Dissertations / Theses: 'MIT Program in Health Sciences and Technology'

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Mateus, Ashley (Ashley Marie). "Evaluation of teledermatology in the Veterans Health Administration." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/97827.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2015.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 269-287).
Telehealth technologies are being employed to increase access, quality of care, and cost containment. However, there are no widely accepted measures of telehealth performance and little information about long-term changes in access. The Veterans Health Administration (VHA) is advantageous for telehealth research because of the widespread implementation, organic development of multiple distinctively structured programs, and national electronic medical records. Using teledermatology, one of the earliest and most widely adopted uses, a set of recommended performance metrics are established and a select few are evaluated across the different programs. Store and forward (SF) teledermatology, taking a picture and sending it to a dermatologist for asynchronous evaluation, is the prominent method of care. In SF programs there is variation in the level of follow-up care available locally. Some locations have "surrogate dermatology providers" that are trained to do basic treatments and procedures. Based on four site visits and twenty-five interviews with stakeholders, recommendations for performance measurements were created. VHA is already in the process of executing three of the measures nationally: image quality, time to consult response, and patient satisfaction. Additionally, VHA has the data available to measure time to treatment, post-teledermatology utilization of care, travel distance, and wait-times. Finally, VHA should improve data to create future metrics regarding: cost, particularly payment for outside dermatologists; provider satisfaction; and quality of care through chart review or adverse event reporting. Using administrative databases, the metrics for which data were available were retrospectively evaluated. At a national level for 2013, entry into the care process through teledermatology is associated with faster time to treatment than entry from an in-person referral for both melanoma (teledermatology median: 62 days; in-person consult median: 70 days; p=0.002) and non-melanoma skin cancer (teledermatology median: 79 days; in-person consult median: 88 days; p<0.001). There was little consistency in the post-teledermatology care utilized across programs. Testing three programs with different resources used for local follow-up care, travel distance saved over 2013 was calculated. The program with surrogate dermatology providers had the most travel saved per patient. Implementation of teledermatology had no statistically significant impact on in-person wait times for dermatology clinics.
by Ashley Mateus.
Ph. D.

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Cooper, Ryan Mcomber. "A generic pathogen capture technology for sepsis diagnosis." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/83966.

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Thesis (Ph. D. in Medical and Engineering Physics)--Harvard-MIT Program in Health Sciences and Technology, June 2013.
"May 2013." Cataloged from PDF version of thesis.
Includes bibliographical references (pages 121-127).
Sepsis is a systemic inflammatory response that results the presence and persistence of microorganisms or their toxins in the bloodstream and it is diagnosed by detecting the presence of pathogens in blood. Despite improvements in modem medicine, sepsis has a high mortality rate that increases rapidly with every hour the patient does not receive optimal antibiotic therapy. Thus, there is a great demand for technologies that can accelerate pathogen detection and sepsis diagnosis. Our lab previously developed a micromagnetic-microfluidic pathogen isolation technology that can selectively remove pathogens from flowing whole human blood with high efficiency using micro- or nano-sized magnetic beads coated with microbe-specific antibodies [1, 2]. However, the identity of the pathogen is not known when a patient first presents with the clinical symptoms of sepsis, and currently, it can take days to a week to identify the specific pathogen type. The goal of this dissertation is to develop a generic pathogen collection technology that can be used to pull bacteria and fungi out of blood or other fluids without first knowing their identity, and to concentrate them for analysis and rapid identification. In Chapter 1, 1 will review the field of sepsis diagnostics and methods that have been employed to confront this challenge. In Chapter 2, I describe the development of a natural human opsonin - Mannose Binding Lectin (MBL) - as a generic pathogen capture molecule. MBL is found in human blood and is part of the innate immune system; it has been previously shown to bind over 90 different types of pathogens, including gram negative and positive bacteria, fungi, viruses and parasites [3-5]. The studies described in this chapter include development and optimization of methods to coat magnetic beads with MBL and demonstration that MBL beads bind to wide range of pathogens with high efficiency in saline and blood. The binding of MBL beads to sample pathogens is tested under a wide range of conditions to determine optimal bead concentration, binding time and sample treatments to maximize binding in blood. In Chapter 3, 1 describe development of a device that efficiently concentrates and visualizes fungi tagged with the magnetic MBL micro beads. Visualization is made possible by controlling the balance of fluidic shear stress and magnetic force on the tagged pathogens in the device, which enables spreading of the beads and bound fungi into a uniform layer that can be quickly quantified with fluorescent microscopy. Chapter 4 describes tools that I have developed to rapidly concentrate and purify magnetically tagged bacteria from blood and other complex samples for polymerase chain reaction (PCR) detection. The MBL-bead approach is used to pull out and concentrate pathogens from large sample volumes, and to remove contaminating human DNA, so that sensitive detection can be carried out using PCR amplification. The efficiency of this new MBL-based, sample pre-concentration method is compared to existing commercial isolation methods for analysis of both blood and food samples. Finally, I discuss the implications of these findings in Chapter 5.
by Ryan Mcomber Cooper.
Ph.D.in Medical and Engineering Physics

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Abudayyeh, Omar O. "Discovery of novel CRISPR enzymes for transcriptome engineering and human health." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/120887.

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Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, September 2018.
Page 399 blank. Cataloged from PDF version of thesis.
Includes bibliographical references (pages 210-229).
RNA plays important and diverse roles in biology, yet molecular tools to measure and manipulate RNA are limited. Recently, the bacterial adaptive immune system, CRISPR, has revolutionized our ability to manipulate DNA, but no known RNA-targeting versions exist. To discover parallel bacterial RNA-targeting systems that could be used for transcriptome engineering, we developed a computational pipeline to mine for novel Class 2 CRISPR systems across more than 25,000 bacterial genomes. Among the many novel CRISPR systems, we found a programmable RNA-targeting CRISPR system, CRISPR-Cas 13, that could provide immunity to E. coli against the ssRNA MS2 phage and biochemically characterized the enzyme. We adapted CRISPR-Casl3 for modulating the transcriptome in mammalian and plant cells by heterologously expressing Casl 3 and engineering the enzyme to precisely knockdown, bind, and edit RNA. Cas 13 knockdown was as efficient as RNA interference, but much more specific, across many transcripts tested. RNA editing with Cas 13 was also highly efficient, with up to 90% base editing rates, and as low as 20 off-targets with engineered specificity versions. Lastly, we combined Cas13 with isothermal amplification to develop a CRISPR-based diagnostic (CRISPR-Dx), providing rapid DNA or RNA detection with single-molecule sensitivity and singlebase mismatch specificity. We used this Casl3a-based molecular detection platform, termed SHERLOCK (Specific High Sensitivity Enzymatic Reporter UnLOCKing), to specifically detect pathogenic bacteria, genotype human DNA, and identify cell-free tumor DNA mutations. Our results establish CRISPR-Cas13 as a flexible platform for RNA targeting with wide applications in RNA biology, diagnostics, and therapeutics.
by Omar O. Abudayyeh.
Ph. D. in Medical Engineering and Medical Physics

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Pawlosky, Annalisa M. (Annalisa Marie). "Single molecule techniques to probe decision-making processes in developmental biology." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/87503.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references.
This work investigates the fundamental processes used by mammalian cells and organisms to make decisions during embryonic development. Current technologies that evaluate biological phenomenon often force a compromise between quantification of gene expression via bulk assays and qualitative imaging of cell and tissue heterogeneity. There are few options that allow for quantitative, high-resolution, single-cell analysis that is robust but not associated with a high degree of technical difficulty or obscured by amplification. Here, we address these issues using two model systems, the developing mammalian inner ear and single mouse embryonic stem cells (mESCs) during the process of X inactivation, to demonstrate our ability to perform single-cell, single-molecule assays that reveal both highly quantitative and spatial information. Accordingly, we adapted a high resolution, single-molecule RNA fluorescent in situ hybridization technique (smFISH) to study gene expression in the inner ear and perform allele-specific detection of the X chromosome in mESCs. We used previously-published smFISH procedures as our initial template for investigating biological signaling phenomena in these two systems. To study gene expression in the mouse inner ear, we developed a modified smFISH strategy to investigate mRNA transcript expression patterns in the cochlea during auditory hair cell development. The mammalian cochlea, a highly specialized and complex organ, beautifully demonstrates both the depth and breadth of the smFISH technique. To assay signaling behavior and topological changes of the X chromosome prior to X inactivation, we incorporated a novel allele-specific modification into the smFISH technique. We investigate the allele-specific expression patterns of eight genes that tile the X chromosome, which were chosen for their varied putative roles before, during and after X chromosome inactivation. Taken together, these two systems recapitulate the strength of the smFISH technique and its adaptations. The goals of this thesis were twofold: (1) expand the smFISH technique to work in specialized mammalian systems such as the cochlea and (2) demonstrate allele-specific DNA topological changes and expression patterns in mESCs. Elucidating high-resolution, single-molecule quantifiable imaging methods for application to complex tissues or allele-specific probing will have profound impacts on future investigations and promote a deeper comprehension of these systems.
by Annalisa M. Pawlosky.
Ph. D.

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Rooney, Michael Steven. "Integrative genomic approaches to dissecting host-tumor and host-pathogen immune processes." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/98722.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2015.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 243-263).
Two parallel research efforts were pursued. First, we conducted a systematic exploration of how the genomic landscape of cancer shapes and is shaped by anti-tumor immunity. Using large-scale genomic data sets of solid tissue tumor biopsies, we quantified the cytolytic activity of the local immune infiltrate and identified associated properties across 18 tumor types. The number of predicted MHC Class I-associated neoantigens was correlated with cytolytic activity and was lower than expected in colorectal and other tumors, suggesting immune-mediated elimination. We identified recurrently mutated genes that showed positive association with cytolytic activity, including beta-2- microglobulin (B2M), HLA-A, -B and -C and Caspase 8 (CASP8), highlighting loss of antigen presentation and blockade of extrinsic apoptosis as key strategies of resistance to cytolytic activity. Genetic amplifications were also associated with high cytolytic activity, including immunosuppressive factors such as PDL1/2 and ALOX12B/15B. Our genetic findings thus provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity. Second, we combined measurements of protein production and degradation and mRNA dynamics so as to build a quantitative genomic model of the differential regulation of gene expression in lipopolysaccharide-stimulated mouse dendritic cells. Changes in mRNA abundance play a dominant role in determining most dynamic fold changes in protein levels. Conversely, the preexisting proteome of proteins performing basic cellular functions is remodeled primarily through changes in protein production or degradation, accounting for more than half of the absolute change in protein molecules in the cell. Thus, the proteome is regulated by transcriptional induction for newly activated cellular functions and by protein lifecycle changes for remodeling of preexisting functions.
by Michael Steven Rooney.
Ph. D.

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Colucci, Lina Avancini. "Quantifying fluid overload with portable magnetic resonance sensors." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/117894.

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Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2018.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 163-173).
The objective of this work was to translate the diagnostic capabilities of magnetic resonance imaging (MRI) to the patient bedside, specifically for the purpose of quantifying fluid overload. MRI is used extensively in clinical medicine, but it is still not used for routine diagnostics due to high cost, limited availability, and long scan times. Many of these impracticalities come from the hardware requirements associated with generating images. Images, however, are not necessary to harness some of magnetic resonance's (MR's) diagnostic potential. This thesis demonstrates that that a single-voxel MR sensor can obtain the same results as a traditional MRI in both phantoms and humans. A clinical study with hemodialysis patients and age-matched healthy controls was performed at MGH. The T2 relaxation times of study participants' legs were quantified at multiple time points with both a 1.5T clinical MRI scanner and a custom 0.27T single-voxel MR sensor. The results showed that the first sign of fluid overload is an increase in the relative fraction of extracellular fluid in the muscle. The relaxation time of the extracellular fluid in the muscle eventually increases after more fluid accumulates. Importantly, these MR findings occur before signs of lower-extremity edema are detectable on physical exam. Two healthy control subjects became dehydrated over the course of the study and the relative fraction of their extracellular fluid decreased. This incidental finding suggests MR can measure the full spectrum of hydration states. Furthermore, a single MRI measurement at a single time point can distinguish fluid overloaded patients from healthy controls. The amplitude associated with extracellular fluid most closely correlates to fluid loss, and these amplitude decreases are detectable with both the MRI and MR sensor. The results of this work point towards a promising future of using cheaper, faster MR sensors for bedside diagnostics.
by Lina Avancini Colucci.
Ph. D. in Medical Engineering and Medical Physics

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Lindemer, Emily Rose. "Quantifiable MRI changes in cerebral white matter and their importance to aging, cognition, and Alzheimer's disease." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/111333.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2017.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 145-162).
Alzheimer's disease (AD) is a neurodegenerative disease for which there are no preventative or therapeutic interventions. It is currently understood to be linked to the accumulation of pathologic proteins in the brain. In the past several decades, a strong body of evidence has accumulated that is suggestive of a vascular-related pathway in AD. A deeper understanding of this phenomenon is critical in advancing our understanding of the AD biological process as well and may lead to the discovery of novel therapeutic targets. A common age-related change in the brain is the development of white matter signal abnormalities (WMSA) as seen on magnetic resonance imaging (MRI). These lesions are related to cognitive function and are thought to be due to compromised integrity of the brain's vascular system. Despite evidence that WMSA are known to influence the clinical progression of AD, we do not currently view AD as a vascular disease nor do we use WMSA as a clinical indicator of AD. This is because we still do not know whether or not WMSA are a distinct phenomenon in AD, their relationship to traditional AD biomarkers, and how they independently contribute to clinical status. In this work, we examine if and how WMSA are related to AD conversion, whether they differ in their spatial distribution between typical aging and AD, and how they are linked to classic pathologic markers of AD. This work also includes technical development for WMSA quantification and baseline studies of WMSA in cognitively healthy aging. The main findings of this work suggest that WMSA are distinctly different in AD than in typical aging and have a unique role in AD progression. This not only motivates the utility of WMSA in our clinical treatment of AD, but also provides insight into the biological underpinnings of the disease process that may lead to novel therapeutic targets.
by Emily Rose Lindemer.
Ph. D.

