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    Professor Emeritus Richard Wurtman, influential figure in translational research, dies at 86

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    Richard Wurtman, the Cecil H. Green Distinguished Professor Emeritus and a member of the MIT faculty for 44 years, died on Dec. 13. He was 86.

    Wurtman received an MD from Harvard Medical School in 1960 and trained at Massachusetts General Hospital before joining the laboratory of Nobel laureate Julius Axelrod at the National Institutes of Health in 1962. In 1967, MIT invited him to start a neurochemistry and neuropharmacology program in the Department of Nutrition and Food Science. In the early 1980s he joined the newly formed Department of Brain and Cognitive Sciences. Wurtman was also deeply involved in the National Institutes of Health-established Clinical Research Center at MIT, which he also directed for 25 years.

    His initial placement in Nutrition and Food Science was fortuitous, recalled Wurtman in a 2011 profile, because it “sensitized me to the fact that nutrients are chemicals the way drugs are chemicals. A compound like folic acid is a vitamin in foods, but when given alone in higher doses it becomes a drug that safeguards the developing nervous system.”

    Wurtman’s search for new biological properties and therapeutic uses of known molecules — hormones, nutrients, or existing pharmaceuticals — was highly fruitful. His research on the pineal gland, which started when he was a medical student, led to the discovery that melatonin, the hormone made by the gland, regulates sleep. 

    “Dick Wurtman was a pioneer in studying the role of neurotransmitters in the brain, and neuroendocrine regulation of normal and abnormal brain function,” says Newton Professor of Neuroscience Mriganka Sur, who served as head of the Department of Brain and Cognitive Sciences from 1997 to 2012. “His work on the impact of nutrition on neurotransmitters such as acetylcholine and on neuronal membrane synthesis laid the groundwork for later translational work on brain diseases such as Alzheimer’s disease.”

    Wurtman’s lab discovered that consuming carbohydrates increases tryptophan levels in the brain and consequently the production of the neurotransmitter serotonin. This led to a long collaboration with his wife Judith Wurtman, an MIT research affiliate, in which they found that carbohydrates were often consumed by individuals as a form of self-medication when they experienced changes in mood, such as late in the afternoon or when suffering from premenstrual syndrome (PMS). The Wurtmans’ research led to the development of Sarafem, the first drug for severe PMS, and a drink, PMS Escape, used for milder forms of this syndrome.

    To commercialize some of his findings, Wurtman founded Interneuron Pharmaceuticals in 1988; the company was renamed Indevus in 2002 and acquired by Endo Pharmaceuticals in 2009.

    Wurtman’s research advanced the idea that substrate availability, and not simply enzyme activity, can control metabolic processes in the brain. He discovered that the dietary availability of neurotransmitter precursors (e.g., acetylcholine, dopamine, and GABA) can increase their levels in the brain and modulate their metabolism. Moreover, he applied this concept to synaptic structural components such as brain phosphatides and found that dietary intake of three rate-limiting precursors — uridine, choline, and the omega-3 fatty acid DHA — led to increased brain phosphatide levels, increased dendritic spine density, and improved memory performance. These findings led to the development of Souvenaid, a specifically formulated multi-nutrient drink based on the three essential phosphatide precursors of Wurtman’s later research. It has been the subject of numerous clinical trials for Alzheimer’s disease, and, most recently, for age-related cognitive decline.

    “Dick Wurtman was a pioneer on studying how nutrients influence brain function,” says Li-Huei Tsai, Picower Professor of Neuroscience and director of The Picower Institute for Learning and Memory. “His nutrient clinical trial work and establishment of the MIT Clinical Research Center have been tremendously helpful for my own work on understanding how high doses of supplement choline could potentially help reduce certain Alzheimer’s risk, and our team’s development of clinical studies at MIT to test Alzheimer’s therapies.”

    “Dick’s legacy resides within the careers of hundreds of trainees and collaborators he launched or enhanced, the 1,000-plus published research articles, his numerous patent awards, and people who benefited from his therapeutic approaches,” says former postdoc Bertha Madras, now a professor of psychobiology at McLean Hospital and Harvard Medical School. “Yet, these quantitative metrics, legacies of research and mentoring, do not illustrate the charitable qualities of this remarkable man. I witnessed his deep intellect, boundless energy, enthusiasm, optimism, and generosity toward trainees, qualities that helped to sustain me during crests and troughs encountered in the adventures of a scientific career. Dr. Richard Wurtman was a creative, brilliant scientist, a mentor, a devoted husband to his beloved wife.”

