New Laser Technique Boosts Accuracy of DNA Sequencing Method
By Mark Dwortzan
Low-cost, ultra-fast DNA sequencing would revolutionize healthcare and biomedical research, sparking major advances in drug development, preventative medicine and personalized medicine. By gaining access to the entire sequence of your genome, a physician could determine the probability that you’ll develop a specific genetic disease or tolerate selected medications. In pursuit of that goal, Associate Professor Amit Meller (BME, MSE) has spent much of the past decade spearheading a method that uses solid state nanopores—two-to-five-nanometer-wide holes in silicon chips that read DNA strands as they pass through—to optically sequence the four nucleotides (A, C, G, T) encoding each DNA molecule.
Now Meller and a team of researchers at Boston University—Professor Theodore Moustakas (ECE, MSE) and research assistants Nicolas Di Fiori (Physics, PhD’13) and Allison Squires (BME, PhD’14)—and Technion-Israel Institute of Technology—have discovered a simple way to improve the sensitivity, accuracy and speed of the method, making it an even more viable option for DNA sequencing or characterization of small proteins.
In the November 3 online edition of Nature Nanotechnology, the team demonstrated that focusing a low-power, commercially available green laser on a nanopore increases current near walls of the pore, which is immersed in salt water. As the current increases, it sweeps the salt water along with it in the opposite direction of incoming samples. The onrushing water, in turn, acts as a brake, slowing down the passage of DNA through the pore. As a result, nanoscale sensors in the pore can get a higher-resolution read of each nucleotide as it crosses the pore, and identify small proteins in their native state that could not previously be detected.
“The light-induced phenomenon that we describe in this paper can be used to switch on and off the ‘brakes’ acting on individual biopolymers, such as DNA or proteins sliding through the nanopores, in real time,” Meller explained. “This critically enhances the sensing resolution of solid-state nanopores, and can be easily integrated in future nanopore-based DNA sequencing and protein detection technologies.”
Slowing down DNA is essential to DNA or RNA sequencing with nanopores, so that nanoscale sensors, like sports referees, can make the right call on what’s passing through.
“The goal is to hold a base pair of DNA nucleotides in the nanopore’s sensing volume long enough to ‘call the base’ (i.e, determine if it’s an A, C, G or T),” said Squires, who fabricated nanopores and ran experiments in the study. “The signal needs to be sufficiently different for each base for sensors in the nanopore to make the call. If the sample proceeds through the sensing volume too quickly, it’s hard for the sensors to interpret the signal and make the right call.”
Other methods designed to slow down DNA in nanopores change the sensing properties of the pore, making it more difficult to ensure accuracy of detected base pairs. Shining laser light on the nanopore alters only the local surface charge, an effect that’s completely reversible within milliseconds by switching the laser off.
As an added bonus, the researchers found that the sudden increase in surface charge and resulting flow of water reliably unblocks clogged nanopores, which can take a long time to clean, significantly extending their lifetime.
Meller and his team characterized the amount of increase in current under varying illumination in many different-sized nanopores. They next aim to explore in greater detail the mechanism underlying the increase in surface current when the green laser is applied to a nanopore, information that could lead to even more sensitivity and accuracy in DNA sequencing.
The research is funded by a $4.2 million grant from the National Institute of Health’s National Human Genome Research Institute under its “Revolutionary Sequencing Technology Development—$1,000 Genome” program, which seeks to reduce the cost of sequencing a human genome to $1,000.
Project Applies Software to Identify Flu Drug Candidates
By Mark Dwortzan
When 17-year-old Eric Chen was preparing his entry for the 2013 Google Science Fair, an online competition for teens with ideas to change the world, he set his sights on finding a systematic way to discover novel compounds for a new kind of anti-flu medicine effective against all influenza viruses, including pandemic strains. While pursuing his research at the National Biomedical Computation Resource at the University of California, San Diego, the high school junior came across just the right software for the job: a computational modeling tool, FTMap, developed by Professor Sandor Vajda (BME, Chemistry) and Research Assistant Professor Dima Kozakov (BME), that was designed to facilitate drug discovery. Applying FTMap to the problem, he was able to pinpoint several candidate compounds.
