In 2006, a discovery opened a new world of possibilities to treat diseases. For the first time, researchers created stem cells without using embryos. The fat cells of the skin were reprogrammed into induced pluripotent stem cells, or iPSCs, which could be differentiated into specialized cells for use in almost any part of the body, from the liver to the brain or heart, and anywhere in between. The areas of the body damaged by the disease could recover again.
But after more than a 10years of research on iPSCs, the process of creating them remains incredibly inefficient. “It has intrigued us that after 10 years of intense research in that direction, the efficiency of the iPSC reprogramming is still only 0.1 percent,” says associate professor Domitilla Del Vecchio. “It is not at the point where you can use it for clinical purposes.”
Del Vecchio and his colleagues hope to change that. Currently, researchers develop iPSCs by supplying synthetic DNA to the nucleus of a somatic cell, such as a skin cell. This synthetic DNA produces high levels of selected proteins, known as transcription factors, with the goal of “pushing” the somatic cell to reprogram it into a stem cell. But putting too much pressure in a cell with such a high level of transcription factors can lead to a highly inefficient process. “If you have a mechanical system, such as a robotic manipulator or a car, and you give it an arbitrary push, you should not expect the system to end up exactly in the configuration you want,” says Del Vecchio.
To solve this problem, Del Vecchio and his team are adding accelerators and brakes to the process. Using mathematical analysis, they can demonstrate that with an appropriate balance the status of pluripotent stem cell can be achieved. With the help of small molecules, synthetic DNA delivered through a virus can produce levels of adjustable transcription factors depending on an objective configuration. This method, called a synthetic genetic feedback controller, can be used to direct the concentration of transcription factors in the cell to the point where it can become a stem cell.
The applications of Del Vecchio’s work may have far-reaching implications for the way illnesses are treated. Researchers could quickly create healthy heart cells for patients with heart disease or beta cells for diabetic patients.
Del Vecchio’s eyes light up when the possibilities are discussed. “It’s high risk,” he admits. “But we want to move in this direction because, if it works, it will be very impressive for society and, therefore, advantageous for us.”
Empowering doctors to create stem cells quickly could change the way many diseases are treated. The research team that the Del Vecchio team is carrying out represents just one example of how mechanical engineering researchers in a wide range of specialties are developing new and innovative ways to deepen our knowledge of the disease and unlock new therapies to treat it.
Diagnose the disease
Understanding the disease begins with the cell. Assistant Professor Ming Guo, who is Professor of Career Development at d’Arbeloff, is interested in crackling the differences between a diseased cell as a way to develop a diagnostic tool and the mechanical properties of a healthy cell and. “Just looking at a healthy cell compared to a diseased cell can be said to be mechanically different,” says Guo.
Stiffness in particular is a key feature to distinguish what type of disease a cell has; For example, cancer cells are known to be soft, while asthma cells are often stiff. Currently, this information is explored through contact-only methods such as atomic force microscopes or optical tweezers, which use a mechanical tip or a laser beam focused on the patient’s tissue to measure cellular properties. Guo and his partners have now created a safer and quick method of analyzing the mechanics of a cell to help formulate a diagnosis by merely taking a small sample of cells and observing them with a standard optical microscope.
“We came up with the method simply by observing the movement of organelles in the cell,” says Guo. The team took videos of cells under a microscope. They tracked the movements of organelles or individual particles inside the cell at frequencies of 10 frames per second and more. Then, by inserting the value of these movements into a generalized form of the Stokes-Einstein equation, they could calculate the exact stiffness of a cell. “We found that high-frequency fluctuation can help us measure cell stiffness and understand its mechanics,” says Guo. Understanding these mechanical properties can help doctors diagnose illnesses in place. Guo began collaborating with doctors at the Massachusetts General Hospital to apply this method to asthma and cancer cells. The hope is that researchers and doctors can evaluate the effectiveness of medications by measuring the mechanics of cells before and after treatment.
While improving diagnostic methods may help detect the disease early, monitoring how diseases grow may be key to developing new therapeutic interventions. Roger Kamm, Distinguished Professor Cecil and Ida Green, and their laboratory use a device that is about the size of a room to track tumor cells as they leave the vascular network and eventually become tumors. These small microfluidic devices can help us understand how cancer metastasizes.
“We have developed a 3-D vascularized network in which we can track cancer cells within a capillary,” says Kamm. “It’s about understanding how cell populations interact; we can see how tumor cells escape from the vessel to invade the surrounding tissue.”
