Jeffrey D. Macklis

Jeffrey D. Macklis' laboratory is directed toward the cellular repair of complex cerebral cortex and cortical output circuitry (including cortico-spinal motor neuron circuitry). The lab focuses on neocortical projection neuron development and sub-type specification; neural progenitor / “stem cell” biology; induction of adult neurogenesis (the birth of new neurons from within); and directed neuronal differentiation and development of connectivity via molecular manipulation of neural progenitors within murine neocortex.

Dr. Macklis is Professor of Stem Cell and Regenerative Biology, Harvard University, and Professor of Neurology [Neuroscience] and of Surgery [Neurosurgery] at Harvard Medical School (HMS); and Program Head, Neuroscience / Nervous System Diseases, Harvard Stem Cell Institute, Harvard University. He is a faculty member in the Harvard University graduate Programs in Neuroscience, Developmental and Regenerative Biology, and Biological and Biomedical Sciences; M.D.-Ph.D. Program; and Molecular and Cellular Biology program; and of the affiliated faculty of the Harvard-Massachusetts Institute of Technology (M.I.T.) Division of Health Sciences and Technology (HST), and the M.I.T. faculty within HST.

He attended M.I.T. (S.B. Bioelectrical Engineering; S.B. Literature), Harvard Medical School (HST Program), and graduate school at M.I.T. within the Harvard-M.I.T. Division of Health Sciences and Technology (HST).  He was a postdoctoral fellow in developmental neuroscience with Richard Sidman at HMS.

Dr. Macklis is the recipient of a number of awards and honors, including a Rita Allen Foundation Scholar Award, an Innovation Award from the NIH Director’s Office, a Soderberg Prize Symposium Lectureship at the Swedish Society for Medicine, The CNS Foundation Award, Pearlstein Scholar Award, Seidman Award in CNS Research, several Hoopes Prizes for excellence in undergraduate research mentoring, and a Senator Jacob Javits Award in the Neurosciences from the NINDS/NIH.

Karen Yee

Dartmouth College, A.B. (Biology); University of Washington, Ph.D. (Molecular and Cellular Biology)

I joined the Macklis lab in the spring of 2011. I serve as the research lab manager and am in charge of maintaining the operations of the lab. This involves negotiating with vendors, ordering and receiving lab equipment and supplies; identifying and assisting in resolving any problems with space, equipment and personnel; and serving as the safety officer for the lab and ensuring that laboratory personnel and laboratory space are compliant with training and all safety regulations. I also oversee the mouse colony and handle most of the administrative responsibility of the colony including ordering animals and maintaining the animal protocols and COMS approvals.

Previously, I was an Instructor/Research Lab Manager in the Dept. of Pathology at Beth Israel Deaconess Medical Center, I designed and carried out experiments to demonstrate that vascular endothelial growth factor B potently increases connexin 43 expression in neonatal rat cardiac myocyte gap junctions by activating VEGFR1, stimulating a signaling pathway that includes PI3Kinase and Map Kinase and increasing trafficking of Cx43 to gap junctions via microtubules. I also directed laboratory operations for a small lab (4-6 people) and maintained a mouse colony (50+ cages).

As a Post-Doctoral Fellow in the Dept. of Pathology, Division Tumor Biology/Angiogenesis at Beth Israel Deaconess Medical Center, I oversaw numerous projects characterizing the role of Thrombospondin-1 (TSP-1), a potent anti-angiogenic, anti-tumorigenic factor, in various mouse models of cancer. I established collaborations with members in the lab and groups outside the lab to develop and characterize three different mouse models of cancers that involved the molecule TSP-1: a) I initiated, developed and characterized a transgenic mouse model for breast cancer in order to study how TSP-1 affects tumor progression at different stages (i.e. initiation to metastasis), b) I Initiated a collaboration to test whether interperiotenal injections of a compound (halofuginone) or recombinant peptides against TSP-1 would inhibit mammary tumor progression in a mouse model of breast cancer, c) I identified overlapping and non-overlapping functions for TSP-1 and integrin αvβ6 by comparing the phenotype in three different lines of transgenic mice.

As Graduate Student in the Molecular and Cellular Biology Program at the University of Washington, I determined that the integrin α5β1 and matrix molecule fibronectin were important in human smooth muscle cell contraction of fibrin clots and adhesion to fibrin clots. I also demonstrated that smooth muscle cells express both α5β1 and fibronectin on their surfaces and these proteins can act as bridge molecules between the cell and the fibrin matrix. I also collaborated with others in the lab to determine the integrin and fibrin expression patterns in diseased vessels.

