Massive Science on Sarkis Mazmanian

Massive Science is a digital science media publication that brings together scientists and the science-curious public. The team at Massive joined us at TEDMED 2018 and covered talks by various speakers including Sarkis Mazmanian. Check out their coverage of Sarkis’ TEDMED 2018 talk below.


The jury’s still out on how the brain really works. But Sarkis Mazmanian, a medical microbiologist at Caltech, thinks the answers to many of the questions we still have about the brain may actually lie further south — in the gut, where trillions of bacteria live. There, these “good” bacteria live peacefully, helping us to break down fiber and absorb nutrients. They are referred to collectively as the gut microbiome. Despite the presence of the blood-brain-barrier (BBB), a tightly regulated border between the brain and circulating blood, the gut and the brain are in constant communication, either through incoming and outgoing nerves, or through small molecules that can pass through the BBB. Remarkably, many of these molecules are not produced by the human body — they’re made by the bacteria in our microbiome.

The composition of our gut microbiome is often thought to be established as we pass through the birth canal, and greatly modified through our immediate environment in the first few years of life. After that, the microbiome becomes largely resistant to new bacteria. Interpreting this “gut-brain” axis has been the focus of Mazmanian’s work, revealing complex interactions between the gut and the brain, which increasingly look connected to everything from thoughts and emotions, to potentially the onset of certain brain disorders including Autism Spectrum Disorder and Parkinson’s disease.

Bacteroides fragilis, a common bacteria that occurs in the gut, oblong spheres stained pink.
Bacteroides fragilis. CDC.

You may be wondering a few things. How do trillions of bacteria establish themselves in our gut in the first place? How do our immune systems differentiate between the bacteria that make up our microbiome, and other harmful bacteria that makes us sick? Mazmanian says, “I think our microbiome, having evolved in the context of the immune system, have learnt to co-op with the immune system.” He adds, “Instead of trying to combat or invade the immune system, they actually engage it.” The good bacteria actually have a vested interest in their hosts being able to selectively attack dangerous bacteria, either because the “good” bacteria may also be harmed, either directly, or indirectly if their hosts perish. So, instead of avoiding immune cells, these beneficial bacteria have developed properties which redirects the immune response in a way that doesn’t cripple it. The “good” bacteria are spared, and the immune system is not prevented from attacking other pathogens. In this way, an amicable symbiosis is achieved, in which the gut microbiome is able to thrive in the warm, moist, nutrient-rich intestines. In fact, research carried out by graduate student Gregory Donaldson in Mazmanian’s lab suggests that one microbe in particular, called Bacteroides fragilis, might have even achieved long-term stability in the gut because of an immune response involving an antibody called IgA, which actually helps anchor it to the gut wall.

Mazmanian believes that our microbiome may influence many diseases. A few years ago, Mazmanian and his group noticed that children with autism — a neuropsychiatric disorder where children suffer from behavioral deficits, such as decreased vocalisation and social interaction, as well as repetitive behavior — also experience digestive issues, such as abdominal cramps and bloating. This was a clue that bacteria could be involved in the disease process. Other clues were that risk factors for autism include having a caesarean section, formula feeding, and taking antibiotics in childhood, all of which change the microbiome.

Mazmanian thinks the same may be true of Parkinson’s disease, a neurodegenerative disorder where neurons in the brain die, leading to motor symptoms like tremors, difficultly in walking, and rigidity. Like with autism, Parkinson’s patients often have gut symptoms. Strikingly, 80 percent of the three million people in the U.S. that suffer from Parkinson’s disease also suffer constipation—symptoms that sometimes precede the onset of motor symptoms. Interestingly, people who have had their vagus nerve, a potential highway between the gut and the brain, removed during surgery, are less likely to develop Parkinson’s disease.