Impressed with the project and its potential, an international panel of scientists recently named Chen as winner of the 2013 Google Science Fair Grand Prize and of its 17-18 age category. Chen beat out 89 other semifinalists (whittled down to 15 finalists in July) from across the globe who submitted projects advancing solutions to everything from cancer detection to environmental protection. At the awards ceremony in Google’s headquarters in Mountain View, California in late September, he received $50,000 in scholarship funding, a 10-day trip to the Galapagos Islands, and other gifts.
Chen used FTMap to search for novel compounds that could shut down endonuclease, a critical viral protein that enables flu viruses to survive and thrive. Combining FTMap results with biological studies, he identified a number of novel, potent endonuclease inhibitors.
“Chen’s success demonstrates that the FTMap server provides insightful analysis of protein binding sites and thus facilitates drug discovery,” said Kozakov. “Introduced in 2011, FTMap already has more than 1,000 regular users worldwide, and it is easy enough to use that even a talented high school student can generate spectacular results.”
In a nutshell, FTMap searches the surfaces of proteins such as endonuclease for areas that can bind to candidate drug molecules.
“The program places small organic molecules as molecular probes to find binding ‘hot spots’ that are important for protein-drug interactions, and to select specific functional groups [of atoms within the molecular probes] that tend to bind with the highest affinity at these locations,” Vajda explained. “The information provided by FTMap can be used both for virtually screening large libraries of available compounds and for the design of new molecules that incorporate the functional groups identified by the mapping.”
Top-Tier Faculty to Advance High-Impact Field
By Mark Dwortzan
Synthetic biology brings together engineers, biologists and other life science researchers to conceive, design and build molecular biological systems that rewire and reprogram organisms to perform specified tasks. The field promises not only to yield new insights into biology but also to spark new technologies that could revolutionize healthcare, energy and the environment, food production, materials and global security. Recognizing the wide-ranging potential of synthetic biology and the trailblazing efforts of many of its faculty, the College of Engineering has launched the BU Center of Synthetic Biology (CoSBi) to advance this emerging discipline.
Poised to take a nationally preeminent role in advancing synthetic biology research, CoSBi unites core engineering faculty members that bridge diverse research interests, including microbial and metabolic engineering, immuno-engineering, cell reprogramming, computer-aided design and automation, single-cell analyses and systems modeling. In addition, the center involves leading researchers across the university with expertise in systems biology, leveraging their ability to reverse-engineer natural biological networks to help in the modeling, design and forward-engineering of synthetic biological networks with novel functions.
“We envision that CoSBI will serve as a focal point for activities in synthetic biology at Boston University and the larger Boston area, and help to advance the field toward applications in biomedical research, healthcare and other areas,” said Professor James J. Collins (BME, MSE, SE), one of the pioneers of synthetic biology, who directs the center.
CoSBi is located at 36 Cummington Mall, taking advantage of the newly renovated wet and dry facilities on the second floor and computational space on the third floor. Core faculty include Collins; Assistant Professor Ahmad “Mo” Khalil (BME), the center’s associate director; Assistant Professor Douglas Densmore (ECE, BME, Bioinformatics); and Assistant Professor Wilson Wong (BME), with 11 associate faculty members drawn from the College of Engineering, College of Arts & Sciences, and School of Medicine.
To advance its research agenda, CoSBi is expected to attract substantial government funding, major industrial collaborators and top-notch graduate students and postdoctoral fellows. The center will develop and support large-scale, collaborative projects, organize an annual symposium on synthetic biology featuring prominent researchers from around the world, and host a regular seminar series showcasing research leaders in the field.
To enable students of all levels to learn about the fundamentals and practice of synthetic biology and explore their interests in the intersection of engineering and molecular biology, the center will play an active role in supporting research training, education and outreach activities. Center administrators aim to appoint new research faculty and staff; develop new fellowships for and facilitate mentoring of graduate students and postdoctoral associates; design new courses and produce educational videos; run international synthetic biology competition teams and summer workshops; and build community for undergraduate, graduate and postdoctoral students studying synthetic biology.
