The relationship between humans and robots is full of feedback loops: how our brain processes what we see, feel, and act affects how the intelligent machine reacts and vice versa. Understanding this feedback loop will enable us to design better day-to-day automated systems. For instance, operations performed with surgical robots are guided with the surgeon’s movement. My research in the UW BioRobotics Laboratory investigates how the human brain adapts to technology. I programmed a haptic paddle to apply timed forces on human subjects to investigate how uncertainty, in the form of a disturbance, affects response over time. Understanding how human behavior changes is crucial for improving automated systems that can be simulated by the haptic paddle such as cable-driven surgical robots. We apply the haptic paddle to model forces a surgeon may experience during surgery, such as tough tissues or other disturbances, while operating a robotic surgical device. As we measure the participant’s learning curve over longer periods and more trials, the participant builds a better understanding of how to react relative to their force exerted on to the paddle. By increasing our understanding of how the human brain works, we can begin to improve precision of surgical operation.

Essential tremor (ET) is a movement disorder characterized by kinetic and postural tremor that affects an estimated 7 million people in the U.S. alone. Deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus of the thalamus is an established medical therapy for the treatment of ET and has been shown to decrease tremor symptoms significantly for patients in which traditional pharmaceutical therapies have proven insufficient. There are limitations to continuous DBS treatment however, with battery replacement surgeries necessary every few years as well as the presence of side effects such as dysarthria, paresthesia, and gait ataxia. Adaptive DBS (aDBS), with its use of internal or external markers as feedback to modulate stimulation parameters, presents a promising avenue through which to mitigate these concerns. However, current aDBS methods typically employ a binary, “on-off,” control system, which may introduce new complications to consider. One such complication is rebound effect, a transient increase in tremor severity immediately following the deactivation of DBS before levelling out to a steady state. However, clinical observations of rebound in ET have been mixed in the literature, which results in an ambiguity about the potential for effect on an aDBS system. To clarify this mixed literature and quantify the potential impact that the rebound effect may have on an aDBS system, we collected inertial measurements from the tremoring arm during the spiral and line drawing tasks of the Fahn-Talosa-Marin tremor rating assessment task. This task was used to characterize rebound over a ~40 minute time window, over which we observed the rebound effect in all three of our patients. Our results indicate that rebound effect should be taken into account when designing aDBS systems, pointing towards the development of a non-binary aDBS system.
 

Autism Spectrum Disorder (ASD) is a chronic developmental disorder classified by deficits in social communication and restricted or repetitive patterns of behavior. A highly comorbid disorder with ASD is Attention Deficit Hyperactivity Disorder (ADHD) characterized by inattention, hyperactivity, and impulsivity. Deficits in empathy and facial affect recognition have been observed in children with ASD and ADHD. Through the APEX 5-week intensive Summer Treatment Program (STP), the UW Autism Center integrates naturalistic therapy for children diagnosed with ASD and/or ADHD aged 6 to 12. Within this evidence-based program, children develop social and behavioral skills through structured recreational and learning activities. During the summer of 2019, we collected the Positive and Negative Affect Schedule for Children (PANAS-C) from 120 participants ages 6-12 weekly. The PANAS-C measures youth anxiety and mood by asking participants to rate each emotion, five positive and five negative, on a point scale from 1 (not at all) to 5 (very much). Through multiple regression analyses, we aim to examine child affect through the PANAS-C within the context of variables such as age, gender, and diagnosis. We hypothesize that during participation in the summer treatment program, positive affect ratings will increase as negative affect ratings decrease. We expect that the combination of integrative social skills training, positive reinforcement, and acquisition of behavioral skills, will increase positive affect for children in this setting.

The field of regenerative medicine is approaching the goal of using stem cell therapy to replace part of an organ that has been damaged irreversibly. Our laboratory differentiates kidney organoids, 3D multicellular structures that functionally and compositionally resemble the respective organ they model, from human iPSCs (induced pluripotent stem cells). However, organoids we work with are largely avascular, whilst organs in vivo are highly vascularized. Our goal for this project is to build a microfluidic, vascular platform in which organoids can grow. To accomplish this, we adopted a microfluidic chip which was fabricated using soft lithography. Consequently, PDMS (polydimethylsiloxane), a polymer commonly used in soft lithography, was molded and bound to a glass coverslip using plasma binding. With this platform, we successfully engineered microvascular networks through vasculogenesis and angiogenesis and optimized the protocol of vascularization to sustain the cells by submerging the microfluidic chip in cell culture medium. Human umbilical vein endothelial cells and human lung fibroblasts were suspended in fibrinogen ECM (extracellular matrix), seeded into the microfluidic chips with micropillars to contain the cells within their respective channels, and developed into 3D microvascular networks with visible lumen. We then stained the vasculature with endothelial cell markers (i.e. CD31, CD54, VWF) and tested the perfusability by flowing polysterene beads through the microfluidic chip, observing the retention of polysterene beads within the vessels. Finally, we altered our design, specifically the height and width of the channels, to incorporate kidney organoids. Currently, we are using this platform for vascularizing kidney organoids and simultaneously implementing a flow system to induce shear stress on the microvasculature to attain physiological parameters. Ultimately, we aim to vascularize a kidney organoid to demonstrate the vascularization of stem cell tissue in vitro and see growth of tissue within our system, which would further our process in the translation pathway from bench to bedside for kidney regenerative medicine.

