New study shines light on how to better engineer fluorescent proteins

Posted September 22, 2017 by Jennifer Huber
Categories: biology, Health

Tags:

Researchers have now captured the ultrafast changes of green fluorescent proteins as they transition between a dark and fluorescent state, using an X-ray laser at the SLAC National Accelerator Laboratory.

Green fluorescent proteins (GFPs), originally found in the jellyfish Aequorea victoria, have helped transform biomedical research. Their green glow has acted like a flashlight on the inner workings of cells, illuminating pathways and processes in lab dishes and living animals since it was discovered in 1961. The protein acts as a molecular switch depending on the conditions, flipping from dark to glowing when excited by light. Scientists attach these fluorescent tags to other proteins to track their activity — studying how cancer cells spread, how HIV infections progress, how genes are expressed and much more.

Although researchers have used these proteins for decades, they were unable to observe how GFPs flipped between their dark and glowing states until now. The transition was too fast for traditional X-ray imaging techniques. So an international collaboration of scientists recently used SLAC’s Linac Coherent Light Source, one of the world’s fastest and brightest X-ray lasers, to excite the proteins and take snapshots of the fluorescent molecules in action.

These images were used to investigate what happened as GFP flipped states — with the hope of engineering GFP to make this happen even faster. They found that the protein became momentarily stuck between a dark and glowing state, as reported in Nature Chemistry.

“After a picosecond, a very short time, this molecular switch is stuck between on and off,” said Martin Weik, PhD, a scientist at the Institute of Structural Biology in Grenoble, France, in a recent news release. “People have predicted this, but to actually confirm it experimentally is extremely exciting. It’s as if there is a door and it’s neither closed nor completely open; it’s half open. And now we are learning what can go through the door, what might be blocking it and how it works in real-time.”

The team discovered that an amino acid partially blocked the doorway, slowing the GFP’s ability to flip states. Using this knowledge, they then engineered a mutated version of the protein with a smaller amino acid that could switch more quickly — creating a brighter and more efficient fluorescent tag that can observe cellular processes more precisely.

“We think that this approach will open a world of possibilities to tailor and create proteins,” Weik said in the release. “We not only have the structure of the molecule, but now we can see what is happening between one static state and the other.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Advertisements

Misconceptions about opioid use: A Medicine X discussion

Posted September 17, 2017 by Jennifer Huber
Categories: Event, Health

Tags: ,

Photo courtesy of Stanford Medicine X

We often hear about the “opioid crisis” and its devastating effects — more than 90 Americans die every day from an opioid overdose and about 2 million suffer from substance use disorders involving prescription opioids. But, argued panelists at a Stanford Medicine X session on the topic yesterday, the issues are often oversimplified in public discussion and by the media, which stigmatizes opioid users and contributes to misconceptions.

The afternoon panel — which Larry Chu, MD, moderator and executive director of Medicine X, deliberately called “Opioids in America” instead of “The Opioid Crisis” — offered a broad range of perspectives from patients and physicians. Among the misconceptions discussed by the panel:

  • Only drug addicts use opioids: Joe Riffe, an ePatient and paramedic, explained, “If you use opioids, you’re seen as weak or a drug addict or a drug seeker. I’ll never take an opioid on duty, but I’m forced to use them because I’m in too much pain from my amputation. And it’s really looked down upon, especially in the medical community.”
  • People choose to be opioid addicts: Ashley Elliott, a recovering addict, artist and psychology major, noted, “People that are addicted to opioids don’t want to be. And if you’re a recovering addict, finding a doctor who is willing to treat you as a human as opposed to an addict is difficult.” Thomas Kline, MD, PhD, a patient and geriatric medicine specialist in Raleigh, North Carolina, agreed: “People with opioid addictions have been lepers for years and now another 9 million people have become lepers because they take pain medicine.”
  • Opioids are readily available: “Opioids are not being thrown at patients like candy, as it’s sometimes portrayed in the media,” said Heather Aspell, a patient, artist, attorney and disability advocate. “We actually have to go through so many hoops to get our medication. Beyond simply getting the prescription from a doctor, it can be challenging to even find the medication. I get refused by pharmacies regularly.”
  • Doctors are adequately treating pain: Anesthesiologist and pain medicine specialist Frank Lee, MD, told the audience, “Data shows that we’re doing a terrible job for a lot of populations, including cancer patients, surgery patients and chronic pain patients. Now is the time to re-evaluate the paradigm. We don’t need more guidelines. We need to work together, providers and patients, to re-exam this pain-treatment paradigm.”
  • We handle prescription opioids like other countries: “I think the biggest misconception is that the United States is normal in how it handles prescription opioids,” said Stanford addiction expert Keith Humphreys, PhD. He later added, “The United States’ opioid use dwarfs any other nation by a very large factor. So we over prescribe. And at the same time, there are people who absolutely need these medications and don’t get them. So we also under prescribe. As my friend Sean Mackey, MD, PhD, says, we shouldn’t be pro-opioid or negative-opioid; we should be pro-patient.”