“Synthetic biology is reshaping the discipline of biology, and attracting students and researchers with a diverse set of backgrounds,” said Khalil. “A central goal of CoSBi will be to prepare the next generation of synthetic biologists for this multidisciplinary type of research at an early stage, and to challenge them to think conceptually and creatively about how engineering can help in understanding life.”
Provides Up to $1.5M Research Funding for Five Years
By Mark Dwortzan
Assistant Professor Wilson W. Wong (BME) has received a 2013 National Institutes of Health (NIH) Director’s New Innovator Award, which supports exceptionally creative, early-career researchers pursuing highly innovative projects with the potential to transform their field of endeavor and bring about improved health outcomes. Chosen from hundreds of applicants from across the US, Wong and other award recipients will be announced at the High Risk-High Reward Research Symposium on November 18-20 in Bethesda, Maryland.
The award, which provides up to $1.5 million in funding for five years, will support Wong’s efforts to develop the next generation of personalized smart cancer therapy. His goal is to take a cancer patient’s immune system cells and install novel genetic programs to control when, where and how strongly the engineered cells should respond to cancer cells.
“I am ecstatic to receive the award,” said Wong. “This grant will give me the resources that I need to hire more people, conduct more studies and complete this project.”
Wong applies synthetic biology to rapidly and predictably engineer desired properties in human immune cells to treat diseases. He is particularly interested in engineering genetic circuits to improve the efficacy and safety of adoptive T-cell therapy, a treatment for leukemia and related blood cancers—and potentially other tumors—in which a patient’s immune system is reprogrammed. The treatment entails removing millions of a patient’s T-cells (a kind of white blood cell) and inserting new genes that make it possible for the T-cells to kill cancer cells. When the modified T-cells are returned to the patient’s veins, they ideally replicate and kill the cancer.
Wong joins Assistant Professor Xue Han (BME), who received the award in 2012.
By Mark Dwortzan
The College of Engineering has funded five new projects through the Dean’s Catalyst Award (DCA) grant program, each focused on technologies with the potential to make a significant impact on society. The projects will receive a total of $114,000 to develop novel techniques to advance these technologies.
Established by Dean Kenneth R. Lutchen in 2007 and organized by a faculty committee, the annual DCA program encourages early-stage, innovative, interdisciplinary projects that could spark new advances in a variety of engineering fields. By providing each project with seed funding, the awards give full-time faculty the opportunity to develop collaborations and generate initial proof-of-concept results that could help secure external funding.
This year’s DCA-winning projects could yield new applications in healthcare, energy, information systems and defense.
Associate Professor Tyrone Porter (ME, BME) and Professor Jianlin Gong (MED) will apply their DCA funding to design and test a new method to encapsulate the drug cisplatin—the standard of care for ovarian cancer—in nanoparticles. Conventional high-dose chemotherapy with cisplatin has led to severe kidney dysfunction, but the researchers’ strategic packaging of the drug within polymer nanoparticles could enable it to target ovarian cancer cells while dramatically reducing its toxic effects on the kidneys.
Assistant Professor Aaron Schmidt (ME) and Associate Professor Srikanth Gopalan (ME, MSE) plan to engineer an efficient thermoelectric material that can recover waste heat at temperatures between 700 and 1000 degrees Celsius and convert it to electricity. Such materials can be retrofitted to boilers, furnaces, power plants and diesel engines to improve overall energy efficiency.
Assistant Professor Jonathan Klamkin (ECE, MSE) aims to develop ultra-high-speed and energy-efficient nanophotonic devices that exploit graphene, a single layer of carbon atoms that’s less than one nanometer thick and exhibits unique electrical and optical properties that can significantly improve the performance of electronics, optoelectronics, sensors and photovoltaics. Nanophotonic devices that incorporate graphene layers in a silicon photonics platform could be used in optical interconnects for data centers and high-performance computers, and in image sensors.
Assistant Professor Wilson Wong (BME) and Associate Professor Heng-ye Man (Biology) propose to create a novel set of tools that will allow genetic manipulation of specific populations of mammalian neurons so as to better understand the structure and function of individual cell types in the human brain. Such understanding would help clarify which cell populations are responsible for specific neural functions that are essential for cognition and the progression of neurological diseases such as Parkinson’s and schizophrenia.
