October 2012

Biologically inspired innovation

Exterior of Harvard University’s Wyss Institute

The Wyss Institute’s pursuit of alternatives is gaining momentum
 

At lab benches and computer desks throughout the Wyss Institute for Biologically Inspired Engineering in Boston, researchers are attempting to solve some of humanity’s most pressing problems. The questions its scientists are asking are not uncommon: How can we discover more effective drugs? How can we solve the global energy crisis? But the possible answers they’re developing are atypical, such as using autonomous microrobots to diagnose and treat diseases.

Part engineer, part biologist, researchers at Wyss (pronounced “Vees”) are combining the power of synthetic biology, microfabrication technology and tissue engineering principally to understand how biological systems work and to manipulate and re-engineer them in the lab in a way we could never have done before. Researchers such as Pamela Silver and George Church, both synthetic biologists, hope that their work — and their colleagues’ work — will have far-reaching health, environmental and economic benefits.

Silver and Church are among 17 full-time faculty members at Wyss whose research programs are supported in part by a more than $125 million institutional gift intended to foster a very special kind of environment. “The Wyss has been instrumental in bringing the right people together and providing the right atmosphere,” Silver emphasizes. The institute allows the researchers the freedom to operate in entirely new fields, and this is at the heart of the institute’s mission.

What is the Wyss?
The institute emerged in 2008, when it was known initially as the Harvard Institute for Biologically Inspired Engineering. In a bid to blend the understanding of basic engineering and biological processes, fields that had a long and successful history at Harvard University, and apply them to the burgeoning number of medical and environmental issues in the modern world, a multidisciplinary team of Harvard-based faculty were convened by the provost to discuss the future of bioengineering in Boston.

Then, in 2009, Harvard business school alumnus and Swiss engineering magnate Hansjörg Wyss donated $125 million, and the story of the Wyss Institute began in earnest. That money from Wyss, who was then chief executive officer of the medical-implant manufacturing company Synthes, which recently was sold to Johnson & Johnson, allowed those at the institute to pursue high-risk scientific endeavors and to begin to realize the potential of a new research model, described in the institute’s mission statement as one of “innovation, collaboration and technology translation.”

Photo of Pamela Silver 
Silver

Organs on a chip
This capital injection has allowed one of Wyss’ groups to confront, head-on, one major challenge facing modern drug-discovery programs: Why do animal models so often fall short of predicting the biological effects of drugs in humans?

“Animal models often fail to predict results in human clinical trials, and this has had a devastating effect on drug development,” says Don Ingber, who is the leader of the biomimetic microsystems platform and founding director of the Wyss Institute as well as a professor at Harvard Medical School and Boston Children’s Hospital. “Not only have costs skyrocketed, but fewer and fewer good drugs are in the pipeline, and so fewer good drugs are reaching patients.”

 
Researchers need to model human biology accurately in the lab to develop new treatments. Think of heart disease or lung cancer: Scientists simply can’t test novel drugs on human beings, yet the kinds of models they do use on a day-to-day basis (cell lines or rodents, for example) are the kinds of models that might lead them astray if they are not careful. But imagine if they were able to model human physiology without turning to rodents or nonhuman primates; this is where Wyss’ researchers come in.

BY THE NUMBERS


  • 3: The number of years it took to generate initial funding for the institute
     
  • $125 million: Harvard’s largest single philanthropic donation in its history — from alumnus Hansjörg Wyss
     
  • 9: The number of universities and hospitals around Boston collaborating with the institute, including the Dana Farber Cancer Institute and the Massachusetts General Hospital
     
  • 25: The number of open positions on the institute’s recruitment page
     
  • $12.3 million: The amount received from the Defense Advanced Research Projects Agency to develop a spleen-on-a-chip device to diagnose sepsis rapidly
     
  • 53: The number of peer-reviewed publications the institute produced in the first five months of 2012
     
  • 1: The average number of Science or Nature papers published per month by the institute’s 17 faculty over the first three years of its existence
     
  • 17: The number of faculty members affiliated with the institute
 

In 2010, the Ingber group reported in the journal Science the development of a human “lung on a chip.” This in vitro model system was designed to mimic the functioning of a lung alveolus and uniquely showcases the group’s focus on not just creating synthetic tissues but creating synthetic organs where multiple tissues types interact.

The team was able to co-culture the three major tissue components of the lung within a hollow channel in a single microfluidic chip composed of a clear, flexible silicone. Spanning the channel was a malleable and porous membrane coated with extracellular matrix. On one side resided human lung epithelial cells with air introduced above their surface to mimic the air sac, while on its underside grew human lung capillary endothelial cells with flowing culture medium representing blood within a pulmonary vessel. This channel was bordered on both sides by two additional hollow channels that experienced cyclic suction, which caused the neighboring tissue–tissue interface to undergo rhythmic stretching and relaxation, thus mimicking physiological breathing motions.

This device recapitulated pulmonary barrier functions normally seen only in vivo, and, when human immune cells were added to the flowing blood, they were able to respond to the addition of pathogenic bacteria to the surface of the lung by adhering to the endothelium, migrating across the two tissue layers and engulfing invaders. Moreover, because the chip is clear, all of those processes could be visualized at high resolution and in real time. It is this system that is being pioneered to study the effects of novel treatments for lung disease.

For nearly three decades, Ingber and co-workers have been championing the idea that one of the most important factors in controlling the function of a particular organ or tissue is the mechanical forces that the cells experience in their natural microenvironments. “In the early days, biologists were skeptical or had no interest” in the role of tissue mechanics, Ingber says, but now this research is showing that it clearly has an effect that scientists can harness, in this case to create new in vitro assays.

The team has another nine systems in development (including the previously published gut on a chip) and is currently pursuing ways to connect them together to generate “an instrument that can probe, manipulate and analyze multiorgan system responses to replace animal testing,” Ingber says. The group recently entered into a project with the Defense Advanced Research Project Agency worth up $37 million to develop an automated human-body-on-a-chip model leveraging its organ-on-chip technologies.

Still, Danny McAuley, a clinical professor in intensive care medicine with an interest in developing novel therapies for lung disease at Queen’s University in Belfast, U.K., stresses the importance of not forgetting human testing. “[We] probably need better characterization of existing models to confirm data identified in models translates to human disease rather than new models,” he says. He predicts that no in vitro model will completely replace human testing, but they “might be useful as a stop point in drug development.”

Furthermore, Ingber’s team is actively pursuing ways to combine its cell biology work with the other projects going on at the institute, such as those being done by synthetic biologists like Silver and Church.

Photo of the laboratory at Harvard University’s Wyss Institute 
The Wyss Institute aims to foster a friendly, collaborative research environment for scientists and clinicians.

A synthetic way of life
Silver’s lab — along with colleagues James Collins and Church — focuses on the manipulation of both prokaryotic and eukaryotic genomes and on developing new ways to do so. These synthetic biologists seek to engineer and build novel, man-made alternatives to our genes and pathways to construct living organisms or cells with well-defined outputs and, hence, new or improved functions.

The Church lab has been at the forefront of developing easier and cheaper genomic technologies. “We’ve helped lower the cost of sequencing about a million-fold and of engineering genomes using DNA from chips by similar amounts,” Church says. His lab, by helping to make genomics cheaper, faster and more accessible, has advanced fields ranging from ecology to medicine via chemistry and science policy.

There is no handbook for synthetic biologists to follow; they have had to develop their own sets of principles and rules, and those at the Wyss are at the leading edge of that work. As Silver explains, “Biology is not like electrical engineering in that it works in three dimensions — no wires — and over time scales that can be long. We seek new computational strategies and to move beyond trial and error in building complex biological systems.”

Meanwhile, Silver and Church recently co-headed Harvard’s International Genetically Engineered Machine — or iGEM — team, a group of biology students in an annual international synthetic biology competition aimed at the creation of devices to solve a particular issue. The team’s project focused on the development of a system to engineer synthetic gene circuits in plants rapidly and easily.

The team altered existing plasmid vectors to accommodate DNA modules from the Biobricks parts registry, a standardized catalogue of genes, vectors and regulatory elements. As a proof of principle, they inserted a gene encoding the protein miraculin (a peptide that makes sour tastes become sweet) into Arabidopsis to alter the taste of a bitter plant significantly without altering sugar content.

Christina Agapakis, a postdoctoral researcher at the University of California, Los Angeles, and one of the researchers supervising the iGEM team, explains that the team wasn’t allowed actually to taste their plants, so officially nobody knows for sure what it tasted like. However, she emphasizes, “We hope that these tools inspire and enable other iGEM teams to work with plants so that the toolkit can grow further.”

Bringing it all together
As Ingber looks to the future of his group’s organs-on-chip model, he says, “Finally, we can start by building the simplest model that re-creates physiological functions of interest and then add back cells one by one to explore their relevance for any response of interest.” But beyond cell biology, synthetic biology and genomics will have large parts to play as Wyss researchers come better to understand and manipulate human biology, which hopefully will pay off in terms of novel treatments for now-incurable diseases.

“We are collaborating with Don on enabling us to move from organs on chips to personalized and synthetic versions,” Church explains. He is planning on aligning his work on personalized genomics with the Ingber group to uncover how our genetics influence cell or organ functioning. This fits nicely with Silver’s vision of introducing her synthetic DNA into Ingber’s systems in a way that truly reflects what the Wyss Institute is all about: innovation through collaboration.

Photo of Donald Ingber 
Don Ingber, founding director of the Wyss Institute and a professor at Harvard Medical School and Boston Children’s Hospital, leads the biomimetic microsystems platform that is engineering new human tissue models.

In attracting so many successful researchers and bringing them into close contact, the Wyss Institute has addressed one key problem with modern science: How do we make it easier to make important discoveries quickly?

“It is easier to do cutting-edge science when mixed in with developing — not just buying — the most cutting-edge engineering, and vice versa,” Church underscores. This is made easier at a research institute fostering the development of life-inspired materials and medical devices that can anticipate disease and correct it before it gets out of hand.

The Wyss has aligned itself with a range of medical centers around the city of Boston, including the Dana-Farber Cancer Institute. “The opportunity to couple engineering expertise at the Wyss Institute with clinical investigation expertise at the Dana-Farber has dramatically accelerated the translation of exciting preclinical findings to testing in cancer patients,” says Glenn Dranoff, associate faculty member at the Wyss Institute and professor of medicine at Dana-Farber, Brigham and Women’s Hospital and Harvard Medical School.

We may never truly understand life until we are able to reconstruct it from scratch, and, as demonstrated by the Ingber, Church and Silver labs, the researchers at the Wyss Institute are trying to get us there with the great hope of answering some of our most pressing questions.

 

Photo of Connor BamfordConnor Bamford (connorggbamford@gmail.com) is a Ph.D. student at Queen’s University in Belfast, U.K.
 
 
 
 
 

View a video from the Wyss Institute about a new in vitro approach to drug screening by mimicking the complicated mechanical and biochemical behaviors of a human lung. Click here to check out the Wyss Institute’s YouTube channel.
 

 
 


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