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Promise and Progress - Engineering Cures

Engineering Cures: Physicians and Engineers Working Together to Fight Cancer
Issue No. 2012

Engineering Cures

By: Valerie Matthews Mehl
Date: December 20, 2011

Johns Hopkins Physicians, Scientists, and Engineers Working Together to Fight Cancer

Engineering Cures
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Dan Stoianovici and team have developed a revolving needle that works like a drill, rotating as it enters an organ, creating less force against the tissue and therefore, providing more precise placement.

Johns Hopkins Physicians, Scientists and Engineers Working Together to Fight Cancer
Add engineers to the list of specialists engaged in the fight against cancer.  It is not unexpected.  Johns Hopkins is revered for its brain trust and the willingness and desire of its leadership to apply knowledge to improving the health and wellbeing of humans. Johns Hopkins, after all, was the site of the first department of biomedical engineering—the very first organized effort that applied the tools of engineering to human medicine. It is a brilliantly simple concept. Gather together the smartest people, give them the freedom to pursue novel approaches, and good ideas will almost always result. This is perhaps the cornerstone of Johns Hopkins’ pioneering success in so many fields.  With world-class programs in engineering and medicine and with some of the most talented scientists in both fields, why not bring them together. 

“More interaction stimulates creative ideas,” says Kimmel Cancer Center Director William Nelson. “It leads to connecting two things together that have never been connected before.  With more of this happening it is almost certain that something innovative will come about.”

The Cancer Center at Johns Hopkins was built on the premise of collaboration.  The urgency of the problem demanded no less.  Laboratories were located directly off of the patient wings to ensure the quick transfer of discoveries from scientists to clinicians. 

Nowhere at Johns Hopkins was the physician-scientist, those who work both at the bench and the bedside, more visible than in the Cancer Center.  Kimmel Cancer Center investigators and clinicians were doing “translational” medicine—transferring basic science discoveries to cancer medicine—long before there was a word for it. 

Therefore, it is not surprising that a new and different type of collaboration has emerged.  This way of working, one could say, is in our metaphorical “genes.”

Pioneering discoveries in genetics and epigenetics by Johns Hopkins Kimmel Cancer Center investigators have revealed the very origins of cancer and uncovered new targets for treatment and drugs that hit these targets. Engineers bring technologies that allow researchers to pick the best target, deliver drugs effectively to the target, and monitor whether or not it gets the job done.  Cancer researchers made personalized cancer medicine possible. Engineers made it doable.

“We have to ask ourselves, ‘Why is Johns Hopkins so successful?’” says Dean of the Whiting School of Engineering Nicholas Jones,  “The collaborations between investigators in the trenches all the way up through the Deans and Directors of departments surely must have something to do with it.” 

Collaborations between oncologists and engineers are certainly not new to the Kimmel Cancer Center.  Diseases like cancer demand forward-thinking study, and our investigators have always looked to innovation to develop new methods to control and cure cancer.  Engineers and physicists, including John Wong, Justin Hanes, and Martin Pomper work in the cancer center with the sole purpose of using their skills to aid oncologists in diagnosing and treating cancer. Surgeons like Michael Choti have solicited the expertise of engineers for more than a decade to bring added precision through image guidance and robotics to cancer surgery. 

Every instrument used and the process by which they operate were developed by engineers.

Under the leadership of Jones, the Whiting School of Engineering has infused considerable resources into the department to accommodate the growth in clinically relevant programs, such as nanotechnology, computer science, and robotics.  In recent years, he has added a new engineering building and a computational and robotics facility.  New programs, including the Engineering in Oncology Center, Institute for Nanobiotechnology, the Center for Cancer Nanotechnology Excellence, The Center for Nanomedicine, and Physical Science Oncology Center fund and foster research projects between Kimmel Cancer Center scientists and engineers.

The strength of these collaborations and their potential to improve healthcare has not gone unnoticed.  If investments are a measure of our success, then the Kimmel Cancer Center and Whiting School have earned high marks.  Both have recently received separate $30 million gifts. These funds will help support personalized approaches to treating cancer, stemming from Johns Hopkins research that distinguishes unique genetic and epigenetic differences among individual patients’ cancers, explaining, at least in part, why traditionally developed drugs help some people and not others.