 

To study how the gut may influence neurological diseases, Mazmanian completely removed the gut microbiome of mice that are genetically engineered to develop autism or Parkinson’s. He found these mice no longer exhibited symptoms of Parkinson’s or autism, suggesting that the microbiome is involved in both diseases. Mazmanian had stumbled on a remarkable discovery. “When we made these germ-free sterile mice, it gave us a research tool that we can now use for other purposes.” Next, he took fecal samples (which contain intact microbiomes of their donors), from both Parkinson’s patients and healthy controls. He put these samples into bacteria-free sterile mice genetically modified to over-express a protein called α-synuclein (αSyn, which is associated with Parkinson’s disease). The mice implanted with microbiomes from people who had Parkinson’s had much worse symptoms than the mice who received microbiomes from a healthy control. Similarly, when mice with autistic behaviors that had their microbiomes removed were given certain beneficial bacteria recovered from neurotypical humans , Mazmanian’s team were able to reduce their vocalisation deficits and repetitive behaviors.

Of course, these studies have only been carried out in mice, since there are ethical issues with replacing a healthy human’s microbiome with one from a Parkinson’s patient. However, Mazmanian says that dozens of papers have shown that the gut microbiome in autistic people and Parkinson’s patients are different. The cause of these differences — maybe ethnicity, geography, genetics or diet — is unclear, but Mazmanian’s mouse experiments have led him to a provocative hypothesis. He thinks some forms of autism and Parkinson’s may not arise in the brain at all, but in the gut. By targeting the microbiome, in a personalized way, he hopes to develop a viable therapeutic.

It’s not just the gut that sends signals to the brain. Weirdly, the brain also communicates with the gut, although understanding this process has been more challenging. Members of Mazmanian’s lab have been trying to better understand brain –> gut communication by working with neuroscientists using genetic engineering techniques, brain lesion studies, and studying the vagus nerve. Anecdotally, we rely on “gut-feelings” or “gut-instincts” to help us make decisions, sometimes we experience “gut-reactions” in response to an experience, and when we are overcome with anxiety or excitement, we often feel it in in our gut as a stomach-ache or “butterflies.” These turns of phrase suggest what these scientists suspect: that our brains send signals to our gut via our nervous system in response to queues in the environment.

Mazmanian’s lab are trying to not just identify the bacteria that inhabit our guts, but what these bacteria are doing. “We take a reductionist approach in the fact that we work with single organisms we can genetically manipulate,” he says. “I want to manipulate both the bacteria and the host,” isolting each on a molecular level to identify the mechanisms by which they work.

Conversely, Mazmanian likens many traditional drug treatments to pouring oil all over the engine of a car, in the hope that some might get into the right place. He thinks the future of medicine is in “drugs from bugs,” saying, “Someday, you and I may go to the doctor and be prescribed a pill with a live bacteria inside of it as the remedy.”


About the author: Yewande Pearse was born and bred in North London. She is now a Research Fellow based at LA Biomed, in affiliation with the University of California, Los Angeles (UCLA). She completed her PhD in Neuroscience at the Institute of Psychiatry in 2016, which focused on the potential use of gene therapy for the treatment of Batten disease, a fatal neurological pediatric disease. She is now working on stem cell gene therapy using CRISPR-Cas9 to treat Sanfilippo Syndrome. Before completing her PhD, she worked in the areas of Stroke and Huntington’s disease research and also worked in a care capacity, with people living with Autism, suicidal ideation, dementia and HIV Associated Neurocognitive Disorder.

Jason Shepherd on Scientific Discovery

Taking on the major challenge of understanding how experience shapes neural networks and how circuits are modified by proteins/genes,  Jason Shepherd has garnered worldwide recognition through the research in his lab, Shepherd Lab at the University of Utah School of Medicine. At TEDMED 2018, Jason shared why we might have viruses to thank for the biology behind memory storage and encoding. Watch his Talk “How an ancient virus spread the ability to remember” and read his about his journey through Scientific Discovery below. 


What goes into scientific discoveries? Movies will have you think that discoveries are made by lone geniuses in moments of inspiration. The reality is that this is rarely the case, scientific discovery is a long and often tedious process that requires a team of people. In my own research lab, we recently made a surprising connection between two seemingly unrelated topics; viruses and memory. 