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Radovic-Moreno, Aleksandar Filip. "Bacteria-targeting nanoparticles for managing infections." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/79250.

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Thesis (Ph. D. in Chemical and Biomedical Engineering)--Harvard-MIT Program in Health Sciences and Technology, 2013.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Bacterial infections continue to be a significant concern particularly in healthcare settings and in the developing world. Current challenges include the increasing spread of drug resistant (DR) organisms, the side effects of antibiotic therapy, the negative consequences of clearing the commensal bacterial flora, and difficulties in developing prophylactic vaccines. This thesis was an investigation of the potential of a class of polymeric nanoparticles (NP) to contribute to the management of bacterial infections. More specifically, steps were taken towards using these NPs (1) to achieve greater spatiotemporal control over drug therapy by more targeted antibiotic delivery to bacteria, and (2) to develop a prophylactic vaccine formulation against the common bacterial sexually transmitted disease (STD) caused by Chlamydia trachomatis. In the first part, we synthesized polymeric NPs containing poly(lactic-co-glycolic acid)- block-poly(L-histidine)-block-poly(ethylene glycol) (PLGA-PLH-PEG). We show that these NPs are able to bind to bacteria under model acidic infection conditions and are able to encapsulate and deliver vancomycin to inhibit the growth of Staphylococcus aureus bacteria in vitro. Further work showed that the PLGA-PLH-PEG-based NPs demonstrated the potential for competition for binding bacteria at a site of infection from soluble protein and model phagocytic and tissue-resident cells in a NP composition dependent manner. The NPs demonstrated low toxicity in vitro, were well tolerated by mice in vivo, and circulated in the blood on timescales comparable to control PLGA-PEG NPs. In the second part, we used PLGA-PLH-PEG-based NPs to design a prophylactic vaccine against the obligate intracellular bacterium Chlamydia trachomatis, the most common cause of bacterial STD in the world. Currently, no vaccines against this pathogen are approved for use in humans. We first formulated NPs encapsulating the TLR7 agonist R848 conjugated to poly(lactic acid) (R848-PLA) in PLGA-PLH-PEG-based NPs, then incubated these R848-NPs with UV-inactivated C. trachomatis bacteria in acidity, forming a construct. Mice immunized with this vaccine via genital or intranasal routes demonstrated protection from genital infection post immunization in a primarily CD4⁺ T cell-dependent manner. These results may suggest avenues for future work in designing and developing more targeted drug therapies or vaccine formulations for managing bacterial infections using polymeric nanoparticles.
by Aleksandar Filip Radovic-Moreno.
Ph.D.in Chemical and Biomedical Engineering

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Berezina, Maria Andrey. "Medial olivocochlear efferent (MOC) effects on stimulus frequency otoacoustic emissions (SFOAEs) and auditory-nerve compound action potentials (CAP) in guinea pigs." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/97822.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, February 2015.
Cataloged from PDF version of thesis. "February 2015."
Includes bibliographical references.
In humans, SFOAEs can non-invasively assess MOC strength and, may predict the MOC reduction of damage from traumatic sounds. However, the functionally important MOC effect is inhibition of auditory-nerve (AN) responses. Understanding the relationship between MOC effects on SFOAEs and AN CAPs is important for understanding SFOAE generation and for development of clinical tools that use these measures. This thesis presents several novel data sets that address MOC effects on SFOAEs, CAPs and the relationship between them in guinea pigs. Classic theory indicates that SFOAEs come from cochlear irregularities that coherently reflect energy at the peak of the traveling wave (TW), and that reflected energy arrives in the ear canal as a single wave at certain delay. Contrary to theory, in humans and chinchillas there have been reports of SFOAEs having multiple components with different delays, and that lowfrequency SFOAE delays are too short. The first thesis aim used time-frequency analysis to show that guinea pigs have frequency regions over which SFOAEs appear to have multiple components. However, we argue that the multiple components can be a simple result of variations in the patters of irregularities near the TW peak and are not necessarily indicative of multiple SFAOE sources. From comparison of our SFOAE delays with previously reported neural delays, we hypothesize that short SFOAE delays at low frequencies arise from a cochlear motion with a group delay shorter than the TW group delay. Aim 2 investigated how SFOAEs are affected by brainstem electrical stimulation of MOC fibers and found that MOC activation sometimes inhibited and sometimes enhanced SFOAEs. MOC stimulation always decreased CAP sensitivity which rules out SFOAE enhancement from increased cochlear amplification. We propose that shock-evoked MOC activity increases cochlear irregularity which results in increased SFOAE amplitudes. Aim 3 investigated the relationship between MOC effects on SFOAEs and tone-pip-evoked AN CAPs at same frequency and sound level. The ratio of the MOC effect on the SFOAE to the MOC effect on the CAP showed a highly-significant decrease (p<0.001) as the strength of MOC stimulation was increased. Although this observation was unexpected, several hypothesis to explain it are presented.
by Maria Andrey Berezina.
Ph. D.

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Krishnaswamy, Pavitra. "Algorithms for enhanced spatiotemporal imaging of human brain function." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/95844.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2014.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references (pages 123-142).
Studies of human brain function require technologies to non-invasively image neuronal dynamics with high spatiotemporal resolution. The electroencephalogram (EEG) and magnetoencephalogram (MEG) measure neuronal activity with high temporal resolution, and provide clinically accessible signatures of brain states. However, they have limited spatial resolution for regional dynamics. Combinations of M/EEG with functional and anatomical magnetic resonance imaging (MRI) can enable jointly high temporal and spatial resolution. In this thesis, we address two critical challenges limiting multimodal imaging studies of spatiotemporal brain dynamics. First, simultaneous EEG-fMRI offers a promising means to relate rapidly evolving EEG signatures with slower regional dynamics measured on fMRI. However, the potential of this technique is undermined by MRI-related ballistocardiogram artifacts that corrupt the EEG. We identify a harmonic basis for these artifacts, develop a local likelihood estimation algorithm to remove them, and demonstrate enhanced recovery of oscillatory and evoked EEG dynamics in the MRI scanner. Second, M/EEG source imaging offers a means to characterize rapidly evolving regional dynamics within an estimation framework informed by anatomical MRI. However, existing approaches are limited to cortical structures. Crucial dynamics in subcortical structures, which generate weaker M/EEG signals, are largely unexplored. We identify robust distinctions in M/EEG field patterns arising from subcortical and cortical structures, and develop a hierarchical subspace pursuit algorithm to estimate neural currents in subcortical structures. We validate efficacy for recovering thalamic and brainstem contributions in simulated and experimental studies. These results establish the feasibility of using non-invasive M/EEG measurements to estimate millisecond-scale dynamics involving subcortical structures. Finally, we illustrate the potential of these techniques for novel studies in cognitive and clinical neuroscience. Within an EEG-fMRI study of auditory stimulus processing under propofol anesthesia, we observed EEG signatures accompanying distinct changes in thalamocortical dynamics at loss of consciousness and subsequently, at deeper levels of anesthesia. These results suggest neurophysiologic correlates to better interpret clinical EEG signatures demarcating brain dynamics under anesthesia. Overall, the algorithms developed in this thesis provide novel opportunities to non-invasively relate fast timescale measures of neuronal activity with their underlying regional brain dynamics, thus paving a way for enhanced spatiotemporal imaging of human brain function.
by Pavitra Krishnaswamy.
Ph. D.

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Gorman, Bryan Robert. "Multi-scale imaging and informatics pipeline for in situ pluripotent stem cell analysis." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/97824.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2015.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 86-97).
Human pluripotent stem (hPS) cells have the ability to reproduce indefinitely and differentiate into any cell type of the body, making them a potential source of cells for medical therapy and an ideal system to study fate decisions in early development. However, hPS cells exhibit a high degree of heterogeneity, which may be an obstacle to their clinical translation. Heterogeneity is at least partially induced as an artifact of removing the cells from the embryo and culturing them on a plastic dish. hPS cells grow in spatially patterned colony structures, which necessitates in situ quantitative single-cell image analysis. This dissertation offers a tool for analyzing the spatial population context of hPS cells that integrates automated fluorescent microscopy with an analysis pipeline. It enables high-throughput detection of colonies at low resolution, with single-cellular and sub-cellular analysis at high resolutions, generating seamless in situ maps of single-cellular data organized by colony. We demonstrate the tool's utility by analyzing inter- and intra-colony heterogeneity of hPS cell cycle regulation and pluripotency marker expression. We measured the heterogeneity within individual colonies by analyzing cell cycle as a function of distance. Cells loosely associated with the outside of the colony are more likely to be in G1, reflecting a less pluripotent state, while cells within the first pluripotent layer are more likely to be in G2, possibly reflecting a G2/M block. Our analysis tool can group colony regions into density classes, and cells belonging to those classes have distinct distributions of pluripotency markers and respond differently to DNA damage induction. Our platform also enabled noninvasive texture analysis of live hPS colonies, which was applied to monitoring subtle changes in differentiation state. Lastly, we demonstrate that our pipeline can robustly handle high-content, high-resolution single molecular mRNA FISH data by using novel image processing techniques. Overall, the imaging informatics pipeline presented offers a novel approach to the analysis of hPS cells, which includes not only single cell features but also spatial configuration across multiple length scales.
by Bryan Robert Gorman.
Ph. D.

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Dixit, Atray (Atray Chitanya). "Methods for bounding genetic nonlinearities." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/117897.

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Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2018.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Complex hierarchical structures are a hallmark of life. Within multicellular organisms, the building blocks of these structures are cells; within cells, they are genes. The interdependence of these building blocks is difficult to measure but is integral to the biological processes of health and disease, which emerge from the dynamism of thousands of interacting genes. This cooperativity manifests in particular mutations which accumulate over the course of cancer progression, gender-specific medical conditions, and transcription factor cocktails used to reprogram differentiated cells into stem cells. However, it is experimentally intractable to test the significance of perturbing every unique combination of genes. Instead, we explore gross features of this interaction space to determine how prevalent these synergies are. We take a top-down approach, creating new methods to measure the effects of removing genes from the full set. In the first, we develop a method to measure the transcriptional response to genetic perturbations across hundreds of thousands of cells revealing opposing classes of transcription factors regulating the immune response of dendritic cells. In the second, we create a method to measure how millions of combinations of genetic perturbations impact the growth rate of cancer cell lines.
by Atray Dixit.
Ph. D. in Medical Engineering and Medical Physics