The Kimmel Cancer Center received its gift, a grant from the Commonwealth Foundation for Cancer Research, to create a Center for Personalized Cancer Medicine. It supports collaborations and research that accelerate the pace of developing targeted therapies based on the distinctive cellular fingerprint of each individual patient’s cancer. The Whiting School of Engineering grant comes from Johns Hopkins alumnus John C. Malone and will be used to foster interdisciplinary research efforts where researchers will collaborate with colleagues from other Hopkins divisions to learn to tailor therapies for individual patients and devise systems-based approaches to medical problems, with an initial emphasis on cancer. 

 “This is a watershed moment,” says Nelson, M.D., Ph.D.  “There are many opportunities for engineers and physicians to make cancer medicine better.  Across a whole spectrum of components—molecular genetics, epigenetics, imaging, diagnostics, and treatment—we are doing pioneering work in engineering and in medicine.  Hopkins is probably better positioned than anyone to make revolutionary advances in human diseases, like cancer, that could only be imagined a decade ago.  It’s just a question of how we bring it all together.”

Genetics, Epigenetics, and Physics 

Cancer is a genetic disease.  That was proven by researcher Bert Vogelstein and team who first illustrated it in colon cancer, laying out an accumulation of genetic errors over time that cause cancer to arise and grow.  Since that pioneering work in the 1980s, the same team has mapped the genetic blueprint of nearly 100 cancers.  Other errors, called epigenetic events, that alter the DNA without mutating it were also proven by Kimmel Cancer Center researchers to contribute to the origination and progression of cancer. 

Now with collaborations through the Engineering department’s Physical Science Oncology Center, Johns Hopkins teams are deciphering a third contributor called physical oncology.  It is focused on solving the mystery of how cancer cells break away from the original tumor and form new tumors in other parts of the body.  This little understood process is called cancer metastasis, and it is at the heart of what makes the disease so deadly.  Cancers that spread are cancers that kill.

“Every tumor has mutations. But now, we are also looking at its structural differences,” says Kimmel Cancer Center investigator and pancreas cancer expert Anirban Maitra. “What are the physical consequences of the genetic and epigenetic events on the cell?

How does it change the cell structurally so that it can become metastatic? ” asks Maitra.  Epigenetics expert Stephen Baylin agrees.  “We know that cancer cells have the ability to reprogram to respond to and see cues in their environment,” says Baylin.  “Understanding what these cues are would be very helpful.”

Maitra says genetic events happen first in cancers, but it’s what happens afterwards that scientists must begin to take a look at to get the full picture.  We need only look to lower life forms like worms and plants to know there is more.  “Worms have as many protein encoding genes as humans, yet humans are more evolved. There are layers of regulation and cellular characteristics beyond coding genes that we don’t yet fully understand and some of them likely sustain cancer” he says.

Maitra has teamed up with Denis Wirtz, a chemical and biomolecular engineer and director of the Physical Sciences Oncology Center to help unravel some of these mysteries.  “If we all take pieces of the puzzle, we can figure this out,” says Maitra. 

“Johns Hopkins is ahead of the game here because we do not work in isolation.  Multidisciplinary collaborations aimed at moving research discoveries to patient care are the Hopkins model.  Human tissue and clinical research are revered and encouraged here.  We recognize that engineers are doing vibrant research that is directly relevant to our work, so it only makes sense that we engage in collaborations.”

Wirtz developed a technology that, in minutes, can take thousands of distinct  structural measurements on tens of thousands of individual different cells.  It’s not easy for a cancer cell to metastasize. “It’s like a steeple chase. The cancer cell has many obstacles to overcome,” says Wirtz.  It must break away from the original tumor and the organ from which it arose, squeeze into narrow capillaries, make it through the sheer force of the bloodstream, and set up residence in a new and foreign environment. 

Maitra and Wirtz are working to uncover the physical changes to a cell that help drive it away from its home and, against all odds, allow it to survive and thrive in a new and foreign place.  Most cancers can be cured if they are detected and treated before they have begun to spread.  If researchers can figure out how metastasis occurs, they could develop ways to prevent the deadliest event in cancer progression. 