This connection was made through observation, rather than through inspiration. We study a gene called Arc, which is essential for making long-lasting memories in the brain. A focus of my lab is to understand how and why this gene is so important for information storage. A technician in the lab, Nate Yoder, wanted to study the biochemistry of Arc protein. To do this, we engineered bacteria to produce a ton of Arc protein that we could purify. Nate found, however, that Arc protein behaved strangely. It seemed like it was much bigger than predicted and this was probably because single Arc proteins were clumping or aggregating. Perhaps we were just unable to purify Arc properly. Still, Nate was curious to know what the protein looked like so with the help of Adam Frost he took some images of Arc protein using an electron microscope. This allowed him to resolve Arc protein at very high magnification. Strikingly, instead of clumps of protein, we saw these beautiful “soccer ball” structures (image 1). 

This observation led us down a rabbit hole of unique biology. Turns out these soccer ball structures look just like the protein shells or capsids that viruses make. Why would a neuronal protein form something that looks like a virus capsid?! We are still trying to understand this surprising discovery, but Arc seems to have retained many properties of viruses. Oh yes, and we think that this gene evolved from an ancient ancestor of the retroviruses, like HIV, called retrotransposons. These rogue elements, along with ancient viral infections have left us with bloated genomes comprising of up to 50% of our own human DNA. In some cases, it seems, evolution has used these sequences and repurposed them to create new genes. Wild! 

Back to the process of doing science. Another common fallacy is that science results in black and white answers. In biology, this is rare. Scientists can be wrong in their interpretation of the data. They can be wrong in how they designed an experiment and the results can be messy. The key is replication and figuring out many different ways to get at the answer. For example, another lab headed by Vivian Budnik and work led by her postdoctoral fellow Travis Thomson independently found that a gene that looked like Arc in the fly, also seemed to behave like a virus. When we purified the fly Arc protein, we also saw that it could form capsids. So here we have two examples of different genes having retained the ability to form virus-like capsids! Even more surprising, we think that the fly Arc gene is actually unrelated to the mammalian gene; evolution repurposed a similar kind of retrotransposon in the fly lineage 100s of millions of years after the mammalian Arc gene.

If it happened twice, it probably happened many times more. We and others are on the hunt to find other genes that may have similar properties. Most important for my own research, we want to understand why you need a virus-like protein to make long-term memories. All of this reinforces, to me, the intricate and complicated path evolution has taken that has led to the amazing structure of the human brain. We hope that this science will not only lead to understanding how the brain works, but potentially to applications like gene therapy. Currently, we rely on modified viruses to get gene therapy into human cells but these still elicit an immune response and are often not very efficient. What if we could use proteins that look like viruses but are already made in our bodies? Nature often has the best solutions to hard problems; we just have to figure out how. It takes a team of dedicated people and a little bit of luck to reveal Nature’s secrets. 


TEDMED & Massive Science: TEDMED boasts a proud partnership with Massive Science, a digital science media publication that brings together scientists and the science-curious public. The team at Massive joined us onsite at TEDMED 2018, and by various speakers including Jason Shepherd. Check out their coverage of Jason’s TEDMED 2018 talk: “A protein in your brain behaves like a virus, infecting your cells with memories.

Massive Science on Lydia Bourouiba

TEDMED is proud to partner with Massive Science, a digital science media publication that brings together scientists and the science-curious public. The team at Massive joined us onsite at TEDMED 2018, and covered talks by various speakers including Lydia Bourouiba. Check out their coverage of Lydia’s TEDMED 2018 talk below.


In 1934, Williams Wells was the first scientist to convincingly describe airborne transmission of diseases in the context of tuberculosis. He introduced the notion of  two main routes of pathogens spread: large droplets, which fall due to gravity, and small droplets, which waft through the air as they evaporate. It is believed that pathogens like Tuberculosis are transmitted through large droplets, whereas diseases like measles could through small ones, although evidence remain controversial and debated. 

It may surprise you that for more than 80 years—despite new diseases, new means of travel, and new technology—our understanding of these basic routes haven’t changed much. Not until recently, when Lydia Bourouiba, associate professor at the Massachusetts Institute of Technology and director of the Fluid Dynamics of Disease Transmission Laboratory, began to revisit these fundamentals and redefine how we think about respiratory disease transmission—literally from the ground up.

