netbet sports betting

Antibiotic resistance: How to prevent the next public health emergency
Emma H. Yee, Steven S. Cheng, Grant A. Knappe, and Christine A. Moomau | MIT Science Policy Review
August 25, 2020

netbet sports betting

Antibiotics are a vital component of global health. By killing or inhibiting the growth of bacteria, antibiotics treat infections like pneumonia, staph, and tuberculosis.By preventing infections, they enable major medical procedures such as surgeries and chemotherapy. However,bacteria are becoming increasingly resistant to current antibiotics, causing an estimated 34,000 deaths annually in the US. Left unchecked, antibiotic resistance will have major public health consequences, causing over 5 million deaths each year by 2050. Major causes of this crisis are the misuse of existing antibiotics and the slow development of new antibiotics. To incentivize responsible use, governments and institutions are initiating education programs, mandating comprehensive hospital antibiotic stewardship programs, and funding the development of rapid diagnostics. To bring new antibiotic drugs to market, the US government and other non-governmental organizations are funding scientific research toward antibiotic development.Additional incentives are being pursued to improve the commercial viability of antibiotic development and protect drug developers from the unique challenges of the antibiotic market. With diligent efforts to improve responsible use and encourage novel antibiotic drug discovery, we can decrease the global disease burden, save money, and save lives.

Antibiotics are drugs that kill or inhibit the growth of bacteria, and we have them to thank for the 25-year increase in American life expectancy in the last century[1,2]. In 1900, the three leading causes of death were bacterial infections: pneumonia, tuberculosis, and diarrhea/enteritis[3]. Penicillin, the first antibiotic, was discovered in 1928. But it was not until World War II, when wounded soldiers were more likely to die from infections than the injuries themselves, that governments realized penicillin’s life-saving potential[4]. The US government began developing and mass-producing penicillin through unprecedented public, private, and international collaborations, prompting a new era of antibiotics. Antibiotics are now used to treat a myriad of common infections like strep throat, meningitis, tuberculosis, tetanus, urinary tract infections, and food poisoning. They also enable medical procedures that otherwise create a high risk of infection, such as invasive surgery, organ transplantation, and chemotherapy[5]. However, antibiotics are not “one size fits all”; certain types of antibiotics are only effective against certain kinds of bacteria, and all antibiotics are ineffective against viruses[6].

Antibiotics kill or inhibit bacterial growth via various mechanisms of action; they might attack the protective bacterial cell wall, interfere with bacterial reproduction, or interrupt production of molecules necessary for the bacteria’s survival[7]. However, bacteria reproduce and evolve rapidly, changing over time to resist an antibiotic’s destructive mechanism of action. In fact, the more we use antibiotics, the faster bacteria evolve to resist those antibiotics. As bacteria reproduce, random DNA mutations will occur. Most random mutations have no effect on the bacteria, but sometimes a mutation will give the bacteria a special ability to resist an antibiotic—for instance, the mutation may change the cellular target of the antibiotic, or allow the bacteria to pump the drug out of the cell. When an antibiotic is used on bacteria, most of the population will die, but if any of the bacteria have one of these resistance-conferring mutations, they will survive and continue to reproduce, until the entire population is resistant[5]. The use of antibiotics therefore creates environments where bacteria with antibiotic resistance mutations are more likely to survive and reproduce, while susceptible bacteria are gradually killed off.

Figure 1: Use of an antibiotic gradually increases the prevalence of resistant bacteria. If any cell has developed characteristics allowing it to resist attack by an antibiotic, it is more likely to survive and multiply.

This means that, over time, the bacteria that cause infections in humans are more and more likely to be resistant to common antibiotics. It is important to note that bacteria develop antibiotic resistance–not people. But when people use lots of antibiotics, they change bacterial populations such that more and more bacteria are resistant to those antibiotic drugs. This illustrates the double-edged sword nature of antibiotic use: antibiotics are immensely valuable for combating countless infections and enabling medical procedures, but the more we use them, the less valuable they become.

Today, antibiotic resistance is accelerating at alarming rates. The Centers for Disease Control and Prevention (CDC) estimates there are 3 million antibiotic resistant infections in the US every year, causing at least 34,000 deaths[5]. Globally, at least 700,000 deaths occur due to resistant infections, most of which are bacterial; the actual number is likely higher due to poor reporting and surveillance[8]. The prospect of widespread antibiotic resistance threatens to bring society into a post-antibiotic age where infections are more expensive and difficult to treat. This is a threat to not only public health but also the economic stability of the healthcare system[9] and national security[10].

Figure 2:Annual global deaths due to different factors. Antimicrobial resistance (AMR) accounts for resistance from bacteria, as well as fungi, viruses, parasites, and other microbes[15].
This review will focus on medical use of antibiotics in humans in the US, but antibiotic use in animals and agriculture are also major contributors to the current crisis[6]. It is also critical to understand that combating antibiotic resistance will require global cooperative action because infection-causing bacteria spread rapidly between cities, countries, and continents. A large part of addressing antibiotic resistance in the US is assisting and coordinating with other governments, especially those in low-income countries which have the highest instances of antibiotic resistance, but the fewest resources to deal with it[11]. It is also vital to understand the causes of antibiotic resistance in the US and effective actions US institutions can take.

Misuse and Overuse of Antibiotics

Overuse of antibiotics is a major contributor to the rapid proliferation of antibiotic resistant infections. It is estimated that US doctors’ offices and emergency departments prescribe about 47 million unnecessary antibiotic courses annually, amounting to 30% of all antibiotic prescriptions[12]. Many studies show that even when illnesses do require antibiotics, prescribed time courses are significantly longer than national guidelines[13, 14].

Rapid Diagnostics and Antibiotic Prescriptions: A major cause of ubiquitous antibiotic overuse is a lack of rapid methods for diagnosing infections. Physicians rely on tests that usually take days to weeks to identify if an infection is bacterial and, if so, which antibiotics will be most effective. Waiting this long can be harmful or even fatal for patients[15]. Therefore, physicians usually prescribe broadly effective antibiotics while knowing little about the nature of the infection[15]. This can save lives, but if the infection is caused by a virus or resistant bacteria, the antibiotics will not treat the illness and will give resistant strains a chance to further multiply, leaving patients susceptible to additional infections.

With growing awareness in the last 5-10 years that appropriate antibiotic use is difficult with current diagnostics, the CDC, the National Institute of Allergy and Infectious Diseases (NIAID), and the Biomedical Advanced Research and Development Authority (BARDA) have collectively awarded hundreds of millions of dollars to state health departments, businesses, and universities to develop rapid diagnostics[16]. BARDA and NIAID also organized a $20 million prize, the Antimicrobial Resistance Diagnostic Challenge[17], and fund the global non-profit, CARB-X, which has invested $82.5 million in 55 projects worldwide for antibiotic resistance research, including diagnostics[18]. This surge in resources and funding has increased rapid diagnostic development. For example, the NIAID funded development of BioFire’s FilmArray[19], which is now an FDA-cleared diagnostic test available for purchase in the US[20]. In just an hour, it tests patient samples for several common types of bacteria, viruses, and yeast, including antibiotic resistant ones[21].

However, new diagnostic technologies have limited effectiveness when they fail to meet practical cost and resource requirements. Cepheid’s GeneXpert MTB/RIF test, for example, can diagnose tuberculosis infection and determine resistance to rifampicin, a common antibiotic for tuberculosis, in 2 hours[22]. Unfortunately, it has not been used as widely as initially expected[23], mainly because the equipment costs $17,000, not counting training and set-up costs[24]. This illustrates another major shortcoming of current diagnostic technologies: high healthcare infrastructure and cost requirements that render them inaccessible to many people.

