Science

How to Hack a Cell

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Wong’s New Platform Makes It Easier to Program Living Cells

The human body is made up of trillions of cells, microscopic computers that carry out complex behaviors according to the signals they receive from each other and their environment. Synthetic biologists engineer living cells to control how they behave by converting their genes into programmable circuits. A new study published by Assistant Professor Wilson Wong (BME) in Nature Biotechnology outlines a new simplified platform to target and program mammalian cells as genetic circuits, even complex ones, more quickly and efficiently.

“The problem synthetic biologists are trying to solve is how we ask cells to make decisions and try to design a strategy to make the decision we want it to,” said Wong. “With these circuits, we took a completely different design approach and have created a framework for researchers to target specific cell types and make them perform different types of computations, which will be useful for developing new methods for tissue engineering, stem cell research and diagnostic applications, just to name a few.”

Historically, engineered genetic circuits were inspired by circuit design in electronics, following a similar approach using transcription factors, proteins that induce DNA conversion to RNA, which is tricky to work with because it’s hard to predict an entirely new strand of genetic code. Mammalian cells are especially tricky to work with because they are a much more variable environment and express highly complex behaviors, rendering the electronics approach to circuit design time consuming at best and unreliable at worst.

Wong’s approach uses DNA recombinases, enzymes that cut and paste pieces of DNA sequences, allowing for more targeted manipulation of cells and their behavior. The result is a platform named “BLADE,” or “Boolean logic and arithmetic through DNA excision,” referring to the computer language the cells are programmed with and the computations they can be programmed to carry out. BLADE will allow researchers to use different signals, or inputs, in one streamlined device to control the outputs, or behaviors, of the cells they target.

“The idea was to build a system simple and flexible enough that it can be customized in the field to get any desired outcome using one simple design, instead of having to rebuild and retry a new design every time,” said Benjamin Weinberg, graduate student in Wong’s laboratory and first author on the paper. “Essentially, with BLADE, you can implement any combination of computations you want in mammalian cells. For this particular paper, we might not have built the particular behavior you need, but we wanted to illustrate that using BLADE, you should be able to build the circuit you need to fulfill the behavior you are looking for.”

The paper published in Nature Biotechnology outlines over one hundred examples of circuits that were successfully built using the BLADE platform. Weinberg noted that the researchers intentionally built complex circuits with complicated functions to illustrate the possibilities using their design, including some that program human cells to add or subtract numbers. He uploaded the design plans to an open-source online repository so that other researchers could begin downloading the tools to use in their projects immediately. Weinberg will continue to refine the technology and incorporate into a software program to make it even easier to use, while Wong plans on using the platform to explore medical diagnostic applications.

“Before BLADE, any one of these circuits would have taken several years to build and make functional and then you would have to use trial-and-error to make it work the way you want it to,” said Wong. “I have been doing synthetic biology research for 15 years and I’ve never seen such a complex circuits work on the first try like with this platform. We’re excited to get it out there so people can start using it, and we’re excited to see what they come up with.”

Boston University College of Engineering

Appears on: BU ENG Website, BU Research

Study Supports Final Pivotal Trial of Bionic Pancreas

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Damiano Nets $12M in Supplemental NIH Funding to Move Forward with Trial

On the heels of winning $12 million in supplemental funding from the National Institutes of Health (NIH) to conduct a major, multi-center, national clinical trial of his iLetTM bionic pancreas, Professor Edward Damiano (BME) has co-authored a study in The Lancet that affirms the technology’s effectiveness in managing type 1 diabetes (T1D) better than current conventional methods.

“This award provides us with significant resources to collect the final clinical data required by the US FDA for regulatory approval, which will pave the way for us to bring the bionic pancreas to market,” says Damiano.

