Week in BioE (January 24, 2018)

Using AI to Better Understand Cancer Immunology

ImmunoMap
A T cell with receptors highlighted in red

T lymphocytes in the immune system play a vital role in the body to recognize invasion by an outside element. When foreign bacteria enter the body, receptors on the T cell surface detect antigens associated with the bacteria and send a signal deploying phagocytes to attack and defeat the invading bacteria. While evolution and vaccination make the immune system very efficient, the inability of T cell receptors (TCRs) to detect cancer makes normal T cells relatively ineffective in resisting cancer. One of the ways to overcome this limitation of the immune system is to better understand how the TCRs respond to antigens. Analyses of the proteins involved in TSR responses are useful but limited by several factors, including the dizzying amount of data involved. Data analysis techniques have been helpful but have offered little information about the general reactions of TSRs, rather than how they react to specific antigens.  

A possible solution to this obstacle is ImmunoMap, developed by scientists collaborating between Johns Hopkins University and Memorial Sloan Kettering Cancer Center. In a study recently published in Cancer Immunology Research, the authors, led by Jonathan P. Schneck, M.D., Ph.D., a professor of pathology at Johns Hopkins associated with the university’s Institute for Cell Engineering and Institute for Nanobiotechnology, describe their creation and deployment of ImmunoMap, a group of artificial intelligence algorithms that use machine learning to process large amounts of sequencing data and compare data from different antigens with each other.

The authors trained ImmunoMap initially using data from a mouse model of melanoma, in which the algorithm demonstrated significantly better performance than traditional methods. Subsequently, ImmunoMap was applied to patient response data from a melanoma clinical trial of the chemotherapy agent nivolumab. The algorithm discovered a new group of patients that would respond positively to nivolumab treatment — a finding missed by popular past methods. More testing of ImmunoMap is necessary, but the technology could make significant contributions to the monitoring of cancer patients receiving chemotherapy. In addition, it could to help to better predict response in patients before they begin specific chemotherapy regimes.

Wearables Improving Health

Among the most troubling health disparities related to global wealth inequality is the higher rate of mortality among children suffering from cancer. Fever is a common symptom of children undergoing cancer treatment, and this symptom may indicate more serious health issues that require the attention of a doctor. However, continuously monitoring skin temperature in children from low resource settings is difficult. Seeking to help remedy this problem, undergraduate engineering students at Harvard collaborated with the Dana-Farber/Boston Children’s Cancer & Blood Disorders Center’s Global Health Initiative to develop tools for earlier fever detection and treatment.

In a course taught by David Mooney, Ph.D., Robert P. Pinkas Family Professor of Bioengineering at Harvard, students developed a wearable device that sounds an alarm when the wearer needs medical help. The app can send patients’ recorded messages to their doctors, who can then review the temperature data and messages from the children before responding. Fashioned like a wristwatch, the extra-durable and waterproof device will next move into pilot testing among a larger patient population.

Meanwhile, at Northwestern, John A. Rogers, Ph.D., the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering, and Neurological Surgery in Northwestern’s McCormick School of Engineering, has partnered with cosmetics giant L’Oréal to create the world’s smallest wearable. The device, which is smaller than an adult fingernail, measures UV sun exposure for the wearer and can tell when they should go back inside instead of risking overexposure. Unsurprisingly, it’s solar powered, and it was demonstrated a couple of weeks ago at a consumer electronics show in Las Vegas.

 

Growing Hydrogels Like Human Tissue

Scientists at Carnegie Mellon University and Nanyang Technological University in Singapore have collaborated in a process to create polyacrylamide gels that grow in a manner resembling natural tissue. K. Jimmy Hsia, Ph.D., Professor of Biomedical Engineering at Carnegie Mellon, is co-lead author of a new study in PNAS describing this new growth mode.

In the study, Dr. Hsia and his coauthors report that, in the same way that growth factors secreted by a living organism affect the generation of new tissue, oxygen can be modulated to control how hydrogels grow. Moreover, while growth is under way, the process could be continued to efficiently manage the mass transfer of nutrients from cell to cell. Finally, the authors detail the mechanical processes that help to shape the final product. With this new process, the ability to design and create materials for applications such as robotics and tissue engineering comes a step closer to resembling living tissue as closely as possible.