Widespread access to rapid diagnostics is not just about fairness, it’s a necessity. Antibiotic resistance will remain a problem in the US as long as it is a problem anywhere in the country netbet sports betting appor the world due to inevitable intra- and international bacterial transmission. Many recently developed rapid diagnostics cost $100-$250 per test[25, 26]. These diagnostic innovations are promising and valuable in filling part of the gap in rapid diagnostics, but their benefits will not be felt by the majority of global hospitals and patients that cannot afford or support high cost, high tech diagnostic investments. Increasing institutional funding in the last 10 years has resulted in new rapid diagnostics for identifying and characterizing infections, a potential step towards reducing antibiotic misuse and subsequent development of antibiotic resistance. However, ensuring accessibility of technological improvements is essential in combating antibiotic resistance.

Prescribing Practices: Updating prescription standards and educating healthcare workers and patients on responsible antibiotic use is another key step in reducing antibiotic overuse. In the US, patients are often prescribed antibiotics for far longer than necessary. Two recent studies found that 70% of patients with sinus infections and 70% of adults hospitalized with pneumonia were given antibiotics for 3 or more days longer than recommended[13, 14]. Oftentimes, this stems from an out-of-date belief that longer is better in terms of preventing the development and spread of resistant bacteria. In fact, the opposite is true. Shorter courses of antibiotics lower the selective pressure for development of resistance. This was illustrated in a study of pediatric antibiotic use[27], where children prescribed 5 days of amoxicillin for the treatment of respiratory infections were less likely to carry antibiotic resistant Streptococcus pneumoniae in their nasal passage than their peers who were treated for 10 days. These children were also found to be less likely to transmit resistant bacteria to others.

In many cases, common antibiotic treatments can be shortened without affecting the outcome. A trial of pneumonia patients found that the standard 8-day course of amoxicillin can be shortened to just 3 days with equal symptom relief and fewer side effects[28]. Similarly, treatment of ventilator-associated pneumonia can be effectively shortened from 14 to 8 days[29]. In some cases, shortened antibiotic courses have actually improved patient outcomes. A reduced course for urinary tract infections from 14 days to 7 days is not only effective, it also prevents post-treatment yeast infections[30].

As scientists and clinicians become more aware of the dangers of resistance, more studies are being conducted to determine the minimum amount of antibiotic required to adequately treat infections. The Infectious Diseases Society of America has also updated their Clinical Practice Guidelines to reflect findings that shorter treatment schedules are often just as effective, are easier to comply with, and reduce development and spread of resistant bacteria[31]. Performing
minimum effective antibiotic treatment trials is costly in the short term, but necessary to safely revise guidelines and save on long-term healthcare costs.

Public misunderstanding and misinformation regarding antibiotics also contribute to their overprescription. In many clinical settings where antibiotics are not necessary, patients may believe antibiotics are the most effective treatment and push their doctors to inappropriately prescribe them. For example, patients often seek antibiotics for viral respiratory illnesses (i.e. cold and flu), despite antibiotics being ineffective against viral infections[5]. It has been demonstrated that patient expectation of antibiotics or physician perception of this desire have a significant influence on antibiotic prescription[32–34].

Table 1: Antibiotic overuse is caused largely by shortcomings in diagnostic technologies and prescribing practices, but there are many possible ways to address these challenges.

Efforts to address this issue include educational initiatives for the public and antibiotic stewardship programs for healthcare providers. One such initiative was France’s national campaign to reduce antibiotic use, launched in 2001[35]. France, Europe’s largest antibiotics consumer, sought to address the problem through physician training and a public health campaign called “Antibiotics are not automatic”. This campaign spread public awareness that overusing antibiotics leads to resistance, and, during the winter flu season, that antibiotics kill bacteria – not the viruses responsible for most respiratory infections. Concurrently with this initiative, antibiotic use in France dropped by over 25% from 2000 to 2007, highlighting the ability of public health education to change clinical outcomes. In recent years, steps have been taken both in the US and internationally to encourage responsible antibiotic use via education, updated prescribing standards, and other courses of action. In 2016, the Joint Commission on Hospital Accreditation, an organization that accredits US healthcare organizations, mandated antibiotic stewardship programs in US hospitals that participate in Medicare and Medicaid. The Joint Commission issued standards cited from the CDC’s Core Elements of Hospital Antibiotic Stewardship Programs[36], including educating staff, healthcare practitioners, patients, and their families on responsible antibiotic use and resistance, appointing a pharmacist leaders to improve hospitals’ antibiotic use, tracking and reporting antibiotic prescribing and resistance patterns, and developing protocols for specific antibiotic use cases, such as pneumonia. The number of hospitals reporting an antibiotic stewardship program that meets all the CDC’s Core Elements doubled between 2014 and 2017[37], and will likely increase further, with stewardship programs now tied to accreditation. On an international scale, the UN and CDC have pushed for global implementation of One Health responses by releasing recommendations for engaging all members of society—governments, businesses, healthcare workers, etc.—in coordinated and strategic efforts to address antibiotic resistance[8]. Comprehensive promotion of responsible antibiotic use is vital to maintaining their usefulness for as long as possible, especially given the difficulty of developing new antibiotics.

Revitalizing the Antibiotic Pipeline

While it is important that existing antibiotics are prescribed cautiously and used responsibly, all antibiotics inevitably encounter resistance[38]. Consequently, continuously developing antibiotics with novel mechanisms of action—the method that an antibiotic uses to kill bacteria—that circumvent existing resistances will remain essential. However, developing these new drugs is costly; it can take well over a decade and cost more than $2 billion, with a 90% failure rate looming over the project[38]. Clinical trials, which require large, diverse populations to demonstrate evidence of drug superiority, account for 65% of the risk-adjusted cost for developing antibiotics[15]. The difficulty of antibiotic drug development is illustrated by the 2019 FDA approval of lefamulin, which marked the first approval of an IV/orally-administered antibiotic with a novel mechanism of action in two decades[39]. Scientific challenges inhibit discovery significantly. The immediately apparent antibiotic candidates have been developed, and discovering antibiotics with new mechanisms of action is challenging. It is now thought that any new, effective antibiotics will need multiple capabilities for killing bacteria, making their discovery more complex[3]. Emerging approaches in antibiotic discovery such as deep learning algorithms are promising technologies to solve these scientific challenges, but are far from bringing new antibiotics to patients[40].

In addition to scientific obstacles, the economics of antibiotic development have reduced innovation and output. The free market is failing to meet society’s antibiotic needs via multiple pathways[41]. Traditional sales-based models, in which revenue is directly proportional to the volume of sales, are antagonistic towards society’s goal of sustainable antibiotic use[2]. Evidence of the current system’s failure is the drastic decrease in antibiotic research programs[3] and the sparse output of new [2]. To address these challenges, policymakers are crucial actors; they can facilitate fertile economic conditions using a combination of 1) “push” policies to galvanize antibiotic discovery and development efforts and 2) “pull” policies to create profitable
economic conditions, incentivizing industry to work in this area. Simultaneously, these policies must be supplemented by sufficient regulations to ensure sustainable and equitable usage, broadly maximizing overall societal benefits.

Push Policies: Push policies drive companies to conduct antibiotic research and clinical trials[42] by providing monetary resources to antibiotic developers. Push policies are realized via grants and pipeline coordinators. Government grants allow both academia and industry to investigate antibiotic candidates and conduct clinical trials. Pipeline coordinators are agencies that ensure governmental funding is distributed efficiently across development stages. Coordinators are essential to ensuring equitable funding distribution across antibiotic candidates and identifying gaps and needs in the antibiotic pipeline from basic research through production. These vehicles have broad precedents and have demonstrated effectiveness at stimulating early stage scientific research. Current estimates show $550 million is spent annually on push spending, though some recommendations show that this number should be $800 million to fully meet the demand for antibiotic research[42]. However, push policies and spending do not completely address the major economic issues.