Kelly Deneen

Boston College, B.A. (History, Black Studies); Simmons College, M.S. (Library and Information Science)

I joined the Macklis Lab in early 2011 as Dr. Macklis' Faculty Assistant. Prior to my arrival in the lab, I worked for several years at the Boston College Law Library, first as a Law Library Assistant and then as an Administrative Assistant to the Associate Dean for Library and Technology Services. During this time, I earned my M.S. in Library and Information Science from Simmons College. Boston College is where I earned my B.A. in History and Black Studies (now African and African Diaspora Studies).

In addition to my work at Harvard, I am a Teen Services Librarian at the Watertown Free Public Library.

Ryann Fame

College of William and Mary, B.S. (Chemistry and Biology)

I joined the Macklis lab in the spring of 2007 as a graduate student in the Department of Molecular and Cellular Biology.  My research interests focus on the genetic/ molecular controls over cortical neuron development; specifically, callosal projection neuron specification and diversity. Building on comparative gene expression analyses in the Macklis lab, I am currently investigating the temporal developmental role of genes that are enriched in callosal projection neurons in collaboration with Jessica MacDonald.  It is my desire that in contributing to better understanding of the genetic controls over specific cortical subtypes, this work will shed light on neural regeneration and repair of adult neurons and give a deeper understanding of subtle callosal abnormalities such as those found in autism spectrum disorders.           

Before beginning my studies at Harvard, I received my B.S. in Chemistry and Biology with honors from the College of William and Mary in Virginia.  There I completed my thesis under the supervision of Professor Margaret Saha investigating early fate specification of GABAergic and glutamatergic neurons in Xenopus.  I also worked with Professor Alain Ghysen at the Université de Montpellier II investigating secondary neural connections from the posterior lateral line ganglion to the hindbrain in developing zebrafish.

Mollie Woodworth

MIT, S.B., S.B. (Brain and Cognitive Sciences; Biology)

I joined the Macklis lab in summer 2007 as a Ph.D. student in the Biological and Biomedical Sciences program. I am interested in the way a limited repertoire of developmentally-expressed transcription factors can generate the amazing cellular diversity of the adult mammalian brain. Working in collaboration with Luciano Custo Greig, I have chosen to focus on one such transcription factor, identified in earlier work in the lab to be centrally important for the development of corticospinal motor neurons (CSMN) in the cortex; although this transcription factor is necessary for proper CSMN axon extension to the spinal cord, little is known about the specific molecular differentiation programs it executes. I am investigating the mechanisms by which this central regulator of CSMN differentiation acts alone and in concert with other genes to instruct specific aspects of CSMN development. I hope that by learning more about the normal development of CSMN, I will shed light on strategies to repair them in pathological states such as amyotrophic lateral sclerosis and spinal cord injury.

I completed my undergraduate studies at MIT, and graduated in 2006 with bachelor's degrees in biology and in brain and cognitive sciences. As an undergraduate, I worked in Morgan Sheng’s lab, where I investigated the functions of several postsynaptic density proteins in hippocampal projection neurons.

Cameron Sadegh

MIT, S.B., S.B. (Biology; Chemical Engineering)

I joined the Macklis laboratory in the fall of 2009, with an interest in the development (neuronal subtype specification) of corticospinal motor neurons (CSMN), which are the brain neurons directly damaged by spinal cord injury and which degenerate in amyotrophic lateral sclerosis (ALS, more commonly known as "Lou Gehrig's disease").

In particular, I am applying our scientific field's knowledge of CSMN development to enable the directed differentiation of embryonic stem cells into relevant neocortical neuron subtypes. I hope my work will inform future drug screening or cellular repair strategies for spinal cord injury or Lou Gehrig's disease.

I am currently an MD-PhD candidate at Harvard Medical School (PhD candidate in the Program in Neuroscience since 2008; MD candidate in the joint Harvard-MIT Division of Health Sciences & Technology since 2006). Before entering Harvard, I graduated from MIT in 2006 with Bachelor of Science degrees in Biology and in Chemical Engineering, with a minor in Biomedical Engineering. While at MIT, I worked in the Lodish laboratory, where I first studied the role of apoptosis in erythropoiesis, and later studied cell surface receptor proteolysis and signaling in lung epithelial cells.

