This Week in BioE (July 6, 2017)

Bioengineering of Genes and DNA

Since Watson and Crick published their initial studies detailing the double helix structure of DNA in the early 1960s, what we know about genetics and the nucleic acids underlying them has grown enormously. Consequently, what bioengineering can do with DNA and genes continually expands.

One fascinating bioengineering field that emerged in the past decade was DNA origami, which uses the well-established binding across DNA elements to create three-dimensional structures out of linear DNA sequences. Recent work has utilized this feature of DNA construction to make machines, rather than just parts, out of DNA.

Yonggang Ke, Ph.D., of Georgia Tech/Emory’s Department of Biomedical Engineering, constructed machines made of DNA that consist of arrays of units that can “switch” between “settings” by changing shape. A change in shape of one unit of an array can cause the other units in the array to shift; these changes are stimulated by inserting a previously deleted strand of DNA into the array. Although it has been known for some time that DNA could be used to store and transmit information, Dr. Ke’s research team proved for the first time that these arrays could be shaped physically into machines in the shapes of rectangles and tubes.

genes dna
DNA under a microscope

While we learn more about how to make DNA-based devices, we are also creating new technologies to manipulate DNA more rapidly.  Scientists at Rutgers and Harvard developed a process whereby thousands of genes could be cloned at one time to create enormous libraries of proteins. To achieve this goal, the authors used a technology called LASSO (long-adapter single-strand oligonucleotide) probes, which they have already used to clone a library using a human microbiome sample.

Instead of the traditional process of cloning one gene at a time, the team led by Professor Biju Parekkadan, Ph.D. at Rutgers, invented a technology to clone hundred of genes simultaneously. These cloned DNA segments are much longer than the length of DNA cloned with standard techniques, allowing us to test the functional significance of these much longer DNA segments.  The technology could impact a number of scientific fields because we will finally learn how long stretches of protein function — some parts may degrade other proteins, while other parts will interact and modify other proteins (e.g., phosphorylation, a key process in epigenetics). These new discoveries can be key for discovering new ways to engineer proteins and to manufacture new drugs that mimic the function of nature’s DNA products.

Using Sweat as a Biosensor

While the field learns more about the molecular-level control of DNA, we are also taking advantage of new micro- and nanoscale manufacturing processes to capture diagnostic information from easily accessible body fluids. Many clinical diagnostics use chemical measurements from blood to diagnose a disease or to take corrective action. This is not an ideal procedure because it requires either the collection of blood at a laboratory or the repeated collection of small blood volumes through a pinprick.  Either one hurts.

Bioengineers at the University of Texas at Dallas developed a wearable diagnostic device to detect cortisol, glucose, and IL-6 in body sweat, eliminating any painful needle sticks.  Its transmissions vary, but if optimized, the device could replace the painful and inconvenient practice of sticking one’s finger to obtain a drop of blood for glucose testing, which many patients with diabetes must do several times per day. Although insulin pumps have been available for some time, these are invasive devices that must be worn at all times.

New Faculty Joining Penn Bioengineering

We are thrilled to announce the successful recruitment of three (!) new faculty members to the department. We conducted a national faculty search and could not decide on one — we wanted all three of our finalists!  We are very happy that they chose Penn and think we can provide an amazing environment for their education and research programs.

new faculty hughes
Alex Hughes, Ph.D.

Alex Hughes, Ph.D., will join us in the Spring 2018 semester. Dr. Hughes comes to us from the University of California, San Francisco (UCSF), where he is a postdoctoral fellow. Alex’s research regards determining what he calls the “design rules” underlying how cells assemble into tissues during development, both to better understand these tissues and to engineer methods to build them from scratch

new faculty bugaj
Lukasz Bugaj, Ph.D.

Lukasz Bugaj, Ph.D., will arrive in the Spring 2018 semester. Dr. Bugaj is also coming here from UCSF following a postdoc, and his work is in the field of optogenetics — a scientific process whereby light is used to alter protein conformation, thereby giving one a tool to manipulate cells. In particular, Lukasz’s research has established the ability to induce proteins to cluster ‘on demand’ using light, and he wants to use these and other new technologies he invented to study cell signaling in stem cells and in cancer.

new faculty mitchell
Mike Mitchell, Ph.D.

Mike Mitchell, Ph.D., will also join us in the Spring 2018 semester after finishing his postdoctoral fellowship at MIT in the Langer Lab. In his research, Dr. Mitchell seeks to engineer cells in the bone marrow and blood vessels as a way of gaining control over how and why cancer metastasizes. Mike’s work has already had impressive results in animal models of cancer. His lab will employ tools and concepts from cellular engineering, biomaterials science, and drug delivery to fundamentally understand and therapeutically target complex biological barriers in the body.