People and Places

Engineers at Virginia Tech have been awarded a $1.1 million grant from the Virginia Research Investment Committee to develop a device that uses low-energy electric fields for the treatment of brain tumors. Rafael Davalos, Ph.D., L. Preston Wade Professor of Biomedical Engineering and Mechanics, is the chief investigator on the grant.

The Department of Biomedical Engineering has announced the appointment of Kam W. Leong, Ph.D., as the Samuel Y. Sheng Professor of Biomedical Engineering. Dr. Leong earned his Ph.D. in chemical engineering from the University of Pennsylvania and taught at Duke and Johns Hopkins before arriving at Columbia in 2006. He was previously the James B. Duke Professor of Biomedical Engineering at Duke. Congratulations to Dr. Leong!

Week in BioE (September 29, 2017)

An Immune Cell Atlas

atlas
A human B cell

The human immune system deploys a variety of cells to counteract pathogens when they enter the body. B cells are a type of white blood cell specific to particular pathogens, and they form part of the adaptive immune system. As these cells develop, the cells with the strongest reactions to antigens are favored over others. This process is called clonal selection. Given the sheer number of pathogens out there, the number of different clonal lineages for B cells is estimated to be around 100 billion. A landscape like that can be difficult to navigate without a map.

Luckily, an atlas was recently published in Nature Biotechnology.  It is the work of scientists collaborating between Penn’s own Perelman School of Medicine and faculty from the School of Biomedical Engineering, Science and Health Systems at our next-door neighbor, Drexel University. Using tissue samples from an organ donor network, the authors, led by Nina Luning Prak, MD, PhD, of Penn and Uri Heshberg, Ph.D., of Drexel, submitted the samples to a process called deep immune repertoire profiling to identify unique clones and clonal lineages. In total, they identified nearly a million lineages and mapped them to two networks: one in the gastointestinal tract and one that connects the blood, bone marrow, spleen, and lungs. This discovery suggests that the networks might be less complicated than initially thought. Also, it confirms a key role for the immune system in the gut.

Not only does this B cell atlas provide valuable information to the scientific community, but it also could serve as the basis for immune-based therapies for diseases. If we can identify these lineages and how clonal selection occurs, we could identify the most effective immunological cells and perhaps engineer them in the lab. At the very least, the extent to which scientists understand how B cells are formed and develop has received an enormous push with this research.

Understanding Muscle Movement

Natural movements of limbs require the coordinated activation of several muscle groups. Although the molecular composition of muscle is known, there remains a poor understanding of how these molecules coordinate their actions to confer power, strength, and endurance to muscle tissue. New fields of synthetic biology require this new knowledge to efficiently produce naturally inspired muscle substitutes.

Responding to this challenge, scientists at Carnegie Mellon University, including Philip R. LeDuc, Ph.D.,  William J. Brown Professor of Mechanical Engineering and Professor of Biomedical Engineering, have developed a computational system to better understand how mixtures of specific myosins affect muscle properties. Their method, published in PNAS, uses a computer model to show that mixtures of myosins will unexpectedly produce properties that are not the average of myosin molecular properties. Instead, the myosin mixtures coordinate and complement each other at the molecular level to create emergent behaviors, which lead to a robustness in how the muscle functions across a broad range. Dr. LeDuc and his colleagues then confirmed their model in lab experiments using muscle tissue from chickens. In the future, this new computational method could be used for other types of tissue, and it could prove useful in developing treatments for a variety of disorders.

Determining Brain Connectivity

How the brain forms and keeps memories is one of the greatest challenges in neuroscience. The hippocampus is a brain region considered critical for remembering sequences and events. The connections made by the hippocampus to other brain regions is considered critical for the hippocampus to integrate and remember experiences. However, this broad connectivity of the hippocampus to other brain areas raises a critical question: What connections are essential for rewiring the brain for new memories?