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Castleberry, Steven Andrew. "Controlled local delivery of RNA : regulating tissue morphogenesis." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/98724.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2015.
Page 283 blank. Cataloged from PDF version of thesis.
Includes bibliographical references.
RNA interference (RNAi) is a powerful technology that provides a means to alter the expression of a specific protein based on a targeted RNA sequence. This is done by taking advantage of existing cellular machinery present within all eukaryotic cells which use short double-stranded RNA sequences as guides for RNA induced silencing. The potential for RNAi in medicine is enormous, providing a new approach to treat the complex biological dysregulation underlying many diseases. This promise of a new branch of therapeutics however has been mired with difficulties. RNA is quickly degraded by nucleases that are prevalent in the blood and throughout the body, it is highly immunogenic, and systemic delivery is complicated by high clearance rates. As such, developing formulations for the effective delivery of short RNAs presents significant hurdles. Local delivery can limit numerous unwanted systemic side effects of therapies and it maintains the highest therapeutic index possible in a targeted area before clearance. As such, the local delivery of siRNA may hold just as much potential as systemic delivery with significantly reduced complications. Layer-by-layer (LbL) assembly is a robust method that has been successfully demonstrated for the localized and sustained delivery of many biologic therapeutics and biomolecules. Developing an LbL film capable of delivering siRNA locally would offer a powerful new approach to the treatment of local disorders. This approach could be combined with existing medical devices to improve patient outcomes by directly addressing pathologic dysregulation in the area of interest. One field where the local treatment of dysregulation could be of particular interest is that of wound healing. Wound healing is a complex and highly synchronized process of multiple biological pathways, consisting of an assortment of cytokines, growth factors, and varied cell types which evolves over time. The development of a drug delivery system that can locally modify cell behavior on the basic level of gene transcription would be a powerful tool to alter the dynamics of wound healing. There are many known complications of wound healing, ranging from chronic ulcerative wounds to hypertrophic contractile scars, which dramatically affect the lives of tens of millions of patients every year. Through RNA interference, one could specifically target the key mediators of these complications, providing a means to more effectively regulate the wound healing process in vivo. The capability to deliver siRNA locally to address these complications is a significant advance in the current state of wound treatment. As such, this work presents an opportunity to substantially improve the current standard of treatment for patients and their wound healing outcomes. Herein, we present the design and preclinical evaluation of a number of strategies to develop ultra-thin polymer coatings for the controlled delivery of RNA both in vitro and in vivo. We used Layer-by-Layer assembly to create siRNA containing polymer-based films that can sustain the release of complexed siRNA over physiologically relevant timescales for local delivery into tissues. We describe the development of the first high-throughput approach for LbL assembly and screening and its use to identify lead candidate film architectures for RNA delivery. We then apply these findings to treat dysregulation in two distinct animal models; a chronic diabetic mouse wound model and a third-degree bum model in rats, targeting three different genes of interest independently. These coatings were demonstrated to effectively coat a number of medically relevant substrates including bandages, sutures, surgical staples, nanoparticles, microparticles, and microneedles. This body of work provides insight into how siRNA can be incorporated into thin film assemblies and the design criteria to achieve successful gene knockdown in vitro and in vivo.
by Steven Andrew Castleberry.
Ph. D.

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Bhatia, Gaurav. "Estimating evolutionary parameters and detecting signals of natural selection from genetic data." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/90171.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Even prior to the elucidation of the structure of DNA, the theoretical foundations of population genetics had been well developed. Advances made by Sewall Wright, John B.S. Haldane, and Ronald A. Fisher form the basis with which we understand the statistical dynamics of evolution and inheritance. Using this foundation, recent advances in DNA profiling technologies have enabled genome-wide analysis of thousands of individuals from a diverse array of human populations. These new analyses can answer fundamental questions about human population differences, natural selection, and admixture. However, with this deluge of newly available data, confusion about statistical methods may lead to misleading conclusions about human population history and natural selection. We view it as imperative to put analyses of population differences on sound statistical footing. In the course of this thesis, we have developed methods and reanalyzed existing results in two related areas: the detection of natural selection and estimation of genetic distance. Throughout our work, we have strived for statistical rigor, attempting to understand variation in previously reported results and provide a resource for other researchers in our field. Where necessary, we have made simplifying assumptions about evolutionary processes but have attempted to state these clearly and validate their reasonableness using simulations. Our efforts have culminated in three projects that will be described in the subsequent chapters: (1) A model based approach to detect natural selection in 3 populations (2) A protocol to generate consistent estimates of FST and, (3) Reanalysis of previously reports of selection in African Americans since the arrival of their ancestors in the Americas. We note that our work is just part of a rich literature on population and evolutionary genetics. We have attempted to cite this literature in detail and have published our own methods to enable others to utilize and improve upon them.
by Gaurav Bhatia.
Ph. D.

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Oliva, Jorge Nuria. "Localized and disease-selective drug delivery using adhesive hydrogels for treatment of locally advanced TNBC." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/104611.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2016.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 111-117).
Triple negative breast cancer (TNBC) is an aggressive form of cancer that represents 20% of invasive breast cancers, and about 15% are locally advanced at time of presentation. TNBC is negative for estrogen and progesterone receptor, as well as for HER2, and hence it is not treatable with common endocrine treatment such as tamoxifen or Herceptin. Systemic neoadjuvant therapy has been established as the preferred therapeutic approach for locally advanced breast cancer, downstaging the disease and preventing mastectomy. However, complications of systemic chemotherapy are devastating. Local therapy would prevent high concentrations of circulating drug and reduce off-target tissue retention. Yet, the means to attain ideal release kinetics and selective uptake remain elusive. I developed a novel class of biocompatible and biodegradable adhesive materials based on dendrimer and dextran that can coat the tumor and locally release doxorubicin in a controlled manner. Doxorubicin was conjugated to the dendritic component of the adhesive hydrogel to form a pro-drug capable of being released over time as the hydrogel degrades at a pre-programmed rate. The pro-drug was further modified with a ligand capable of sensing and discerning between healthy and cancer cells and facilitating uptake through receptor-mediated endocytosis (RME). The platform developed herein provides a paradigm shift in the way we treat cancer, in a local, selective and targeted manner, to impart optimal clinical outcome.
by Nuria Oliva Jorge.
Ph. D.

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16

Ren, Yin Ph D. Massachusetts Institute of Technology. "Tumor-penetrating delivery of small interfering RNA therapeutics." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/72914.

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Thesis (Ph. D. in Medical Engineering)--Harvard-MIT Program in Health Sciences and Technology, 2012.
Vita. Cataloged from PDF version of thesis.
Includes bibliographical references (p. 234-250).
Efforts to sequence cancer genomes have begun to uncover comprehensive lists of genes altered in cancer. Unfortunately, the number and complexity of identified alterations has made dissecting the underlying biology of cancer difficult, as many genes are not amenable to manipulation by small molecules or antibodies. RNA interference (RNAi) provides a direct way to assess and act on putative cancer targets. However, the translation of RNAi into the clinic has been thwarted by the "delivery" challenge, as small interfering RNA (siRNA) therapeutics must overcome clearance mechanisms and penetrate into tumor tissues to access cancer cells. This thesis sought to develop nanotechnology-based platforms to rapidly discover and validate cancer targets in vivo. First, we developed versatile surface chemistries for nanoparticle tumor targeting. Leveraging new discoveries in amplified transvascular transport, we designed a siRNA delivery system that integrates the tumor specificity and tissue-penetrating ability of tumor-penetrating peptides with membrane penetration properties of protein transduction domains to direct siRNA to tumors in vivo. Second, we utilized this delivery system to bridge the gap between cancer genomic discovery and in vivo target validation. Comprehensive analysis of ovarian cancer genomes identified candidate targets that are undruggable by traditional approaches. Tumor-penetrating delivery of siRNA against these genes potently impeded the growth of ovarian tumors in mice and improved survival, thereby credentialing their roles in tumor initiation and maintenance. Lastly, we described efforts extending this platform for clinical translation. Mechanistic studies identified functional properties that favored receptor-specific siRNA delivery. We also explored a strategy to improve the microdistribution of successively dosed siRNA therapeutics through modulating the tumor microenvironment. Finally, we investigated the utility of the system in primary human tumors derived from patients with ovarian cancer. Together, these findings illustrate that the combination of cancer genomics with the engineering of siRNA delivery nanomaterials establishes a platform for discovering genes amenable to RNAi therapies. As efforts in genome sequencing accelerate, this platform illustrates a path to clinical translation in humans.
by Yin Ren.
Ph.D.in Medical Engineering

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17

Haseley, Nathan Scott. "A single-cell perspective on infection." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/103500.

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Thesis: Ph. D. in Bioinformatics, Harvard-MIT Program in Health Sciences and Technology, 2016.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 83-94).
The clinical course of infection is ultimately determined by a series of cellular interactions between invading pathogens and host immune cells. It has long been understood that these interactions, even when they occur in tissue culture models, give rise to a wide variety of different outcomes, some beneficial to the host, others to the pathogen. These cellular interactions, however, are typically studied at a bulk level; masking this cell-to-cell variation, losing important information about the full range of possible host-pathogen interactions, and leaving the mechanistic basis for these different outcomes largely unexplored. Here, we present a system that combines single-cell RNA sequencing with fluorescent markers of infection outcome to directly correlate host transcription signatures with infection outcome at the single cell level. Applying this system to the well-characterized model of Salmonella enterica infection of mouse macrophages, we found: 1) Unique transcription signatures associated with bacterial exposure and bacterial infection, 2) Sustained high levels of heterogeneity in immune pathways in infected macrophages, and 3) A novel subpopulation of macrophages characterized by high expression of the Type I Interferon response after infection. Upon further investigation we found that this heterogeneity in the host Type I Interferon response was the result of heterogeneity in the population of infecting bacteria, namely in the extent of PhoPQ-mediated LPS modifications. This work highlights the importance of heterogeneity as a characteristic of bacterial populations that can influence the host immune response. It also demonstrates the benefits of examining infection with single-cell resolution.
by Nathan Scott Haseley.
Ph. D. in Bioinformatics

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18

Helman, Elena. "Somatic retrotransposition in the cancer genome." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/87504.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, February 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 128-144).
Cancer is a complex disease of the genome exhibiting myriad somatic mutations, from single nucleotide changes to various chromosomal rearrangements. The technological advances of next-generation sequencing enable high-throughput identification and characterization of these events genome-wide using computational algorithms. Retrotransposons comprise 42% of the human genome and have the capacity to "jump" across the genome in a copy-and-paste manner. Recent studies have identified families of retrotransposable elements that are currently active. In fact, retrotransposons constitute a major source of human genetic variation, and somatic retrotransposon insertions have been implicated in several cancers, including an insertion into the APC tumor suppressor in a colorectal tumor. Because of the highly repetitive nature of these elements, however, the full extent of somatic retrotransposon movement across cancer remains largely unexplored. To this end, we developed TranspoSeq, a computational framework that identifies retrotransposon insertions from paired-end whole genome sequencing data, and TranspoSeq- Exome, a tool that localizes these insertions from whole-exome data. TranspoSeq identifies novel somatic retrotransposon insertions with high sensitivity and specificity in simulated data and with a 94% validation rate via site-specific PCR. Next, we applied these methods to wholegenomes from 200 tumor/normal pairs and whole-exomes from 767 tumor/normal pairs across 11 tumor types as part of The Cancer Genome Atlas (TCGA) Pan-Cancer Project. We discover more than 800 somatic retrotransposon insertions primarily in lung squamous, head and neck, colorectal and endometrial carcinomas, while glioblastoma multiforme and acute myeloid leukemia show no evidence of somatic retrotransposition. Moreover, many somatic retrotransposon insertions occur in known cancer genes. TranspoSeq-Exome uncovers 35 additional somatic retrotransposon insertions into exonic regions, including an insertion into an exon of the PTEN tumor suppressor in endometrial cancer. Finally, we integrate orthogonal genomic and clinical data to characterize features of retrotransposon insertion and samples that exhibit extensive somatic retrotransposition. We present a large-scale, comprehensive analysis of retrotransposon movement across tumor types using next-generation sequencing data. Our results suggest that somatic retrotransposon insertions may represent an important class of tumor-specific structural variation in cancer and future studies should incorporate this form of somatic genome aberration.
by Elena Helman.
Ph. D.

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19

Lau, Hew Mun. "Disease marketing and patient coping : a research study." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/78159.