The study was conducted with Damiano’s long-time clinical partner Steven Russell, MD, PhD, at Massachusetts General Hospital (MGH), along with clinical partners Bruce Buckingham, MD, at Stanford University, John Buse, MD, PhD, at the University of North Carolina, and David Harlan, MD, at the University of Massachusetts. It tracked adult T1D patients over two 11-day periods, one using the bihormonal bionic pancreas (which dispenses the hormones insulin and glucagon as needed) and the other using the conventional insulin pump therapy for diabetes management. On days when patients were on the bionic pancreas, their average blood glucose levels were significantly lower compared to their standard treatment, and they reported fewer episodes of hypoglycemia (low blood sugar). The bionic pancreas performed even better overnight, which is a period of particular concern for people with T1D.

“Patients with type 1 diabetes worry about developing hypoglycemia when they are sleeping and tend to let their blood sugar run high at night to reduce that risk,” says Russell. “Our study showed that the bionic pancreas reduced the risk of overnight hypoglycemia to almost nothing without raising the average glucose level. In fact, the improvement in average overnight glucose was greater than the improvement in average glucose over the full 24-hour period.”

The results of The Lancet study are promising, especially as Damiano and his colleagues move forward with conducting the final pivotal clinical trials under the $12 million funding from the NIH, supplementing a previous $1.5 million award he received in 2015. The nine-month trial will test the safety and efficacy of the bihormonal bionic pancreas in adults with T1D, a crucial step in the medical device approval process. Additional funding is being sought to extend this study to the pediatric population and to fund a separate final pivotal trial to test the safety and efficacy of the insulin-only configuration of the iLet bionic pancreas in adults and children with T1D.  The researchers are also seeking funding to conduct separate studies to test the safety and efficacy of the insulin-only and glucagon-only configurations of the iLet bionic pancreas in people with other glycemic control disorders such as type 2 diabetes, hyperinsulinism, insulinoma and many others.

Soon after his son, David, developed T1D as an infant almost 17 years ago, Damiano began working with his team on the bionic pancreas. The technology that they have developed optimizes blood sugar levels by using their mathematical dosing algorithms to automatically calculate and precisely dispense two hormones every five minutes: insulin, when blood sugar levels are high; and glucagon, when they are low. When he and his clinical collaborators at MGH began human trials nearly nine years ago, the tests were done in a hospital setting using a laptop-based system. They switched to their iPhone-based system nearly four years ago, and began trials outside of the hospital in diabetes summer camps in children and in the home-use setting in adults.  Over the past three years, they have been developing their iLet bionic pancreas platform, which integrates all of the components of their iPhone-based platform into a single, compact, handheld device, which is about the size of the original iPhone. The two chambers within the iLet house one vial of insulin and one of glucagon, or just one or the other depending on how the iLet is configured.

“The iLet really is three devices in one, and is flexible enough to treat different chronic conditions of glycemic dysregulation,” says Damiano. “But obtaining the appropriate approvals for those other uses will require additional trials, so we will continue to work on securing funding for those indications.”

Damiano’s goal of providing an easy-to-use, safe, and effective system to help his son and others with T1D now seems within reach. Whereas the final pivotal trial for the bihormonal configuration of the iLet won’t begin recruiting participants another 18 months or so, Damiano hope to begin recruiting participants for the final pivotal trial for the insulin-only configuration of the iLet in about a year. David will begin his freshman year at BU in the fall of 2017, and while Damiano had long hoped that David would head off to college with a bionic pancreas, he now knows that he will fall short of achieving that goal by about a year.

“The reality is, David probably won’t get the iLet until his sophomore year at BU, and even then, he’ll have to start with the insulin-only configuration because the bihormonal configuration won’t be ready until his junior or senior year,” says Damiano. “However, whenever I reflect upon this, I also remind myself that practically every aspect of our endeavor is truly unprecedented – it’s an experiment in the making – so if it takes an extra year or two to get it right on balance, I think it will be worth it.”