After the panel discussion, Medicine X executive board member Nick Dawson moderated a town hall — pushing the panel and audience to think boldly about potential solutions. Among attendees’ suggestions was to change how prescriptions are written by going beyond a numeric pain scale to identify the goal for the pain medication, being more specific about what is being treated on the script and creating a certification process for patients with chronic pain that is recognized by pharmacists.

Near the end of the session, Bruce Greenstein, the United States Department of Health and Human Services’ chief technology officer, announced an opioid challenge summit and code-a-thon taking place in Washington, D.C. this December. And Chu closed things out with a hopeful note: “I started out this conference asking us to think outside the box about these tough topics, and I think we made a start on that today. … We’re reducing the stigma about opioids by talking about it and we’re raising awareness. Let’s keep talking.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Cureus medical journal aims to be the “digital scrub sink of the 21st century”

Posted September 13, 2017 by Jennifer Huber
Categories: Health

Tags:

Photo courtesy of John Adler

I’ve struggled through the slow and often painful process of publishing, both as an author and peer reviewer. So I was curious about the medical journal Cureus, which aims to preserved scientific quality while making this process free, easy and efficient. To learn more, I spoke with its founder, John Adler, MD, a Stanford professor in neurosurgery, emeritus.

Why did you start the Cureus Journal of Medical Science?

“I started Cureus because I was dissatisfied with the existing world of medical journals, which have become increasingly preoccupied with tenure and prestige. The ‘best journals in the world’ are now largely the province of a small community of elite academics from places like Stanford, Harvard and Yale, but the large majority of patients are cared for outside these institutions. Unlike most journals, Cureus focuses on the observational and practical side of clinical medicine, which is of great importance to nearly all patients.

About eight years ago, I had trouble publishing a paper on a surgical procedure for which I’m an acknowledged world expert. It was such a hassle — even for an insider, a big name doctor from a big name institution. This experience inspired me to start Cureus to enable more rapid and free publication.” 

How did you come up with the name Cureus?

“Cureus embodies a double entendre: ‘Cure’ ‘us,’ the goal of community-supported scientific journalism. And ‘curious,’ the embodiment of the best scientific thinking.

Why does Cureus focus on case studies?

“We’re moving towards a world of precision medicine with the basic premise that we’re all unique and don’t all have the same response to a treatment. So I argue that the ultimate kernel of truth is at the individual patient level and therefore we need to be documenting the stories of individuals even more. Any important discovery of medicine started basically with a case study — a key observation.

Surgeons learn many of their best tricks over the scrub sink, by talking to another surgeon about something she just figured out a few days ago. Cureus would like to be the digital scrub sink of the 21st century. The existing big journals play an important role, but their rigid standards prevent the publication of the myriad small, practical secrets that you learn as a practicing physician — and that’s what interests me.” 

How does Cureus work?

“An efficient peer review happens before an article is published and then there is a post publication scoring process. Every reader is invited to give a numerical score. However, someone who has deep domain knowledge as a specialist in a specific field gets more votes over a general practitioner.