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Thesis (S.M.)--Harvard-MIT Program in Health Sciences and Technology, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 80-87).
BACKGROUND: There is a high prevalence of disease marketing actions in the United States that are targeted towards patients with chronic illness. However, no study has assessed the direct effects of these marketing actions on patient coping attitudes and behaviors. OBJECTIVES: This study aims to investigate whether the mere presence of disease marketing impacts patient coping and if so, how do they affect patients' coping attitudes and behaviors. METHODS: We conducted a controlled experiment using online questionnaires to assess the disease perceptions, coping decisions and disease disclosure behaviors of 108 subjects. The subjects were divided into two groups where the experimental group (N = 55) was shown marketing actions associated with a fictitious disease called Karlsen's Disease while the control group (N = 53) was not shown any marketing actions. The subjects were then asked a series of questions related to health-related coping behaviors and non-health related social behaviors. T-tests and chi-square analyses were used to analyze the behavioral differences between the experimental (high-marketing) and control (no-marketing) groups. RESULTS: Subjects in the high-marketing group were overall significantly more willing to draft a will than subjects in the no-marketing group (t(106) = 2.64, p = 0.01); High-marketing group subjects were overall significantly more likely to wear a medical ID bracelet than no-marketing group subjects (c²(1, N = 108) = 3.71, p = 0.05); Among subjects who were willing to request a menu accommodation at a dinner party, those who were in the high-marketing group were significantly more likely to disclose their disease to the party host (c²(1, N = 90) = 4.65, p = 0.03); Subjects in the high-marketing group were also significantly more likely to anticipate greater understanding from the party host towards their menu accommodation request. When controlled for gender, women in the high-marketing group were more likely to join a patient support group (t(61) = 1.75, p = 0.09), and less likely to ask family and friends to shave their heads in show of solidarity (t(18) = -1.97, p = 0.07) than women in the no-marketing group; Men in the high-marketing group were more likely than men in the no-marketing group to disclose their health condition to the dinner party host (c²(1, N = 47) = 3.61, p = 0.06). Finally, among subjects with at least a 4-year college degree, those in the high-marketing group were more willing than those in the no-marketing group to wear a face mask to protect themselves from airborne pathogens in crowded public places (t(61) = 1.79, p = 0.08). CONCLUSIONS: Based on our results, the presence of disease marketing is anticipated to have a general positive impact on patient coping attitudes and behaviors. Chronically ill patients exposed to disease marketing actions are expected to anticipate less stigma from others, have increased willingness to disclose their illness and adopt health seeking behaviors. Disease marketing is also expected to have differential impact on patients based on their gender and level of education. Follow-up studies using real patients with chronic illness should be carried out to confirm the findings from this study.
by Hew Mun Lau.
S.M.

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20

Li, Leon Daliang. "Microfluidic enabling technologies for measurement of the selective permeability of the mucus barrier." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/79247.

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Thesis (Ph. D. in Electrical and Medical Engineering)--Harvard-MIT Program in Health Sciences and Technology, 2013..
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 64-72).
Mucus is a biological hydrogel which lines the wet (non-keratinized) epithelia of the body. Mucus provides a gateway between the cells of the epithelium and the outside world, and is postulated to provide a selective filtering function which is critical to physiological functioning and has been implicated in diseases. Currently, much of the mechanisms and criteria of this selective filtering function is not well understood. In this thesis, we contribute novel microfluidic devices to characterize the selective permeability properties of the mucus barrier. Microfluidics provides the engineering ability to create channels with precise geometries, fluid flow capability, and allow chemical concentration gradients. Our devices mimic the physiological environment of the mucosa and enable improved measurements of the mucus layer selective permeability. The first microfluidic device mimics the acid barrier function of the stomach mucus layer. This device reproduces on-chip the secretion of mucus by the gastric mucosa into an acidic stomach lumen. We use this device to demonstrate that the secretion of mucins, the glycoprotein structural component of mucus, contributes significantly to the acid barrier function by continuously binding H'. The second microfluidic device probes the permeability of the mucus barrier to nanoscale peptides, as a model for drug molecules and in vivo signaling molecules. The device enabled the creation of a mucus layer next to a flowing aqueous layer, mimicking the in vivo mucus layer and lumen of the gastrointestinal, respiratory, and female reproductive tracts. Peptides added to the aqueous flow diffused across the mucus barrier interface into the mucus layer. This device demonstrated that the mucus barrier provides selective permeability to nanoscale peptides based on electrostatic interactions, and suggest novel surface functionalization strategies for drug carriers to improve mucosal drug delivery. Taken together, this thesis provides new microfluidic tools to probe the selective permeability function of the mucus barrier. Using the microfluidic tools, we show new mechanistic understanding of this barrier.
by Leon Daliang Li.
Ph.D.in Electrical and Medical Engineering

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21

German, Alexandra Elisa. "Paxillin-dependent control of tumor angiogenesis." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/87505.

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Thesis: Ph. D. in Medical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 108-122).
Angiogenesis- the growth of new capillaries from existing vessels- is required for tumor growth; however, tumor vessels exhibit abnormal structure and function, which impairs the targeted delivery of anti-cancer agents. While directional migration of capillary endothelial cells is critical for normal angiogenesis, the mechanism by which oriented capillary cell migration is controlled or how it is deregulated during tumorigenesis is unknown. Recently our lab reported that the focal adhesion protein, paxillin, is required for directional migration of fibroblasts. Endothelial cells also express paxillin and localize it in their focal adhesions. Thus, I set out to analyze whether paxillin influences directional migration of endothelial cells. When the expression of paxillin is knocked down in endothelial cells, this enhances their migration but decreases their directional persistence in vitro and in vivo in migration, angiogenesis and developmental assays. Having confirmed that paxillin plays a central role in controlling oriented capillary cell migration, I then studied the mechanism by which it contributes to normal microvessel network formation and tumor angiogenesis. I found that paxillin knockdown increases microvessel density but causes loss of sprout orientation. These characteristics resemble those of tumor vasculature, and, in fact, studies revealed that tumors inhibit paxillin expression in endothelial cells in vitro and in vivo by secreting soluble factors, such as the potent angiogenic factor VEGF. Mechanistically, paxillin knockdown decreases expression of the VEGF receptor neuropilin 2 (NRP2) but not VEGF receptor 2, and this is mediated by the transcription factor GATA2. Direct knockdown of NRP2 also increases endothelial cell migration and vessel density in vitro and in vivo and these effects are rescued by over expressing paxillin. In summary, these studies have led to the discovery of a new mechanism for control of directional endothelial cell migration during angiogenesis that is mediated by paxillin-NRP2 signaling. Importantly, this previously unknown mechanism is deregulated in tumor angiogenesis, which may contribute to the enhanced, disorganized microvasculature that is hallmark of cancer. These findings also revealed a new function for the focal adhesion protein, paxillin, as a mediator of tumor angiogenesis, and elucidated a novel mechanism for control of the expression of NRP2.
by Alexandra Elisa German.
Ph. D. in Medical Engineering

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22

Laserson, Uri. "High-throughput methods for characterizing the immune repertoire." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/79246.

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Thesis (Ph. D. in Biomedical Engineering and Computational Biology)--Harvard-MIT Program in Health Sciences and Technology, February 2013.
"September 2012." Cataloged from PDF version of thesis.
Includes bibliographical references (p. 147-160).
The adaptive immune system is one of the primary mediators in almost every major human disease, including infections, cancer, autoimmunity, and inflammation-based disorders. It fundamentally functions as a molecular classifier, and stores a memory of its previous exposures. However, until recently, methods to unlock this information or to exploit its power in the form of new therapeutic antibodies or affinity reagents have been limited by the use of traditional, low-throughput technologies. In this thesis, we leverage recent advances in high-throughput DNA sequencing technology to develop new methods to characterize and probe the immune repertoire in unprecedented detail. We use this technology to 1) characterize the rapid dynamics of the immune repertoire in response to influenza vaccination, 2) characterize elite neutralizing antibodies to HIV, to better understand the constraints for designing an HIV vaccine, and 3) develop new methodologies for discovering auto-antigens, and assaying large libraries of protein antigens in general. We hope that these projects will serve as stepping-stones towards filling the gap left by low-throughput methods in the development of antibody technologies.
by Uri Laserson.
Ph.D.in Biomedical Engineering and Computational Biology

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23

Bonner, Daniel Kenneth. "Understanding barriers to efficient nucleic acid delivery with bioresponsive block copolymers." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/70811.

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Thesis (Ph. D.)--Harvard-MIT Program in Health Sciences and Technology, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references.
The delivery of nucleic acids has the potential to revolutionize medicine by allowing previously untreatable diseases to be clinically addressed. Viral delivery systems have been held back by immunogenicity and toxicity concerns, but synthetic vectors have lagged in transfection efficiency. This thesis describes the rational design and systematic study of three classes of bioresponsive polymers for nucleic acid delivery. A central theme of the study was understanding how the structure of the polymers impacted each of the intracellular steps of delivery, rather than solely the end result. A powerful tool for efficiently quantifying endosomal escape was developed and applied to each of the material systems described. First, a linear-dendritic poly(amido amine) -poly(ethylene glycol) (PAMAM-PEG) block copolymer system previously developed in our lab was evaluated and its ability to overcome the sequential barriers of uptake, endosomal escape, and nuclear import were characterized. Next, a class of crosslinked linear polyethyleimine (xLPEI) hyperbranched polymers, which can contain disulfideresponsive linkages, were synthesized and investigated. It was demonstrated that free polymer in solution, not the presence of a functional bioresponsive domain, was responsible for the highly efficient and relatively nontoxic DNA delivery of this promising class of crosslinked polyamines. Finally, this analysis was applied to siRNA delivery by a library of amine-functionalized synthetic polypeptides. The pH-responsive secondary structure, micelle formation, and ester hydrolysis were studied prior to the discrete barrier-oriented analysis of the siRNA delivery potential of this library. It is hoped that the tools, materials, and systemic analysis of structure-function relationships in this thesis will enhance the process of discovery and development of clinically relevant gene carriers.
by Daniel Kenneth Bonner.
Ph.D.

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24

Horwitz-Martin, Rachelle L. (Rachelle Laura). "Acoustic features of impaired articulation due to amyotrophic lateral sclerosis." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/113789.

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Thesis: Ph. D. in Biomedical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2017.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 213-227).
Progressive bulbar motor deterioration resulting from amyotrophic lateral sclerosis (ALS) leads to speech impairment. Despite the devastating consequences of speech impairment to life quality, few options are available to objectively assess speech motor involvement. The overarching goal of this research was to derive objective measures of speech acoustics that can be used to support clinical decision making. To achieve this goal, we obtained 121 speech samples from 33 patients with ALS who repeated the phrase "Buy Bobby a puppy" five times in succession. In total, 342 acoustic features were semi-automatically extracted from each speech recording. Pearson correlations were computed between each feature and three metrics of overall speech severity: sentence intelligibility, speaking rate, and communication efficiency. The findings were grounded within a physiologic framework where acoustic features were grouped into one of three domains that when combined, were hypothesized to broadly characterize articulatory performance: articulatory specification, articulatory coupling, and articulatory consistency. To obtain the most accurate prediction of ALS with the features we extracted, we compared two machine learning algorithms: linear regression and random forest. In shuffle-split cross-validation, the strongest mean Pearson correlations we obtained between actual and predicted intelligibility, speaking rate, and communication efficiency were 0.67, 0.74, and 0.77, respectively (SD=0.077, 0.050, and 0.059, respectively). Of the three domains, the specificity features were the most strongly associated with intelligibility impairments (mean r=0.68), and coupling was the most strongly associated with slower speaking rate (mean r=0.73). Specificity and coupling yielded similar performances in communication efficiency prediction. Other contributions of this thesis are that it is the first to implement a framework of dysarthric speech in terms of three domains: specification, coupling, and consistency; the first to validate automated formant tracking in dysarthric speech; and the first to perform an in-depth investigation into physiologically-inspired acoustic features that describe articulatory impairments of patients with ALS. Novel findings include the presence of abnormal formant coupling patterns, which may suggest greater tonguejaw coupling, in patients with more severe dysarthria due to ALS. Areas of future research involve further feature discovery, improved analysis methods, and a deeper understanding of relations to articulatory kinematics.
by Rachelle L. Horwitz-Martin.
Ph. D. in Biomedical Engineering

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25

Ye, Hongye. "An intraperitoneal implantable drug delivery device for the treatment of ovarian cancer." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/87501.