Figure 3:A combination of push and pull policies are necessary to generate conditions to revitalize the antibiotic pipeline. Currently, only push policies are implemented. Pull policies can de-link an antibiotic’s development from its economic success, which is projected to increase the development rate of antibiotics that society needs.

Pull Policies: The primary goal of push policies is to jump start research and development in antibiotic discovery, but issues remain with the current market structure for antibiotics. This is illustrated by the fact that companies are failing after bringing important antibiotics to market. For instance, the biopharmaceutical company Achaogen successfully developed the antibiotic plazomicin in 2018, but filed for bankruptcy the following year due to insufficient profits from plazomicin[43]. Why would a company that successfully brings a new antibiotic to market fail? Antibiotics are generally prescribed for short periods of time (usually under two weeks), modern health policies support reducing or delaying the use of new antibiotics, and the market lifetime of antibiotics is reduced due to the inevitable development of resistance[44].Overall, these realities minimize sales of the new antibiotic and thus the profits of the developing company. In response, policymakers have proposed pull policies to de-link the sales of the new antibiotic to the economic reward given to the developers, improving the economic viability of developing new antibiotics. These netbet sports betting apppull policies are supported by the Infectious Diseases Society of America[45]. By de-linking sales from economic reward, the revenue from a new antibiotic is not purely based on the sales volume of that antibiotic. For example, a market entry reward (MER) — a large monetary sum given to developers of novel antibiotics upon successful drug approval — can be used to partially or fully de-link the number of sales from the economic reward. Multiple groups, such as the Boston Consulting Group, have estimated that a $1 billion MER per antibiotic is sufficient, suggesting that this award amount would lead to twenty novel antibiotics for society over the next three decades[42, 46].

An important supplement to any MER policy is the antibiotic susceptibility bonus (ASB)[47]. The ASB rewards companies that develop antibiotics that are effective over long periods of time. As an antibiotic remains effective against target bacteria, companies receive monetary awards. This policy helps better align all stakeholders’ (companies, patients, hospitals, insurance networks) interests towards generating and maintaining effective antibiotics. Companies will no longer have an incentive to oversell antibiotics, as they will receive more money the longer their drug is effective. This supplemental policy could safeguard MERs against abuse, and incentivize the development of antibiotics that act in society’s best interest: to develop effective treatments for long periods of time.

Another potential pull policy is the long-term supply continuity model (LSCM)[42], which addresses how companies respond once market exclusivity for a drug ends due to patent expiration. Suppliers may respond to loss of market exclusivity by either manufacturing fewer units in the case of a modest market or by increasing sales through marketing and promotion. Both actions are detrimental to public health in the case of an antibiotic, either promoting antibiotic overuse or making it harder for people who need the antibiotic to get it. The LSCM addresses this by having a country or group of countries make an agreement with manufacturers to produce a predetermined amount of the respective antibiotic for a specified price. This model to generate a predictable supply of an antibiotic acts as a pull mechanism by making the market for novel, essential antibiotics more sustainable for manufacturers.

Pull policies also have some downsides. For one, pull policies only reward successful antibiotic discovery campaigns; the inherent risk in developing these drugs may still dissuade companies. Also, while push policies have been validated with real world results, pull policies have not been evaluated as extensively. To encourage companies to work in this area, push policies, as well as pull policies, are needed to lower the risk of failed discovery programs. To develop the new drugs that society needs, companies need funding to start research and development and economic incentives to take the drugs to market.

Conclusion Proliferation of antibiotic resistance in bacteria is a major public health problem that is only accelerating. This crisis is caused by overuse of existing antibiotic drugs and lagging development of new ones. To address the former, many US and international institutions are working to improve current diagnostic practices and adopt standards for responsible antibiotic use. Increasing funding for rapid diagnostics R&D, initiating educational programs, and mandating the adoption of comprehensive hospital antibiotic stewardship programs are possible ways to reduce antibiotic overuse. To encourage the development of novel antibiotic drugs, many organizations have also subsidized research and development in this area. Additional incentives are being pursued to improve the commercial viability of antibiotic development and protect drug developers from the risks of the antibiotic market. Antibiotic resistance is a major global health crisis, but with efforts to improve responsible use and end the almost 40-year drought of novel antibiotic drug discovery[48], we can take steps to prevent the next public health emergency. 4“The right of the people to be secure in their persons, houses, papers, and effects, against unreasonable searches and seizures, shall not be violated, and no warrants shall issue, but upon probable cause supported by oath or affirmation, and particularly describing the place to be searched, and the persons or things to be seized.”

Acknowledgements

We thank Erika Madrian for her input in shaping the manuscript.

Citation

Yee, E. H., Cheng, S. S., Knappe, G. A. & Moomau, C. A. Antibiotic resistance: How to prevent the next public health emergency. MIT Science Policy Review 1, 10-17 (2020).

A computational approach to cancer

Toni-Ann Nelson transformed remote summer research into an opportunity to learn a new set of tools for analyzing tumors.

Raleigh McElvery
August 20, 2020

Toni-Ann Nelson has wanted to find a cure for cancer ever since she was nine years old and lost her grandfather to the disease. “I remember thinking there must be something that the doctors and scientists were missing,” she recalls. “It just couldn’t be that complicated.” Now one semester away from earning her degree in molecular biology, Nelson is realizing cancer is just that — complicated. After conducting cancer research during MIT’s Summer Research Program in Biology (MSRP-Bio), she understands much more about the intricacies of tumors and metastasis. But she’s also glimpsed just how many cellular puzzles remain to be solved.

Growing up in Jamaica, Nelson enjoyed all her science classes, but preferred biology because she knew it would provide the foundation to probe cancer. She graduated as the valedictorian of her high school class, and earned a scholarship to Alcorn State University in Mississippi, where she began in the spring of 2017.

Alcorn doesn’t have any cancer research facilities, so Nelson secured a position as an undergraduate researcher in Yan Meng’s plant tissue culture lab. For three years, Nelson aimed to improve viral disease resistance in sweet potatoes. Even though she wasn’t conducting clinical research, she mastered key molecular biology techniques like PCR, gel electrophoresis, and tissue culture.

“Fundamental research is important because many times finding a cure requires starting with the basics, and understanding what’s going on inside the cell,” she says.

When Nelson was accepted into MSRP-Bio as a Gould Fellow and assigned to work in Tyler Jacks’ lab, she was elated to get her first hands-on cancer research experience. But in April 2020 — two months before the program was slated to begin — MIT’s campus temporarily shut down due to the COVID-19 pandemic, and MSRP-Bio 2020 became a remote learning experience.

As a result, Nelson and her MSRP-Bio cohort conducted their research from home. She took on a computationally-intensive project that was conducive to remote work and required taking an online quantitative methods class. In a manner of weeks, she learned an entirely new set of skills, including programming languages like Python.

“I always thought that I wouldn’t need those types of computational tools as part of my cancer research,” she explains. “But working at MIT was enlightening, because it showed me that they are key to understanding disease. I can definitely see myself using them on my own projects in the future.”

Pink and purple histology image
Light micrograph of a lung adenocarcinoma. Credit: Vasilena Gocheva/Jacks Lab, Koch Institute

The Jacks lab studies the genetic events that contribute to cancer, and Nelson’s project centered on lung adenocarcinoma. The predominant form of non-small cell lung cancer, it begins in alveolar type II (AT2) cells. Past studies showed that, as the tumor progresses, AT2 cells change state and lose their original identity. Nelson wanted to determine which genes and proteins underlie this evolution. Her analyses showed that genetic markers characteristic of AT2 cells tend to decrease over time, while markers denoting faster-growing “high grade” tumors become more prevalent.