    “Dick was an inspiration, a motivation, and a guide to all his students and colleagues in shaping thoughts to be precise and purposeful,” says Tony Nader PhD ’89, who did his doctoral research with Wurtman. “His rigorous scientific approach and the application of his findings have contributed to make life better. His legacy is huge.”

    Richard and Judith Wurtman have also made a lasting philanthropic impact at MIT. They endowed a professorship in the Department of Brain and Cognitive Sciences in honor of the late Institute Professor and provost Walter Rosenblith; the chair was held first by Ann Graybiel, who is now an Institute Professor; Nancy Kanwisher is the current Walter A. Rosenblith Professor of Cognitive Neuroscience. The Wurtmans have also been longtime supporters of MIT Hillel.

    Elazer R. Edelman, the Edward J. Poitras Professor in Medical Engineering and Science at MIT, professor of medicine at Harvard Medical School, and director of the MIT Institute for Medical Engineering and Science, recalls that Wurtman was also supportive of the Harvard-MIT Program in Health Sciences and Technology: “He changed our school and our world — he and Judith coupled immense charity with exceptional intellect and they made us all better for it.”

    Richard Wurtman is survived by his wife, Judith; daughter Rachael; son David and daughter-in-law Jean Chang; and grandchildren Dvora Toren, Yael Toren and Jacob Vider.  More

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      in Environment

      Keeping indoor humidity levels at a “sweet spot” may reduce spread of Covid-19

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      We know proper indoor ventilation is key to reducing the spread of Covid-19. Now, a study by MIT researchers finds that indoor relative humidity may also influence transmission of the virus.

      Relative humidity is the amount of moisture in the air compared to the total moisture the air can hold at a given temperature before saturating and forming condensation.

      In a study appearing today in the Journal of the Royal Society Interface, the MIT team reports that maintaining an indoor relative humidity between 40 and 60 percent is associated with relatively lower rates of Covid-19 infections and deaths, while indoor conditions outside this range are associated with worse Covid-19 outcomes. To put this into perspective, most people are comfortable between 30 and 50 percent relative humidity, and an airplane cabin is at around 20 percent relative humidity.

      The findings are based on the team’s analysis of Covid-19 data combined with meteorological measurements from 121 countries, from January 2020 through August 2020. Their study suggests a strong connection between regional outbreaks and indoor relative humidity.

      In general, the researchers found that whenever a region experienced a rise in Covid-19 cases and deaths prevaccination, the estimated indoor relative humidity in that region, on average, was either lower than 40 percent or higher than 60 percent regardless of season. Nearly all regions in the study experienced fewer Covid-19 cases and deaths during periods when estimated indoor relative humidity was within a “sweet spot” between 40 and 60 percent.

      “There’s potentially a protective effect of this intermediate indoor relative humidity,” suggests lead author Connor Verheyen, a PhD student in medical engineering and medical physics in the Harvard-MIT Program in Health Sciences and Technology.

      “Indoor ventilation is still critical,” says co-author Lydia Bourouiba, director of the MIT Fluid Dynamics of Disease Transmission Laboratory and associate professor in the departments of Civil and Environmental Engineering and Mechanical Engineering, and at the Institute for Medical Engineering and Science at MIT. “However, we find that maintaining an indoor relative humidity in that sweet spot — of 40 to 60 percent — is associated with reduced Covid-19 cases and deaths.”

      Seasonal swing?

      Since the start of the Covid-19 pandemic, scientists have considered the possibility that the virus’ virulence swings with the seasons. Infections and associated deaths appear to rise in winter and ebb in summer. But studies looking to link the virus’ patterns to seasonal outdoor conditions have yielded mixed results.

      Verheyen and Bourouiba examined whether Covid-19 is influenced instead by indoor — rather than outdoor — conditions, and, specifically, relative humidity. After all, they note that most societies spend more than 90 percent of their time indoors, where the majority of viral transmission has been shown to occur. What’s more, indoor conditions can be quite different from outdoor conditions as a result of climate control systems, such as heaters that significantly dry out indoor air.