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Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 111-116).
Ovarian cancer is the fifth leading cause of cancer-related deaths in women and the deadliest gynecologic cancer. The current standard treatment for advanced ovarian cancer includes a minimally invasive cytoreduction surgery, followed by intravenous (IV) or intraperitoneal (IP) chemotherapy with cisplatin and taxol. Clinical trials showed that the IP cisplatin treatment regimen was able to prolong overall survival by 16 months but only 42% of subjects completed all cycles of the IP therapy. The primary reason for the early termination of the IP treatment is catheter-related complications. The implantation of the catheter is also a complex procedure that can only be performed at premier centers by trained personnel. An alternative for IP administration that eliminates catheter-related complications and simplifies IP drug administration would therefore allow more patients to enjoy the benefits of IP therapy. A drug delivery device for use in a mouse model was developed as a tool to prove that maintaining a low constant cisplatin concentration in the peritoneal cavity and serum would improve the treatment outcome and reduce drug-related toxicity in ovarian cancer, compared to periodic IP bolus drug infusion. The device demonstrated highly linear and easily tunable in vitro release and exhibited excellent in vitro-in vivo correlation. Investigations of the device pharmacokinetics in vivo proved that the device was able to maintain a low and constant cisplatin concentration both locally in the peritoneal cavity and in the serum over up to six weeks. In vitro cytotoxicity of continuous cisplatin dosing with various human ovarian cancer cells lines was demonstrated. An in vivo xenograft SKOV-3 tumor model was established and optimized to reflect the distribution of ovarian cancer metastases in humans. The device achieved effective tumor growth retardation without systemic toxicity. An IP bolus injection scheme with a similar area-under-curve (AUC), however, caused severe bone marrow depletion. The results verified that the treatment efficacy correlates with the AUC but not the peak concentration, Cma. These promising preclinical results highlight the potential of this new therapeutic regimen to change the course of ovarian cancer care and warrant the need for designing a human device before proceeding to human trials.
by Hongye Ye.
Ph. D. in Medical Engineering and Medical Physics

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26

Lysaght, Andrew Christopher. "Characterization of cochlear transcription, translation and energy extraction in aging and noise-induced pathology." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/95864.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 147-163).
Success in otologic practice is currently limited by the diagnostic tools and treatment options available to address an individual's specific presentation of hearing loss. This limitation results from insufficient characterization of the inner ear's biochemical environment as well as physical hurdles associated with accessing inner ear tissues. The encapsulation of the hearing organ within a bony shell and delicate nature of its tissues make standard tissue biopsy techniques impossible and leave many imaging methods impractical. This thesis sought to approach these clinical limitations in two ways: (1) performing novel transcriptional and translational characterizations of inner ear tissues and (2) development of a novel technique to access and communicate diagnostic information from within the inner ear. The first part of this thesis employs whole transcriptome shotgun sequencing to study murine inner ear transcriptional activity in young, healthy animals as well as changes associated with organ aging and noise-induced auditory neuropathy, an important mechanism of hearing impairment in humans. Knowledge of the inner ear's transcriptional behavior (Part I) is coupled with novel translational insights provided by high-throughput tandem mass-spectrometry (Part III) studies of human inner ear fluids obtained from healthy and pathologic populations. These studies illuminate homeostatic mechanisms employed by the highly specialized inner ear tissues, providing a critical knowledge-base for inner ear scientists and pharmacologists, and identify important expression-level changes which occur during the onset and progression of inner ear pathologies. While these high-throughput studies offer the powerful ability to gain a wealth of knowledge into which genes are active within the inner ear, functional assessment of the specific role these genes play must be assessed in a more focused manner. Phenotypic characterization of mice with specific genetic mutations (Part II) has been performed to provide critical insight into the specific role Fgf23 plays in development and maintenance of the auditory system. The second arm of this thesis seeks to provide clinical practicality to the above work by developing a method to safely access the inner ear environment to gather and communicate diagnostic information (Part IV). A guinea pig model was utilized to develop an approach to insert microelectrodes into the fluid spaces of the inner ear in order to harness and monitor the natural electrochemical gradient of the organ. The useful energy extracted from this "biological battery" was used to power a combined microchip/radio transmitter capable of performing voltage-sensing operations within endolymph and wirelessly relaying this information to an external receiver. This study was the first to utilize a mammalian electrochemical potential to power an electronic device. By performing this task while preserving the integrity of the hearing organ this work provides the first, critical proof-of-concept demonstration toward clinically-applicable sensing and therapeutic devices powered by the inner ear. Further refinement of this technique into a long-term, fully-implantable device will enable previously impossible longitudinal studies of organ behavior in awake, behaving subjects and the incorporation of sensing modalities into current inner ear prostheses to monitor biochemical changes and maximize patient benefits.
by Andrew Christopher Lysaght.
Ph. D.

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27

Hickox, Ann E. "Noise-induced cochlear neuronal degeneration and its role in hyperacusis -- and tinnitus-like behavior." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/79245.

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Thesis (Ph. D. in Speech and Hearing Bioscience and Technology)--Harvard-MIT Program in Health Sciences and Technology, 2013.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 46-57).
Perceptual abnormalities such as hyperacusis and tinnitus often occur following acoustic overexposure. Although such exposure can also result in permanent threshold elevation, some individuals with noise-induced hyperacusis or tinnitus show clinically normal thresholds. Recent work in animals has shown that noise exposure can cause permanent degeneration of the cochlear nerve despite complete threshold recovery and lack of hair cell damage (Kujawa and Liberman, J Neurosci 29:14077-14085, 2009). Here we ask whether this noise-induced primary neuronal degeneration results in abnormal auditory behavior, indexed by the acoustic startle response and prepulse inhibition (PPI) of startle. Responses to tones and to broadband noise were measured in mice exposed either to a neuropathic exposure causing primary neuronal degeneration, or to a lower intensity, nonneuropathic noise, and in unexposed controls. Mice with cochlear neuronal loss displayed hyper-responsivity to sound, as evidenced by lower startle thresholds and enhanced PPI, while exposed mice without neuronal loss showed control-like responses. Gap PPI tests, often used to assess tinnitus, revealed spectrally restricted, as well as broadband, gap-detection deficits in mice with primary neuronal degeneration, but not in exposed mice without neuropathy. Crossmodal PPI tests and behavioral assays of anxiety revealed no significant differences among groups, suggesting that the changes in startle-based auditory behavior reflect a neuropathyrelated alteration specifically of auditory neural pathways. Despite significantly reduced cochlear nerve response, seen as reduced wave 1 of the auditory brainstem response, later peaks were unchanged or enhanced, suggesting neural hyperactivity in the auditory brainstem that could underlie the abnormal behavior on the startle tests. Taken together, the results suggest a role for cochlear primary neuronal degeneration in central neural excitability and, by extension, in the generation of tinnitus and hyperacusis.
by Ann E. Hickox.
Ph.D.in Speech and Hearing Bioscience and Technology

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28

Crema, Matthew V. "Can the phased array stimulation strategy be implemented using the advanced bionics cochlear implant?" Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/107333.

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Thesis: S.M., Harvard-MIT Program in Health Sciences and Technology, 2016.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 179-189).
Cochlear implants are devices that aim to restore a measure of hearing to the deaf by converting acoustic signals to electric stimuli delivered to electrodes implanted in the inner ear. Theoretically, the phased array stimulation strategy described by van den Honert and Kelsall (2007) provides much better control over the neural excitation patters elicited by electric stimulation by taking advantage of potential field superposition in the implanted cochlea, to construct stimuli for optimally selective excitation of auditory nerve fibers. If the phased array strategy can be implemented using a commonly-implanted commercial cochlear implant system, the strategy could be effectively evaluated in a relatively large sample of patients to determine whether it provides better speech reception than currently available systems. This thesis investigates whether the phased array strategy can be implemented using the Advanced Bionics Clarion CH or HiRes90k cochlear implant. It is shown that for realistic cochlear implant electrode impedance magnitudes, the Advanced Bionics cochlear implant current sources will deliver monopolar current suitable for the necessary measurement of transimpedance with less than 7% error. Transimpedance matrix estimates were obtained in 11 ears in 10 cochlear implant subjects. Measurements reveal that in some test subjects, low impedance current paths exist between implanted electrodes that may cause current leakage through unintended electrodes. Researchers and clinicians should consider using this transimpedance matrix estimation technique to screen for patients or research subjects who could benefit from compensatory changes to their speech processors. The results of this thesis suggest that the phased array strategy can be implemented successfully when the limitations of the internal power supply documented in this document are taken into account. It is recommended that the transimpedance matrix in a given test subject be measured on the day of any psychophysical testing because of the potential impact of variability in transimpedance over time.
by Matthew V. Crema.
S.M.

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29

Preis, Julia Kay. "Market incentives for pandemic influenza vaccines." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/78155.

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Thesis (S.M. in Health Sciences and Technology)--Harvard-MIT Program in Health Sciences and Technology, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 60-61).
It has been estimated that 100 million plus individuals could perish if a virulent influenza pandemic were to occur. In wake of the 2009-10 H1N1 pandemic and in an era of economic austerity, however, industry lacks clear incentives to invest in vaccines for other high-risk strains. The cyclic nature of pandemics also means we can expect another influenza pandemic within the next 20 years. In this environment, design of incentive mechanisms for funding development of vaccines against strains with known pandemic potential, but for whom vaccine technology is currently lacking, would be welcomed. This research explores which novel incentive mechanisms could induce investment in and development of processes for production of vaccines for these high risk strains. Interviews with vaccine developers and funding agencies and analysis of the pipeline of influenza vaccines in development were conducted. This thesis finds that there is a dearth of vaccines against influenza strains of known pandemic potential, such as H2, H7 and H9; that current pandemic preparedness efforts are not focused on these strains; that funding for pandemic preparedness efforts in H2, H7 and H9 would help incentivize development of vaccines against these strains; and that support for seasonal influenza, regulatory changes, alignment of public and private sector goals, and increased vaccine acceptance are also required to incentivize the development of vaccines against strains of known pandemic potential such as H2, H7 and H9. Furthermore, this thesis recommends that policy makers increase funding for pandemic preparedness so that programs may be initiated or expanded to include additional high risk influenza strains; that US and EU regulatory regimes for pandemic influenza vaccines be harmonized; and that governments promote public awareness of the importance of influenza vaccination.
by Julia Kay Preis.
S.M.in Health Sciences and Technology

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30

Teo, Grace Sock Leng. "The multiple migratory mechanisms of systemically infused mesenchymal stem cells to sites of inflammation." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/90176.

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Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2014.
331
"June 2014." Cataloged from PDF version of thesis.
Includes bibliographical references (pages 124-139).
Systemically infused mesenchymal stem cells (MSC) are being explored for their immunomodulatory therapeutic potential in multiple inflammatory pathologies. This therapeutic potential has been associated with the ability of MSC to accumulate at sites of inflammation following infusion. However, there is a poor understanding of the mechanisms that mediate MSC trafficking to inflamed tissue. Here, we first introduce key concepts in MSC biology and cellular trafficking, and highlight the relevance of MSC trafficking. We also introduce key concepts in cellular trafficking, particularly the leukocyte homing cascade, as a framework to approach MSC trafficking. Then, we review the field of MSC trafficking in the second chapter, particularly the methods employed to study MSC trafficking and associated challenges. In the third chapter, we study MSC ability to perform transendothelial migration, a specific step in the process of MSC trafficking, using high resolution confocal and dynamic imaging techniques. We found that MSC transmigration is associated with both leukocyte-like and novel mechanisms, including nonapoptotic migratory blebbing. In the fourth chapter, we address the importance of non-endothelial factors in MSC trafficking to inflamed tissues, including mechanical trapping in small vessels, secondary interactions with endogenous immune cells and vascular permeability. Finally, we conclude by proposing an integrated model of mesenchymal trafficking versus hematopoietic trafficking, and highlight the potential role of the intravascular compartment as a major site of MSC immunomodulation. We believe that this body of work has a broad impact on our understanding of MSC biology and therapeutic potential, our comprehension of mesenchymal cell trafficking (including metastasis) and the design of cell delivery strategies for clinical translation.
by Grace Sock Leng Teo.
Ph. D. in Medical Engineering and Medical Physics

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31

Silcox, Christina Elise. "Feasibility of a predictive model of Hsp70b-activated gene therapy protein expression during ultrasound hyperthermia." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/90174.

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Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 101-113).
Gene therapy has been heralded as a possible approach to a variety of diseases and conditions, ranging from cancer and heart disease to blindness and neurodegenerative diseases. However, progress in gene therapy requires a delivery system that can control when and where the therapeutic proteins will be generated. Our study was performed to determine the feasibility of attaching heat-inducible promoters to genes of interest in order to control activation of the gene in vivo via ultrasound-induced hyperthermia monitored by MRI thermometry. We first demonstrated that gene therapy-mediated gene expression could be spatially and temporally controlled with this method. Further studies were subsequently performed to determine if the activation of a particular heat-inducible gene, Hsp70b, could be quantified and predicted a priori during hyperthermia, thus allowing advance knowledge of the protein levels over time. Experiments indicated that as the temperature and duration of a hyperthermic shock increased, peak expression levels of Hsp70b mRNA also increased until a saturation level was reached. In addition, as the duration of a hyperthermic shock increased, the time during which Hsp70b mRNA remained elevated also increased. Most significantly, a correlation was found between total Hsp70b mRNA production generated by thermal shock and thermal dose, a predictor of dose often used in hyperthermia therapies. The relationship found between total Hsp70b mRNA production and thermal dose suggests that a real-time predictive model of therapeutic protein dose kinetics after ultrasound-induced hyperthermia for gene therapy is feasible. However, the creation of such a model would require further precision experimentation for which ultrasonically-induced hyperthermia is not suited. A final study was performed and found that Hsp70b was not activated by the mechanical stress caused by ultrasound. These results confirm that a predictive model applicable to ultrasonically-induced hyperthermia could be developed using waterbath techniques that will allow tighter control of temperature.
by Christina Elise Silcox.
Ph. D. in Medical Engineering and Medical Physics

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Makhlouf, Miriam L. "Neuroimaging investigation of the motor control disorder, dystonia with special emphasis on laryngeal dystonia." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/79249.