“The kinetics of these gene expression changes that are happening early on are still poorly understood,” she explains. “It just goes to show how complicated this pathology is, which I find even more fascinating.”

Once researchers can pinpoint the genes and proteins that drive changes in cancer cell state, they’ll be better equipped to design drugs that target and prevent metastatic processes.

Although Nelson couldn’t visit the lab in person, as on-campus research slowly began ramping up again, her graduate student mentor Amanda Cruz would show her around during their video conference calls. Cruz also helped Nelson explore the scientific literature, choose studies for the lab’s journal club, and perform computational analyses.

Given the unprecedented circumstances, Nelson says having a solid support system was key to her success. Nelson and her MSRP cohort also relied on one another for encouragement, and were each assigned a graduate student “pal” for guidance outside of lab.

“The program catered to our every need, and it’s structured to ensure that someone will always check up on you if you’re feeling alone,” Nelson says. “I never expected to get so much from this experience, especially because I’m not physically on campus. But what I learned this summer was so much more than I could ever have anticipated.”

Her time in the Jacks lab has solidified her fervor for cancer research, and she intends to apply to cancer biology PhD programs in order to continue this line of inquiry. “I’ve realized there’s still so much more to learn,” she says, “but we’re getting there.”

Top image courtesy of Toni-Ann Nelson
Posted: 8.19.20
Solving molecular mysteries

Diego Detrés spent the summer probing protein function and collaborating with MIT researchers remotely from his home in Puerto Rico.

Raleigh McElvery
August 17, 2020

When he was young, Diego Detrés wanted to become a magician in order to learn the tricks of the trade and transform enigma into fact. Now a fourth-year industrial microbiology major at University of Puerto Rico at Mayagüez, he’s on track to become a researcher while chasing a similar aim. To Detrés, the complex biological processes that continue to stump researchers are akin to acts of magic — although deciphering them is much more complicated than pulling a rabbit out of a hat. As a participant in MIT’s Summer Research Program in Biology (MSRP-Bio), he’s getting closer to parsing the mechanisms behind molecular mysteries.

After his magician phase but before developing an affinity for biology, Detrés was on track to become a professional boxer in Puerto Rico. In high school, he spent hours each night reading about nutrition to supplement his training. Before long, he found himself entranced by the intricacies of the metabolic processes that allow cells to convert food into energy.

At the University of Puerto Rico at Mayagüez, he wanted to continue exploring biology and focus on medicine. “My plan was to become a doctor, because I thought that’s what you do with a biology degree,” he says. “It also seemed like the best way to make an impact on people’s lives.”

But Detrés’ first semester was cut short when hurricane Maria tore through Puerto Rico in September 2017. His spring classes were canceled as the island reeled in the aftermath, so he joined a relief project headed by his university to bring help and legal aid to local communities. “It wasn’t scientific research, but it did show me that understanding a problem is critical to finding an effective solution,” he recalls. “It also allowed me to explore other ways in which I could impact other people.”

Group photo
Detrés (third from left) and his undergraduate research mentor, Carlos Ríos Velázquez (fourth from left)

NetBet live casinoDetrés’ first lab experience came the next summer at the University of Minnesota, where he studied the genetics of maize. That internship affirmed his interest in biology but shifted his gaze away from medicine and towards fundamental research.

“I really liked being at the bench,” he says. “I fell in love with working in lab and basic science. It’s fundamental knowledge that’s important for the building blocks of science; you might discover something today that will help a lot of people later on.”

When he returned home to the University of Puerto Rico at Mayagüez that August, Detrés was accepted into the Maximizing Access to Research Careers (MARC) Program, which is sponsored by the National Institute of General Medical Sciences and provides research-related opportunities and a special science curriculum. He joined the lab of Carlos Ríos Velázquez, investigating novel antibiotic resistance genes within the gut microbiome of the Caracolus marginella snail, and helping Ríos Velázquez teach biology workshops to high school students.

“He gave me a background in science when I didn’t have one, and I want to do the same for other people,” Detrés says. “I hope to teach eventually.”

In January 2020, Detrés was invited to come to MIT for the annual Quantitative Methods Workshop, a seven-day boot camp that introduces students to tools for analyzing experimental data. He enjoyed the “feel” of campus, and decided to apply to MSRP-Bio in hopes of returning in June.

Although the Covid-19 pandemic prevented the Institute from hosting in-person summer programs, Detrés has been gleaning the MIT experience from his apartment in Puerto Rico. His days are filled with Zoom meetings featuring faculty and graduate student talks, group hangouts, informal exercise sessions, musical jams, and cooking classes. He was also named a 2020 MSRP-Bio Gould Fellow. “Even remotely, I’ve gotten to know the MSRP cohort really well, and the faculty have been very interactive,” he says.

He’s been conducting research in Eliezer Calo’s lab for the past two months, running literature searches and bioinformatic analyses. Like Detrés, Calo grew up in Puerto Rico and attended MSRP-Bio. Now, Calo is a professor in MIT’s Department of Biology. His lab investigates RNA metabolism to inform developmental disorders and cancer research.

Detrés is focusing on a family of RNA helicases called DEAD-box ATPases, or “DDXs,” which are involved in every step of RNA metabolism. These proteins are conserved across many species, and contain a core amino acid sequence that helps catalyze reactions with other molecules in the cell.

However, the Calo lab suspects that the less-conserved sequences near the ends of the proteins may be more critical for specialized function. Detrés is investigating what it is about these terminal sequences that determines DDXs’ specific roles in RNA metabolism.

Student with Bunsen burner
Detrés in the Ríos Velázquez lab at the University of Puerto Rico at Mayagüez

This summer, he showed that DDX proteins are more likely to lack a stable structure near one end, known as the C-terminus, compared to other closely-related helicases. These findings will help the Calo lab better understand the relationship between DDX’s functional specificity and its intrinsically disordered regions like the C-terminus.

“Most of these proteins are essential for life, and yet we don’t really know how they’re involved in so many dynamic processes,” Detrés says. “It’s been interesting to analyze already-existing data in ways that allow us to investigate novel possibilities.”

Working from home has been challenging to say the least. Not having the in-person support from his labmates has been difficult. On the other hand, spending so much time with his family has been enjoyable.

“I had to make a routine for myself that allowed me to work effectively from home, as well as maintain my physical and mental well-being,” he says. “Program activities also gave us the chance to be physically active and to interact with other students”.

Detrés aims to return for a second summer of MSRP next year, hopefully in person.

“Since starting MSRP, I’ve noticed a lot of changes in myself,” he says. “The more I get into research, even remote research, the more I realize it’s what I want to do. Science is not about being really smart; it’s about being really curious.”

As Detrés continues to follow his curiosity, the inner workings of the cell are becoming more comprehensible — but no less mesmerizing.

Photos courtesy of Diego Detrés
Posted: 8.18.20
New gene regulation model provides insight into brain development

A well-known protein family binds to many more RNA sequences than previously thought to help neurons grow.

Raleigh McElvery
August 17, 2020

In every cell, RNA-binding proteins (RBPs) help tune gene expression and control biological processes by binding to RNA sequences. Researchers often assume that individual RBPs latch tightly to just one RNA sequence. For instance, an essential family of RBPs, the Rbfox family, was thought to bind one particular RNA sequence alone. However, it’s becoming increasingly clear that this idea greatly oversimplifies Rbfox’s vital role in development.

