Towards Regulatable AI Systems: Technical Gaps and Policy Opportunities

There is increasing attention being given to how to regulate AI systems. As governing bodies grapple with what values to encapsulate into regulation, we consider the technical half of the question: To what extent can AI experts vet an AI system for adherence to regulatory requirements? We investigate this question through two public sector procurement checklists, identifying what we can do now, what we should be able to do with technical innovation in AI, and what requirements necessitate a more interdisciplinary approach

Targeted Delivery of Bioactive Molecules for Vascular Intervention and Tissue Engineering

Cardiovascular diseases are the leading cause of death in the United States. Treatment often requires surgical interventions to re-open occluded vessels, bypass severe occlusions, or stabilize aneurysms. Despite the short-term success of such interventions, many ultimately fail due to thrombosis or restenosis (following stent placement), or incomplete healing (such as after aneurysm coil placement). Bioactive molecules capable of modulating host tissue responses and preventing these complications have been identified, but systemic delivery is often harmful or ineffective. This review discusses the use of localized bioactive molecule delivery methods to enhance the long-term success of vascular interventions, such as drug-eluting stents and aneurysm coils, as well as nanoparticles for targeted molecule delivery. Vascular grafts in particular have poor patency in small diameter, high flow applications, such as coronary artery bypass grafting (CABG). Grafts fabricated from a variety of approaches may benefit from bioactive molecule incorporation to improve patency. Tissue engineering is an especially promising approach for vascular graft fabrication that may be conducive to incorporation of drugs or growth factors. Overall, localized and targeted delivery of bioactive molecules has shown promise for improving the outcomes of vascular interventions, with technologies such as drug-eluting stents showing excellent clinical success. However, many targeted vascular drug delivery systems have yet to reach the clinic. There is still a need to better optimize bioactive molecule release kinetics and identify synergistic biomolecule combinations before the clinical impact of these technologies can be realized

BTK isoforms p80 and p65 are expressed in head and neck squamous cell carcinoma (HNSCC) and involved in tumor progression

Here, we describe the expression of Bruton’s Tyrosine Kinase (BTK) in head and neck squamous cell carcinoma (HNSCC) cell lines as well as in primary HNSCC samples. BTK is a kinase initially thought to be expressed exclusively in cells of hematopoietic origin. Apart from the 77 kDa BTK isoform expressed in immune cells, particularly in B cells, we identified the 80 kDa and 65 kDa BTK isoforms in HNSCC, recently described as oncogenic. Importantly, we revealed that both isoforms are products of the same mRNA. By investigating the mechanism regulating oncogenic BTK-p80/p65 expression in HNSSC versus healthy or benign tissues, our data suggests that the epigenetic process of methylation might be responsible for the initiation of BTK-p80/p65 expression in HNSCC. Our findings demonstrate that chemical or genetic abrogation of BTK activity leads to inhibition of tumor progression in terms of proliferation and vascularization in vitro and in vivo. These observations were associated with cell cycle arrest and increased apoptosis and autophagy. Together, these data indicate BTK-p80 and BTK-p65 as novel HNSCC-associated oncogenes. Owing to the fact that abundant BTK expression is a characteristic feature of primary and metastatic HNSCC, targeting BTK activity appears as a promising therapeutic option for HNSCC patients

Engineered blood vessels with spatially distinct regions for disease modeling

Tissue engineered blood vessels (TEBVs) have great potential as tools for disease modeling and drug screening. However, existing methods for fabricating TEBVs create homogenous tissue tubes, which may not be conducive to modeling focal vascular diseases such as intimal hyperplasia or aneurysm. In contrast, our lab has a unique modular system for fabricating TEBVs. Smooth muscle cells (SMCs) are seeded into an annular agarose mold, where they aggregate into vascular tissue rings, which can be stacked and fused into small diameter TEBVs. Our goal is to create a platform technology that may be used for fabricating focal vascular disease models, such as intimal hyperplasia. Because tubes are fabricated from individual ring units, each ring can potentially be customized, enabling the creation of focal changes or regions of disease along the tube length. In these studies, we first demonstrated our ability to modulate cell phenotype within individual SMC ring units using incorporated growth factor-loaded degradable gelatin microspheres. Next, we evaluated fusion of ring subunits to form composite tissue tubes, and demonstrated that cells retain their spatial positioning within individual rings during fusion. By incorporating electrospun polycaprolactone cannulation cuffs at each end, tubes were mounted on bioreactors after only 7 days of fusion to impart luminal medium flow for 7 days at a physiological shear stress of 12 dyne/cm2. We then created focal heterogeneities along the tube length by fusing microsphere-containing rings in the central region of the tube between rings without microspheres. In the future, microspheres may be used to deliver growth factors to this localized region of microsphere incorporation and induce disease phenotypes. Due to the challenges of working with primary human SMCs, we next evaluated human mesenchymal stem cells (hMSCs) as an alternative cell source to generate vascular SMCs. We evaluated the effects of microsphere-mediated platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and transforming growth factor beta-1 (TGF-β1) delivery on ring thickness, proliferation, and contractile protein expression over a 14 day period. Finally, we created a structurally distinct region of smooth muscle within tissue tubes by fusing human aortic SMCs in a central region between hMSC rings. In summary, we developed a platform technology for creating modular tubular tissues that may be further developed into an in vitro intimal hyperplasia model. It may also be modified to model other focal vascular diseases, such as aneurysm, or to create other types of multi-tissue tubular structures, such as trachea