Bourouiba began her career by studying the mathematics of how fluids flow, specifically looking at fluids with turbulent or chaotic dynamics/motion. When she moved to Toronto shortly after the SARS epidemic, she realized that similar mathematical principles could be useful in modeling how diseases spread. That’s when she began to use mathematics in epidemiology, and in particular, the limitations of top-down modeling with mechanistic understanding of the fundamental mechanisms governing the patterns observed. “I started seeing these gaps in understanding transmission in particular, and [seeing] that fluid dynamics could help fill such gaps,” explains Bourouiba.

Traditionally, scientists have created epidemiological models by developing equations, based on a variety of parameters that describe how diseases are transmitted between people and populations. However, many of these parameters are fitted to data and not based on physical principles—like how sneezing actually transmits disease, or what factors influence how far sneeze droplets may travel or persist. 

Bourouiba thinks that improving the accuracy of these parameters and framework of modeling would greatly improve predictive power and intervention strategies. “If one doesn’t have a mechanism to rationalize [the parameters] down to something we can directly measure, validate, and control, one ends up fitting data to models,” says Bourouiba, rather than designing models that incorporate underlaying physics. “One loses predictability power and ability to control.”

So Bourouiba moved to MIT as an NSERC Postdoctoral Fellow and Applied Mathematics Instructor, and then as faculty, and began to try to explain how diseases are transmitted globally based on how they are transmitted between you and your neighbor. Equipped with a range of experimental optical and biophysics methods, including, direct visualization and measurements, such as with high-speed imaging, microscopy, fluid flow models, and patients, Bourouiba and her team are now answering fundamental questions about the mechanisms of respiratory disease transmission.

During TEDMED, Bourouiba showed how the physics of turbulent puff cloud of air emitted during exhalations, suspending and trapping drops within them, radically  change the range of pathogen deposition and contamination, thus, shifting the paradigm away from the small versus large droplet framework of Wells into the mechanistic description of exhalations including information of time and space, needed for monitoring, infection control and prevention,  and risk assessments. 

The next step is understanding how a exhalations coupled with ambient environment and patient physiology in infection, including when infected with flu, can inform early detection and intervention.  Her broad findings have already identified suggestions for disease control that can be implemented, influencing a variety of public health protocols and policies.

But she still has further questions—like how the size of droplets can impact our susceptibility to disease. “The properties that exhalations and their payload influence also efficacy of infection upon exposure, for example influencing,  their deposition in the lungs,” says Bourouiba. “We are working at elucidating the whole process, accounting for coupled physiology, immunology, microbiology, and fluid processes, to construct the full picture of those  that have particularly high abilities to transmit certain respiratory diseases effectively.”

This could inform how we manage numerous high impact pathogens. Take tuberculosis, a disease that infects up to a third of the world’s population. Researchers know its symptoms begin deep in the lungs, but further characterizations of when, how, and why people produce infectious droplets could improve how we handle patient care and research.

Bourouiba is excited about the multi-year study she’s leading with a diverse collaborations she put in place to  include clinicians, infection control specialists, microbiologists, immunologists, and virologists, for the study of transmission of influenza. Pioneering work in this interdisciplinary field isn’t easy. But Bourouiba says that ten to twenty years of this kind of research could lead to dramatic, tangible results, useful for a variety of pathogens. Considering the long and often uncertain process of developing new vaccines and diagnostics for infectious diseases, her approach to defining evidence-based prevention strategies is a vital piece of the puzzle. “You have to be doing both [prevention and treatment research].” It’s also becoming ever more important. Because of rising antibiotic resistance and increase in connectivity, and emergence and re-emergence of pathogens, she explains, “We might be going into an era [similiar] to pre-antibiotic times, which is extremely concerning.”

Bourouiba’s work is an important step toward redefining disease transmission, and infection control and prevention, moving the fundamentals from descriptions to measurable and quantifiable mechanisms. Truly understanding how people get each other sick will help us design protocols, policies, and tools to help people stay healthy and prevent epidemics and pandemics.