In the coming month, we’ll feature podcasts of interview with each of the new faculty members, as well as with Konrad Kording, so be sure to keep an eye out for those.

And to our new faculty, welcome to Penn!

Setton Named WashU BME Chair

Setton
Lori A. Setton, Ph.D.

Lori A. Setton, Ph.D., a major innovator in the field of tissue regeneration and repair and a member of the Penn Bioengineering Departmental Advisory Board, has been named chair of the Department of Biomedical Engineering at Washington University in St. Louis. Her appointment begins on August 1.

An alumna of Princeton (BSE) and Columbia (MS, Ph.D.) with degrees in mechanical engineering, Dr. Setton was on the faculty at Duke until 2015, when she moved to WashU. Over the last decade or so, she has coauthored nearly 150 peer-reviewed research papers in the field of biomedical engineering, establishing a sterling reputation as a scientist and researcher.

In addition to her distinguished career in research and academia, she is also the current president of BMES, where she has been a pioneer in fostering greater diversity within the field, both in instituting a partnership with the National Society for Black Engineers (NSBE) and as a mentor at Duke, where the introduction of a mentoring program to increase diversity among under-represented minorities has been particularly successful.

“We are thrilled that Lori was recognized with this significant leadership opportunity,” said David Meaney, Ph.D., chair of the Bioengineering Department at Penn. “As a key academic on our department advisory board, Lori’s incisive input on Penn Bioengineering has been invaluable as we grow and change as a department. I know she will be an outstanding leader for WashU.”

This Week in BioE (June 29, 2017)

Bioengineering Organ Systems

Two news stories this week detailed how bioengineering and biomedical engineering are transforming how human organ systems could be better manipulated for positive effects on health.

organ systemsOne of the critical organ transplant shortages  in medicine is the gap between patients needing a liver transplant (around 13,000 each year) and the those receiving a transplant (about 7,000). For many years, bioengineers tried to build liver tissue in sophisticated 2D and 3D structures. Yet we never really knew how nature ‘interpreted’ these structures. A research team at Cincinnati Children’s Hospital led by Takanori Takebe, MD, reported in Nature that mimicking the 3D shape of the liver was a critical part of making engineered organoids of liver show the same behavior as liver tissue in vivo. These findings show just how important form is for function in nature, bringing us a step closer to alleviating the pressure on organ transplants lists by providing engineering organs.

Not all organs need completely reconstructed replacements. Another critical target organ in the tissue engineering field is the pancreas, which is critical in regulating insulin release.  The nationwide increase in diabetes is only placing more emphasis on finding technologies to augment pancreatic function. Engineers at Duke report in Nature Biomedical Engineering that they could control glucose levels for over a week with a single injection of a new compound they synthesized in the lab.  Rather than many daily injections of insulin for controlling glucose levels in diabetics, this could lead to far less frequent injection.

Machine Diagnosis

We hear quite a bit about Big Data nowadays. This captures a very large field that includes methods to analyze bits of data reliably and quickly to establish patterns (i.e., machine learning) that can help us uncover very new and interesting relationships. Nearly all of this work focuses on narrow data streams, which means the data are largely linked to each other within a category. One example of a narrow data stream is the collection of different types of imaging scans (CT, MRI, PET) from the same patient, collated and compared to better establish how different areas of the brain function. Another example of a narrow data stream is the data contained in a patient’s electronic health record, where it includes facts from the patient’s visits with their physician and specialists.

One interesting thread that is emerging in Big Data is when one starts to cross narrow data streams and create ‘data fabric.’  This means that scientists and engineers are cross-correlating data that seem incompatible with each other, yet they are proving amazingly predictive.  One recent example is when we cross the analysis of speech — one of the earliest machine learning applications — with genetic screening data from patients. Remarkably, scientists at the University of Wisconsin-Madison developed an automated screening system that could analyze audio recordings and determine with 81% accuracy whether the speaker had Fragile X syndrome, a genetic disorder that can have a range of cognitive effects, indicated by genetic screening data. Creating these types of data fabrics could be very powerful in the future because it can use a relatively easy and accessible technology (speech recognition) as an early indicator for more through disease confirmation (genetic testing) and subsequent intervention.