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Thesis (Ph. D. in Speech and Hearing Bioscience and Technology)--Harvard-MIT Program in Health Sciences and Technology, 2013.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Laryngeal dystonia (LD) is the focal laryngeal form of the neurological movement disorder called dystonia, a condition that often changes in severity depending on the posture assumed and on voluntary activity of the affected body area. Pathophysiology of dystonia is unknown. This thesis employed a combination of diffusion tensor and functional magnetic resonance imaging (DTI and fMRI) studies to investigate the structure and function of the basal ganglia (BG) in dystonia patients. Fractional anisotropy (FA) and probabilistic diffusion tractography analyses were used to investigate the questions of whether LD patients exhibited altered connectivity between BG and brainstem regions and whether FA and tractography could be used to predict differences in clinical presentations of dystonia. Findings of this study support the hypothesis that connections between the BG and brainstem may play a role in dystonia pathophysiology and may be used to predict differences in clinical presentations of dystonia. An fMRI study was carried out to investigate whether abnormally sustained BG activity observed after performance of a finger tapping task in hand dystonia patients may represent an amplification of a normal motor control mechanism. As dystonia has been hypothesized to result from overactivation of normal postural programs, this study aimed to investigate the question of whether the sustained BG activity was a normal feature observed in motor control tasks requiring more precision. Results suggest that cerebellar cortex is recruited particularly during fine motor control.
by Miriam L. Makhlouf.
Ph.D.in Speech and Hearing Bioscience and Technology

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33

Coutu, Jean-Philippe. "Distinct contribution of white matter damage to the clinical syndrome of Alzheimer's disease." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/103503.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2016.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 152-168).
Alzheimer's disease is a neurodegenerative disorder affecting over 5.1 million individuals in the United States today. The dementia exhibited with the disease is currently thought to be primarily due to amyloid plaques and neurofibrillary tangles. However, several other changes occur, including severe white matter damage that is yet to be fully understood. Such white matter damage includes white matter lesions (WML), which are more common in individuals with Alzheimer's disease than in non-demented individuals. WML are of presumed vascular origin because they show features of small-vessel disease and are more prevalent in individuals with vascular risk. It is currently unclear whether WML are linked to the neurodegenerative pathologies of Alzheimer's disease or are an independent factor that influences clinical course. In this work, we used sensitive diffusion MRI measures to determine that the tissue properties of WML slightly differed microstructurally between individuals with Alzheimer's disease and non-demented controls, and were strongly related to ventricular enlargement. In order to further understand the role of WML, we factored the volume of WML with four other neuroimaging markers affected in Alzheimer's disease and discovered two statistically distinct factors presumed to be due to differing underlying disease processes. One process strongly related to volume and tissue properties of WML, ventricular enlargement, age and cerebral perfusion, while the other process related to imaging markers associated with neurodegeneration. A decrease over time in the first process, interpreted as the age- and vascular-related factor, led to similar cognitive decline as the neurodegenerative factor independently, demonstrating the potential added therapeutic benefit of targeting this disease process that is distinct from the classical neurodegenerative component of the disease.
by Jean-Philippe Coutu.
Ph. D.

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34

Ullal, Adeeti (Adeeti Vedantham). "Micro and nanotechnology for cancer treatment." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/83968.

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Thesis (Ph. D. in Biomedical Engineering)--Harvard-MIT Program in Health Sciences and Technology, 2013.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 92-101).
Cancer is responsible for over 7.6 million deaths worldwide; the majority of patients fail to respond to drugs or become resistant over time. In order to gain a better understanding of drug efficacy in patients, we developed three diagnostic technologies to address limitations in sample acquisition and improve the scale and sensitivity of current cancer diagnostic tools. In the first section, we describe a hybrid magnetic and size sorting microfluidic device that isolates rare circulating tumor cells from peripheral blood. The self-assembled magnetic sorter creates strong magnetic fields and effectively removes leukocytes tagged with magnetic nanoparticles. The size sorting region retains the remaining cells in single cell capture sites, while allowing small red blood cells to pass through 5pm gaps. The device achieves over 103 enrichment, up to 96% recovery of cancer cells and allows for on-chip molecular profiling. In the second section we use a magnetic nanoparticle decorated with small molecule drugs to assay target expression and drug binding in mock clinical samples of cancer cells spiked into whole blood. Specifically, we modify a PARP inhibitor (Olabarib) and conjugate it to a dextran coated iron oxide nanoparticle. We measure the presence of the drug nanosensor based on the change in T2 relaxation time using a miniaturized, handheld NMR sensor for point-of-care diagnosis. In the final section, we detail a photocleavable DNA barcoding method for understanding treatment response via multiplexed profiling of cancer cells. We validate our method with a 94 marker panel on different cell lines with varying treatments, showing high correlations to gold standard methods such as immunofluorescence and flow cytometry. Furthermore, we demonstrate single cell sensitivity, and identify a number of expected biomarkers in response to cell treatments. Finally, we demonstrate the potential of our method to help in clinical monitoring of patients by examining intra- and inter-patient heterogeneity, and by correlating pre and post-treatment tumor profiles to patient response. Together, we show how these technologies can help overcome clinical limitations and expedite advancements in cancer treatment.
by Adeeti Ullal
Ph.D.in Biomedical Engineering

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35

Gymrek, Melissa A. "Characterizing variation at short tandem repeats and their role in human genome regulation." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/103501.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2016.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 225-251).
A central goal in genomics is to understand the genetic variants that underlie molecular changes and lead to disease. Recent studies have identified thousands of genetic loci associated with human phenotypes. These have primarily analyzed point mutations, ignoring more complex types of variation. Here we focus on Short Tandem Repeats (STRs) as a model for complex variation. STRs are comprised of repeating motifs of 1-6bp that span over 1% of the human genome. The level of STR variation and its effect on phenotypes remains mostly uncharted, mainly due to the difficulty in accurately genotyping STRs on a large scale. To overcome bioinformatic challenges in STR genotyping, we developed lobSTR, an algorithm for profiling STRs from high throughput sequencing data. lobSTR employs a unique mapping strategy to rapidly align repetitive reads, and uses statistical learning techniques to account for STR-specific noise patterns. We applied lobSTR to generate the largest and highest quality STR catalog to date. This provided the first characterization of more than a million loci and gave novel insights into population-wide trends of STR variation. We used our catalog to conduct a genome-wide analysis of the contribution of STRs to gene expression in humans. This revealed that STRs explain 10-15% of the cis heritability of expression mediated by common variants and potentially play a role in various clinically relevant conditions. Overall these studies highlight the contribution of STRs to the genetic architecture of quantitative traits. We anticipate that integrating repetitive elements, specifically STRs, into genome-wide analyses will lead to the discovery of new genetic variants relevant to human conditions.
by Melissa A. Gymrek.
Ph. D.

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36

Camargo, Támara Mauricio. "Economic potential of a point-of-care CD4+ T cell count diagnostic in Mexico : a case study for low-end disruption diagnostics in middle of the pyramid Latin America." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/78154.

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Thesis (S.M. in Health Sciences and Technology)--Harvard-MIT Program in Health Sciences and Technology, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 92-95).
Disruptive models of innovation are starting to appear in healthcare. In the US, for instance, retail medicine clinics are changing the way in which patients satisfy their basic medical needs. In Mexico, similar retail medicine models (e.g. Farmacias Similares) are also disrupting healthcare delivery for basic medical needs. Disruptive innovations, however, are not limited to healthcare delivery, but also change the face of devices and diagnostics markets. A low CD4+ T cell count is the primary clinical indicator for HIV/AIDS disease progression, and thus is used as the primary trigger to initiate antiretroviral therapy. An entire diagnostic industry has emerged around CD4+ T cell counts for the management and treatment of HIV/AIDS patients. The diagnostic gold standards of CD4+ counts are flow cytometers. These large, capital intensive devices are commonly located in central laboratory settings, typically in urban areas. In developing nations, particularly, suburban and rural regions have no access to flow cytometers and typically face logistical problems of blood sample transportation and loss to follow-up of patients. Point-of-Care (POC) diagnostics promise disruptive models in diagnostics that will increase access, enhance care, and help better allocate healthcare resources. The concept of POC embodies the trade-off of lower "quality" (usually in the form of lower specificity and sensitivity) in exchange for higher "convenience" (i.e. better accessibility and portability, and significantly lower cost). POC diagnostics promise typical low-end and new-market disruptions in medical diagnostics and devices. Cambridge-based Daktari Diagnostics is one of such companies focused in POC diagnostics. It has developed a CD4+ T cell count diagnostic device for the management and treatment of HIV/AIDS patients. It is hypothesized in this thesis that there exists a relevant unmet medical need for POC CD4 count diagnostics in the Mexican HIV/AIDS market. In order to evaluate this hypothesis, secondary sources were reviewed, as well as primary interviews conducted across the Mexican HIV/AIDS healthcare landscape. While this hypothesis was evaluated on a preliminary basis only, responses suggested a relevant, albeit not urgent, medical need for POC CD4 count diagnostics. This primary hypothesis evaluation is extended by and complemented with market size estimations, and competitive dynamic discussions, that arrive at the following preliminary conclusions: the current market opportunity in Mexico ranges from baseline of ~100,000 tests per year to an upper bound potential of ~200,000 tests per year. In the context of this potential opportunity, Daktari's CD4 count diagnostic device is well positioned, as defined by diagnostic quality, technological characteristics, and competitive offering, to obtain a portion of this estimated market opportunity in Mexico.
by Mauricio Camargo Támara.
S.M.in Health Sciences and Technology

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37

Wang, Eric T. (Eric Tzy-shi). "Alternative isoform regulation in myotonic dystrophy." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/70816.

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Thesis (Ph. D.)--Harvard-MIT Program in Health Sciences and Technology, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Myotonic dystrophy (DM) is the most common form of adult onset muscular dystrophy, affecting more than 1 in 8000 individuals globally. The symptoms of DM are multi-systemic and include myotonia, severe muscle wasting, cardiac arrhythmias, cataracts, gastrointestinal dysfunction, and cognitive deficits. DM is caused by the expansion of CTG or CCTG repeat sequences expressed in noncoding portions of RNA, which sequester or activate RNA splicing factor proteins, leading to widespread deleterious changes in transcriptome isoform usage. We developed a method for studying transcriptomes, RNAseq, which provides a high resolution, digital inventory of gene and isoform expression. By applying RNAseq to human tissues and cell lines, we discovered that essentially 92-94% of all human genes are alternatively spliced, 86% of them with a minor isoform frequency 15% or more. We found that the majority of alternative splicing and alternative polyadenylation and cleavage events are tissue-regulated, and that patterns of these RNA processing events are strongly correlated across tissues, implicating protein factors that may regulate both types of events. We applied this method towards the goal of identifying transcriptome changes occurring in DM, focusing on the Muscleblind-like (MBNL) family of RNA binding proteins, which are functionally inactivated by CUG or CCUG repeats. Using RNAseq to profile tissues and cells depleted of MBNLs, we found that MBNL1 and MBNL2 co-regulate hundreds of redundant targets. MBNL1 UV cross-linking and immunoprecipitation, followed by sequencing (CLIPseq), was used to identify the in vivo transcriptome-wide binding locations of MBNL1, and facilitated the construction of a context-dependent RNA map for MBNL1 splicing regulation. Extensive 3' UTR binding of MBNL1 was found to localize mRNAs to membrane compartments of mouse myoblasts, suggesting a new global function for MBNLs, and additional mechanisms by which MBNL depletion can lead to DM symptoms.
by Eric T. Wang.
Ph.D.

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38

Jain, Isha Himani. "Oxygen, the invisible orchestrator of metabolism and disease : a focus on mitochondrial And peroxisomal dysfunction." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/113788.

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Abstract:

Thesis: Ph. D. in Health Sciences and Technology: Computer Science, Harvard-MIT Program in Health Sciences and Technology, 2017.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Variations in atmospheric oxygen levels can be traced over evolutionary time and track closely with the development of multicellular life, speciation events, appearance of placental mammals and the creation of a cardio-respiratory system. As the final electron acceptor for aerobic ATP production, oxygen allows energy-intensive metabolic pathways to exist. Furthermore, oxygen is the most utilized substrate for known biochemical reactions, surpassing even ATP and NAD+. As a result, variations in oxygen levels have far-reaching consequences on human physiology and health. Mitochondrial disorders are the most common inborn errors of metabolism, affecting approximately 1 in 5000 live births. Patients can present in infancy or adulthood with symptoms affecting multiple organ systems including blindness, deafness, muscle weakness, developmental delay and severe neurological impairment. Unfortunately, there are currently no proven therapies for mitochondrial disorders. My thesis work has focused on combining systems biology, animal physiology and cellular metabolism approaches to develop new therapies for these disorders. More specifically, I have identified hypoxic breathing, equivalent to living at 4500m altitude, as protective in the setting of severe mitochondrial disease. First, I performed a genetic screen and found paradoxically, that hypoxic breathing and hypoxia responses are protective in mitochondrial disease. I then characterized the physiology and preclinical regimens of hypoxia therapy, laying the groundwork for translation to human patients. Fascinated by such a vital role for oxygen in human disease, I went on to define adaptive pathways in varying oxygen tensions. This work highlights the differential reliance on entire organelles at extreme oxygen levels. And finally, I studied the metabolic and proteomic consequences of defects in peroxisome metabolism and disease.
by Isha Himani Jain.
Ph. D. in Health Sciences and Technology: Computer Science

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39

Cai, Shanqing. "Online control of articulation based on auditory feedback in normal Speech and stuttering : behavioral and modeling studies." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/70812.