      Could indoor relative humidity have affected the spread and severity of Covid-19 around the world? And could it help explain the differences in health outcomes from region to region?

      Tracking humidity

      For answers, the team focused on the early period of the pandemic when vaccines were not yet available, reasoning that vaccinated populations would obscure the influence of any other factor such as indoor humidity. They gathered global Covid-19 data, including case counts and reported deaths, from January 2020 to August 2020,  and identified countries with at least 50 deaths, indicating at least one outbreak had occurred in those countries.

      In all, they focused on 121 countries where Covid-19 outbreaks occurred. For each country, they also tracked the local Covid-19 related policies, such as isolation, quarantine, and testing measures, and their statistical association with Covid-19 outcomes.

      For each day that Covid-19 data was available, they used meteorological data to calculate a country’s outdoor relative humidity. They then estimated the average indoor relative humidity, based on outdoor relative humidity and guidelines on temperature ranges for human comfort. For instance, guidelines report that humans are comfortable between 66 to 77 degrees Fahrenheit indoors. They also assumed that on average, most populations have the means to heat indoor spaces to comfortable temperatures. Finally, they also collected experimental data, which they used to validate their estimation approach.

      For every instance when outdoor temperatures were below the typical human comfort range, they assumed indoor spaces were heated to reach that comfort range. Based on the added heating, they calculated the associated drop in indoor relative humidity.

      In warmer times, both outdoor and indoor relative humidity for each country was about the same, but they quickly diverged in colder times. While outdoor humidity remained around 50 percent throughout the year, indoor relative humidity for countries in the Northern and Southern Hemispheres dropped below 40 percent in their respective colder periods, when Covid-19 cases and deaths also spiked in these regions.

      For countries in the tropics, relative humidity was about the same indoors and outdoors throughout the year, with a gradual rise indoors during the region’s summer season, when high outdoor humidity likely raised the indoor relative humidity over 60 percent. They found this rise mirrored the gradual increase in Covid-19 deaths in the tropics.

      “We saw more reported Covid-19 deaths on the low and high end of indoor relative humidity, and less in this sweet spot of 40 to 60 percent,” Verheyen says. “This intermediate relative humidity window is associated with a better outcome, meaning fewer deaths and a deceleration of the pandemic.”

      “We were very skeptical initially, especially as the Covid-19 data can be noisy and inconsistent,” Bourouiba says. “We thus were very thorough trying to poke holes in our own analysis, using a range of approaches to test the limits and robustness of the findings, including taking into account factors such as government intervention. Despite all our best efforts, we found that even when considering countries with very strong versus very weak Covid-19 mitigation policies, or wildly different outdoor conditions, indoor — rather than outdoor — relative humidity maintains an underlying strong and robust link with Covid-19 outcomes.”

      It’s still unclear how indoor relative humidity affects Covid-19 outcomes. The team’s follow-up studies suggest that pathogens may survive longer in respiratory droplets in both very dry and very humid conditions.

      “Our ongoing work shows that there are emerging hints of mechanistic links between these factors,” Bourouiba says. “For now however, we can say that indoor relative humidity emerges in a robust manner as another mitigation lever that organizations and individuals can monitor, adjust, and maintain in the optimal 40 to 60 percent range, in addition to proper ventillation.”

      This research was made possible, in part, by an MIT Alumni Class fund, the Richard and Susan Smith Family Foundation, the National Institutes of Health, and the National Science Foundation. More

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      in Security

      Structures considered key to gene expression are surprisingly fleeting

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      In human chromosomes, DNA is coated by proteins to form an exceedingly long beaded string. This “string” is folded into numerous loops, which are believed to help cells control gene expression and facilitate DNA repair, among other functions. A new study from MIT suggests that these loops are very dynamic and shorter-lived than previously thought.

      In the new study, the researchers were able to monitor the movement of one stretch of the genome in a living cell for about two hours. They saw that this stretch was fully looped for only 3 to 6 percent of the time, with the loop lasting for only about 10 to 30 minutes. The findings suggest that scientists’ current understanding of how loops influence gene expression may need to be revised, the researchers say.