A trait-based approach to understanding the evolvability of viral host-range expansions

For decades, scientists have been fascinated by the ease with which viruses, seemingly simple life forms, evolve new feats of innovation. One viral innovation relevant to humans is gaining infectivity on a new host type. Although numerous instances of viral host-range expansion have been documented, we still lack the ability to predict them reliably. In part, this is because many factors affect whether a host shift will occur, ranging from molecular interactions to host behavior. To increase the tractability of this problem, scientists are beginning to ask whether viruses might vary in their innate evolvability, or capacity for adaptive evolution. I focused on the role of stability, here defined as thermodynamic stability, an intrinsic trait of viral proteins thought to enhance evolvability. Using the well-studied host-range expansion of bacteriophage λ, I first showed how mutations that confer expanded host range destabilize the receptor binding protein and allow it to assume alternative conformations with new binding activity. Then, I showed that among λ genotypes varying in stability, the most evolvable tended to be the most unstable, and the stable genotypes that did evolve gained destabilizing mutations. Instability promoted the evolution of new host range, in contrast to the widely cited consensus that stability enhances evolvability. I discovered one λ genotype that exhibited high stability and evolvability, but it grew poorly, suggesting a three-way tradeoff between stability, evolvability, and reproduction. This result led to another question: if traits that affect current fitness, like stability and reproductive rate, trade off with future evolutionary capacity, then which traits most influence the outcome of coevolutionary arms races between viruses and their hosts? I examined which traits influence λ’s ability to overcome host resistance and maintain infectivity on its coevolving host bacteria. The fast-reproducing, evolvable, but unstable genotype emerged most successful, suggesting that lineages that initially appear poorly adapted may give rise to progeny that persist due to their capacity to evolve. This work suggests that a positive, linear relationship between stability and evolvability does not hold in all scenarios, with important implications for predicting viral emergence and selecting genotypes for phage therapy

Vascularized Tissue Organoids

Tissue organoids hold enormous potential as tools for a variety of applications, including disease modeling and drug screening. To effectively mimic the native tissue environment, it is critical to integrate a microvasculature with the parenchyma and stroma. In addition to providing a means to physiologically perfuse the organoids, the microvasculature also contributes to the cellular dynamics of the tissue model via the cells of the perivascular niche, thereby further modulating tissue function. In this review, we discuss current and developing strategies for vascularizing organoids, consider tissue-specific vascularization approaches, discuss the importance of perfusion, and provide perspectives on the state of the field

Viral protein instability enhances host-range evolvability.

Viruses are highly evolvable, but what traits endow this property? The high mutation rates of viruses certainly play a role, but factors that act above the genetic code, like protein thermostability, are also expected to contribute. We studied how the thermostability of a model virus, bacteriophage λ, affects its ability to evolve to use a new receptor, a key evolutionary transition that can cause host-range evolution. Using directed evolution and synthetic biology techniques we generated a library of host-recognition protein variants with altered stabilities and then tested their capacity to evolve to use a new receptor. Variants fell within three stability classes: stable, unstable, and catastrophically unstable. The most evolvable were the two unstable variants, whereas seven of eight stable variants were significantly less evolvable, and the two catastrophically unstable variants could not grow. The slowly evolving stable variants were delayed because they required an additional destabilizing mutation. These results are particularly noteworthy because they contradict a widely supported contention that thermostabilizing mutations enhance evolvability of proteins by increasing mutational robustness. Our work suggests that the relationship between thermostability and evolvability is more complex than previously thought, provides evidence for a new molecular model of host-range expansion evolution, and identifies instability as a potential predictor of viral host-range evolution