Wirtz likens a cancer cell that metastasizes to a decathlon athlete.  A decathlon competition, whose winner is considered the world’s greatest athlete, features competitors who have physical attributes that make them stronger, faster, and simply more adept than other athletes.   “Millions of cells are shed by tumors every day, but only one or two of them will have what it takes to become metastatic. These are the decathlon cells.  We need to figure out what the physical properties are that give these cells an edge,” says Wirtz.

Maitra and Wirtz are now using his cellular measurement tool in the laboratory on human cancer cells to identify specific cellular characteristics that may determine how aggressive a cancer will be and how it will respond to treatment. Monitoring and measuring how cells change will allow scientists to predict which ones are likely to become the lethal, metastatic type. 

“This kind of technology allows us to further personalize cancer medicine,” says Maitra. Within the next few years, Wirtz and Maitra hope to move the technology into clinical use to help select drugs that will work best against a cancer based on the genetic, epigenetic, and physical characteristics of tumor cells. “The engineers have the coolest tools around, and they are looking to us for the right biological uses,” says Maitra. “Now, we can use this new tool to correlate gene abnormalities with particular cellular characteristics and drug sensitivity so that we can get the most effective treatments to each patient.” 

Engineering as Applied to Cancer Medicine

Denis Wirtz refers to Kimmel Cancer Center Deputy Director Stephen Baylin as Mr. Epigenetics.  The title was bestowed for Baylin’s work in linking biochemical alterations in the DNA environment to the initiation and growth of cancer.  These non-mutational alterations are categorized as epi—in addition to—genetic. The work of Baylin and his colleagues, clinician-scientists James Herman and Malcolm Brock, resulted in some of the first uses of epigenetic abnormalities as cancer biomarkers for diagnosis and to predict how a cancer would respond to treatment.  Now Center for Cancer Nanotechnology Excellence engineer Jeff Wang is helping move these trailblazing therapeutic discoveries forward more rapidly.

In 2008, lung cancer research by Brock, Herman, and Baylin found epigenetic alterations to any or all of four genes caused cancers to be more aggressive.  Depending upon the combination of altered genes, the recurrence rates of the lung cancers studied increased two to 25-fold. Based on these findings, clinician-scientists Ros Juergens, Charles Rudin, and Brock initiated a clinical study of epigenetic therapy for patients with advanced and heavily treated lung cancer, and a small percentage of patients experienced very robust and long-lasting responses.

With funding from Stand Up to Cancer (SU2C), Rudin, Brock and team are hoping to develop these findings into a personalized treatment approach for lung cancer, and Wang’s work in developing a nano-based assay to test for alterations in these and other genes is central to that.

SU2C support allowed the researchers to do an unusual thing—to go back and find out what happened to the patients they thought they didn’t help. They reviewed the records of patients who were participating in a clinical trial of epigenetic therapy because their lung cancers had not responded to standard therapy.  Specifically, Rudin, Brock and team were interested in some 40 patients who were taken off of the epigenetic treatment trial because their tumors continued to grow.  What they found surprised them all.  Although many patients seemed to progress while on therapy, many, including those who had received just two or three treatments, had unprecedented and long lasting responses.  The team poured over every scan and every clinical report, and even re-biopsied some tumors, and could come up with only two explanations. Either the epigenetic therapy sensitized their cancers to subsequent treatment with standard drugs or their improvement was a direct response to the targeted therapy.

Targeted therapies do not work like the old cytotoxic chemotherapies, which do not discriminate between cancer cells and normal cells.  Instead they specifically seek out and reprogram the malfunctioning mechanism within cancer cells that is causing the tumors.  As a result, Baylin says, targeted therapies shrink tumors more slowly over time as they make their repairs and genes are returned to normal function. 

Jerry Morton, a 61-year-old retired firefighter, was building a sandbox for his grandson two years ago when he learned he had small cell lung cancer. The cancer had already spread throughout his lungs and to his liver.  “I didn’t expect to live long enough to complete it,” says Morton.  “Today, that sandbox is finished.”  Morton’s tumors melted away on the epigenetic treatment.  When he recently developed a new, small tumor of the same type Rudin, Brock, and team again tried epigenetic therapy, and Morton, once again, appears to be benefitting.  “The team has evidence that the status of epigenetic alterations in these four genes, assayed in the blood by sensitive technologies that Dr. Wang is working to perfect, can predict the good responses in patients like Mr. Morton,” says Baylin.  "It is a perfect illustration of the value of collaborative research and translational, personalized cancer medicine.” 