To offer an explanation for this question, a team of scientists in Hong Kong published a paper in PNAS in which they report on a study conducted in rats using resting-state function MRI. The study team, led by Ed X. Wu, Ph.D., of the University of Hong Kong, found that stimulation of a region deep in the hippocampus would propagate more broadly out into many areas of the cortex. The stimulation frequency affected how far this signal propagated from the hippocampus and pointed out the ability for frequency-based information signals to selectively connect the hippocampus to the rest of the brain. Altering the frequency of stimulation could affect visual function, indicating that targeted stimulation of the brain could have widespread functional effects throughout the brain.

Although human and rodent brains are obviously different, these findings from rats offer insights into how brain connectivity emerges in general. Similar studies in humans will be needed to corroborate these findings.

Seeing Inside a Tumor

Years of research have yielded the knowledge that the most effective treatments for cancer are often individualized. Knowing the genetic mutation involved in oncogenesis, for instance, can provide important information about the right drug to treat the tumor. Another important factor to know is the tumor’s chemical makeup, but far less is known about this factor due to the limitations of imaging.

However, a new study published in Nature Communications is offering some hope in this regard. In the study, scientists led by Xueding Wang, Ph.D., associate professor of biomedical engineering and radiology at the University of Michigan, used pH-sensing nanoprobes and multiwavelength photoacoustic imaging to determine tumor types in phantoms and animals. This new technology is based on the principle that cancerous cells frequently lower the pH levels in tissue, and designing probes with properties that are pH sensitive provides a method to find tumors with imaging methods and also treat these tumors.

With this technology, Dr. Wang and his colleagues were able to obtain three-dimensional images of pH levels inside of tumors. Importantly, it allowed them to noninvasively view the changes in a dye injected inside the tumor. Although a clinical application is years away, the information obtained using the Michigan team’s techniques could add significantly to our knowledge about tumorigenesis and tumor growth.

The Role of Bacteria in MS

The growing awareness of how bacteria interact with humans to affect health has led to the emergence of new scientific areas (e.g., human microbiome). Research findings from scientists collaborating between Caltech and UCSF suggest bacteria can play a role in the onset of multiple sclerosis. These investigators include Sarkis K. Mazmanian, Ph.D., Luis B. and Nelly Soux Professor of Microbiology and a faculty member in the Division of Biology and Biological Engineering at Caltech. Reporting their research results in PNAS, the researchers found several bacteria elevated in the MS microbiome. Study results showed that these bacteria regulated adaptive immune responses and helped to create a proinflammatory milieu. The identification of the bacteria interacting with immunity in MS patients could result in better diagnosis and treatment of this disabling disease.

People and Places

Faculty members at the University of California, Irvine, including biomedical engineer Zoran Nenadic, Ph.D., have received an $8 million grant to develop a brain-computer interface. The research using this grant aims to restore function in people with spinal cord injuries. Also, at the University of Texas, Austin, the lab of Amy Brock, Ph.D., an assistant professor in the Department of Biomedical Engineering, has received a three-year $180,000 R21 grant from the National Cancer Institute to develop a barcoding platform to isolate cancer cell lineages and to identify genetic targets for treatment.

Week in BioE (August 10, 2017)

Preventing Transplant Rejection

rejection
A healthy human T cell, one of the key immune system cells.

Organ transplantation is a lifesaving measure for people with diseases of the heart, lungs, liver, and kidneys that can no longer be treated medically or surgically. The United Network for Organ Sharing, a major advocacy group for transplant recipients, reports that a new person is added to a transplant list somewhere in America every 10 minutes. However, rejection of the donor organ by the recipient’s immune system remains a major hurdle for making every transplant procedure successful. Unfortunately, the drugs required to prevent rejection have serious side effects.

To address this problem, a research team at Cornell combined DNA sequencing and informatics algorithms to identify rejection earlier in the process, making earlier intervention more likely. The team, led by Iwijn De Vlaminck of the Department of Biomedical Engineering, report in PLOS Computational Biology that a computer algorithm they developed to detect donor-derived cell-free DNA, a type of DNA shed by dead cells, in the blood of the recipient could predict heart and lung allograft rejection with a 99% correlation with the current gold standard. The earlier that signs of rejection are detected, the more likely it is that an intervention can be performed to save the organ and, more importantly, the patient.