If an article is scored many dozens of times, then we get a very good measure of the article’s quality. Ultimately, Cureus aspires to use the collective wisdom of all physicians.”

What are your goals?

“Today we are publishing just over 1000 articles each year, but the goal is to annually publish millions of medical stories that are peer-reviewed, curated and widely disseminated. These published stories can then also provide the substrate for subsequent analysis through machine learning. Currently, so much of machine learning is based on mining electronic medical records, which are primarily billing records and therefore deeply flawed sources of information. So I want to make it easier for doctors — who each day make important clinical observations — to document them.

I’m not going to be the computer scientist who reveals hidden truths from this data. But I want to be the guy who changes the world by helping people collect the data. It takes a certain scale and we need to be about three orders of magnitude bigger. But once we are, watch out!”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Awe, anxiety, joy: Researchers identify 27 categories for human emotions

Posted September 11, 2017 by Jennifer Huber
Categories: Health

Tags: , ,

Scores of words describe the wide range of emotions we experience. And as we grasp for words to describe our feelings, scientists are similarly struggling to comprehend how our brain processes and connects these feelings.

Now, a new study from the University of California, Berkeley challenges the assumptions traditionally made in the science of emotion. It was published recently in the Proceedings of the National Academy of Sciences.

Past research has generally categorized all emotions into six to 12 groups, such as happiness, sadness, anger, fear, surprise and disgust. However, the Berkeley researchers identified 27 distinct categories of emotions.

They asked a diverse group of over 850 men and women to view a random sampling of 2185 short, silent videos that depicted a wide range of emotional situations — including births, endearing animals, natural beauty, vomit, warfare and natural disasters, to name just a few. The participants reported their emotional response after each video — using a variety of techniques, including independently naming their emotions or ranking the degree they felt 34 specific emotions. The researchers analyzed these responses using statistical modeling.

The results showed that participants generally had a similar emotional response to each of the videos, and these responses could be categorized into 27 distinct groups of emotions. The team also organized and mapped the emotional responses for all the videos, using a particular color for each of the 27 categories. They created an interactive map that includes links to the video clips and lists their emotional scores.

“We sought to shed light on the full palette of emotions that color our inner world,” said lead author Alan Cowen, a graduate student in neuroscience at the UC Berkeley, in a recent news release.

In addition, the new study refuted the traditional view that emotional categories were entirely distinct islands. Instead, they found many categories to be linked by fuzzy boundaries. For example, there are smooth gradients between emotions like awe and peacefulness, they said.

Cowen explained in the release:

“We don’t get finite clusters of emotions in the map because everything is interconnected. Emotional experiences are so much richer and more nuanced than previously thought.

Our hope is that our findings will help other scientists and engineers more precisely capture the emotional states that underlie moods, brain activity and expressive signals, leading to improved psychiatric treatments, an understanding of the brain basis of emotion and technology responsive to our emotional needs.”

The team hopes to expand their research to include other types of stimuli such as music, as well as participants from a wider range of cultures using languages other than English.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Using history as a guide to end tobacco addiction

Posted September 8, 2017 by Jennifer Huber
Categories: Health

Tags: , , , ,

Photo courtesy of Robert Proctor

The public’s opinion of tobacco use has dramatically changed over time. Gone are the days when cigarette companies advertise using slogans like “fresh as mountain air” or “more doctors smoke Camels than any other cigarette.” We now know that cigarettes cause blindness and tuberculosis, among many other conditions, and are highly addictive.

But in the era of nicotine e-cigarettes that are touted as cool and harmless, have we really changed our ways? I spoke with Robert Proctor, PhD, a professor of history at Stanford, to learn about his work.

What inspired you to research the history of cigarette design?

“Cigarettes are the world’s leading preventable cause of death, killing about 6 million people worldwide every year.  A physician might hope to heal a thousand or perhaps ten thousand people over a career, but what if we could save these 6 million people annually?  It was this hope of saving lives that led to my exploring how cigarettes have been designed, and how they might be stopped.”

Where do you find your research materials?