In humans, aging is a major risk factor for high-mortality diseases such as cancer, heart disease, and Alzheimer’s, all of which do not currently have cures. One hypothesis is that by treating the aging process underlying these maladies, the progression of the diseases will also be alleviated. It has been found that many of the aging processes in the single celled eukaryote, Saccharomyces cerevisiae are also conserved in multi-cellular eukaryotes such as humans. One characteristic of aging yeast is the accumulation of extra-chromosomal rDNA circles (ERCs). rDNA is a repetitive region of the genome that encodes for ribosomes: cellular machinery that produces proteins. ERCs are small pieces of rDNA that become excised from the chromosome during homologous recombination. It is commonly thought that ERCs are a consequence of aging and that they build up over time and lead to cell death. My project investigates if ERCs have an evolutionary function that has been selected for. It is known that older yeast cells survive better on non- optimal carbon sources, such as galactose, compared to young yeast cells. I hypothesize that ERCs aid aging yeast cells in surviving on non-optimal carbon sources as an evolutionary adaptation. Sir2 suppresses the creation of ERCs and I have controled the amount of ERCs that accumulate in the cells by using a strain of yeast with a Sir2 deletion alongside a strain with Sir2 overexpression. I grew these strains on either dextrose or galactose to see if varying Sir2 activity affects old cells ability to grow on non-optimal carbon sources. Then I passaged these strains over many generations on glucose or galactose to see if ERC accumulation is favored in non-optimal carbon environments. We will also be quantifying ERC copy number through gel electrophoresis and quantitative Southern blotting.

Aging is the single largest risk factor for many diseases, including Alzheimer’s disease (AD). Therefore, many of the molecular mechanisms that cause aging may also contribute to the onset and progression of aging-related diseases. Our approach to tackling the progression of AD takes a biology of aging standpoint, where screening compounds (FDA approved or naturopathic) that impact lifespan may help identify therapies for AD. This is a novel approach with the potential to accelerate clinical translation. This study uses a human Amyloid-beta (Aß) protein-expressing C. elegans strain that becomes progressively paralyzed with age. Utilizing a novel robotic imaging system (the WormBot), we show the impact these compounds have on AD progression through quantification of a delay in paralysis, then behavioral data and health metrics are collected by tracking worm motility over their entire lifespan. Three compounds have been identified to delay paralysis: Thioflavin T, alpha-lipoic acid and resveratrol, all of which we have shown to increase lifespan. We expect to see Thioflavin-T to have a strong influence on paralysis due to its disruption in Aß aggregation. Resveratrol and alpha-lipoic acid's inflence is expected to be associated with its impact on increasing lifespan. Both behavior and binary paralysis results under these three compounds exposure provide holistic insight into mechanisms of Aß toxicity and could lead to promising treatments that have the potential to increase the quality of life for Alzheimer’s disease patients.

Ageing is intrinsic to life, and its progression is a major risk factor for many high-morbidity diseases. Through examination of the cellular processes that govern aging, we hope to gain insight into how to reduce not only the rate of aging, but the incidence of associated diseases as well. Genomic instability is one of the key hallmarks of ageing and occurs in both the mitochondrial and nuclear genomes of both humans as well as less complex invertebrate models. Furthermore, loss of mitochondrial DNA stability is also associated with a loss of nuclear genome stability. In addition to producing essential electron transport chain proteins, mitochondria also produce essential iron-sulfur cluster proteins that are necessary for repair functions within the nuclear genome. Our goal is to disentangle the connections between nuclear and mitochondrial genome degradation using fluorescent reporters in Saccharomyces cerevisiae, in conjunction with a novel microfluidic system. Nuclear DNA degradation will be measured using RAD52::GFP, a component of the DNA-damage repair pathway, while the mitochondrial response will be observed with RTG1::mCh, which signals mitochondrial dysfunction. Since RTG1 and RAD52 both localize to the nucleus during DNA damage events, the relative concentrations of these proteins and their temporal patterning will reveal which system tends to fail first. We have engineering a novel strain of Saccharomyces cerevisiae that satisfies these flourescent properties, and will use a microfluidic chip to explore the interaction between both the nuclear and mitochondrial DNA, and determine the timing and causality of the genomic feedback loop that has been previously described.