Meanwhile, at Yale, scientists have used nanoparticles to fight transplant rejection. Publishing their findings in Nature Communications, the study authors, led by Jordan S. Pober, Bayer Professor of Translational Medicine at Yale, and Mark Saltzman, Goizueta Foundation Professor of Chemical and Biomedical Engineering, used small-interfering RNA (siRNA) to “hide” donated tissue from the immune system of the recipient. Although the ability of siRNA to hide tissue in this manner has been known for some time, the effect did not last long in the body. The Yale team used poly(amine-co-ester) nanoparticles to deliver the siRNA that extended and extended its duration of effect, in addition to developing methods to deliver to siRNA to the tissue before transplantation. The technology has yet to be tested in humans, but provides an exciting new approach to help solve the transplant rejection challenge in medicine.

Africa in Focus

A group of engineering students at Wright State University, led by Thomas N. Hangartner, professor emeritus of biomedical engineering, medicine and physics, traveled to Malawi, a small nation in southern Africa, to build a digital X-ray system at Ludzi Community Hospital. Once on site, Hangartner and his student team trained the staff to use system on patients. The group hopes they have made a significant contribution to improving the standard of care in the country, which currently allocates only 9% of its annual budget to healthcare. While the project admitted has limited impact, it’s important to bear in mind that expanding public health on a global level is a game of inches. The developing world will rise to the standards of the developed world one village at a time, one hospital at a time.

Speaking of Africa, the recent Ebola outbreak in West Africa had global implications and prompted many international organizations to identify better methods to identify early signs of outbreak. Since diseases like Ebola can spread rapidly and aggressively, detecting the outbreak early can save thousands of lives. To this end, Tony Hu of Arizona State University’s School of Biological and Health Systems Engineering has partnered with the U.S. Army to develop a platform using porous silicone nanodisks that, coupled with a mass spectrometer, could be used to detect Ebola more quickly and less expensively. In particular, by determining the strain of the Ebola virus detected, treatment could be more specifically individualized for the patient. Dr. Hu presents the technology in a video available here.

Neurotech News

Karen Moxon, professor of biomedical and mechanical engineering at the University of California, Davis, recently showed that rats with spinal injuries recovered to a more significant extent when treated with a combination of serotonergic drugs and physical therapy. Dr. Moxon found that the treatment resulted in cortical reorganization to bypass the injury. Many consider combining two different drugs to treat a disease or injury; Moxon’s clever approach used a drug in combination with the activation of cortical circuits (electroceuticals), and approach that was not considered possible with some types of spinal cord injuries.

At Stanford,  Karl Deisseroth, professor of bioengineering and of psychiatry and behavioral sciences, led a study team that recently reported in Science Translational Medicine that mice bred to have a type of autism could receive a genetic therapy that caused their brain cells to activate differently. Although the brains of the autistic mice were technically normal, the mice were unsocial and lacked curiosity. Treatment modulated expression of the CNTNAP2 gene, resulting in increased sociability and curiosity. Their findings could have tremendous implications for treating autism in humans.

Elsewhere in neurotech, Cornell announced its intention to create a neurotech research hub, using a $9 million grant from the National Science Foundation. Specializing in types of neurological imaging, the new NeuroNex Hub and Laboratory for Innovative Neurotechnology will augment the neurotech program founded at Cornell in 2015.

Academic Developments

Two important B(M)E department have developed new programs. In Montreal, McGill University has introduced a graduate certificate program in translational biomedical engineering (video here). Also at the annual meeting of the American Society for Engineering Education in Columbus, Ohio, an interdisciplinary group of scholars from Worcester Polytechnic Institute, including three professors of engineering, presented a paper entitled “The Theatre of Humanitarian Engineering.” The authors developed an experimental role-playing course in which the students developed a waste management solution for a city. According to the paper’s abstract, a core misunderstanding about engineering is the belief that it exists separately from social and political contexts. With the approach they detail, the authors believe they could address the largely unmet call for greater integration of engineering with the humanities and social sciences on the academic level.