Associate Professor Sheryl Grace (ME) and Professor David Mountain (BME) will use their DCA funding to conduct a pilot study to investigate whether infrasound (frequencies below 20 Hz) and low-frequency noise (ILFN) can lead to symptoms reported by residents living near some wind turbine installations. Known as “wind turbine syndrome,” these symptoms include nausea, vertigo and disturbed sleep. The researchers plan to determine if ILFN directly activates the vestibular system or outer hair cells of the inner ear and subsequently triggers such symptoms in humans.
New Method Could Accelerate Diagnosis and Treatment
By Mark Dwortzan
Diagnosing and pinpointing the most effective treatment for a bacterial infection can take several days. Patients must wait as clinicians culture bacteria from a sample of the infected site, test its response to different candidate antibiotics, and select the most effective choice. Meanwhile, they’re given broad spectrum antibiotics that could be far less effective, leaving them prone to spreading the infection and generating antibiotic- resistant bacteria.
Now a new diagnostic approach that Assistant Professor Ahmad S. Khalil (BME) and ProfessorJames J. Collins (BME, MSE, SE) are exploring could avoid time-consuming culturing and identify the most suitable antibiotic in just a few hours, leading to rapid treatment and infection containment.
To develop a culture-free diagnostic device for bacterial infections, Khalil and Collins have received a two-year, $260,000 research grant from the Institut Merieux, a for-profit organization in France that advances solutions to combat infectious diseases and cancers. Drawing on work by Collins elucidating how antibiotics kill bacteria and Khalil’s expertise in microfluidics and diagnostic devices, the researchers aim to create a universal diagnostic platform that can quickly assess antibiotic susceptibility for a wide range of bacterial infections.
“Our goal is to be able to perform antibiotic susceptibility testing across a full spectrum of antibiotics on a single chip,” said Khalil, who was recently appointed as an Innovation Career Development Professor. “And to do this as rapidly as possible.”
To launch the study, which is also supported by the Wallace H. Coulter Foundation, the researchers are subjecting samples of the most common bacterial infection, urinary tract infection (UTI), with antibiotics that target UTIs, and determining which antibiotics are most effective. They’re also building prototypes of microfluidic chips they’ll use to automate the process.
“Our two-year goal is a proof-of-principle that demonstrates that our technology works across a range of bacteria and resistance mechanisms,” said Khalil.
Grants for research that could produce usable technology
By Rich Barlow, BU Today
From faster-working electronics to a more energy-efficient electric grid: we might summon part of the future if only we could figure out how to mass-produce carbon nanotubes, tiny cylinders of carbon atoms that in some cases can conduct electricity 1,000 times faster than copper. If Ramesh Jasti can crack this nano-nut—he’s trying—the world could benefit while BU would reap the intellectual property rights.
That potential for inventing future license-able technology has earned Assistant Professor Jasti (Chemistry, MSE) one of two appointments this year as an Innovation Career Development Professor. The second went to Assistant Professor Ahmad (Mo) Khalil (BME), for his work in synthetic biology.
“I will use the financial support to pursue some very new ideas that we are developing in the lab,” said Jasti. “This research will lay the foundation for the next generation of intellectual property and licensing opportunities.”
Khalil said his research seeks to understand “the complex molecular networks” powering cellular behaviors. One example: “how microbes respond and adapt to new environments and stress. We are actively translating this research to provide new insight into antibiotic resistance and into new technologies for rapidly diagnosing and treating infectious diseases.”
The Innovation Career Development Professorship, he says, will help pay for efforts to “translate some of our early technologies aimed at curbing the spread of multi-drug-resistant bacteria,” as well as for developing genetic therapies.
“These Innovation Career Development Professorships celebrate just what is possible when some of the brightest minds across so many diverse fields come together,” said Jean Morrison, University provost. “Professors Jasti and Khalil are bridging disciplines and truly taking their research to the next level, developing technology that is at once novel and translational. Both will be making an impact for many years to come, and we are excited to support their success.”
Jasti, who joined BU’s faculty in 2009, earned a doctorate at the University of California at Irvine. The Innovation Professorship is the latest in a string of honors he has received this year, including a research fellowship from the Alfred P. Sloan Foundation and a 2013 BU Ignition Award, given to help researchers translate their discoveries into products and services.