With such promising results, Baylin and team are now planning another trial for newly diagnosed patients.  If findings continue to show that the epigenetic-targeted therapy works, Wang figures prominently in the wide clinical application.  What Brock, Herman, and Baylin  do in their basic science laboratory to screen for the epigenetic alterations would be difficult to routinely do in a clinical lab, so they asked for help from engineers.  Wang, who works in the Institute for Nanobiotechnology, is using nanotechnology, engineering at a molecular level, to develop a broad-based test that could be used routinely in any clinical laboratory to predict which patients would benefit from the targeted therapy. “This facet is critically important in taking these therapies beyond our own walls.  Without the nano-tech approach, testing for the alterations might be too cumbersome for a clinical lab,” says Baylin.   If ongoing trials confirm the earlier findings, Wang’s test can help ensure that the Johns Hopkins-based discovery becomes available to lung cancer patients everywhere.

Engineering Molecules

Nanotechnology, in essence, refers to the field of engineering that focuses on ultra tiny functional devices and structures that are so minute they cannot be seen by the human eye.  Think of it as engineering at the molecular level.  Like their scientist counterparts in molecular genetics, engineers who specialize in nanotechnology work in the realm of invisibility and had to develop new technologies just to perform their craft. 

Where nanotechnology intersects with medicine is the focus of the Johns Hopkins Institute for Nanobiotechnology. It began in 2006, bringing together scientists and students from engineering, physics, chemistry, biology, medicine, and public health to apply the technology to the treatment of diseases.  It was the brainchild of Peter Searson and Denis Wirtz, both engineers, whose work was centered on the physical sciences.  They began to wonder what Johns Hopkins engineers and physicists could contribute if they collaborated with medical scientists and directed their research toward health care and medicine. 

Research teams comprise both engineers and medical research scientists, a point Searson says cannot be overstated.  “The engineers attend lab meetings and visit the clinic and work directly with clinicians so that we understand the problems clinicians are facing,” says Searson.  The model has been quite successful earning the Institute two large NIH center grants; one for the Physical Science Oncology Center and another for the Center for Cancer Nanotechnology Excellence (CCNE).

“Physicians and engineers approach problem solving in different ways,” says cancer immunology expert Hy Levitsky, who trained in bioengineering before going into medicine and is now working with engineers to improve cancer vaccines.  “As an oncologist, I can point to a problem, but I don’t have the expertise to know the spectrum of possible solutions.  Engineers can look at the problem from a very different perspective. When we bring the two perspectives together, we arrive at unique approaches we may not have otherwise found.”

A Trojan Horse for the Cancer War

Justin Hanes, a chemical and biomedical engineer specializing in nanotechnology for cancer treatment, explains that a nanoparticle is to a soccer ball what a soccer ball is to the planet earth.  Suffice it to say that we’re talking very small.

As small as they are, part of their value in cancer medicine is that they are bigger than other things.  Nanoparticles are much larger than small molecules—agents commonly used to treat cancer.  Hanes says hundreds of thousands of small molecules can fit into one nanoparticle.  As a result, they can be loaded up like a Trojan horse and sent out to deliver their cargo to tumors.

Hanes is a member of the CCNE, which has the specific aim of using nanotechnology to improve the treatment of cancer.  He is excited about the prospects of nanotechnology to  improve the delivery of anticancer drugs and combat toxicities.  “Right now, we use systemic cancer therapies, which are incredibly useful, but typically a very small percentage of the chemotherapy ends up in the tumor.  The rest of it poisons normal cells throughout the body,” explains Hanes.  He uses nanotechnology in an attempt to reverse that ratio so that anticancer drugs go directly to tumors with very little injury to normal cells.   “Think of a tumor as a weed in a prized rose garden.  What we do now is spray the entire rose garden with weed killer,” says Hanes.  “But, we can only spray so much poison or we risk killing the roses.”  The project he is working on with lung cancer experts Charles Rudin and Craig Peacock is a nano-based treatment that seeks out and targets cancer cells.  “Like a pre-addressed envelope, we are developing methods to direct them to where we want them to go,” says Hanes.