Members of the Rbfox family are among the best-studied RBPs and have been implicated in mammalian brain, heart, and muscle development since their discovery 25 years ago. They influence how RNA transcripts are “spliced” together to form a final RNA product, and have been associated with disorders like autism and epilepsy. But this family of RBPs is compelling for another reason as well: until recently, it was considered a classic example of predictable binding.

More often than not, it seemed, Rbfox proteins bound to a very specific sequence, or motif, of nucleotide bases, “GCAUG.” Occasionally, binding analyses hinted that Rbfox proteins might attach to other RNA sequences as well, but these findings were usually discarded. Now, a team of biologists from MIT has found that Rbfox proteins actually bind less tightly — but no less frequently — to a handful of other RNA nucleotide sequences besides GCAUG. These so-called “secondary motifs” could be key to normal brain development, and help neurons grow and assume specific roles.

“Previously, possible binding of Rbfox proteins to atypical sites had been largely ignored,” says Christopher Burge, professor of biology and the study’s senior author. “But we’ve helped demonstrate that these secondary motifs form their own separate class of binding sites with important physiological functions.”

Graduate student Bridget Begg is the first author of the study, published on August 17 in Nature Structural & Molecular Biology.

“Two-wave” regulation

After the discovery that GCAUG was the primary RNA binding site for mammalian Rbfox proteins, researchers characterized its binding in living cells using a technique called CLIP (crosslinking-immunoprecipitation). However, CLIP has several limitations. For example, it can indicate where a protein is bound, but not how much protein is bound there. It’s also hampered by some technical biases, including substantial false-negative and false-positive results.

To address these shortcomings, the Burge lab developed two complementary techniques to better quantify protein binding, this time in a test tube: RBNS (RNA Bind-n-Seq), and later, nsRBNS (RNA Bind-n-Seq with natural sequences), both of which incubate an RBP of interest with a synthetic RNA library. First author Begg performed nsRBNS with naturally-occurring mammalian RNA sequences, and identified a variety of intermediate-affinity secondary motifs that were bound in the absence of GCAUG. She then compared her own data with publicly-available CLIP results to examine the “aberrant” binding that had often been discarded, demonstrating that signals for these motifs existed across many CLIP datasets.

To probe the biological role of these motifs, Begg performed reporter assays to show that the motifs could regulate Rbfox’s RNA splicing behavior. Subsequently, computational analyses by Begg and co-author Marvin Jens using mouse neuronal data established a handful of secondary motifs that appeared to be involved in neuronal differentiation and cellular diversification.

Based on analyses of these key secondary motifs, Begg and colleagues devised a “two-wave” model. Early in development, they believe, Rbfox proteins bind predominantly to high-affinity RNA sequences like GCAUG, in order to tune gene expression. Later on, as the Rbfox concentration increases, those primary motifs become fully occupied and Rbfox additionally binds to the secondary motifs. This results in a second wave of Rbfox-regulated RNA splicing with a different set of genes.

Begg theorizes that the first wave of Rbfox proteins binds GCAUG sequences early in development, and she showed that they regulate genes involved in nerve growth, like cytoskeleton and membrane organization. The second wave appears to help neurons establish electrical and chemical signaling. In other cases, secondary motifs might help neurons specialize into different subtypes with different jobs.

John Conboy, a molecular biologist at Lawrence Berkeley National Lab and an expert in Rbfox binding, says the Burge lab’s two-wave model clearly shows how a single RBP can bind different RNA sequences — regulating splicing of distinct gene sets and influencing key processes during brain development. “This quantitative analysis of RNA-protein interactions, in a field that is often semi-quantitative at best, contributes fascinating new insights into the role of RNA splicing in cell type specification,” he says.

A binding spectrum

The researchers suspect that this two-wave model is not unique to Rbfox. “This is probably happening with many different RBPs that regulate development and other dynamic processes,” Burge says. “In the future, considering secondary motifs will help us to better understand developmental disorders and diseases, which can occur when RBPs are over- or under-expressed.”

Begg adds that secondary motifs should be incorporated into computer models that predict gene expression, in order to probe cellular behavior. “I think it’s very exciting that these more finely-tuned developmental processes, like neuronal differentiation, could be regulated by secondary motifs,” she says.

Both Begg and Burge agree it’s time to consider the entire spectrum of Rbfox binding, which are highly influenced by factors like protein concentration, binding strength, and timing. According to Begg, “Rbfox regulation is actually more complex than we sometimes give it credit for.”

Citation:
“Concentration-dependent splicing is enabled by Rbfox motifs of intermediate affinity”
Nature Structural & Molecular Biology, online August 17, 2020, DOI: 10.1038/s41594-020-0475-8
Bridget E. Begg, Marvin Jens, Peter Y. Wang, Christine M. Minor, and Christopher B. Burge

Top illustration: Some RNA-binding proteins like Rbfox (gold ellipses) help tune gene expression and control biological processes by latching onto more RNA sequences (black and gold lines) as their concentration increases (teal shading). Credit: Bridget Begg
Posted: 8.17.20
SMART research enhances dengue vaccination in mice
Singapore-MIT Alliance for Research and Technology
August 13, 2020

Researchers from the Singapore-MIT Alliance for Research and Technology (SMART), MIT’s research enterprise in Singapore, have found a practical way to induce a strong and broad immunity to the dengue virus based on proof-of-concept studies in mice. Dengue is a mosquito-borne viral disease with an estimated 100 million symptomatic infections every year. It is endemic in over 100 countries in the world, from the United States to Africa and wide swathes of Asia. netbet online sports bettingIn Singapore, over 1,700 dengue new cases were reported recently.

The study is reported in a paper titled “Sequential immunization induces strong and broad immunity against all four dengue virus serotypes,” published in NPJ Vaccines. It is jointly published by SMART researchers Jue Hou, Shubham Shrivastava, Hooi Linn Loo, Lan Hiong Wong, Eng Eong Ooi, and Jianzhu Chen from SMART’s Infectious Diseases and Antimicrobial Resistance (AMR) interdisciplinary research groups (IRGs).

The dengue virus (DENV) consists of four antigenically distinct serotypes and there is no lasting immunity following infection with any of the DENV serotypes, meaning someone can be infected again by any of the remaining three variants of DENVs.

Today, Dengvaxia is the only vaccine available to combat dengue. It consists of four variant dengue antigens, one for each of the four serotypes of dengue, expressed from attenuated yellow-fever virus. The current three doses of immunization with the tetravalent vaccine induce only suboptimal protection against DENV1 and DENV2. Furthermore, in people who have not been infected by dengue, the vaccine induces a more severe dengue infection in the future. Therefore, in most of the world, the vaccination is only given to those who have been previously infected.

To help overcome these issues, SMART researchers tested on mice whether sequential immunization (or one serotype per dose) induces stronger and broader immunity against four DENV serotypes than tetravalent-formulated immunization — and found that sequential immunization induced significantly higher levels of virus-specific T cell responses than tetravalent immunization. Moreover, sequential immunization induced higher levels of neutralizing antibodies to all four DENV serotypes than tetravalent vaccination.

“The principle of sequential immunization generally aligns with the reality for individuals living in dengue-endemic areas, whose immune responses may become protective after multiple heterotypic exposures,” says Professor Eng Eong Ooi, SMART AMR principal investigator and senior author of the study. “We were able to find a similar effect based on the use of sequential immunization, which will pave the way for a safe and effective use of the vaccine and to combat the virus.”

Upon these promising results, the investigators will aim to test the sequential immunization in humans in the near future.