Khalil received a PhD from MIT. He joined the BU faculty last year, after three years working at the University as a postdoctoral fellow. Earlier this year, he was given ENG’s Award for Teaching Excellence as well as an Institut Merieux Research Grant Award. Last winter, BU asked Khalil to make a video plea against the federal budget cuts known as sequestration, focusing on the hit to his work. The Association of American Universities posted the video and others in its unsuccessful effort to thwart the cuts.
Innovation Career Development Professorships are funded by the Office of Technology Development via licensing fees paid by firms for BU-developed intellectual property. The professorships, created in 2008, recognize assistant professors whose research the University expects will produce future licensed technology. The provost selects the professors, who receive three-year appointments and annual research accounts, while their BU schools receive money to partially offset their salaries.
Technology Could Improve Health Outcomes in Developing World
By Mark Dwortzan
An estimated 50 percent of medicines distributed in developing countries are either counterfeit or significantly substandard, resulting in countless medical complications and deaths. To address this problem, Associate Professor Muhammad Zaman (BME, MSE) and Boston University graduate students Darash Desai (BME) and Andrea Fernandes (SMG, SPH) are developing PharmaCheck, a fast, portable, user-friendly detector for screening counterfeit and substandard medicines. To test a medication, a user places a pill into a small testing box which instantly reports the amount of active ingredient found in the pill.
The device’s clear potential to dramatically improve health outcomes in resource-limited countries has attracted significant funding over the past year, and now its developers have received one of nine $18,500 Entrepreneurial Team (E-Team) “Stage Two” grants from the National Collegiate Inventors and Innovators Alliance (NCIIA), which promotes technology innovation and entrepreneurship in higher education. The grant package includes an intensive workshop to help the team further develop its business strategy, followed by six monthly sessions of business coaching—and eligibility for up to $50,000 in additional funding.
“We are absolutely thrilled to receive the funding from NCIIA, which will enable our students to further develop PharmaCheck and conduct field and market research that will be absolutely critical for its long-term success and impact,” said Zaman.
Funding from the NCIIA and other agencies will support the team’s efforts to complete its first prototype; perform extensive, hands-on testing in the field in Ghana; and conduct analysis of the medicine supply chain in developing countries to pinpoint where poor-quality medicines are introduced. The team’s ultimate goal is to enable users from pharmacists to regulatory authorities to effectively and easily control the quality of medicine delivered to patients.
“Our hope is that PharmaCheck will help support and increase medicine quality testing around the world and ensure that medicines intended to save lives do just that,” said Desai. “The opportunity to work on everything from conceptual and technical development to business strategy and scale-up has been an invaluable learning experience that’s surprisingly uncommon in graduate work.”
Focused on marketing and funding for PharmaCheck, Fernandes aims to ensure that the device reaches the people it’s intended to serve.
“All of the market research data that we’ve collected indicates that there is a real need and willingness to pay for this capability,” she said. “The challenge is how to create a business model around this technology to sustain economies of scale and create impact.”
Through grants and intensive training, the NCIIA E-Team program supports the next generation of innovators striving to improve the lives of underserved populations in developing countries and meet critical social and environmental needs in the U.S. Since NCIIA’s founding in 1995, more than 180 companies have launched as a result of early-stage support from NCIIA grants and training.
More information about PharmaCheck, including a video presentation, is available here.
By Mark Dwortzan
A novel method for detecting and delivering healing drugs to newly formed micro-cracks in bones has been invented by a team of chemists and bioengineers at Boston University and Penn State University co-led by Professor Mark Grinstaff (BME, MSE, Chemistry).
The method uses tiny, self-powered nanoparticles, or nanomotors, to deliver the drugs directly to the cracks. The energy that revs the motors of the nanoparticles and sends them rushing toward the crack comes from a surprising source—the crack itself. As a crack emerges in a bone, minerals leach out as positively charged particles, or ions, which pull the negatively charged nanoparticles toward the crack.