Boston University College of Engineering

Originally published on January 4, 2017

Appears on: BU ENG Website

An Internet of Cars

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Cassandras Nets Grant to Develop Smart Car Technology

Drivers who commute in and out of Boston — deemed as one of the worst U.S. cities for traffic — have all experienced the misery of rush hour. Now, Professor Christos Cassandras (SE, ECE) is part of a research group aiming to ease commuting, and the resulting air pollution, by developing efficient, smart vehicle technology under a $4.4 million grant from the Energy Department’s Advanced Research Projects Agency-Energy NEXTCAR program.

“Right now, the car’s awareness of its surrounding relies completely on the eyes and ears of the driver operating it,” says Cassandras. “But when you look at the data, humans are terrible drivers. Humans get distracted, they get tired, they can’t react as quickly to sudden or multiple simultaneous changes. But computers thrive in an environment like that, so what we want to do is create a technology that allows the car that can access information about its environment on its own, process it and act accordingly, and communicate it to other vehicles and infrastructure. Essentially, we want to create an internet of cars.”

Working with researchers at the University of Michigan and the Oak Ridge National Laboratory, and Bosch as a corporate partner, the goal of the project is to design a control technology that enables a plug-in hybrid car to communicate with other cars and city infrastructure and act on that information. By providing cars with situational self-awareness, they will be able to efficiently calculate the best possible route, accelerate and decelerate as needed and manage their powertrain. The idea, says Cassandras, is to improve the efficiency of vehicles to the point where you can drive from point A to point B without stopping, which would have transformative positive effects.

“You can reduce fuel and energy consumption, which benefits the environment and lessens our dependence on expensive energy sources and you make the traffic system work more efficiently by reducing congestion,” says Cassandras. “The government would be satisfied if we could increase these efficiencies by 20 percent.”

Currently, obstacles like stoplights, heavy volume, and poorly designed infrastructure that causes bottlenecking contribute to heavy traffic. The constant stopping and starting not only wastes energy, but also expels the most harmful emissions into the atmosphere. On top of environmental effects, there is a human element to snarled traffic as well. This project seeks to shift this paradigm to one where travelers cooperate with each other instead of compete with each other.

“It’s hard not to behave selfishly when driving when we are all competing for the same space or to make the same green light, or to pass each other so we can reach our destinations faster. When you think of it, it’s total anarchy,” says Cassandras. “The price of this anarchy can be measured with the difference of this selfish traffic control versus social-optimal traffic control, and the only way to really achieve better social-optimal control is to remove the person from the equation and let the car make these decisions as long as safety is always guaranteed.”

The project—Ultimately Transformed and Optimized Powertrain Integrated with Automated and Novel Vehicular and Highway Connectivity Leveraged for Efficiency, or UTOPIAN VEHICLE — has several parts. Cassandras will helm several phases of the project, including one that focuses on the eco-routing algorithms to help establish the connection between vehicles, infrastructure and the environment.

Other partners will work on the cars themselves. On the spectrum of automobile autonomy, this project will generate a car that performs some functions automatically but will still require human input, which may help ease the public with the transition towards smart cars.

Boston University College of Engineering

Originally published on November 14, 2016

Appears on: BU ENG Website

Khalil Wins NIH ‘New Innovator Award’

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Project Will Focus on Combating Antibiotic-Resistant Bacteria

The improper and excessive use of antibiotics has led to the rise of “superbugs,” treatment-resistant bacteria causing a public health crisis of global proportions. To help combat this problem, Assistant Professor Ahmad “Mo” Khalil (BME) has been awarded a New Innovator Award under the High-Risk, High Reward program sponsored by the National Institute of Health (NIH). His proposed project will focus on developing new and rapid techniques for diagnosing antibiotic resistance to more effectively manage and treat gonococcal infections.

“The Center for Disease Control and Prevention keeps a running list of high-priority antibiotic-resistant bacteria, and N. gonorrhoeae is high on that list,” says Khalil. “It’s spreading very quickly and we are basically at the last line of defense in terms of options, so being able to prescribe the proper treatment quickly is critical.”