The work was supported by the National Research Foundation (NRF) Singapore through the SMART Infectious Disease Research Program and AMR IRG. SMART was established by MIT in partnership with the NRF Singapore in 2007. SMART is the first entity in the Campus for Research Excellence and Technological Enterprise (CREATE) developed by NRF.  SMART serves as an intellectual and innovation hub for research interactions between MIT and Singapore, performing cutting-edge research of interest to both Singapore and MIT. SMART currently comprises an Innovation Centre and five IRGs: AMR, Critical Analytics for Manufacturing Personalized-Medicine, Disruptive and Sustainable Technologies for Agricultural Precision, Future Urban Mobility, and Low Energy Electronic Systems. SMART research is funded by the NRF Singapore under the CREATE program.

The AMR IRG is a translational research and entrepreneurship program that tackles the growing threat of antimicrobial resistance. By leveraging talent and convergent technologies across Singapore and MIT, they aim to tackle AMR head-on by developing multiple innovative and disruptive approaches to identify, respond to, and treat drug-resistant microbial infections. Through strong scientific and clinical collaborations, they provide transformative, holistic solutions for Singapore and the world.

Iain Cheeseman earns a Global Consortium for Reproductive Longevity & Equality (GCRLE) Scholar Award
Buck Institute
August 10, 2020

The Global Consortium for Reproductive Longevity and Equality (GCRLE) at the Buck Institute for Research on Aging, made possible by the Bia-Echo Foundation, announces its inaugural recipients of its GCRLE Scholar Awards. The 22 recipients comprise a global group who share a vision of advancing research to better understand the underlying causes of female reproductive aging. Grantees were selected by a Scientific Advisory Council composed of leaders in the fields of Aging and Reproductive Biology. Grantees range from early career scientists to established scholars in the field.

“I am incredibly excited by the potential impact for the GCRLE. The ability to convene a diverse community from across institutions will positively and constructively impact this field and move science forward in a way that simply would not be possible otherwise,” says GCRLE Pilot Award recipient Iain Cheeseman, PhD, of the Whitehead Institute for Biomedical Research at MIT. GCRLE Junior Scholar Award recipient Lynae Brayboy, MD of Charité-Universitätsmedizin, Berlin adds, “I think reproductive scientists can often exist in isolation and don’t have the unique experience GCRLE is fostering…I think it also very challenging for physician scientists to find support in the field of reproductive aging and reproductive biology in general.”

The mission of the GCRLE is to support breakthrough research on reproductive aging through funding, training, infrastructure, programs to support women in science, and a collaborative intellectual network. The GCRLE network will enable grantees and all consortium members to pursue support and collaboration across multidisciplinary approaches and institutions, thereby establishing a foundation on which to grow a diverse and sustainable research ecosystem.

Grants totaling $7.4 million will be awarded over 2 years, with flexibility in budgeting for maximum creativity and non-traditional support such as childcare. “We are thrilled to welcome these promising researchers as our very first grant recipients.” says Jennifer Garrison, PhD, GCRLE Faculty Director and Assistant Professor at the Buck Institute for Research on Aging. “The GCRLE unites two disciplines – reproductive science and geroscience – in an unprecedented way to investigate an area of biology that has tangible societal and clinical implications. Our goal is to foster truly bold, innovative scientists with the potential to transform the field. Beyond funding, we are building an infrastructure to grow a vibrant community and developing creative programs to break down gender barriers in scientific research careers. This is the beginning of something big!”

The GCRLE is anchored at the Buck’s Center for Female Reproductive Longevity and Equality which was established in 2018 with a gift from attorney and entrepreneur Nicole Shanahan. The Center is the first research facility in the world focused solely on reproductive equality and ovarian aging, a key determinant not only of fertility but of overall health and longevity. The GCRLE was established in 2019 with a gift from Shanahan’s Bia-Echo Foundation to build the global ecosystem for this new and exciting field of research.

2020 Inaugural GCRLE Scholars

The Senior Scholar Award supports established investigators who are thought leaders in their fields and are recognized for substantial contributions of creative and productive research.

2020 Senior Scholar Award Recipients:

Holly Ingraham, Ph.D.
University of California, San Francisco
“Identifying Novel Drivers in Central Control of Female Reproduction”

Coleen Murphy, Ph.D.
Princeton University
“Defining a “Clock” for Female Reproductive Decline”

Mary Zelinski, Ph.D.
Oregon Health & Science University
“Interventions for Ovarian Aging”

The Junior Scholar Award supports newly independent investigators with outstanding promise as they are establishing their own labs.

2020 Junior Scholar Award Recipients:

Bérénice Benayoun, Ph.D.
University of Southern California
“Establishing new age-relevant mouse models of menopause”

Lynae Brayboy, M.D.
Charité – Universitätsmedizin, Berlin
“Dysfunctional MDR-1 disrupts mitochondrial homeostasis in the oocyte”

Ingrid Fetter-Pruneda, Ph.D.
Universidad Nacional Autónoma de México
“The molecular and cellular basis of high fecundity in social insects”

Amanda Kallen, M.D.
Yale University
“Ovarian Senescence as a Novel Driver of Female Reproductive Aging”

The Pilot Award is designed to foster innovative collaborative or novel research projects that have the potential for high impact and high reward at an accelerated rate.

Pilot Award Recipients:

Ivana Celic, Ph.D.
Tulane University
“LINE1 Retrotransposons in Female Reproductive Aging”

Iain Cheeseman, Ph.D.
Whitehead Institute/MIT
“Analyzing centromere rejuvenation during female reproductive aging”

Marco Conti, M.D.
University of California, San Francisco
“mRNA translation program and oocyte aging”

Arjumand Ghazi, Ph.D.
University of Pittsburgh
“Genetic & Chemical Modulation of Splicing to Combat Reproductive Senescence”

Polina Lishko, Ph.D.
University of California, Berkeley
“Endocannabinoid signaling in the mammalian ovary and reproductive longevity”

Zita Santos, Ph.D., Carlos Ribeiro, Ph.D.
Champalimaud Foundation, Portugal
“Metabolic reprogramming, dietary nutrients and food cravings in ovary aging”

Yousin Suh, Ph.D.
Columbia University
“Genetic Control of Ovarian Aging in Humans”

The Postdoctoral Scholar Award supports training imaginative junior scientists who will lead the next generation of reproductive aging researchers.

2020 Postdoctoral Scholar Award Recipients:

Cristina Quesada Candela, Ph.D.
University of Pittsburg​
“Proteasomal Targets Driving Meiotic Failure During Reproductive Aging”

Ana Milunovic Jevtic, Ph.D., D.V.M.
University of California, Berkeley
“The role of endocannabinoid hydrolase ABHD2 in the ovarian aging”

Gul Bikem Soygur Kaya, Ph.D.
University of California, San Francisco
“How duration of meiotic prophase affects development and aging of oocytes”

Min Hoo Kim, Ph.D.
University of Southern California
“Elucidating causal effects of the microbiome on reproductive aging”

Seungsoo Kim, Ph.D.
Columbia University Medical Center
“Integrative bioinformatic analysis of human ovarian aging and healthspan”

Olfat Malak, Ph.D.
Buck Institute for Research on Aging
“Role of sympathetic transmission in the regulation of ovarian aging”

Farners Amargant i Riera, Ph.D.
Northwestern University
“Targeting fibrosis and inflammation to extend reproductive longevity”

Zijing Zhang, Ph.D.
University of Arkansas for Medical Sciences
“The impact of ovarian macrophage population on mouse ovarian aging”

About the Global Consortium for Reproductive Longevity and Equality

The Buck Institute, through the generous support of the Bia Echo Foundation, has launched a novel, global collaborative Consortium dedicated to facilitating and accelerating research on female reproductive longevity and equality. The end of fertility sets off a cascade of negative health effects in a woman’s body. As a society, every aspect of a woman’s life is influenced by the fact that reproductive capacity is limited — overall health, family planning, career decisions. The downstream consequences are clear, but why women undergo a precipitous decline in fertility at midlife and what sets it in motion are a mystery. Despite its profound impact on health and well-being, female reproductive aging is an understudied topic.