“The Legacy Tobacco Documents Library is a real treasure.  I use it to explore the industry’s myriad secret projects — like Project Subculture Urban Marketing, a secret Reynolds campaign from the 1990s to target gays and the homeless in San Francisco.  I also use it to find out what they’ve been adding to cigarettes—like diammonium phosphate, a free-basing agent used to boost the potency of the nicotine molecule. I also use it to find out who has been working for the industry, as grantees or expert witnesses. Historically that included dozens of Stanford professors, but I don’t know any still working in that capacity today.”

What do you think about the FDA’s plan to reduce nicotine in cigarettes?

“As I explained in a recent op-ed for the New York Times, the Food and Drug Administration will try to mandate the reduction of nicotine in cigarettes to a sub-addictive level. However, they will encounter ferocious resistance from the industry, which sees nicotine as the indispensable ingredient of their business. For beginning smokers, nicotine is actually a negative in the smoking experience. Once addicted, most smokers regret having started. It will be crucial for the FDA to reduce nicotine sufficiently to make sure new users don’t become addicted. De-nicotinization is easy. Multiple techniques are available to achieve this, including genetic technologies and some of the same techniques used to de-caffeinate coffee.”

Have you also studied e-cigarettes?

“I have studied e-cigarettes but not as intensively. Many of the same techniques once used to market traditional cigarettes have been revived for e-cigarettes and other vaping devices, as Robert Jackler, MD, and his colleagues have shown so beautifully. E-cigarettes may help some smokers quit, but they are more likely to renormalize smoking and act as gateways to regular cigarettes. They also serve as bridge products to keep smokers from quitting nicotine entirely, which is why the big cigarette makers have all launched new vaping devices.”

What more can be done?

“Physicians often know the right thing to do, but may not have the power to make that happen — that is medical impotence.  A third of all cancer deaths, for example, are caused by cigarettes. Just knowing that, though, isn’t enough to do any good, since there are powerful forces dedicated to making sure we keep pulling smoke into our lungs. Much more could be done to solve such problems — the new age minima for purchasing cigarettes should help. I also believe we need to explore what I call ‘the causes of causes.’  Cigarette smoking causes disease, but what causes cigarette smoking?  Too often we end with the individual, rather than going upstream to the source of the problem in the first place. Stop the manufacture of cigarettes, for example, and you stop having to yank out tumors from lungs or putting people on oxygen. We need more upstream thinking in the practice of medicine.

We also need to think more about health in our own community. For instance, Stanford got a failing grade from the Santa Clara County Public Health Department in 2011 as the most cigarette-friendly campus in the Bay area — for allowing the sale and use of cigarettes on campus.  We did finally manage get the sale of cigarettes in the student union stopped, after years of painful protest.”

 

Editor’s note: Stanford has a smoke-free environment policy that prohibits smoking in all buildings, facilities, vehicles, covered walkways and during indoor or outdoor athletic events. Smoking has been banned on the School of Medicine campus for a decade. 

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

 

A look at health care reform — in China

Posted September 6, 2017 by Jennifer Huber
Categories: Health

Tags: , ,

Photo courtesy of Karen Eggleston

The struggles with health insurance reform here in the United States piqued my curiosity about what we could learn from other countries. I reached out to Karen Eggleston, PhD, a senior fellow at the Freeman Spogli Institute for International Studies at Stanford, who researches health care systems and health reform in Asia, especially China.

What is health insurance like in China?

“The original system was linked to the centrally planned economy. Communes in rural areas supported the barefoot doctors and state-owned enterprises provided people with health care coverage in the urban areas. But when China converted to a market-based economy, this had to change. So long story short, they’ve put into place a new system of health coverage based on government subsidized insurance for rural and non-employed urban populations, as well as an employee-based medical insurance for the employed urban population. As I like to tell my US colleagues, if you think providing coverage for 40 million uninsured people is a challenge then think about covering over 800 million uninsured — that’s what China was dealing with.

Many westerners would be surprised to know that Chinese have almost complete freedom when choosing their doctor or hospital.”

How has this expanded coverage impacted health and survival?