Luciano Custo Greig

Yale University, B.S., M.S. (Molecular, Cellular, and Developmental Biology)

I am an MD student at Harvard Medical School and a PhD candidate in the Biological and Biomedical Sciences program at the Harvard Graduate School of Arts and Sciences. Since joining the Macklis lab in the fall of 2009, I have been investigating the functions of two transcription factors that control neocortical projection neuron differentiation in collaboration with Mollie Woodworth. Projection neurons establish the basic framework of long-range connections between different areas of the neocortex and between the neocortex and subcortical structures. I am particularly interested in corticospinal motor neurons (CSMN), large pyramidal neurons that reside in layer V of primary motor cortex and extend axons to the spinal cord to initiate voluntary movement. CSMN are clinically important because they are damaged in spinal cord injury and degenerate in amyotrophic lateral sclerosis (ALS) and related upper motor neuron diseases. I hope that our research will inform new therapeutic strategies to repair damaged circuits by generating replacement neurons in vitro or by recruiting endogenous precursors to produce them in vivo.

Prior to starting my graduate studies at Harvard, I attended Yale University, where I completed B.S. and M.S. degrees in Molecular, Cellular and Developmental Biology. During my M.S. thesis in the laboratory of Elke Stein, I studied netrin receptor function during cerebellar development and signaling pathways these receptors utilize to control cytoskeletal growth cone dynamics.

Alexander Murphy

MIT, S.B. (Nuclear Engineering)

I joined the Macklis lab in the summer of 2011 as a graduate student in Neurobiology. My research interests center on elucidating molecular wiring mechanisms that guide projection neuron axons to diverse, distant targets with remarkable precision. I graduated from MIT in June 2010 with my degree in Nuclear Engineering, and worked as an undergraduate in Susumu Tonegawa's lab at the Picower Institute investigating local protein synthesis and capture in hippocampal spines.

Zhaoying Xu

Grinnell College, B.A. (Biological Chemistry, Neuroscience)

I joined the Macklis lab in the summer of 2012 as a Ph.D. student in the Program in Neuroscience at Harvard. My research interests focus on the molecular and developmental controls over the specification and differentiation of corticostriatal projection neurons (CStrPN), which are the central neuronal population affected in Huntington’s disease.

Prior to beginning my studies at Harvard, I graduated from Grinnell College in May 2011 with a bachelor degree in Biological Chemistry and a concentration in Neuroscience, working with Professor Leslie Gregg-Jolly on regulation of DNA damage responses in prokaryotes Acinetobacter. In addition, I worked as an undergraduate in David Miller’s lab at Vanderbilt studying the neuronal wiring specificity in the C. elegans motor circuit and in Leslie Vosshall’s lab at Rockefeller investigating the molecular basis of post-fasting feeding responses in Drosophila.

Kadir Ozkan

Middle East Technical University, B.S. (Molecular Biology and Genetics)

I joined the Macklis Lab in November 2010 as a visiting graduate student from Bogazici University, Istanbul. Working in close collaboration with Hari Padmanabhan, we aim to develop approaches for cellular repair of complex cortical circuitry, particularly corticospinal motor circuitry which degenerates in Amyotrophic Lateral Sclerosis (ALS) and is damaged by spinal cord injury. Specifically, we aim to activate key developmental transcriptional programs in progenitor cells of the postnatal brain, to direct these cells into specific neuronal subtypes. We are also interested in the transcriptional regulation of progenitors following the neurogenesis-to-gliogenesis switch in late embryonic development, to enable better manipulation of postnatal progenitor cells.

Prior to beginning my studies at Harvard, I received my BS degree in Molecular Biology and Genetics from Middle East Technical University (METU) in Ankara, and my MS degree from Bogazici University, Istanbul.  For my master's thesis, under the supervision of Prof. A. Nazli Basak, I worked on temporal expression analysis of angiogenesis-related genes in brain development. I also worked in Prof. Turker Kilic’s lab at the Marmara University on anti-angiogenic therapy approaches for brain tumors and arteriovenous malformations.

Maria Jose Galazo

Autonoma University of Madrid, Ph.D.

My general research interest lies in the developmental biology of the cerebral cortex, especially in the assembly of cortical networks, and more recently in the potential application of developmental biology studies to re-formation of neuronal circuits. 

During my Ph.D at the Medical School of the Autonoma University of Madrid, I studied the anatomical distribution of the Reelin protein in different philogenetic groups like primate, carnivores and rodents, and its potential role in the developing and adult brain. Also, I studied the establishment and maintenance of the connections from the matrix neurons in the thalamus to the cortex, during the embryonic and postnatal life, and the interaction with intrinsic cortical circuits and feed-back cortical circuits to the thalamus. 