The Global Consortium for Reproductive Longevity and Equality (GCRLE) is advancing research to better understand the underlying causes of female reproductive aging. This has implications for everyone – we think that understanding the limits on reproductive capacity will provide important clues about aging in other tissues.  Through funding, collaboration, and innovation, we hope to accelerate the pace of discovery and inform the path to intervention. We believe we can profoundly alter the societal balance toward equality for women by defining what leads to menopause and developing interventions to slow or reverse it. Our goal is to build the field to understand the basic biological mechanisms that trigger female reproductive senescence, from the earliest NetBet live casinostages through to menopause, and ultimately leverage this understanding to intervene and balance the scales.  Contact info@gcrle.org for more information and to find out how to join the GCRLE today! https://buckinstitute.org/gcrle/

About the Buck Institute for Research on Aging

Our success will ultimately change healthcare. At the Buck, we aim to end the threat of age-related diseases for this and future generations by bringing together the most capable and passionate scientists from a broad range of disciplines to identify and impede the ways in which we age. An independent, nonprofit institution, our goal is to increase human health span, or the healthy years of life. Globally recognized as the pioneer and leader in efforts to target aging, the number one risk factor serious diseases including Alzheimer’s, Parkinson’s, cancer, macular degeneration, heart disease, and diabetes, the Buck wants to help people live better longer.  Learn more at: https://buckinstitute.org

About the Bia-Echo Foundation

Bia-Echo Foundation is a private foundation, founded by Nicole Shanahan that aims to accelerate social change in order to establish a fair and equitable society for future generations to thrive. We invest in changemakers at the forefront of innovation who are tackling some of the world’s greatest challenges within our core areas of equality-based investment:  Reproductive Longevity & Equality, Criminal Justice Reform and Healthy and Livable Ecosystems. https://www.biaecho.org

To distinguish contexts, animals think probabilistically, study suggests
Picower Institute
August 3, 2020

Among the many things rodents have taught neuroscientists is that in a region called the hippocampus, the brain creates a new map for every unique spatial context – for instance, a different room or maze. But scientists have so far struggled to learn how animals decide when a context is novel enough to merit creating, or at least revising, these mental maps. In a study in eLife, MIT and Harvard researchers propose a new understanding: The process of “remapping” can be mathematically modeled as a feat of probabilistic reasoning by the rodents.

The approach offers scientists a new way to interpret many experiments that depend on measuring remapping to investigate learning and memory. Remapping is integral to that pursuit, because animals (and people) associate learning closely with context, and hippocampal maps indicate which context an animal believes itself to be in.

“People have previously asked ‘What changes in the environment cause the hippocampus to create a new map?’ but there haven’t been any clear answers,” said lead author Honi Sanders. “It depends on all sorts of factors, which means that how the animals define context has been shrouded in mystery.”

Sanders is a postdoc in the lab of co-author Matthew Wilson, Sherman Fairchild Professor in The Picower Institute for Learning and Memory and the departments of Biology and Brain and Cognitive Sciences at MIT.  He is also a member of the Center for Brains, Minds and Machines. The pair collaborated with Samuel Gershman, a professor of psychology at Harvard on the study.

Fundamentally a problem with remapping that has frequently led labs to report conflicting, confusing, or surprising results, is that scientists cannot simply assure their rats that they have moved from experimental Context A to Context B, or that they are still in Context A, even if some ambient condition, like temperature or odor, has inadvertently changed. It is up to the rat to explore and infer that conditions like the maze shape, or smell, or lighting, or the position of obstacles, and rewards, or the task they must perform, have or have not changed enough to trigger a full or partial remapping.

So rather than trying to understand remapping measurements based on what the experimental design is supposed to induce, Sanders, Wilson and Gershman argue that scientists should predict remapping by mathematically accounting for the rat’s reasoning using Bayesian statistics, which quantify the process of starting with an uncertain assumption and then updating it as new information emerges.

“You never experience exactly the same situation twice. The second time is always slightly different,” Sanders said. “You need to answer the question: ‘Is this difference just the result of normal variation in this context or is this difference actually a different context?’ The first time you experience the difference you can’t be sure, but after you’ve experienced the context many times and get a sense of what variation is normal and what variation is not, you can pick up immediately when something is out of line.”

The trio call their approach “hidden state inference” because to the animal, the possible change of context is a hidden state that must be inferred.

In the study the authors describe several cases in which hidden state inference can help explain the remapping, or the lack of it, observed in prior studies.

For instance, in many studies it’s been difficult to predict how changing some of cues that a rodent navigates by in a maze (e.g. a light or a buzzer) will influence whether it makes a completely new map or partially remaps the current one and by how much. Mostly the data has showed there isn’t an obvious “one-to-one” relationship of cue change and remapping. But the new model predicts how as more cues change, a rodent can transition from becoming uncertain about whether an environment is novel (and therefore partially remapping) to becoming sure enough of that to fully remap.

In another, the model offers a new prediction to resolve a remapping ambiguity that has arisen when scientists have incrementally “morphed” the shape of rodent enclosures. Multiple labs, for instance, found different results when they familiarized rats with square and round environments and then tried to measure how and whether they remap when placed in intermediate shapes, such as an octagon. Some labs saw complete remapping while others observed only partial remapping. The new model predicts how that could be true: rats exposed to the intermediate environment after longer training would be more likely to fully remap than those exposed to the intermediate shape earlier in training, because with more experience they would be more sure of their original environments and therefore more certain that the intermediate one was a real change.

The math of the model even includes a variable that can account for differences between individual animals. Sanders is looking at whether rethinking old results in this way could allow researchers to understand why different rodents respond so variably to similar experiments.

Ultimately, Sanders said, he hopes the study will help fellow remapping researchers adopt a new way of thinking about surprising results – by considering the challenge their experiments pose to their subjects.

“Animals are not given direct access to context identities, but have to infer them,” he said. “Probabilistic approaches capture the way that uncertainty plays a role when inference occurs. If we correctly characterize the problem the animal is facing, we can make sense of differing results in different situations because the differences should stem from a common cause: the way that hidden state inference works.”

The National Science Foundation funded the research.

This molecule helps sweet-toothed protein complex sense sugar
Eva Frederick | Whitehead Institute
July 28, 2020

In order to grow and thrive, cells need sugar. A repertoire of cellular mechanisms turn unwieldy molecules of glucose and fructose into versatile building blocks for making useful molecules such as lipids, and energy to fuel necessary processes in the cell. But for any of these things to happen, the cells need to sense when sugars are present in the first place — and scientists are still unraveling how they do it.

Now, in a new paper online July 27 in Nature Metabolism, researchers in the lab of Whitehead Institute Member David Sabatini, identify a key molecule that signals to the cell’s growth-triggering complex mTORC1 when there is sugar to be had, leading to a metabolic response. “This discovery puts us another step closer to understanding the biology of mTORC1 and its effects on cellular growth and metabolism,” said Sabatini, who is also a professor of biology at Massachusetts Institute of Technology and investigator with the Howard Hughes Medical Institute.

mTORC1 — short for “mechanistic target of rapamycin complex 1” — is a complex of proteins involved in regulating cell growth and metabolism. Jose Orozco, a fifth-year M.D./Ph.D student in Sabatini’s lab, describes mTORC1 as a sort of cellular licensing board. In order for other parts of the cell to grow and create new products, they must first be “approved” by mTORC1. If there are enough building blocks in the cell to create a certain product, mTORC1 will add a phosphate group to the appropriate “builders” — a signal that allows the building to begin.