“There is a lot of evidence that the expanded health insurance improved access to care and helped protect households from high health care expenditures, but it’s actually pretty difficult to pin down the effects on health and survival.

In a recent study in Health Affairs, we looked at the New Cooperative Medical Scheme that provides health insurance to rural areas. We used the fact that it was introduced over time in different counties to look at the effect it had later, correlating this data with cause-specific mortality data from China’s CDC. We didn’t see a significant impact on mortality rate due to expanded medical coverage.

This was and wasn’t surprising. It may take a long time for the results to manifest. But it’s also quite well known in health economic research that health and survival are often shaped by non-medical factors like lifestyle.”

What are some of the biggest health care challenges in China?

“As China urbanizes hundreds of millions of people at a time, they are changing their diet and living a more sedentary lifestyle. As a result, they’re now getting what are sometimes called the diseases of affluence, such as diabetes. Like many developing countries, China’s healthcare system was setup to deal primarily with acute conditions and to control infectious diseases. Now, they need to sustainably finance and manage programs to prevent and care for people with chronic diseases.

A lot of China’s care is also based in hospitals, so they need to strengthen primary care — ironic for a country so famous for barefoot doctors. Physicians’ career trajectories are better in urban hospitals and patients know that’s where the best physicians are. But new policies are trying to lure patients and doctors to primary care.”

What other factors are affecting health in China?

“China has a rapidly aging population — largely due to their triumph in extending lives by controlling infectious diseases and lifting millions out of poverty, and also related to low fertility. This demographic change reinforces the challenge of preventing and controlling chronic disease.

We also know that people with more education tend to have better health and survival than people with lower education. China’s economic growth has brought a rapid increase in living standards but also a rise in inequality, in both rural and urban areas. One of the best ways to address this is to improve opportunities of education for the disadvantaged. This isn’t typically thought of as a health policy, but actually studies have shown education can have long lasting effects on health and survival.”

This is a reposting of my Scope blog post, courtesy of Stanford School of Medicine.

Artificial Intelligence can help predict who will develop dementia, a new study finds

Posted August 29, 2017 by Jennifer Huber
Categories: Health

Tags: , , , ,

 

If you could find out years ahead that you were likely to develop Alzheimer’s, would you want to know?

Researchers from McGill University argue that patients and their families could better plan and manage care given this extra time. So the team has developed new artificial intelligence software that uses positron emission tomography (PET) scans to predict whether at-risk patients will develop Alzheimer’s within two years.

They retrospectively studied 273 individuals with mild cognitive impairment who participated in the Alzheimer’s Disease Neuroimaging Initiative, a global research study that collects imaging, genetics, cognitive, cerebrospinal fluid and blood data to help define the progression of Alzheimer’s disease.

Patients with mild cognitive impairment have noticeable problems with memory and thinking tasks that are not severe enough to interfere with daily life. Scientists know these patients have abnormal amounts of tau and beta-amyloid proteins in specific brain regions involved in memory, and this protein accumulation occurs years before the patients have dementia symptoms.

However, not everyone with mild cognitive impairment will go on to develop dementia, and the McGill researchers aimed to predict which ones will.

First, the team trained their artificial intelligence software to identify patients who would develop Alzheimer’s, by identifying key features in the amyloid PET scans of the ADNI participants. Next, they assessed the performance of the trained AI using an independent set of ADNI amyloid PET scans. It predicted Alzheimer’s progression with an accuracy of 84 percent before symptom onset, as reported in a recent paper in Neurobiology of Aging.

The researchers hope their new AI tool will help improve patient care, as well as accelerate research to find a treatment for Alzheimer’s disease by identifying which patients to select for clinical trials.

“By using this tool, clinical trials could focus only on individuals with a higher likelihood of progressing to dementia within the time frame of the study. This will greatly reduce the cost and time necessary to conduct these studies,” said Serge Gauthier, MD, a senior author and professor of neurology and neurosurgery and of psychiatry at McGill, in a recent news release.

The new AI tool is now available to scientists and students, but the McGill researchers need to conduct further testing before it will be approved and available to clinicians.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.


%d bloggers like this: