"Working Backward," Feature Article, July 2008

FEATURE FOCUS: BIOENGINEERING

working backward

How does a medical device work? How does a cell function? Reverse-engineer them to find out.

by Jean Thilmany, Associate Editor

Computers are so last century. Software engineers, move over. The present century will be the age of biomedical engineering, according to researchers in the thriving biomedical programs at Drexel University in Philadelphia and at Vanderbilt University in Nashville.

And, of course, they’re not alone.

A portable 3-D laser scanner is used in factories to verify the accuracy of manufactured parts. This one is designed to scan body parts to create customized prosthetics and devices.

Biomedicine applies engineers’ unique design and problem-solving skills to medical research. Engineers work with doctors and scientists to create devices for improved health care. As the field has evolved, so have discovery techniques. At base, biomedical researchers rely on the proven engineering methods that mechanical and electrical engineers call upon. And as the biomedical field has evolved, researchers have sometimes put those engineering methods to use in novel ways, said James Collins, a professor of biomedical engineering at Boston University.

Cellular biologists, for example, might use computational analysis to decipher genome sequences. Mechanical engineers turn to powerful computer programs to run finite-element or computational fluid dynamics analyses.

prosthetic matching

Reverse engineering is one of the most relevant examples of methods that have moved from engineering to find a role in biomedical and other bioscience applications, according to Collins. About 10 years ago, biomedical scientists borrowed the reverse-engineering method from engineers. They’ve spent the ensuing years tweaking it for their everyday use, he said.

As in every field, reverse engineering plays many roles in the biomedical realm.

Take the case of a portable 3-D laser scanner, which can be used in factories to verify the accuracy of manufactured parts, like auto bodies, and which is also used to reverse-engineer complex objects to create CAD or CAM files.

The scanner is used in the medical field to create the prosthetic twin to a body part lost to cancer or trauma, such as a hand or an ear. Doctors profile the remaining body part with the scanner and enter that information into a 3-D modeling program. The model is used to create—often via a process used for rapid prototyping—a prosthesis that is a mirror-image duplicate of the body part with which it will be paired, according to a spokesperson at Creaform in Levis, Quebec. Creaform markets the Handyscan 3-D laser for just such a purpose.

The scanner was recently used to create a natural-looking prosthesis for a patient who had lost the left half of her nose to skin cancer.

Her doctor captured geometry of the right side of her nose with the scanner, modeled the left side to match the right in a 3-D system, and then generated a stereolithography file. The prosthesis was created via rapid prototyping and was worn by the patient while she awaited rhinoplasty. The doctors also referred to the modeling file during the rhinoplasty operation as they created support elements for the flesh and the respiratory tract, according to Creaform.

device design

For an early introduction to the method’s use in both biomedical and engineering fields, reverse engineering is commonly taught to biomedical undergraduates at Vanderbilt University, said Paul King, associate professor of biomedical engineering. He teaches a senior design course in Vanderbilt’s biomedical engineering department. King encourages students to keep reverse engineering in mind as one tool in their skill set as they contemplate senior-level projects. Students from the biomedical, electrical, and mechanical engineering departments often work together to complete a project.

Last school year, two mechanical engineering students and two biomedical students called upon the method to help resolve concerns that Vanderbilt physicians had been having with currently available gastric bands. During gastric bypass surgery, a doctor places the band around the patient’s stomach to essentially make it smaller. Thus, the patient will feel full faster, eat less, and lose weight.

Physicians from Vanderbilt’s Department of Surgery brought the band to students to help resolve problems they’d been having with the design during and after surgery. Physicians visited the classroom to demonstrate glitches with the band and to point out ways it could be improved. Students caught on quickly, King said.

“Typically, a project will come about because a physician from our medical center will tell us, ‘Something is wrong with this device and your students could make it better for us,’ ” King said.

Creaform’s handheld laser scanner is used to treat flattened spots on infant heads. Here, a baby’s skull is scanned to customize the manufacture of a soft-shell helmet.

In order to study how the band worked, students first needed to take it apart to study how it was engineered—their first exercise in reverse engineering. The project served as a good starting point to the students dipping their toes in the engineering waters.

“The band was pretty straightforward. It didn’t require cutting anything apart or X-raying anything, but they could take it apart and see how they could make it better,” King said.

The current band comprises a water-filled bladder that constricts the stomach. King is reluctant to give much detail about the students’ contribution because the device is proprietary. He said the students came up with a purely mechanical solution that has since been purchased by a local medical device company with plans for production.

Other students in King’s class reverse-engineered a similar project with the goal of creating an incontinence device that can be easily controlled by patients with disabilities. The device had to allow for the emptying of the bladder when desired and to indicate the status of the bladder.

The original device had the potential to exert excess pressure on the urethra and could sometimes fail. By the end of the term, the students had redesigned the cuff device to fit better around the urethra. Work continues on a cuff redesign to clamp the urethra optimally without leaking.

The students had access to a currently available device, thanks to Vanderbilt’s medical program. By reverse-engineering the device—literally taking it apart and studying how it fits together—students with little or no medical background could determine exactly how the device worked and how it could be improved, King said.

But students aren’t on their own as they study the device. King and medical professionals are standing by to answer questions.

“For the incontinence device, the urologist gave the students advice and one-half the grade,” King said.

For another project—a depth gauge—students actually purchased a depth gauge for reverse engineering purposes, which King knows from his days in private industry is often a common method of studying a competitor’s product.

“Years ago, we went out and bought one of the other guy’s devices and sat and X-rayed it, and tried to figure out its circuitry,” King said.

look inside a cell

Scientists in the biomedical hybrid fields of systems and synthetic biology call upon reverse engineering in ways that may look foreign to the practicing mechanical or electrical engineer—or even to the practicing biomedical engineer.

Collins, for example, is the principal investigator of the Applied Biodynamics Laboratory at Boston University. Listed as “Collins Lab,” it is among the contributors cited on the Web site syntheticbiology.org. He’s also a researcher in systems biology. He uses reverse-engineering methods in both pursuits, although the technique is applied a little differently than in other uses.

Systems biology, an interdisciplinary field, looks at developing artificial systems, which are often biomechanical.

Synthetic biology, a new area of research, focuses solely on designing and building new biological systems. Synthetic biology often focuses on ways of taking parts of natural biological systems, characterizing and simplifying them, and using them as components of an engineered, biological system.

For instance, Collins and his colleagues are constructing synthetic gene circuits, introducing them into biological networks, and then reverse-engineering the hybrid networks to determine how they react when change is introduced. In that way, they study how the gene would react to a particular drug.

Collins’s gene circuits are simply tiny artificial devices that literally turn on or off in response to an environmental change.

Reverse-engineering methods have become quite popular over the last five years, Collins said. The method is used to determine how biological networks function in order to mimic them and to extend their use.

Take the recently sequenced genome.

“Now that we have these large lists of genes, the next challenge is: How do they lead to actual biological function?” Collins said. “It’s not clear how they work when you only look at the sequencing data.”

When work began, researchers knew the problem of determining biological function was essentially an engineering problem. Still, they relied on scientific methodology to further their quest.

“They looked to understand the genes and networks of cells by cracking them open and analyzing them,” Collins said.

The method was expensive and slow, and didn’t readily provide results. Now, researchers take another tack.

Doctors created a silicon imprint (seen here) of the face of a patient who had lost half her nose to skin cancer, which was then scanned and used to create the prosthesis she would use while she awaited rhinoplasty.

To determine how genes and genomes actually function, researchers like Collins thought to place them in an electrical engineering context.

“We first became interested in thinking about natural networks. We realized they were too challenging for us to make any inroads,” Collins said. “We realized that instead of trying to reverse-engineer natural networks, we could couple engineering techniques with molecular biology to create cells that we could analyze.

“So we thought: Let’s take inspiration from electrical engineers to come up with cells or circuits with functionality that we could model, and then insert them into DNA and then into cells and have them function the way we’d like to,” he added. “We thought we’d determine how they fit in circuits, networks, and pathways, only in this case, the networks and pathways are biologically based, not electrically based.”

The technique studies circuit genes inserted into living cells.

Collins and his team built a biological circuit that they could indeed insert in cells. Following a systems engineering model, researchers introduce different chemicals or change the cell’s environment in order to see how genes and proteins respond. They may, for example, change temperature or turn on a particular gene function, he said.

By studying circuit response to the change—whether it turned off or stayed on—researchers could note important factors about cell response.

“If you do that enough and measure cell response, you should be able to infer the underlying structure of a cell,” Collins said. “Like if you were given an electrical board and given different schemes on and off and measure, and from that infer the underlying structure. We’re basically doing that now in a cell.”

His team is essentially breaking down cell function to study it, much the way King’s students are breaking down their medical device function by breaking it into individual pieces. The difference is that Collins’s team is first building a cell—by introducing an unnatural element, before reverse-engineering function.

Collins’s technique has multiple applications in the biomedical realm.

“The prime one that drove us into the space was to identify proteins and genes you can hit as part of drug therapy,” Collins said.

The researchers can do that by introducing a drug into the manufactured cell to see how it responds. Currently, drug research is mainly done in clinical trials by testing human subjects. Response at the cellular level is hard to measure. Usually, response is measured by studying subjects.

“With drugs, you can see if it did what it was supposed to do, but also nothing else,” Collins said.

Diseased or cancerous cells can also be studied in this up-close way to determine which factors in the body essentially turn on a disease, he added.

Yet, synthetic biology is not without controversy. According to critics, biological circuits can be integrated into organisms to change their interactions or products or, ultimately, to synthesize fundamentally new and possibly hazardous organisms.

So far, research has proceeded without apparent harm. The new field of study—like all other fields encompassed by biomedical engineering—has seen fit to use reverse engineering as an everyday tool.

“There’s no agreement on how it should be done,” Collins said. “There’s a dozen ways to do it out there.”

And each of them, he said, furthers the field.