“The builders in this case are metabolic pathways responsible for the creation of proteins, the regulation of nucleotides, regulation of glycolysis, regulation of fatty acid synthesis,” he says. “None of these builders can sense everything. But mTORC1 can, and it makes this sort of unified decision for the cell, ‘Yes, we have everything we need to grow.’”

One essential component for cellular building is glucose. That means mTORC1 has a sweet tooth by necessity: the complex is only active when there is enough glucose in the cell. When there’s glucose to go around, mTORC1 is “on” and binds to a lysosome, a structure that serves as the cell’s “digestive system”, where it perches to perform its phosphorylation duties. When a cell is starved for glucose, the complex falls off the lysosome, inactive.

Since the early 2010s, scientists have known one way that mTOR proteins sense glucose: when there is no glucose available, the cell inhibits the action of mTORC1 through a pathway involving the protein AMPK. But another study suggested that even without AMPK, mTORC1 can still sense an absence of glucose. “I think a lot of people had written it off as ‘Oh, [the signal] must just be AMPK,’” Orozco says. “But when we tested that hypothesis, we showed that even cells that didn’t have any AMPK were still able to sense glucose availability. That was the observation that started this project.”

To find the mysterious second sugar-sensing process, Orozco and colleagues created cells in which the known signalling protein AMPK was out of the picture. Using these modified cells, they began looking for specific traits of the glucose molecule that might be triggering the response. The team found that sugars that could be broken down by the cell, such as mannose, glucosamine and fructose, were able to activate mTORC1. Non-metabolizable sugars had no effect.

This suggested that the signaling molecule was not glucose itself, but something produced when glucose is taken apart during glycolysis — the biochemical process that breaks down the sugar into usable building blocks. With this in mind, the researchers next combed step by step through glycolysis products to see which ones could be the signal molecule.

The team identified a step of glycolysis that seemed to be key, zeroing  in on a glycolysis product called dihydroxyacetone phosphate, or DHAP. Even in the complete absence of glucose, the researchers could turn on mTORC1 by adding DHAP.

It is difficult to prove exactly why the cell relies on DHAP as a signal, but Orozco has some ideas. For one thing, DHAP later goes on to serve as the backbone of lipids, which are built by a process controlled by mTORC1 — so it would make sense that mTORC1 would respond to its presence or absence. Also, DHAP netbet online sports bettinglevels are extremely sensitive to changes in the amount of cellular glucose, more so than any other glycolysis intermediary. Also, DHAP is a product of both glucose and fructose, which are both important sugars in the human diet.

In the future, the team hopes to understand more. “We don’t know the biochemical details of how DHAP [conveys its message],” Orozco says. “We don’t know the sensor, we don’t know what proteins bind it, and we don’t know if that causes conformational changes in [associated proteins]. That we sort of leave as the enticing next question that we want to tackle.”

At the moment, studying the glucose sensing pathway is purely foundational research. But while there are no clear applications yet, surprises could lurk just around the corner. “Targeting nutrient sensing in mTOR has shown some promise in, of all things, regulating depression and mood,” Orozco says. “That’s interesting, and we don’t really understand why that is the case. How is glucose targeting going to be important? We don’t know yet. But we think it has a lot of potential.”

***

Written by Eva Frederick

Citation:

Orozco, J.M., Krawczyk, P.A., Scaria, S.M. et al. Dihydroxyacetone phosphate signals glucose availability to mTORC1. Nat Metab (2020). https://doi.org/10.1038/s42255-020-0250-5

3 Questions: Jonathan King on the future of nuclear weapons testing

Professor of biology discusses a scientist’s responsibility to speak out about important issues that affect our nation and the world.

Raleigh McElvery | Department of Biology
July 29, 2020

In an open letter published on July 16 in Science, four MIT professors and nearly 70 additional scientific leaders called upon fellow researchers to urge U.S. government officials to halt plans to restart nuclear weapons testing. Corresponding author and professor of biology Jonathan King sat down to discuss the history of nuclear testing, his personal ties to the issue, and his responsibilities as a scientist. He also co-chairs the Nuclear Disarmament Working Group of Massachusetts Peace Action, MIT’s annual Reducing the Threat of Nuclear War conference, and the editorial board of the MIT Faculty Newsletter.

Q: What events have made you passionate about the issue of nuclear weapons testing?

A: I grew up in the shadow of nuclear war, participating in drills at school where you would duck under your desk. During the Cold War, the world’s nations exploded hundreds of dangerous nuclear tests, releasing radioactivity into the atmosphere in order to develop these weapons. I was a college student during the Cuban Missile Crisis, and remember vividly the fear of a nuclear exchange.

Around that time, it became clear to our nation’s leaders that this was not the way to go. In his famous speech at American University, President Kennedy reversed direction. Professor of chemistry at Caltech Linus Pauling led an effort with his wife to back Kennedy and collect 9,000 signatures from scientists endorsing the president’s Partial Nuclear Test Ban Treaty. This was before the internet, so getting 9,000 signatures was not easy, and it had a national impact. I was actually a graduate student at Caltech, following up on Pauling’s work on proteins, when the treaty was ratified and he was awarded the Nobel peace prize for his work.

When I arrived at MIT as an assistant professor, Jerome Wiesner was the Institute president. He was also a key player in pushing the Partial Nuclear Test Ban Treaty, and Kennedy had previously named him chair of the President’s Science Advisory Committee (PSAC). MIT was full of world leaders in nuclear disarmament, including physicists who had worked on the bomb and decided it was a mistake. I’m not a physicist, but I was among the generation at MIT that was very vocal about these issues.

Q: What is the current state of nuclear weapon testing and regulation in the United States, and what concerns do you have about renewed testing?

A: The U.S. hasn’t tested a nuclear weapon since 1992. In that period of time, the Comprehensive Test Ban Treaty (CTBT) was developed by many nations, agreeing not to conduct a nuclear weapons test of any yield. The Senate hasn’t ratified it, but in 2016 the U.S. did adopt UN Security Council Resolution 2310, agreeing to uphold the goal of the CTBT and withhold nuclear testing.

However, the current administration is proposing to modernize nuclear weapons and restart testing, which is both provocative and dangerous. Even if these tests are small, contained, and underground, they will still open the door for other nations to restart testing of their own, and possibly lead to a new nuclear weapons arms race.

When a nuclear weapon — either a conventional bomb or hydrogen bomb — explodes, many radioactive isotopes are produced. Some of them are short-lived and decay quickly, but others like strontium-90 are much longer-lived. These ones can make you sick very slowly, and some can mutate or damage DNA. Even underground tests can leak radioactivity into the atmosphere and environment.

Q: What spurred you and your colleagues to write an open letter to Science, and what was your goal in doing so?

A: Our letter was signed by 70 scientific leaders and Nobel Prize winners, and calls upon the scientific community to warn the nation that this is a dangerous way to go. We also urged the Senate to ratify the CTBT, and pass a new bill introduced by Senator Ed Markey called the Preserving Leadership Against Nuclear Explosives Testing (PLANET) Act — which would prevent spending money on the renewal of testing.

I come from a culture that views scientists as public servants. All my research has been funded by taxpayer dollars, and with that comes a responsibility to help address threats to the community. The very history of my department, the MIT Department of Biology, is tied to scientists taking a stand against social and political issues. I was just a young assistant professor when faculty members like David Baltimore and Ethan Signer led demonstrations to oppose the Vietnam War. It was a very open environment and we supported one another.

These days, science is simply a career. You do your work and you keep your eyes to the bench. But the world can be a better place if we take our eyes off the bench occasionally. So this letter is a reminder to our colleagues: Get involved, and consider it our contribution to the general public who support our research.