Similarly, these data fabrics are allowing us to reduce our own variability in diagnosing diseases. Penn BE alum Anant Madabhushi developed an algorithm at Case Western Reserve University that was 100% accurate at identifying breast cancer by scanning mammograms, exceeding human performance. Technologies such as these that eliminate the possibility of human error could greatly decrease the rates of delayed or faulty diagnosis. Replacing physicians with computers ? I don’t think so. We all need the human touch, especially when it comes to finding out why we are sick. Capturing errors that humans make? I think so.

A Quick Note

Speaking of Penn alumni, Craig Simmons, Ph.D., who was a postdoctoral fellow in the lab of Penn BE secondary faculty member Peter F. Davies, has been named the interim director of the Institute of Biomaterials & Biomedical Engineering at the University of Toronto. His appointment begins next week. Congratulations to Dr. Simmons!

Ducheyne Edits New Biomaterials Text

Ducheyne
Paul Ducheyne, Ph.D.

A Penn Bioengineering professor, Paul Ducheyne, Ph.D., is the editor-in-chief of the new second edition of Comprehensive Biomaterials II, released by Elsevier on June 1. The seven-volume collection, which Dr. Ducheyne edited along with faculty members from the University of California, Berkeley, Queensland University of Technology (Australia), University of Utah, and Johannes Gutenberg University Medical Center (Germany), collects articles written by experts in the field of biomaterials.

According to Elsevier, the articles “address the current status of nearly all biomaterials in the field, their strengths and weaknesses, their future prospects, appropriate analytical methods and testing, device applications and performance, emerging candidate materials as competitors and disruptive technologies, research and development, regulatory management, commercial aspects, and applications, including medical applications.”

In the preface to the collection, Dr. Ducheyne details how his team and Elsevier worked together to assure the continued high impact of the text by issuing it in both a print version and online via Elsevier’s Science Direct platform. He writes further, “It was the objective of the editorial team to compose the publication with chapters that would provide strategic insights for those working in diverse biomaterials applications, research and development, regulatory management, and industry.”

Bioengineering and BDM Go Together

by Joe Maggiore, Bioengineering ’19

BDM stage
Band Dance Music in performance

I’m a rising junior studying Bioengineering at Penn. I’m also the founder of a music group called Band Dance Music (BDM). The overall premise of the group is to take the same music that a DJ plays at a college party but to play it with an 11-piece live band. The idea for this group started before I got to Penn, but it was something that I was confident in pursuing despite all of the other time commitments during the school year.

Starting a band at Penn was definitely a challenge. There are already so many music groups on Penn’s campus that it’s very easy for a group that is just starting out to get drowned out by other more prominent groups. After really pushing marketing hard for auditions, it actually was pretty easy to find students who were interested in the idea behind the group. Interestingly, of the 11 members that are now in the group, nine of them are actually in the School of Engineering and Applied Science.

While bioengineering and band dance music seem like two totally disparate fields, I was actually able to bridge the gap between these areas while taking ENGR105 with Professor Rizk. At the end of this course, we are asked to create a graphical user interface (GUI) that combines the entire course’s material. This GUI is completely free form – it can be in any area of interest that you like.

Since for a while I’d been having trouble arranging music completely by ear, I thought this would be the perfect opportunity to create a GUI that would help me arrange music for the band. There is rarely free time to spare during the school year, so being able to work on a passionate project of mine while also being able to complete my course work was a win-win situation. The GUI definitely took me longer than expected to create since it involved having to process electronic music into parts that would be easier to arrange, but I eventually was able to finish the interface. It featured a tap metronome, a filtering system, and a visual music player so I could streamline the music writing process. Below is a pictures of the GUI I created.

BDM is always looking for more interesting people to join who have a passion for this unique concept for a band. If any bioengineers reading out there are interested, feel free to reach out to me – I’d love to talk more about it. Thanks for reading!

This Week in BioE (June 22, 2017)

Diversifying the Field

One of the ongoing issues in STEM (science, technology, engineering, and medicine) fields is a lack of diversity among students and faculty. Bioengineering stands out among other engineering fields because it enjoys terrific gender diversity. For example, about half of Penn Bioengineers are women, a feature of our class that goes back decades.

diversifyingHowever, diversity extends well beyond gender. For example, the National Research Mentoring Network (NRMN) has been working to increase diversity, including among students with disabilities. A consortium of people and groups providing mentors for science students, the MRMN recently highlighted the American Association for the Advancement of Science’s (AAAS) Entry Point! program, which focuses on helping students with physical disabilities. Mentoring, it turns out is a big part of helping these students succeed.

Another recent development that should help to increase diversity in the field is the awarding of a $1 million grant from the National Science Foundation’s Directorate of Engineering to the University of Wisconsin, Madison, and the College of Menominee Nation (CMN), a native American college in Wisconsin, to collaborate in engineering research and education. The new grant builds on a program begun in 2010 between the colleges to build labs and facilitate the transfer of pre-engineering students from CMN to UWM.