Hanes directs the Center for Nanomedicine where he and his colleagues are currently working on anticancer-drug-filled nanoparticles that can be inhaled into the lung.  His team created the first nanoparticle system that can penetrate the mucus lining the lung airways. In the past, inhaled forms of nano-therapy have failed largely because the lungs’ natural mucus barrier, in place to keep out bacteria and other infectious invaders, swept the drugs away before they could go to work.  When Hanes and team discovered that the mucus lining was more like a net than a blanket, they constructed nanoparticles small enough and slippery enough to get through the holes in the sticky mucus “net.”  

Hanes’ particles are composed of two parts made of molecules routinely used in existing medications. An inner core traps therapeutic agents inside while a dense outer coating allows a particle to slip through mucus nearly as easily as if it were moving through water.  The nanoparticles cause no immune or inflammatory response so drugs travel freely through the lungs, including areas scientists believed were impenetrable, releasing their anticancer cargo over an extended period of time.

Hanes’ nano-based approached could be applied to cancers of any mucus-lined organ, including the colon and cervix.  He said such treatments could be ready for clinical trials in as little as five years and cost about the same as traditional chemotherapy.

On Target Molecular Imaging

Central to targeted therapies is the ability to verify that an agent is hitting its intended target and having an impact against the cancer.  Targeted agents work by killing cancer cells outright or, in some cases, by reprogramming broken mechanisms within the DNA to kill cancer cells more slowly over time.  Traditional radiology, like CT, is focused on anatomy and explores the structure of organs and tumors and primarily measures reduction or growth in the size of tumor over a period of months.  These types of scans cannot see or measure what is going on within the DNA of cancer cells.

This shortfall has led to the field of cancer molecular imaging and the research of forward- thinking scientists like Martin Pomper, a radiology expert who came to Johns Hopkins in the early 1990s because it was one of the few institutions where molecular imaging research was being done. Pomper has collaborated with chemical and biomolecular engineers and other scientists to adapt radiology to the molecular level.

Over the last two decades with advances in genetics and epigenetics leading to new therapies aimed at interfering with these cancer-causing alterations to the DNA, cancer imaging has grown from a developing program of the Kimmel Cancer Center to a formal program vital to its ability to move these new treatments from test tubes to patients.
Pomper says molecular radiology has the ability to image inside the cell and reveal to clinicians when a cancer cell is poised to metastasize, permitting a therapeutic strike before the cancer makes this critical and often deadly transformation.

More recently, Pomper has been developing agents that make cancer cells fluoresce so that they can be tracked and monitored—tracked so that scientists know where new targeted agents are going, and monitored so they know if the agents are having any benefit.  “This helps us to see quickly if drugs are hitting their targets and doing what we expected them to,” says Pomper.  “We can then personalize treatments to individual patients.  We can give one dose of a drug.  If cells light up, we know we have the right drug.  If not, we know to move onto something new, rather than waiting three months for a scan to show that the tumor has grown.”  Currently, this type of molecular imaging is done primarily in research studies and in conjunction with pathology and scans to validate its capabilities.  Once proven, however, Pomper says, it has the potential to complement, if not replace, CTs and some types of pathology obtained in biopsy as the primary method for detecting and monitoring cancers.

Quantum Dots

Light-emitting nanoparticles known as quantum dots are another molecular imaging technique Pomper is exploring with Institute for Nanobiotechnology (INBT) director Peter Searson. These cancer-specific quantum dots are what investigators call theranostics (therapeutic and diagnostic) for their ability to aid both in the detection and treatment of cancer.  Pomper says they can be engineered using a special coating that makes them seek out and bind only to cancer cells, and they can also be loaded with drugs to carry to tumors.  In collaboration with Searson and Anirban Maitra, Pomper is attaching targeting molecules  to quantum dots that are attracted to proteins over-expressed in pancreas cancer and working on methods to make the quantum dots circulate throughout the bloodstream to target tumor cells. “These would be like radioactive warheads that can travel throughout the body and not cause any damage  until they come into contact with a cancer cell,” he says.