I joined the Macklis Lab in July 2007, and since then I have been working in collaboration with Dr. Jason Emsley, in describing the role of a transcriptional regulator that is critical for the development of cortico-thalamic projection neurons. My research goal is to study molecular-genetic controls over the specification and differentiation of cortico-thalamic neurons, specifically the two different components of the cortico-thalamic circuits, as well as some work on corticospinal motor neurons. This projection systems provide the main sensory-motor control output and the main motor output and from the cerebral cortex, respectively.

Jessica MacDonald

University of British Columbia, Ph.D.

My general research interests lie in understanding the molecular regulation of the specification and stage-specific development of neurons. During my Ph.D. at the University of British Columbia, I focused on the role of DNA methylation and down-stream transcriptional regulators in regulating distinct transitional stages of neuronal differentiation during postnatal neurogenesis of olfactory receptor neurons.

Since joining the Macklis lab in August 2008, I have been working in close collaboration with Ryann Fame to examine the molecular-genetic controls over callosal projection neuron (CPN) specification and diversity. CPN, a distinct subtype of excitatory cortical projection neuron, connect the two hemispheres of the brain through the corpus callosum, disruptions of which have been implicated in autism spectrum disorders. We have identified a combinatorially-expressed set of genes that both define CPN as a broad population, and identify novel subpopulations of CPN during embryonic and postnatal development (Molyneaux, Arlotta, J NSci, ‘09), and we are now characterizing the function of a select, focused set of newly identified candidate genes in the development of CPN as a population, as well as distinct subtypes of CPN. Currently, little is known about the molecular development and heterogeneity of CPN, neurons that are critical for bilateral integration of cortical information and have been centrally implicated in autism spectrum disorders. It is my hope that the identification of molecular-genetic controls over CPN development will contribute to our understanding of neurodevelopmental disorders.

Hari Padmanabhan

Tata Institute of Fundamental Research, Ph.D.

During development, projection neurons of the cerebral cortex are generated first from the pallial ventricular zone followed by astrocytes and oligodendrocytes. Since the same population of progenitors give rise to both neurons and glia sequentially, there are switches that are flipped OFF after neurogensis and new switches turned ON to initiate proper gliogenesis. Moreover, during the phase of neurogenesis, spatially restricted transcriptional programs regulate the generation of broad classes of neurons like long distance projection neurons and interneurons from dorsal and ventral ventricular zone, respectively. We are interested in understanding how these are achieved in a precise manner. This project is in collaboration with Eiman Azim, a former graduate student in the lab, and Chris Devine, who is an undegraduate student.

The generation of induced pluripotent cells has demonstarted that terminal differentiation of a cell type may not be an irreversible process. By knowing key molecular controls, it is possible to revert differentiated cells to an immature state and then redirect them along an alternate differentiation pathway. Similarly, differentiated cells can also potentially be directly reprogrammed to other cell types. By understanding the genetic mechanisms that regulate orderely neurogenesis and gliogenesis, we hope to coax cells to switch from one stable state to another. This project is in collaboration with Kadir Ozkan, graduate student in the lab.

Prior to joining the Macklis Lab in October, 2008, I did my PhD at the Tata Institute of Fundamental Research, India. During my thesis research, I studied the role of LIM-domain containing transcription factors and their cofactors in neuronal development in fruit flies and mice.

Alexandros Poulopoulos

University of Göttingen, Ph.D.

I joined the Macklis lab in May 2010, interested in how cortical circuits form. Drawing from diverse backgrounds, colleagues in the lab and I combine methodologies with the aim of identifying novel mechanisms that instruct growing axons as they navigate the complex environment of the developing brain. We employ transplantation, transgenesis, tracing, sorting, and proteomics in order to examine the dynamic cellular crosstalk and molecular interactions that guide neuronal processes to reach meaningful targets and form functional circuits.

Before coming to Boston, I worked on mechanisms of synaptogenesis in the lab of Nils Brose at the Max Planck Institute of Experimental Medicine, receiving a Ph.D. in Neuroscience from the University of Göttingen, Germany in 2008. As an undergrad, I studied Biology at the University of Athens, Greece, working in the lab of Spiros Efthimiopoulos on amyloid processing in dementia.

Vibhu Sahni

Northwestern University, Ph.D.

email: vibhu_sahni [at] harvard [dot] edu

I joined the Macklis lab in September 2009 as a postdoctoral fellow. I am interested in the investigation of the developmental mechanisms in the nervous system and their application in understanding disease process as well as the development of therapeutic strategies for nervous system repair. In the Macklis lab, I am focusing on the development of corticospinal motor neurons (CSMN) in two broad areas: (1) Functional characterization of genes identified by two former members of the lab, Denis Jabaudon and Sara Shnider, as candidates for controlling CSMN subtype-specific development and segmental target specificity. In this study, I am combining both gain- and loss-of-function analyses in CSMN subtypes to examine the roles of these candidate control genes on segmental targeting in the spinal cord. (2) Development of strategies to apply our existing knowledge of CSMN development, that was previously identified in the lab, toward CSMN regeneration after spinal cord injury.

