hard to stick with over the long term, following a water-only plan may be easier said than done.

Burning fat requires water. Dehydration impairs the body’s ability to break down fat for fuel. So, perhaps drinking more water will encourage fat breakdown and, eventually, weight loss.

  • The evidence: Though some animal studies support the idea, I could find no compelling evidence from human studies that drinking extra water helps burn fat as a means to lose excess weight.

Is chronic fatigue syndrome all in your brain?

Chronic fatigue syndrome (CFS) –– or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), to be specific ––  is an illness defined by a group of symptoms. Yet medical science always seeks objective measures that go beyond the symptoms people report.

A new study from the National Institutes of Health (NIH) has performed more diverse and extensive biological measurements of people experiencing CFS than any previous research. Using immune testing, brain scans, and other tools, the researchers looked for abnormalities that might drive health complaints like crushing fatigue and brain fog. Let’s dig into what they found and what it means.

What was already known about chronic fatigue syndrome?

In people with chronic fatigue syndrome, there are underlying abnormalities in many parts of the body: The brain. The immune system. The way the body generates energy. Blood vessels. Even in the microbiome, the bacteria that live in the gut. These abnormalities have been reported in thousands of published studies over the past 40 years.

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Protect yourself from the damage of chronic inflammation.

Science has proven that chronic, low-grade inflammation can turn into a silent killer that contributes to cardiovas­cular disease, cancer, type 2 diabetes and other conditions. Get simple tips to fight inflammation and stay healthy — from Harvard Medical School experts.

LEARN MORE

View Protect yourself from the damage of chronic inflammation.

Who participated in the NIH study?

Published in February in Nature Communications, this small NIH study compared people who developed chronic fatigue syndrome after having some kind of infection with a healthy control group.

Those with CFS had been perfectly healthy before coming down with what seemed like just a simple “flu”: sore throat, coughing, aching muscles, and poor energy. However, unlike their experiences with past flulike illnesses, they did not recover. For years, they were left with debilitating fatigue, difficulty thinking, a flare-up of symptoms after exerting themselves physically or mentally, and other symptoms. Some were so debilitated that they were bedridden or homebound.

All the participants spent a week at the NIH, located outside of Washington, DC. Each day they received different tests. The extensive testing is the great strength of this latest study.

What are three important findings from the study?

The study had three key findings, including one important new discovery.

First, as was true in many previous studies, the NIH team found evidence of chronic activation of the immune system. It seemed as if the immune system was engaged in a long war against a foreign microbe — a war it could not completely win and therefore had to keep fighting.

Second, the study found that a part of the brain known to be important in perceiving fatigue and encouraging effort — the right temporal-parietal area — was not functioning normally. Normally, when healthy people are asked to exert themselves physically or mentally, that area of the brain lights up during an MRI. However, in the people with CFS it lit up only dimly when they were asked to exert themselves.

While earlier research had identified many other brain abnormalities, this one was new. And this particular change makes it more difficult for people with CFS to exert themselves physically or mentally, the team concluded. It makes any effort like trying to swim against a current.

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Web Page Or Webpage Plus More Web Vocabulary Choices

The vocabulary we use when writing about the Internet and technology is constantly evolving. Deciding whether to use web page or webpage is a perfect example, even if both are correct and acceptable.

When we use words that start with web, there is often a choice between a one-word or two-word variant. But which one is correct, or the best choice?

As with many things grammatical and lexical in English, there is no hard and fast rule.

You can only base your decisions on up-to-date dictionary entries, everyday usage, or style guide recommendations.

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In This Ar

Why we use web as a word and prefix

The word web comes from the invention of the World Wide Web (WWW) in 1989 by Tim Berners-Lee.

We still see it today in many internet addresses that include www. before a site name.

Although we still use the word Internet to describe anything online, it is now more commonly known simply as the Web.

Because of this, the word web started to be added to existing words to indicate an online object or activity.

In the early days of the Web, it was common to use the word internet. Who can forget the famous Internet Explorer browser from Microsoft in the mid to late nineties? It was the most popular browser of its day.

Another popular early browser was Netscape Navigator, which shortened the Internet to Net. Because of this, we still often refer to the Internet as the Net.

Once the word web and, to a lesser degree, net, became fixtures in everyday language, they have been added to many existing words to form new words relating to technology.

You can probably think of many, such as web servers, web analysts, web hosts, and web designers.

However, you might also think of webmail, webcam, and webinar.

You can see the problem here. When do you use one word or two?

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Web page or webpage? Web site or website?

These two word choices are probably the most debated in modern language and grammar use for technology terms.

You can find hundreds of forums and social media entries discussing the topic.

When you search for advice from well-known style guides, you will often find conflicting conclusions.

Some say one word, some say two.

The best decision for your writing is to choose the form you feel comfortable using.

You can also look at usage trends. Here are two examples of how word usage changes and evolves.

Let’s start with the trend graph of web page and webpage.

Clearly, web page was the first form from around 1993 and continued to be the most common variant up until around 2010.

But from 2010 onwards, webpage as one word has increased in use consistently, while web page is rapidly declining.

However, the change from two words to one is more dramatic for web site and website.