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Thesis (Ph. D.)--Harvard-MIT Program in Health Sciences and Technology, February 2012.
"February, 2012." Cataloged from PDF version of thesis.
Includes bibliographical references (p. 185-209).
Articulation of multisyllabic speech requires a high degree of accuracy in controlling the spatial (positional) and the temporal parameters of articulatory movements. In stuttering, a disorder of speech fluency, failures to meet these control requirements occur frequently, leading to dysfluencies such as sound repetitions and prolongations. Currently, little is known about the sensorimotor mechanisms underlying the control of multisyllabic articulation and how they break down in stuttering. This dissertation is focused on the interaction between multisyllabic articulation and auditory feedback (AF), the perception of one's own speech sounds during speech production, which has been shown previously to play important roles in quasi-static articulations as well as in the mechanisms of stuttering. To investigate this topic empirically, we developed a digital signal processing platform for introducing flexible online perturbations of time-varying formants in speakers' AF during speech production. This platform was in a series of perturbation experiments, in which we aimed separately at elucidating the role of AF in controlling the spatial and temporal parameters of multisyllabic articulation. Under these perturbations of AF, normal subjects showed small but significant and specific online adjustments in the spatial and temporal parameters of articulation, which provided first evidence for a role of AF in the online fine-tuning of articulatory trajectories. To model and explain these findings, we designed and tested sqDIVA, a computational model for the sensory feedback-based control of speech movement timing. Test results indicated that this new model accurately accounted for the spatiotemporal compensation patterns observed in the perturbation experiments. In addition, we investigated empirically how the AF-based online speech motor control differed between people who stutter (PWS) and normal speakers. The PWS group showed compensatory responses significantly smaller in magnitude and slower in onset compared to the control subjects' responses. This under-compensation to AF perturbation was observed for both quasi-static vowels and multisyllabic speech, and for both the spatial and temporal control of articulation. This abnormal sensorimotor performance supports the hypothesis that stuttering involves deficits in the rapid internal transformations between the auditory and motor domains, with important implications for the neural basis of this disorder.
by Shanqing Cai.
Ph.D.

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40

Cullinane, Conor R. (Conor Ryan). "Evaluation of the Mark III spacesuit : an experimental and computational modeling approach." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/117896.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2018.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 114-118).
Spacesuit Assemblies (SSAs) provide life support for human operators performing extravehicular activities (EVAs). The overall goal of this research was to investigate three research questions to address gaps in the field of spacesuit assembly (SSA) evaluations: [1] What are the mobility and agility limitations causing operators to experience performance decrements when wearing a SSA?; [2] What is causing operators to experience increased joint torques?; and [3] How does the distributed weight of an SSA, transferred to the operator, affect performance? This research leveraged both experimental and computational modeling capabilities to evaluate SSAs with a human-centered focus, in ways previously unachievable. The space suit evaluated for this research was NASA's Mark III (MkIII) Planetary Technology Demonstrator SSA, built to test the next generation in planetary exploration capabilities, improving upon Apollo era technology. The hip brief assembly (HBA) is built with three nested bearings, each with a single rotational degree of freedom that together provide the range of motion, walking efficiency, and kneeling capabilities. An initial investigation, combining a pilot study and supporting modeling, revealed limitations in the current human-SSA system that may impair the operator's mobility/stability and agility. Limitations identified and investigated in this thesis include SSA degrees of freedom (DOFs), the SSA range of motion (ROM) envelope, the bearing resistances, the SSA component's inertial effects, the SSA mass load transfer dynamics, and suit fit. The SSA architecture was modeled as part of the thesis, creating a tool that was useful in the investigation of the human-suit system. The model relied on SSA component geometries and inherent mass/inertia and bearing resistance characteristics to output joint dynamics, rather than requiring those dynamics as an input (which would require extensive experimental setups). The model was used to isolate components that contribute to the measured operator performance degradations and to quantify the extent of their contributions. These investigations lead to suggestions for design requirements and evaluation techniques that can guide future SSA development and evaluations.
by Conor R. Cullinane.
Ph. D.

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41

Trehan, Kartik. "Platforms for exploring host-pathogen interactions in hepatitis C virus infection." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/72917.

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Thesis (Ph. D. in Biomedical Engineering)--Harvard-MIT Program in Health Sciences and Technology, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 114-144).
Afflicting almost 200 million worldwide, hepatitis C virus (HCV) mounts a chronic infection of liver hepatocytes that causes substantial morbidity and mortality. An understanding of host-virus interactions will drive the development of therapeutics, but research is restrained by available experimental tools. Due to the cost and unreliability of existing humanized mouse and primate in vivo models, HCV research is almost exclusively performed using in vitro platforms which suffer from three major limitations. First, challenges in primary hepatocyte culture and the general non-permissiveness of liver cell lines have necessitated the use of a uniquely permissive hepatoma line derived from a single donor, questioning the generalizability of findings to the broader population. Second, this cell line deviates appreciably from native liver in functions central to HCV infection, including innate immune signaling, polarization, and proliferation. Third, infection is typically studied using bulk assays with suboptimal specificity, sensitivity, and content. Here, we describe three technologies for overcoming these limitations in the study of host-virus interactions. We demonstrate their utility in exploring innate immune signaling, a clinically significant component of HCV pathogenesis. Section I describes an in vitro platform for investigating inter-host variations in the natural history of infection and treatment response. We show that directed differentiation of induced pluripotent stem cells (iPSCs) yields patient-specific liver tissue that is permissive to HCV and responds to infection with a robust innate immune response, opening the door to "personalizing" the study and treatment of infection. In Section II, we demonstrate that tissue-engineered, micropatterned co-cultures (MPCCs) of primary hepatocytes and supportive stroma are permissive to HCV, enabling investigations in a more natural host. We then show that innate immune signaling curtails infection in this model, and that its inhibition enhances infection 2-3 orders of magnitude. Lastly, we use MPCCs to uncover a novel liver immunoregulatory mechanism whereby innate immune surveillance is depressed, permitting efficient replication of hepatotropic pathogens. Finally, Section III details a high-content imaging assay that enables visualization and enumeration of single viral genomes in individual cells. We demonstrate that single-cell, multiplexed quantification of viral genomes and host gene transcripts can be used to dissect host-virus interactions, yielding an unexpected positive correlation between stage of infection and response to an innate immune cytokine. The solutions described here will enable the pursuit of previously intractable research questions for HCV and other viruses, accelerating progress towards the development of antivirals and vaccines. Further, the insights gained regarding the interplay between HCV and innate immunity have important clinical ramifications, including a novel therapeutic strategy.
by Kartik Trehan.
Ph.D.in Biomedical Engineering

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42

Gagnon, Louis 1984. "Biophysical modeling of hemodynamic-based neuroimaging techniques." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/84409.

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Thesis (Ph. D. in Medical Engineering and Medical Physics)--Harvard-MIT Program in Health Sciences and Technology, 2013.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 163-182).
Two different hemodynamic-based neuroimaging techniques were studied in this work. Near-Infrared Spectroscopy (NIRS) is a promising technique to measure cerebral hemodynamics in a clinical setting due to its potential for continuous monitoring. However, the presence of strong systemic interference in the signal significantly limits our ability to recover the hemodynamic response without averaging tens of trials. Developing a new methodology to clean the NIRS signal from systemic interference and isolate the cortical signal would therefore significantly increase our ability to recover the hemodynamic response opening the door for clinical NIRS studies such as epilepsy. Toward this goal, a new method based on multi-distance measurements and state-space modeling was developed and further optimized to remove systemic physiological oscillations contaminating the NIRS signal. Furthermore, the cortical and pial contributions to the NIRS signal were quantified using a new multimodal regression analysis. Functional Magnetic Resonance Imaging (fMRI) based on the Blood Oxygenation Level Dependent (BOLD) response has become the method of choice for exploring brain function, and yet the physiological basis of this technique is still poorly understood. Despite the effort, a detailed and validated model relating the signal measured to the physiological changes occurring in the cortical tissue is still lacking. Modeling the BOLD signal is challenging because of the difficulty to take into account the complex morphology of the cortical microvasculature, the distribution of oxygen in those microvessels and its dynamics during neuronal activation. Here, we overcome this difficulty by performing Monte Carlo simulations over real microvascular networks and oxygen distributions measured in vivo on rodents, at rest and during forepaw stimulation, using two-photon microscopy. Our model reveals for the first time the specific contribution of individual vascular compartment to the BOLD signal, for different field strengths and different cortical orientations. Our model makes a new prediction: the amplitude of the BOLD signal produced by a given physiological change during neuronal activation depends on the spatial orientation of the cortical region in the MRI scanner. This occurs because veins are preferentially oriented either perpendicular or parallel to the cortical surface in the gray matter.
by Louis Gagnon.
Ph.D.in Medical Engineering and Medical Physics

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43

Tanenbaum, Laura Melanie. "Design of an intraperitoneal drug-release device for advanced ovarian cancer therapy." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/104610.

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Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2016.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 111-121).
More than 14,000 women in the United States die from ovarian cancer each year. The standard of care is tumor-debulking surgery followed by adjuvant chemotherapy. Combination intraperitoneal (IP) and intravenous (IV) chemotherapy has been shown to lengthen survival over IV therapy alone. Large-volume infusions, drug-associated toxicity, and catheter-associated complications, however, increase morbidity and limit patient adherence, often resulting in discontinuation of IP therapy. The technical skill required for catheter implantation and IP chemotherapy administration has also limited its clinical adoption. The proposed solution is an implantable IP device capable of localized drug delivery that maintains the efficacy of the standard of care and overcomes current clinical challenges. A reservoir-based device was developed to release cisplatin at a constant rate. In vivo studies demonstrated that continuous dosing reduces tumor burden to the same extent as weekly IP injections. The implanted device induced significantly less systemic toxicity compared to IP injections, despite administration of higher cumulative doses. A subsequent in vitro study revealed that greater tumor shrinkage following continuous cisplatin exposure was achieved with smaller tumor nodules. These results support that an implanted device would be maximally effective against microscopic residual disease. In vitro results also illustrated that a human-scale device fabricated from orifice-lined silicone can be designed to release cisplatin continuously at the desired rate. The promising preclinical results in this thesis highlight the potential for this novel IP dosing regimen to improve the treatment of late-stage ovarian cancer and set the stage for development of the proposed human device.
by Laura Melanie Tanenbaum.
Ph. D. in Medical Engineering and Medical Physics

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44

Sun, James Xin. "The human molecular clock and mutation process : a characterization using microsatellite DNA." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/72915.

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Thesis (Ph. D. in Electrical Engineering and Bioinformatics)--Harvard-MIT Program in Health Sciences and Technology, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 102-103).
In the past decade, thousands of human genomes have been catalogued, either by whole-genome sequencing or by targeted genotyping. The variability between human genomes encodes invaluable information about human traits and genetic diseases, as well as human migration patterns and population interactions. A key challenge is to understand and characterize the evolution of the variability between human genomes. In this thesis, I focus on studying human evolution through the use of microsatellites, which are simple repetitive sections of DNA of typically 1-6bp motifs (e.g. CACACACACA) that are highly polymorphic and highly mutable. The first aim is to establish that microsatellites are useful as reliable molecular clocks, such that its evolution highly correlates to time, especially when applied to the time range appropriate for human history. Using existing models of microsatellites, we examine microsatellite data from populations around the world to demonstrate that microsatellites are accurate molecular clocks for coalescent times of at least two million years. These results raise the prospect of using microsatellite data sets to determine parameters of population history. In order to calibrate genetic distances into time, the mutation rate must be known. This leads to the second aim, which is to directly measure the microsatellite mutation rate from largescale pedigree genetics data and provide a precision that is unprecedented. To do so, we use data from over 95,000 individuals in Icelandic pedigrees, genotyped in over 3000 microsatellite loci. Using trio and extended-family based approaches, we discover 2058 denovo mutations. In addition, we also attempt to capture many features that are covariates with the mutation rate, such as parental gender and age. The third aim takes our empirical observations of the microsatellite mutation process to build a new model of microsatellite evolution. This model improves upon the standard random walk model with features we have captured from aim 2. We use a Bayesian coalescent approach to provide a model that estimates the sequence mutation rate, European genetic divergence times, and human-chimpanzee speciation time.
by James Xin Sun.
Ph.D.in Electrical Engineering and Bioinformatics

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45

Jones, Peter Anthony S. M. Massachusetts Institute of Technology. "The Disque Platform for the investigation of islet differentiation to study, treat, and cure Type 1 Diabetes." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/111321.