The microfluidic device consists of two media channels on each side with 3D hydrogel in the middle. The gel is seeded with endothelial cells that creates capillaries where the tumor cells are seen. From there, Kamm and his team use microscopic images to observe every movement the tumor cell makes. From intravasation, when a cancer cell enters the bloodstream, to extravasation, when a tumor cell leaves the bloodstream and becomes metastatic, the cell path is studied with meticulous precision.
“Using microfluidics, we can follow this process over time,” said Kamm. “After the cell successfully enters the metastatic organ, we can see how a single tumor cell begins to multiply for days and how it begins to form a metastatic tumor.”
Microfluidic devices allow Kamm to analyze the forces that influence the behavior of cancer cells. Understanding whether tumor cells push or pull when they leave the capillary and force interactions between endothelial cells and tumor cells to represent potential therapeutic targets to prevent or minimize metastasis.
“We can observe all these different tumor cell lines, treat the different cells and see how that affects the speed at which the tumor cells escape from the vasculature and grow,” says Kamm. This knowledge could open new opportunities in the treatment of cancer and even in the development of new immunotherapies.
Treatment of the disease
Armed with more understanding of how diseases grow and spread, researchers are in a better position to develop new ways of treating, and in some cases curing, diseases. Among them is assistant professor Ellen Roche, who is adopting a unique dual approach to treat heart disease through mechanical and biological therapies.
“The idea is to help the heart mechanically,” says Roche, who also serves as Professor of Career Development Helmholtz at the Institute of Medical Engineering and Science at MIT. “Instead of assuming its function, we simply assist it and increase it using a biomimetic approach.”
Roche uses new techniques such as soft robotics to develop devices that mimic both tissue properties and heart movement. One of these devices is a sleeve that wraps around the heart to help with pumping. Soft robots like this manga use elastomeric materials and fluidic performance to mimic the movement of an organ. “By intelligently designing simple fluid channels and reinforcing soft materials in the right way, you can achieve very complex movements with only elastomeric changes and air or pressurized water,” says Roche.
While working on mechanical therapies to treat congenital heart disease and heart attacks, Roche is also studying how biological therapies can help treat these disorders. She and her team are creating smart devices that provide localized drug administration instead of systemic drug administration.
“One of my main aspirations is to join these mechanical and biological therapies and see how they interact with each other,” says Roche. Understanding how these different therapies interact could help determine the best time sequence for maximum effectiveness. With the help of partners in the cardiac surgery group at Boston Children’s Hospital, Roche is creating and testing models for these therapies. “We want to see if we can treat the disease and regain function using polytherapy instead of just a mechanical or biological approach.”
Rehabilitation of the disease
In cases where the disease is not detected or treated early, researchers are developing tools that help in the recovery process. From the optimization of the design of prosthetic feet or the construction of cheaper wheelchairs, mechanical engineers are finding ways to make better the quality of life of those who live with the consequences of the disease. This work also includes tools and devices that can be used in physical rehabilitation. One of those tools is MIT-MANUS, a robot developed by Professor Neville Hogan to help stroke victims recover and regain mobility.
“They say there are not two identical snowflakes, nor two stroke patients either,” says Hogan. “That makes the problem spectacularly complicated.” Hogan has collaborated with neurologists and neuroscientists to understand the process of basic motor control and recovery in the brain. He used this understanding to create robots that interact with stroke victims and help them recover.
MIT-MANUS was formally designed to help restore motor function in the shoulders and elbows of stroke patients. Patients hold the forearm with a brace attached to a robotic arm and attach to a controller connected to a video screen. On the screen, a video game provides patients with indications to move the arm and wrist. If the patient can not fully move his arm on his own, MIT-MANUS provides guidance and assistance to his movements. The robot tracks and stores this data for analysis by physiotherapists and specialists.
“In the MIT-MANUS clinical trials we discovered that there was a reduction in joint deterioration exerted through the use of the robot,” says Hogan. Over the years, the reach of this robot-assisted therapy for stroke victims has grown beyond the hands and arms. Hogan and his collaborators have set up a robotic gym that helps administer localized therapy to various limbs and joints throughout the body.
Whether it’s building big robots like MIT-MANUS to help rehabilitate stroke victims, trace the tiny organelle movements in the cell or use genetic circuits to create stem cells, mechanical engineers are shaping our fundamental understanding of the illness as the way doctors approach treatments and therapies.