About the author:  Joshua Peters is a PhD student in Biological Engineering at MIT. Around two billion people in the world are infected with a microscopic bug called Mycobacterium Tuberculosis. Despite this, only a fraction develop tuberculosis. And a fraction of those infected – almost 5,000 a day – die. Joshua puts on Stranger Things-esque protection equipment and probes these bacteria to ask, what allows them bacteria to win this tug-of-war? To understand this variation, he looks at how both human and bacteria cells change on a genetic level in response to each other, as a member of the Blainey Lab, located in the Broad Institute, and Bryson Lab, located in the Ragon Institute and MIT.  

Q&A with Elizabeth Howell

TEDMED: In your TEDMED 2018 talk, you mentioned that one way for hospitals to improve the quality of care around childbirth is to implement a bundle program as advised by the Alliance for Innovation on Mental Health. What infrastructural resources are needed to adopt such a program, and who at the hospital should be driving this change? 

Elizabeth Howell: Some of the Alliance for Innovation on Maternal Health patient safety bundles are easier to implement than others and some require little infrastructure or resources. All require sponsorship from individuals within the hospital or healthcare settings. Leadership can come from nursing, physicians, midwives, or hospital administration.

TM: While social determinants of health contribute to racial and ethnic disparities, there remains a component of racial bias in health care. What are some steps that we can take to dismantle providers’ racial bias? Does this happen during medical education or elsewhere?

EH: Addressing providers’ racial bias is important and some medical schools have begun implicit bias trainings for faculty and staff. However, a complex web of factors contributes to disparities. I suggest we tackle disparities brick by brick:

1.  Measure racial disparities in pregnancy outcomes and address them through quality improvement activities in hospitals.

2. Hold hospitals and healthcare organizations accountable for their performance on outcomes.

3. Teach medical students and trainees patient-centered communication strategies, shared decision-making skills, and actions to address implicit bias.

4. Address who institutions are admitting into medical schools and residency programs in an effort to diversify the workforce.

5. Ask how healthcare systems compensate and reward physicians within the system. Make compensation linked to performance on reducing and addressing disparities.

6. Challenge institutions to continually ask themselves whether they are doing everything they can to reduce disparities.

TM: How aware are pregnant women and new mothers of the risks and signs of maternal mortality or morbidity? What is the best way to educate these women on the risks that they face, so that they can take informed steps to protect their health?

EH: Women with obesity, hypertension, diabetes, and other chronic illnesses are at higher risk for complications during pregnancy.  It is important for all reproductive age women, especially for women with chronic illness and these risk factors, to seek healthcare before they become pregnant and receive education about the best steps to protect their health.

TM: If every hospital across the country adopted the highest quality of standard care around childbirth and maternal health, do you think we would still see racial disparities in maternal morbidity and mortality, or do you think that disparities would remain due to other uncontrolled factors?

EH: I believe a meaningful portion of the disparity gap can be closed by improving quality of care across the care continuum and improving standards across all hospitals.  While addressing the larger societal issues that drive racism is important work for scholars from every field, it is not an excuse for delayed action on these tangible steps.

TM: What was the TEDMED experience like for you?

EH: The experience crystallized for me the importance of storytelling in communicating important truths. As a scientist we frequently communicate through tables, data, and graphs but the emotional connection to the problem is often what motivates action.

TM: At TEDMED, we like to think about each talk as having a “gift” –  that thing that reveals new perspectives and profoundly influences our own, or our collective, health. What is the gift you’d like people to receive when watching your TEDMED Talk?

EH: We can save the lives of thousands of women who die or experience severe complications from childbirth every year if we raise standards in EVERY hospital and provide high quality healthcare for ALL women before, during, and after pregnancy.

TM: What was the highlight of your TEDMED experience?

EH: A highlight for me was being introduced by Michael Painter from the Robert Wood Johnson Foundation as a “nice radical… For Liz, there is no division between her passion and her compassion.”