Prior to arriving at the Macklis lab, I completed a Ph.D. in Neuroscience at Northwestern University. During my thesis work under the guidance of Prof. John A. Kessler, I worked on the mechanisms of astrocytic development and investigated their role in astrogliosis and functional recovery after spinal cord injury in the mouse. I completed my undergraduate studies at the University of Mumbai, India.

Samuel Brook

Skidmore College, B.A. (Neuroscience)

I joined the lab in 2012 after graduating with a degree in Neuroscience from Skidmore College.  While at Skidmore, I worked with Dr. Hassan López investigating the long-term, detrimental effects of adolescent exposure to cannabinoids.   I now work closely with Dr. Vibhu Sahni on the functional characterization of genes that control the development and differentiation of corticospinal motor neurons.  I also work with Dr. Maria Galazo studying the developmental biology of the cerebral cortex. I also provide support to the lab through experimental techniques in molecular biology and immunohistochemistry.

Chloe Greppi

Northeastern University, B.S. (Biology)

I joined the lab in May 2011 after graduating from Northeastern University with a degree in Biology and a minor in Italian. I work with Mollie Woodworth and Luciano Custo-Grieg, studying how a transcription factor important in corticospinal motor neuron development executes differentiation programs in the cortex. In addition, I also work with Ryann Fame and Jessica MacDonald, investigating the genetic controls involved in callosal projection neurons and their implication in callosal projection neuron aberrations associated with autism spectrum disorders. I also provide support to the lab through a variety of experimental techniques in molecular biology.

Ben Noble

Emory University, B.S. (Neuroscience and Behavioral Biology)

I joined the lab in June 2012 after graduating from Emory University with a degree in Neuroscience and Behavioral Biology. I work with Jessica MacDonald and Ryann Fame, investigating molecular controls over callosal projection neurons; I hope this will help contribute to our understanding of neurodevelopmental disorders as well. Additionally, I provide technical support to the lab through various experimental techniques in molecular biology.

As an undergraduate, my research focused on understanding how certain genes impact outcome measures associated with addiction. I performed this work with Dr. Shannon Gourley at the Yerkes National Primate Research Center at Emory University.

Jessica Wooton

I joined the lab in the summer of 2012.

I joined the Macklis Lab in the summer of 2010 as an undergraduate concentrating in Neurobiology at Harvard College. I am currently working with post-doctoral fellow and mentor Dr. Hari Padmanabhan to investigate the role of a specific transcription factor in cortical projection neuron development. We are interested in understanding its potential role in influencing the fate of subcerebral, corticothalamic, or callosal projection neuron development. Given that projection neurons are damaged in amyotrophic lateral sclerosis and spinal cord injury, studying particular genetic controls over their development may help contribute to future therapies.

I joined the Macklis lab in January of 2010 as undergraduate student in the biological sciences. I am currently working with Vibhu Sahni, a post doctorate fellow, on the characterization of a specific gene involved in corticospinal motor neuron (CSMN) development. We are investigating its role in areal specification and axonal projections in the spinal cord using both genetic loss and gain-of-function strategies along with immunocytochemical and anatomical tracing techniques.

My previous research experience includes working on a urine test to detect genetic and epigenetic modifications for the early detection of colorectal cancer under the supervision of Dr. Timothy Block at Drexel University in Philadelphia. In addition, I compared an automated and a semi-automated brain parcellation system with respect to the brains of alcoholic individuals under Dr. Gordon Harris at Massachusetts General Hospital.

I am an undergraduate student concentrating in Neurobiology at Harvard College. I joined the Macklis laboratory in February of 2011, and I am currently working closely with Dr. Mollie Woodworth and MD PhD candidate Luciano Custo Grieg to investigate the molecular-genetic controls of corticospinal motor neuron (CSMN) development. CSMN are a clinically significant population of neocortical neurons because they degenerate in amyotrophic lateral sclerosis (ALS), and their damage is central to loss of motor function in spinal cord injury. A better understanding of the molecular-genetic controls necessary for nervous system development may enable strategies for repair, regeneration, or replacement of diseased and damaged neurons.

I joined the lab in 2012 as an undergraduate. I am working with PhD candidate Alexander Murphy and Dr. Alexandros Poulopoulos, investigating molecular mechanisms that influence the development of callosal projection neurons (CPN).