Lawrence F. Brass · University of Pennsylvania · PhdFit
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Lawrence F. Brass
· MD, PhDVerified
University of Pennsylvania · Rehabilitation Medicine
Lawrence F. Brass, MD, PhD, is a Professor of Medicine (Hematology-Oncology) at the Perelman School of Medicine at the University of Pennsylvania. He serves as an Attending Physician at the Hospital of the University of Pennsylvania and is the Director of the Hematology Research Training Program at the University of Pennsylvania. His research interests focus on platelet biology and the mechanisms of platelet activation in response to vascular injury and disease. His work aims to understand how platelets contribute to hemostasis and thrombosis, with the goal of preventing arterial thrombosis while maintaining effective hemostasis. Brass's research employs genetically engineered mouse models and systems biology approaches, and his studies are funded by the NIH Heart, Lung and Blood Institute and the American Heart Association. He has a longstanding interest in the molecular and cellular mechanisms underlying thrombosis and hemostasis, utilizing methods such as gene expression manipulation, intravital microscopy, and computerized modeling. Brass collaborates with various departments and schools, including engineering, medicine, pediatrics, and pharmacology, to advance understanding in this field.
ABSTRACT: Intravital imaging studies have provided insights into the spatial and temporal variations of platelet activation and thrombin generation that occur during hemostasis; however, these studies are generally limited to small vessels due to the practical limitations of imaging in thicker tissues. Recent advances in cleared tissue fluorescence imaging as well as volume electron microscopy (vEM) coupled with machine learning-based image segmentation provide an opportunity for analysis of the 3-dimensional structure of complex tissues. We utilized these technologies to examine hemostatic plugs from murine jugular veins and carotid arteries to investigate the spatial distribution of platelet activation and biochemical responses in these disparate physiologic contexts. Both venous and arterial hemostatic plugs had a heterogeneous structure with regions of sparsely and densely packed platelets. Despite similar injury sizes, arterial hemostatic plugs were at least an order of magnitude larger than venous plugs. The difference in plug size was primarily due to a 19-fold increase in the population of densely packed platelets in the extravascular compartment. Venous plugs displayed significant platelet aggregation extending into the vessel lumen and developed distinctive fibrin and red blood cell-filled cavities. Complementary fluorescence microscopy revealed that platelet activation was spatially heterogeneous in both contexts, with α-granule secretion and phosphatidylserine exposure confined to specific microenvironments, highlighting tightly regulated thrombin activity. Overall, our findings reveal both conserved and distinct mechanisms of hemostatic thrombus formation in different physiologic contexts. They also demonstrate the power of vEM coupled with machine learning-based image segmentation for the quantitative analysis of large imaging data sets from complex tissues.
In 2022, the MD-PhD Competencies Development Workgroup, a subgroup of the Association of American Medical Colleges Group on Research, Education, and Training, initiated a project to define essential competencies for training physician-scientists, with a focus on MD-PhD education programs. The primary objective was to develop a comprehensive toolkit containing well-defined competencies and milestone-based tools to guide the education of individuals in MD-PhD combined degree programs. It is intended to augment, not duplicate, existing MD and/or PhD competency rubrics. A systematic approach was adopted in creating the toolkit, which included opportunities for the physician-scientist training community to contribute their collective experience and knowledge. This article describes the toolkit and its 3 main components: (1) 14 competencies grouped in 4 core domains, (2) a milestone-based assessment tool to track learner progress, and (3) guidelines for implementing the toolkit. This framework can be used to align expectations for learners and mentors, assess learner development, facilitate mentor-mentee conversations, adjust individualized learning goals, and self-identify curricular strengths and gaps. The toolkit can serve as a valuable resource for program directors, faculty mentors, and learners, empowering them to collaboratively shape the next generation of physician-scientists, bridging the worlds of medicine and research.
MD-PhD programs prepare physicians for research-focused careers. The challenge for admissions committees is to select from among their applicants those who will achieve this goal, becoming leaders in academic medicine and biomedical research. Although holistic practices are encouraged, the temptation remains to use metrics such as grade point average, Medical College Admission Test scores, and postbaccalaureate gap length, combined with race and ethnicity, age at college graduation, and sex to select whom to interview and admit. Here, we asked whether any of these metrics predict performance in training or career paths after graduation. Data were drawn from the National MD-PhD Program Outcomes Study with information on 4,659 alumni and 593 MD-PhD graduates of the Albert Einstein College of Medicine and the University of Pennsylvania. The Penn-Einstein dataset included admissions committee summative scores, attrition, and the number and impact of PhD publications. Output metrics included time to degree, eventual employment in workplaces consistent with MD-PhD training goals, and self-reported research effort. Data were analyzed using machine learning and multivariate linear regression. The results show that none of the applicant metrics, individually or collectively, predicted in-program performance, future research effort, or eventual workplace choices even when comparisons were limited to those in the top and bottom quintiles.