Brain Science Developments

Speaking of education, three recent news stories discuss how we might be able to expedite the learning process, increase intelligence, and reward ourselves when we create art. In one of the stories, a company called Kernel is investing $100 million in research at the University of Southern California to determine whether using brain implants, which have been helpful in some patients with epilepsy, can be used to increase or recover memory. If successful, this may bridge one critical treatment gap in neurology. About one out of every three people with epilepsy don’t respond to drug treatment.

In the second story, scientists at the University of Texas at Dallas were awarded a $5.8 million contract from DARPA to investigate the role of vagus nerve stimulation in accelerated learning of foreign languages. Stimulating the peripheral nervous system to activate and train areas of the brain is one more example that our nervous system is connected in ways that we do not yet understand completely. The Department of Defense hopes to use the technology to more quickly train intelligence operatives and code breakers.

Finally, in a third story involving the brain, a professor at Drexel University used functional near-infrared spectroscopy to determine which parts of the brain were activated while participants were making art. Dr. Girija Kaimal’s team found that creative endeavors activate the brain’s rewards pathway, as well as elevating the participants’ self-opinion. So making art always made people feel good about themselves; now we know more of the reasons why.

Ghana Trip to Study Tuberculosis: Day 29

Ghana 29.1
One of our favorite memories was visiting King Otumfuo Nana Osei Tutu II of the Asante region (left to right: Salim, Jason Grosz, David Pontoriero, Kaila Helm, Hope McMahon, Dr. David Issadore, Danielle Tsougarakis, Ethan Zhao, Kathleen Givan, Dr. Miriam Wattenbarger, Katharine Cocherl, Kate Panzer).

David Issadore, a faculty member in the Department of Bioengineering at the University of Pennsylvania teaches an engineering course ENGR566 – Appropriate Point of Care Diagnostics. As part of this course, he and Miriam Wattenberger from CBE, have taken nine Penn students, most of them majoring in Bioengineering, to Kumasi, Ghana, to study the diagnosis of pediatric tuberculosis. While in Ghana, these students are blogging daily on their experiences.

As we woke up early to prepare for the nine-hour flight ahead of us, we all acknowledged that time really does fly. Arriving at the Accra airport, we had to say goodbye to our Ghanaian friends Salim, Uncle Ebo, and Nana Yaa. The month has come and gone. It feels like the trip went quickly, but we have learned so much and gained many valuable experiences along the way. From our hospital and clinic visits, to our interactions with an herbalist and a fetish priestess, we were exposed to many healthcare settings found in Ghana. We had the opportunity to present our pediatric tuberculosis diagnostic ideas to a room filled with researchers and clinicians, getting invaluable feedback from multiple experts. Along with our academic pursuits, we also got to explore the Ghanaian culture and learn about customs, traditions, food, and much more. We met many friendly people along the way. These aspects are the memories that we will remember for years to come. As we move beyond this course, we are excited to continue pursuing our interests in biomedical diagnostics and problem solving that can be applied globally. We would like to thank everyone who helped make this unforgettable experience possible.

Foundational Engineering Theory in Design and Translation

Ramakrishnan
What a nanoparticle remembers during its journey is pictorially represented in the above figure, and this “memory” is crucial in predicting its approach to the blood vessel wall and its subsequent capture by cell surface receptors, collectively determining the efficacy of therapeutic drug delivery. Reprinted from: Ramakrishnan et al, “Motion of a nano-spheroid in a cylindrical vessel flow: Brownian and hydrodynamic interactions,” J Fluid Mech. 2017;821:117-152, with permission of Cambridge UP, owner of copyright.

A recent article coauthored by Ramakrishnan Natesan, a postdoctoral fellow in the Department of Bioengineering who works in the lab of Dr. Ravi Radhakrishnan, and published in the Journal of Fluid Mechanics provides an elegant and rigorous approach to integrate the memory, errant motion, and adhesion effects in the dynamics of colloidal nanoparticles of different sizes and shapes. The method described in the article computationally analyzes how the hydrodynamic forces are influenced by size, shape, and nature of confining boundary amidst blood flow.

In traditional modes of therapeutic treatment, such as a direct intravenous (IV) injection, only a small fraction of injected drug accesses the diseased tissue. Suboptimal therapeutic delivery represents an acute challenge by limiting the efficacy of biotherapeutics. Strategies to address and overcome this challenge may be based on theoretical and computational approaches to in order to help design innovative, quantitative, experimental methods. Targeted therapeutic delivery using nanoparticles coated with specific targeting molecules is such an approach in therapeutic and diagnostic applications.