Through a series of experiments co-led by Penn State Professor Ayusman Sen and described in the international chemistry journal Angewandte Chemie, the research team has demonstrated that a biocompatible nanoparticle can efficiently deliver an osteoporosis drug directly to a freshly cracked bone. In the final experiments, completed in the Grinstaff lab, BU School of Medicine graduate student Jonathan Freedman tested a common osteoporosis drug on live human bone cells.
“The treated bone cells increased in number as compared with those that were not treated with the osteoporosis drug, which confirms other studies that have shown that this drug is effective in repairing human bones,” said Grinstaff.
Unlike conventional methods, in which medications ride passively on the circulating bloodstream, where they may or may not arrive at micro-cracks in a high-enough dosage to initiate healing, the new approach promises to treat, upon formation, micro-cracks that lead to broken bones in patients with osteoporosis and other medical conditions.
“What makes our nanomotors different is that they can actively and naturally deliver medications to a targeted area,” Sen explained. “Current methods, in contrast, involve taking a drug and hoping that enough of it gets to where it is needed for healing.”
The researchers built up to their final experiments, first testing their novel way to deliver medicines to newly formed cracks in a model system using bone from a human tibia and femur and very small fluorescent particles called quantum dots made from a synthetic material. They subsequently tested their system using a natural biological material—an enzyme—which they determined could target a site on human bone and catalyze a biological reaction at the site. Finally, they demonstrated that they could attach an FDA-approved osteoporosis drug onto bio-safe “nanomotor” material that could carry it like a “nanotruck” to a crack in a human bone. When fully loaded, each nanotruck was 30 to 40 times smaller than a red blood cell.
Several more tests and further development will be needed to prove this novel method safe and effective for preventing broken bones in patients with osteoporosis and similar conditions.
Barbara K. Kennedy, director of the Penn State Eberly College of Science Office of Media Relations and Public Information, contributed to this article.
By Mark Dwortzan
Christopher Chen, one of the world’s leading tissue engineering researchers, has joined the Boston University Biomedical Engineering Department faculty. Chen, who was appointed a professor in BME, comes to BU from the University of Pennsylvania, where he served as Skirkanich Professor of Innovation in Bioengineering and founding director of the Center for Engineering Cells and Regeneration.
Chen is widely recognized as a world leader in tissue engineering and mechanobiology—the study of how physical forces and changes in cell or tissue mechanics contribute to development, physiology and disease.
“Dr. Chen is a pioneer and at the forefront of these fields and will be instrumental in significantly expanding our research portfolio as well as our course offerings available in these areas at both the undergraduate and graduate levels,” said Professor Sol Eisenberg, who chairs the BME Department. “He is a very deep thinker, an excellent communicator and a highly creative and collaborative individual.”
“I am excited to be joining the College of Engineering,” said Chen. “In this energetic environment, I expect to continue our work in identifying the fundamental rules that govern how cells assemble to form tissues and organs, and use those insights in regenerative medicine. Boston University has been leading the way in integrating traditional disciplines to address the scientific challenges of tomorrow, and I look forward to accelerating our efforts in this uniquely rich and innovative community.”
Understanding the interactions between cells and their surroundings is at the core of biology and tissue engineering, but few experimental models exist to control these interactions at the cellular scale. Combining microsystems technologies with traditional molecular tools, Chen has developed such models to interact with, probe and manipulate cells, and thereby shed light on a wide range of physiological processes and diseases, engineer artificial tissues, and build hybrid biological/artificial devices for medical and other applications.
Applying microfabrication and nanotechnology techniques to cell and tissue engineering, and regenerative medicine, he has been instrumental in the development of engineered cellular microenvironments used to engineer cell function and guide cell and tissue growth. Through this research, he has sought to identify underlying mechanisms by which cells interact with materials and other cells to build tissues, and to apply this knowledge to better understand the biology of stem cells, tissue vascularization and cancer.
Holding an M.D. from Harvard Medical School, a PhD in medical engineering and medical physics from the Harvard-MIT Health Sciences and Technology Program, and an M.S. in mechanical engineering from MIT, Chen has received the Presidential Early Career Award for Scientists and Engineers, the Mary Hulman George Award for Biomedical Research, the Herbert W. Dickerman Award for Outstanding Contribution to Science, and several other honors. He is a Fellow of the American Institute for Medical and Biological Engineering and editor of the Journal of Cell Science.