The earliest MD-PhD programs were small and enrolled mostly men. Here, we show that since 2014 there has been a steady increase in the number of women in MD-PhD programs, the number of women reaching parity with men in 2023. This change was due to an increase in female applicants, a decrease in male applicants, and an increase in the acceptance rate for women, which had previously been lower than that for men. Data from the National MD-PhD Program Outcomes Study show that training duration has been similar for men and women, as have most choices of medical specialties and workplaces. However, women were less likely to have full-time faculty appointments, fewer had NIH grants, and those in the most recent graduation cohort at the time of the survey reported spending less time on research than men. Previously cited reasons for these differences include disproportionate childcare responsibilities, a paucity of role models, insufficient recognition, and gender bias. Institutions can and should address these obstacles, but training programs can help by preparing their graduates to succeed despite the systemic obstacles. The alternative is a persistent gender gap in the physician-scientist workforce, lost opportunities to benefit from diverse perspectives, and a diminished impact of valuable training resources.
To reduce debt burden and encourage the pursuit of research-focused careers, most MD-PhD programs provide medical school tuition remission and an annual stipend. However, prolonged training compared with MD physicians postpones the time until MD-PhD physicians earn a full salary. We compared lifetime earning potential for MD-PhD physicians in academia with their MD colleagues in the same clinical specialty. We examined the relationship between earning potential based on specialty and the likelihood that MD-PhD physicians reported being engaged predominantly in research. Lifetime earning potential was estimated using 2020-2021 debt and compensation data for 77,701 academic physicians across 47 specialties. Self-reported research effort for 3,025 MD-PhD program alumni in academia was taken from the National MD-PhD Program Outcomes Study. We found that (a) MD-PhD physicians had a lower lifetime earning potential than MD physicians in the same specialty; (b) there was an inverse relationship between earning potential and research effort in different specialties, with MD-PhD physicians in high-earning specialties tending to spend less time on research; and (c) despite this, MD-PhD physicians in academia were more likely to choose clinical fields that allow more time for research.
Previous studies on attrition from MD-PhD programs have shown that students who self-identify as Black are more likely to withdraw before graduating than Hispanic students and students not from groups underrepresented in medicine (non-UIM). Here, we analyzed data collected for the National MD-PhD Program Outcomes Study, a national effort to track the careers of over 10,000 individuals who have graduated from MD-PhD programs over the past 60 years. On average, Black trainees took slightly longer to graduate, were less likely to choose careers in academia, and were more likely to enter nonacademic clinical practice; although, none of these differences were large. Black graduates were also more likely to choose careers in surgery or internal medicine, or entirely forego residency, and less likely to choose pediatrics, pathology, or neurology. Among those in academia, average research effort rates self-reported by Black, Hispanic, and non-UIM alumni were indistinguishable, as were rates of obtaining research grants and mentored training awards. However, the proportion of Black and Hispanic alumni who reported having NIH research grants was lower than that of non-UIM alumni, and the NIH career development to research project grant (K-to-R) conversion rate was lower for Black alumni. We propose that the reasons for these differences reflect experiences before, during, and after training and, therefore, conclude with action items that address each of these stages.
ABSTRACT: Nonmuscle cell contractility is an essential feature underlying diverse cellular processes such as motility, morphogenesis, division and genome replication, intracellular transport, and secretion. Blood clot contraction is a well-studied process driven by contracting platelets. Megakaryocytes (MKs), which are the precursors to platelets, can be found in bone marrow and lungs. Although they express many of the same proteins and structures found in platelets, little is known about their ability to engage with extracellular proteins such as fibrin and contract. Here, we have measured the ability of MKs to compress plasma clots. Megakaryocytes derived from human induced pluripotent stem cells (iPSCs) were suspended in human platelet-free blood plasma and stimulated with thrombin. Using real-time macroscale optical tracking, confocal microscopy, and biomechanical measurements, we found that activated iPSC-derived MKs (iMKs) caused macroscopic volumetric clot shrinkage, as well as densification and stiffening of the fibrin network via fibrin-attached plasma membrane protrusions undergoing extension-retraction cycles that cause shortening and bending of fibrin fibers. Contraction induced by iMKs involved 2 kinetic phases with distinct rates and durations. It was suppressed by inhibitors of nonmuscle myosin IIA, actin polymerization, and integrin αIIbβ3-fibrin interactions, indicating that the molecular mechanisms of iMK contractility were similar or identical to those in activated platelets. Our findings provide new insights into MK biomechanics and suggest that iMKs can be used as a model system to study platelet contractility. Physiologically, the ability of MKs to contract plasma clots may play a role in the mechanical remodeling of intravascular blood clots and thrombi.