Imaging in Cancer Vaccines

In another example of targeting and monitoring treatments, cancer immunology expert Hy Levitsky is working with engineer Jeff Bulte to improve cancer vaccines.  Bulte, a radiologist and biomedical, chemical, and biomolecular engineer, has devised a way for Levitsky to monitor and track the activity of immune-boosting cells in response to cancer vaccines.

Several key biological events must occur after injection with a cancer vaccine to get the immune system to kill cancer cells.. Levitsky says the antigens contained in the vaccine must move from the injection site into the lymph nodes, where immunity is initiated. Cells, called antigen-presenting cells, have the pivotal job of capturing the antigens and delivering them to the lymph nodes. This critical step of antigen transport is often the place where vaccine therapy breaks down.  “If we don’t get this step to happen efficiently, there is no hope that the vaccine will work,” says Levitsky. As a result, clinicians almost always use adjuvants—additional treatments given in conjunction with cancer vaccines to help antigen-presenting cells make the journey to the lymph nodes.

Bulte and Levitsky recruited M.D., Ph.D.-student Chris Long to work jointly between the two laboratories to devise a method to quantify this process of antigen delivery.  Long developed a technology that uses MRI (magnetic resonance imaging) and iron nanoparticles to track these vaccine-transporting cells. The magnetic iron particles become visible when exposed to a strong magnetic field, such as that used in MRI. Long was the first scientist to show that antigen presenting cells can capture iron-particle labeled antigens  and be tracked inside the body.  Before this work, cells could only be labeled through contrast agents administered outside of the body. The method allows Levitsky to know exactly how many antigen-presenting cells capture vaccine antigen and make it to the lymph nodes and also to test how well vaccine adjuvants are improving this transport.

“Within three to five days of vaccination, we can see if the vaccine is working as it should,” says Levitsky.  “Adjuvants are almost always given with vaccine therapy, so this technology aids us in a critical area of cancer research.”  More important, Levitsky says it could be moved to humans quickly.  “All pieces of this project—the adjuvants, MRI, and contrast—have already been used safely in humans, just not in this way,” he says. 

Cancer Imaging Devices

Scientists in the Department of Biomedical Engineering make image-guided devices for diagnosis and treatment of diseases, including cancer. 

Devices that produce remarkably clear and detailed images of cells are aiding oncologists, radiation oncologists, and surgeons in the detection and treatment of cancer. Xingde Li adapted a device he developed to look at the walls of blood vessels and arteries for use in cancer.  Li’s optical imaging device can be placed in a patient’s esophagus where it  produces super-high resolution images of the esophageal wall.  The images are so clear clinicians are able to decipher normal cells from a benign inflammatory condition called Barrett’s esophagus that can predispose those affected to developing esophageal cancer.

A similar device is in development to assist neurosurgeon Alfredo Quiñones-Hinojosa in delicate brain cancer surgery.  When removing a tumor from the brain, the command center for all that is human, surgeons work diligently to protect brain tissue not invaded by the tumor.  Surgeons walk a clinical tightrope—they must remove as many tumor cells and as few normal cells as possible.  Leave tumor cells behind and the tumor may return, but harm normal brain cells, and the patient could lose important mental and physical functions.  Typically, surgeons will start at the border of the tumor, painstakingly shaving off very small sections, piece by piece. Figuring out when they are finished can be a difficult problem, so Li is working on a microscopic device that surgeons can place against cells to quickly distinguish tumor cells from normal cells.

Department chairman Elliot McVeigh and team also are working to make lung cancer detection safer and more accurate.  The quality of CT scans has improved so greatly that it can detect tiny tumors in the lung no larger than a few grains of rice. This type of early detection, occurring before a cancer produces any symptomatic evidence of its existence, could allow for earlier intervention.  To intervene, particularly with targeted therapies personalized to the specific DNA alterations in a tumor, clinicians must be able to get an accurate biopsy of the tumor. Usually this is done through bronchoscopy, but it is not an exact method.  “I’ve watched many bronchoscopies, and sometimes it can take 10 to 20 attempts to get the right tumor sample,” says McVeigh.  “This can be very traumatic for the lung and the patient.  We want to help the physician get the important cells while causing the least amount of tissue

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