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Thesis: S.M. in the Concentration of Mechanical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2017.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 28-31).
There is a critical health care need to generate large numbers of beta cells for transplantation. In Type 1 Diabetes (T1D), insulin-producing beta cells in the islets of Langerhans within the pancreas, which support glucose homeostasis, are destroyed in an autoimmune attack. The ensuing loss of glycemic control leads to serious complications, requiring life-long insulin injections and close monitoring, while shortening lifespan by 11-13 years. In the face of a three percent annual increase in T1D incidence, there is a grave lack of transplantable material, and very few patients are able to receive an islet transplant each year. Recent advances in stem cell differentiation have enabled the production of large quantities of insulin-producing beta-like cells in vitro, bringing hope to the field. However, the efficiency and yield of such production methods remains unacceptably low, with high batch-to-batch variability, and the function of these cells is unstable. Moreover, the ability to probe the conditions that affect differentiation outcomes is limited by the scale, cost, and complexity of existing culture systems. The present work focuses on the Disque Platform, a biomimetic screening platform for the investigation of islet cell differentiation. The Disque Platform allows for the formation of differentiating 3D micro-tissues within an automation-friendly design, and is capable of systematically manipulating the developing stem cell niche in order to identify chemical and physical cues that enhance beta cell production. Significantly, the Disque Platform consistently differentiates beta-like cells from pancreatic progenitor cells, with similar efficacy to existing high-volume production methods. Furthermore, it achieves superior differentiation outcomes compared to the 2D culture systems tested, and is able to respond to interventions when conventional systems cannot produce a clear signal or readout. Together, these data support the ability of the Disque Platform to investigate specific interventions to enhance beta-cell differentiation. It is hoped that the Disque Platform can serve as a springboard for beta cell and islet study within the diabetes community, and that these advances can contribute towards a cure for Type 1 Diabetes.
by Peter Anthony Jones.
S.M. in the Concentration of Mechanical Engineering

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46

Fox, Sharon Elizabeth M. D. "Cerebral hemodynamic response to faces and emotions in infants at high risk for autism." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/70813.

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Thesis (Ph. D.)--Harvard-MIT Program in Health Sciences and Technology, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 109-144).
The incidence of autism spectrum disorders (ASD) has risen alarmingly in the United States, and is now thought to affect approximately 1 in 110 live births. Early diagnosis and intervention is the only treatment proven effective in cases of autism, however the behavioral tests currently available cannot make this diagnosis until at least two years of age. A lack of normal attention to faces and abnormal face processing is a cognitive deficit common to nearly all individuals with autism spectrum disorder, and this deficit is likely present from a very early age. The primary goal of this dissertation is therefore to characterize the specific neural response of face processing in infants with near-infrared spectroscopy (NIRS), and to then apply these measures to the study of abnormal face processing in infants at high risk for autism. In order to achieve these objectives, the work described herein aims to: 1) characterize the hemodynamic response to faces in normal infants at six months of age as measured by the Hitachi ETG-4000 functional Near-Infrared Spectroscopy (fNIRS) system; 2) Simultaneously measure orbitofrontal hemodynamic responses to social/emotional engagement and the response to faces in infants at high risk for autism as compared to low risk controls; and 3) Utilize a novel method of condition-related component selection and classification to identify waveforms associated with face and emotion processing in 6-7-month-old infants at high risk for ASD, and matched low-risk controls. Our results indicate similarities of response waveforms, but differences in both the spatial distribution, magnitude, and timing of oxy-hemoglobin and deoxy-hemoglobin responses between groups. Our findings represent the first identification of neuroimaging markers of a functional endophenotype at six months of age that may be associated with high risk of ASD. These results support a model of altered frontal lobe structure through evidence of altered hemodynamic response and/or functional activity in the high risk infant group, and these changes may, in turn, contribute to the development of ASD in specific individuals.
by Sharon Elizabeth Fox.
Ph.D.

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47

Rohter, Sofia Vallila. "Learning ability in post-stroke aphasia : success, strategy use and implications for therapy." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/87502.

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Thesis: Ph. D. in Speech and Hearing Biosciences and Technology, Harvard-MIT Program in Health Sciences and Technology, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 103-111).
Aphasia is an impairment in the expression or comprehension of language that results from stroke, traumatic brain injury or progressive neurological disease. Approximately one million people in the United States suffer from aphasia, with the prevalence projected to increase to two million by 2020. Research has shown that speech-language therapy, the treatment for aphasia, can significantly improve people's ability to communicate. However, a major limitation in the field of aphasia rehabilitation is the lack of predictability in patients' response to therapy and the inability to tailor treatment to individuals. We hypothesize that learning represents a critical, underexplored factor in aphasia rehabilitation. Predicting whether a patient will improve following therapy may depend more upon that individual's ability to learn new information in general than upon a specific ability to relearn and master language. In this thesis I report a series of experiments that introduce a new approach that looks beyond language, proposing that the answer to developing efficacious, individually tailored therapies lies in a better understanding of the mechanisms of nonverbal learning in individuals with aphasia. We first explore learning success on a test of nonlinguistic category learning to examine whether learning differences arise among individuals with aphasia and non-aphasic controls. In Experiment 2, we probe the impact of stimulus manipulations on learning success. Experiment 3 presents an investigation into the relationship between learning score and language therapy outcomes. Finally, in Experiment 4, we examine the strategies used to perform our task in order to better understand how information is processed during probabilistic category learning. Results support the hypothesis that aphasia differentially affects language and learning networks. Instruction method and stimulus complexity were found to impact learning success and strategy use in individuals with aphasia. Furthermore, a positive correlation was found between learning scores and success with language therapy, suggesting that there is an informative relationship between learning ability and therapy outcomes. Findings draw attention to underlying processes that have not yet been the focus of research in aphasia, yet likely contribute to outcomes with therapy and present a gateway towards individualizing therapy and improving the predictability of patient outcomes.
by Sofia Vallila Rohter.
Ph. D. in Speech and Hearing Biosciences and Technology

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48

Yaung, Stephanie J. (Stephanie Jinyu). "Towards in vivo editing of the human microbiome." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/98573.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2015.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references (pages 174-199).
The human microbiota consists of 100 trillion microbial cells that naturally inhabit the body and harbors a rich reservoir of genetic elements collectively called the microbiome. Efforts based on metagenomic sequencing of microbiomes associated with healthy and diseased individuals have revealed vast effects of microbiota on human health. However, compared to the expanding amount of sequence data, little is known about the function of these microbes and their genes. Furthermore, current clinical approaches to modify the microbiota face several challenges, including colonization resistance in competitive environments such as the gut, and imprecise ecological perturbations using antibiotics and fecal transplants. The fundamental objective of this research is to develop safe methods to genetically edit the microbiome in vivo to promote human health. The abilities to introduce commensally fit strains and to control specificity of microbial modulations are critical steps towards ecological engineering of healthy microbiota. This thesis describes strategies to investigate, propagate, and ultimately engineer desired functions in microbiota. In particular, we developed a temporal functional metagenomics method to identify genes that improved microbial fitness in the mammalian gut in vivo. We also built foundational tools for delivering genetic elements and immunizing endogenous microbiota against acquiring antibiotic resistance and toxins. In addition to leveraging bacterial conjugation and the prokaryotic defense system CRISPR-Cas9, we employed bacteriophages for depleting native strains to empty the niche for an engineered version. Our work enables applications in engineering probiotic strains with augmented fitness and anti-pathogenesis properties, tempering host autoimmunity, and combating hospital-acquired infections and enteric diseases.
by Stephanie J. Yaung.
Ph. D.

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49

Canseco, José Antoni. "Tissue engineering the anterior cruciate ligament : a regenerative medicine approach in orthopaedic surgery." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/83965.

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Thesis (Ph. D. in Biomedical Engineering)--Harvard-MIT Program in Health Sciences and Technology, 2013.
Vita. Cataloged from PDF version of thesis.
Includes bibliographical references (pages 85-97).
Anterior cruciate ligament (ACL) injuries affect over 200,000 Americans yearly, and many occur in young athletes. Current treatment options include tendon autografts and cadaveric allografts. However, these approaches often lead to secondary medical problems, such as donor-site morbidity and immune rejection. Furthermore, in younger patients these grafts fail to grow, leading to additional complications and underlining the need for the development of new approaches that improve the healing and repair of ligaments and tendons. This thesis aims to develop a technique to engineer ACL from autologous mesenchymal stem cells (MSC) and primary ACL fibroblasts using the basic principles of Tissue Engineering. The first part of the thesis characterizes MSCs isolated from tibial bone marrow as an alternative to hip-derived marrow aspirates. The proximity of the tibia to the surgical site of ACL reconstructions makes it a viable source of marrow derived-MSCs for ligament repair, with less stress for the patient and increased flexibility in the operating room. Characterization was performed by fluorescenceactivated cell sorting for MSC-surface markers, and assays to differentiate MSCs towards adipogenic, osteogenic and chondrogenic lineages. The second part of the thesis describes the effects of in vitro co-cultures of ACL fibroblast and MSC on the expression of ligament-associated markers. The goal was to optimize the cell-cell ratio in order to maximize the positive effects of co-cultures on ligament regeneration. Co-cultures of ACL fibroblasts and MSCs were studied for 14 and 28 days in vitro, and the effects assessed with quantitative mRNA expression and immunofluorescence of ligament markers Collagen type I, Collagen type III and Tenascin-C. Finally, based on the enhancing effect observed in co-cultures, the thesis explores a method to regenerate ACL using a three-dimensional polyglyconate scaffold seeded with cell-hydrogel suspensions containing ACL fibroblasts and MSCs. Constructs were analyzed biochemically and by immunofluorescence after 4 weeks in culture with and without mechanical stimulation. Together, our results establish an experimental framework from which a new technique for ACL repair can be developed. The ultimate goal is to foster the design of a one-stage surgical procedure for improved primary ACL augmentation repair that can soon be translated into clinical practice.
by José Antonio Canseco.
Ph.D.in Biomedical Engineering

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50

Ramanan, Vyas. "Genomic profiling and perturbation of Hepatitis B virus infection." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/107341.

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Thesis: Ph. D. in Biomedical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2016.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 136-153).
The Hepatitis B virus (HBV) has, at one time or another, infected one third of the world's population, and over 300 million people worldwide are chronically infected, leading often to progressive liver damage, cirrhosis, and the development of hepatocellular carcinoma over decades. While an effective vaccine exists, imperfect vaccine penetrance and perinatal transmission result in the continuous establishment of chronic infection in new patients, for whom there is very little chance for a cure. This thesis sought to move closer toward the development of consistently curative treatments for HBV by developing novel model systems to study HBV infection, profiling the host response to this infection to nominate targets for therapeutic intervention, and repurposing novel genome editing tools to directly attack the long-lived viral form that is resistant to cure. First, we use micro-patterning tools and directed differentiation protocols to develop primary adult human hepatocyte and iPS-derived hepatocyte models of HBV infection, respectively, which enable us to test antiviral therapies with multiple mechanisms of action and identify a significant interferon-driven response to HBV infection. Second, we use global transcriptional profiling of this response in multiple human hepatocyte donors to identify candidate genes and pathways that are putatively important for viral infection, and demonstrate significant variability in this infection response between donors and virus sources. We then confirm the importance of nominated virus-regulated genes by showing that pharmacological inhibition of these targets - such as heat shock proteins - restricts viral infection in both primary hepatocytes and cell lines. Finally, we provide a proof of concept for using the CRISPR/Cas9 system to directly attack HBV. We show that carefully selected guide RNAs can direct CRISPR-based inhibition of HBV both in vitro and in vivo. We importantly show that Cas9 can directly cleave and direct degradation of the long-lived, episomal HBV cccDNA, resulting in >1 log-fold reductions in cccDNA in both constitutively HBV-producing and newly HBV infected cells. Overall, this work takes steps toward both elucidating HBV biology, and accelerating the path toward novel treatments for this disease.
by Vyas Ramanan.
Ph. D. in Biomedical Engineering

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Dissertations / Theses on the topic 'MIT Program in Health Sciences and Technology'

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