Background: Contractility of non-muscle cells plays a crucial role in various cellular processes including motility, morphogenesis, division, genome replication, intracellular transport, and secretion. Platelet-induced blood clot contraction is an essential process which plays a role in preventing bleeding and in thrombotic disorders. Megakaryocytes (MKs), which are the precursor cells of platelets, share many proteins and structures with platelets. However, little is known about the ability of MKs to contract and interact with extracellular matrix proteins such as fibrin. Previously, the non-muscle myosin II contractility was shown to be essential for MK migration within the bone marrow, to avoid premature proplatelet formation, and to allow branching of proplatelets. Recent studies have identified MKs in lung and brain tissues, as well as associated with thrombi in deceased COVID-19 patients. Notably, patients with severe COVID-19 exhibit elevated MK counts in their blood, indicating potential involvement in hemostasis and thrombosis. Nevertheless, the specific mechanisms by which MKs can contribute to clot contraction remain unknown. Methods: Human induced pluripotent stem cells (iPSC) were differentiated into HPCs followed by expansion to megakaryocytes (iMKs) and analyzed by flowcytometry. Clot formation and contraction were initiated by adding thrombin and calcium to platelet-free-plasma with resuspended iMKs. A combination of real-time macroscale optical tracking, high-resolution confocal microscopy and biomechanical measurements were applied to elucidate the contractile cellular mechanisms and mechanotransduction pathways in iMKs, and ultimately comparing them with platelets. Results: Flowcytometry analysis of unstimulated and thrombin-stimulated iMKs revealed that the major fraction of unstimulated cells expressed αIIbβ3 and GPIbα (~78%), but did not bind PAC-1, a monoclonal antibody specific for the activated conformation of αIIbβ3. Stimulation of iMKs with 1U/ml of thrombin resulted in PAC-1 binding (~68%), indicating activation of aIIbb3. The optical tracking of clot size change over time revealed that thrombin-stimulated iMKs were able to shrink macroscopic plasma clots with biphasic kinetics, similar to platelets. iMK-containing clots and platelet-reach-plasma clots equalized by the total cell surface area demonstrated comparable contraction rates and extent of contraction. The average maximal contractile force per individual iMK in the clot was found to be 145±98nN. In the presence of blebbistatin, the mean final extent and velocity of clot contraction of iMK-containing clots reduced in a dose-dependent manner, in comparison to untreated clots. Pretreatment of iMKs with 1μM latrunculin A, an inhibitor of actin polymerization, completely prevented contraction of plasma clots. In addition, contraction of plasma clots by activated iMKs was abrogated by 10μg/ml abciximab, that prevented binding of fibrin(ogen) to integrin a IIbb 3 receptors. The structural mechanisms of iMK contractility involved formation of filopodia and larger cytoplasmic protrusions undergoing extension-retraction cycles after being attached to surrounding fibrin fibers. Contraction of iMKs caused remodeling of the extracellular fibrin matrix by inducing spatial reorientation of fibrin fibers, accumulation of the fibrin mass on the iMK surface, and compaction of the entire fibrin network. Conclusions: We have demonstrated a hitherto unknown ability of individual MKs to shrink fibrin clots and deciphered the cellular mechanisms of contractility of iPSC-derived MKs. The molecular mechanisms of MK-driven fibrin clot shrinkage were shown to be similar or identical to those of activated platelets, involving non-muscle myosin II activity, actin polymerization, and integrin αIIbβ3-fibrin interactions. Our findings provide a novel mechanistic insight into mechanobiology of MKs that may play a role in modulating the properties of hemostatic blood clots and thrombi. In addition, iMKs can be used as model cells with a potential of genetic modifications to study platelet structure and function, including their contractility.