Targeted delivery is inherently a multiscale problem: a broad range of length and time scales govern the hydrodynamic, microscopic, and molecular interactions mediating nanoparticle motion in blood flow and capture due to cell binding. The events following upon the injection of a targeted therapeutic nanoparticle bearing a drug (nanocarrier) include flow through blood vessels and maneuvering around much larger entities in the blood, such as the red blood cells. Nanoparticles eventually break free to approach the wall of the blood vessel — a phenomenon collectively known as margination.

After margination, the nanoparticle is relatively free from the influences of the blood cells but starts to “feel” the approach to the wall. It needs to get excruciatingly close to the wall to stick — a phenomenon known as adhesion or capture. In the backdrop of this arduous journey is the inescapable randomness of its motion caused by Brownian forces, an erratic form of motion that only impacts nanoscale objects. The interplay among fluid forces, Brownian fluctuations, and wall interactions shape the detailed itinerary of the nanoparticle.  How it moves at a given location and given time is intricately coupled with the motion of the surrounding fluid, namely the blood plasma, which is mostly water. Together, they decide to pave the path forward in time described by a “memory function.”

“The optimization of future drug delivery agents, such as targeted therapeutic nanocarriers, could be based on our computations,” Dr. Ramakrishnan says. “This will, in effect, establish a rational computational platform for fast tracking the clinical translation from carrier design to clinical practice.”

Ghana Trip to Study Tuberculosis: Day 28

Ghana 28.2
Students enjoy their last dinner in Ghana at Buka, a Ghanaian and Nigerian restaurant in Accra (left to right: Jason Grosz, Ethan Zhao, Danielle Tsougarakis, Hope McMahon, Salim, Uncle Ebo, Kaila Helm, Kate Panzer, Katharine Cocherl, Kathleen Givan).

David Issadore, a faculty member in the Department of Bioengineering at the University of Pennsylvania teaches an engineering course ENGR566 – Appropriate Point of Care Diagnostics. As part of this course, he and Miriam Wattenberger from CBE, have taken nine Penn students, most of them majoring in Bioengineering, to Kumasi, Ghana, to study the diagnosis of pediatric tuberculosis. While in Ghana, these students are blogging daily on their experiences.

Today marked our last full day in Ghana. In the morning, we set off rather early to start our day in Accra. But first, we had to drop one of our students, Dave, at the airport so he could make his way to Rwanda to visit a college friend. As we traveled to the airport, we had the opportunity to get a better picture of what life is like in Ghana’s capital. It was nice to go back to Accra and see how different it was from Kumasi. It is a much larger city, with various government buildings, people walking about, and large advertising signs every few yards.

Ghana 28.1
Kwame Nkrumah stands with past Vice Provost Roy Nichols in front of the Benjamin Franklin statue on College Green.

Our first stop was the Kwame Nkrumah Memorial Park. Kwame Nkrumah was the first president of Ghana when the country gained independence in 1957. Interestingly, he went to Penn to earn a Master of Arts in philosophy and a Master of Science in education. The mausoleum in Accra contains his and his wife’s bodies. It is surrounded by various water fountains, which are a symbol of life to provide a sense of immortality for Nkrumah. Many Ghanaians want to continue the work that Nkrumah did not get to finish by helping Ghana to continue developing as an independent country. In addition, there is a museum that contains many of his clothes and pictures of him as he met with various world leaders. We even saw a picture of him on Penn’s campus, shaking the hand of then Vice Provost Roy Nichols.

After the tour, we met Dr. Ellis from KCCR for lunch at a nice open-air restaurant, called Buka. Many of us stuck to our favorites of chicken and fried plantains, but some ventured out to try guinea fowl and snails. After lunch, we walked around the area to some nearby vendors, where we were able to shop for last minute gifts. We soon realized how much more expensive Accra was, compared to Kumasi.

We headed back to the hotel to relax a bit before dinner. For our last night in Ghana, we went out to a restaurant that had a live jazz band. We had our last taste of Ghanaian cuisine and had fun dancing to highlife music. Highlife is a genre of music that we only recently learned is popular in both Ghana and Nigeria. To end our last night in Ghana, we headed back to the hotel. After spending some time to prepare, we huddled in the hotel’s lobby for our talent show, and as night turned into morning, we reluctantly headed to our rooms to finish packing for our early departure.

Ghana 28.3
The APOC program began and ended in Accra, the capital of Ghana.