      “Many models in the field have been these pictures of static loops regulating these processes. What our new paper shows is that this picture is not really correct,” says Anders Sejr Hansen, the Underwood-Prescott Career Development Assistant Professor of Biological Engineering at MIT. “We suggest that the functional state of these domains is much more dynamic.”

      Hansen is one of the senior authors of the new study, along with Leonid Mirny, a professor in MIT’s Institute for Medical Engineering and Science and the Department of Physics, and Christoph Zechner, a group leader at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, and the Center for Systems Biology Dresden. MIT postdoc Michele Gabriele, recent Harvard University PhD recipient Hugo Brandão, and MIT graduate student Simon Grosse-Holz are the lead authors of the paper, which appears today in Science.

      Out of the loop

      Using computer simulations and experimental data, scientists including Mirny’s group at MIT have shown that loops in the genome are formed by a process called extrusion, in which a molecular motor promotes the growth of progressively larger loops. The motor stops each time it encounters a “stop sign” on DNA. The motor that extrudes such loops is a protein complex called cohesin, while the DNA-bound protein CTCF serves as the stop sign. These cohesin-mediated loops between CTCF sites were seen in previous experiments.

      However, those experiments only offered a snapshot of a moment in time, with no information on how the loops change over time. In their new study, the researchers developed techniques that allowed them to fluorescently label CTCF DNA sites so they could image the DNA loops over several hours. They also created a new computational method that can infer the looping events from the imaging data.

      “This method was crucial for us to distinguish signal from noise in our experimental data and quantify looping,” Zechner says. “We believe that such approaches will become increasingly important for biology as we continue to push the limits of detection with experiments.”

      The researchers used their method to image a stretch of the genome in mouse embryonic stem cells. “If we put our data in the context of one cell division cycle, which lasts about 12 hours, the fully formed loop only actually exists for about 20 to 45 minutes, or about 3 to 6 percent of the time,” Grosse-Holz says.

      “If the loop is only present for such a tiny period of the cell cycle and very short-lived, we shouldn’t think of this fully looped state as being the primary regulator of gene expression,” Hansen says. “We think we need new models for how the 3D structure of the genome regulates gene expression, DNA repair, and other functional downstream processes.”

      While fully formed loops were rare, the researchers found that partially extruded loops were present about 92 percent of the time. These smaller loops have been difficult to observe with the previous methods of detecting loops in the genome.

      “In this study, by integrating our experimental data with polymer simulations, we have now been able to quantify the relative extents of the unlooped, partially extruded, and fully looped states,” Brandão says.

      “Since these interactions are very short, but very frequent, the previous methodologies were not able to fully capture their dynamics,” Gabriele adds. “With our new technique, we can start to resolve transitions between fully looped and unlooped states.”

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      The researchers hypothesize that these partial loops may play more important roles in gene regulation than fully formed loops. Strands of DNA run along each other as loops begin to form and then fall apart, and these interactions may help regulatory elements such as enhancers and gene promoters find each other.

      “More than 90 percent of the time, there are some transient loops, and presumably what’s important is having those loops that are being perpetually extruded,” Mirny says. “The process of extrusion itself may be more important than the fully looped state that only occurs for a short period of time.”

      More loops to study

      Since most of the other loops in the genome are weaker than the one the researchers studied in this paper, they suspect that many other loops will also prove to be highly transient. They now plan to use their new technique study some of those other loops, in a variety of cell types.

      “There are about 10,000 of these loops, and we’ve looked at one,” Hansen says. “We have a lot of indirect evidence to suggest that the results would be generalizable, but we haven’t demonstrated that. Using the technology platform we’ve set up, which combines new experimental and computational methods, we can begin to approach other loops in the genome.”

      The researchers also plan to investigate the role of specific loops in disease. Many diseases, including a neurodevelopmental disorder called FOXG1 syndrome, could be linked to faulty loop dynamics. The researchers are now studying how both the normal and mutated form of the FOXG1 gene, as well as the cancer-causing gene MYC, are affected by genome loop formation.

      The research was funded by the National Institutes of Health, the National Science Foundation, the Mathers Foundation, a Pew-Stewart Cancer Research Scholar grant, the Chaires d’excellence Internationale Blaise Pascal, an American-Italian Cancer Foundation research scholarship, and the Max Planck Institute for Molecular Cell Biology and Genetics. More