The current clinical methods for diagnosing and treating bacterial infections rely heavily on techniques that have been around since the discovery of penicillin. When a patient presents to a clinic with an infection, a sample is taken and sent to the laboratory, where the bacteria causing the infection is grown out. To determine an effective therapy, the bacteria are then grown in a panel of antibiotics to see which one inhibits bacterial growth, a process called antibiotic susceptibility testing, or AST. It’s a long process that can take days to weeks to elicit an appropriate answer to direct the targeted therapy, which is often a luxury that providers do not have. For certain infections, such as gonorrheal infections, AST is not even performed, making it difficult to know which antibiotic will be the most effective.

Because of these issues, doctors often treat with a broad-spectrum antibiotic instead of a targeted therapy, which has contributed to the rise of antibiotic resistance. Khalil’s proposed project will reengineer AST using synthetic biology, which is the engineering of molecular and cellular systems for useful applications. The resulting technology he aims to develop will allow providers to prescribe a targeted therapy tailored to the particular organism in a matter of hours instead of days.

“When you treat susceptible bacteria with an antibiotic, they express specific RNAs that act as biomarkers that tell you the antibiotic will be an effective treatment, while resistant bacteria do not,” says Khalil. “We are going to be looking at harnessing these molecular signatures as the basis of a new form of rapid AST for N. gonorrhoeae.”

Khalil and his team, collaborating with Tufts University and MIT, will engineer synthetic RNAs to act as biosensors that can detect these specific biomarker RNAs and subsequently express a readable output, such as a color change. Next, they will create a tool that will allow clinicians to prepare a patient sample and test it on a single chip that contains RNA sensors for a full panel of antibiotics, with the best treatment options lighting up. This will provide clinicians with rapid information to determine a targeted therapy for a particular strain of gonorrhea, including antibiotic resistant strains.

In addition to providing networking opportunities for young investigators, as well as initiating access to NIH funding, the New Innovators Award will provide a monetary grant of $1.5 million direct to Khalil’s research project. Recipients of this highly selective honor are chosen based on innovative, ambitious project ideas.

“It is a testament to our department, and to the young people we are hiring, that we currently have three active NIH New Innovator Awardees: Xue Han, Wilson Wong, and now Mo Khalil,” says Professor John A. White (BME), chair of the Biomedical Engineering Department.

“I’m overwhelmed that I was chosen for this award, and it’s a testament to my entire lab and the hard work that they are doing here at BU,” says Khalil, echoing White’s sentiments. “It’s also exciting because synthetic biology is such a new field and this award recognizes its potential to solve real-world problems.”

Boston University College of Engineering

Originally published on October 14, 2016

Appears on: BU ENG website, BU Research

BU ENGineer Fall 2016 Magazine

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I served as the lead writer and managing editor for the Fall 2016 issue of ENGineer magazine.

Notable writing credits:

  • Page 5: “Cells Build Bridges to Heal Damaged Tissue”
  • Page 6: “From Cells to Circuits”
  • Page 7: “Easing the Pain,” “Unfurling on Command”
  • Page 8: “Off the Beaten Path,” “Intel-Cornell Competition”
  • Page 9: “A Point of Light”
  • Page 10-16: “Tech Survivors: How Innovators Make it Through Tech’s Valley of Death”
  • Page 15: “Business Innovation Center Supports Startups”
  • Page 20-21: “Mr. Clean”
  • Page 22-23: “The STEM Advocate”
  • Page 25: “Ünlü Delivers Charles DeLisi Distinguished Lecture”
  • Page 27: “Zhang Receives Technical Achievement Award”
  • Page 28-29: “Commencement Ceremonies Celebrate the Class of 2016”
  • Additionally, I wrote the small pieces of copy that are not accompanied by a byline