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Research Assistan Cover Letter At The McCarroll Lab - Harvard Medical School
The McCarroll Lab - Harvard Medical School
Position Description The successful candidate for this position will contribute to an interdisciplinary research team that is working to understand the genetic and cellular basis of normal human brain function and of brain disorders including Schizophrenia
Bipolar Disorder
and Huntington’s disease. The McCarroll Lab (http://mccarrolllab.org) studies the human brain using a variety of approaches and technologies
many of which we invented in recent years and/or are further developing. These include approaches for analyzing RNA and proteins in thousands of individual cells simultaneously (https://www.youtube.com/watch?v=vL7ptq2Dcf0). Coordination and collaboration within interdisciplinary research teams (that combine biology
statistics and data science) is a key aspect of this research. Job-Specific Responsibilities: Contribute to experimental workflows for profiling the molecular contents and biological states of thousands of individual cells in human brain tissue
contributing to all aspects including planning experiments; creating DNA-barcoding reagents; extracting nuclei from human brain tissue; preparing molecular libraries; and high-throughput sequencing. Optimize and execute molecular-biological reactions such as PCR and DNA extraction. Independently troubleshoot and optimize techniques and technologies. Maintain detailed experimental notes in the lab’s electronic lab notebook. Report experimental results in weekly lab meetings. Contribute to other projects as needed. Basic Qualifications College background or equivalent work experience
preferably in a related discipline. One to two+ years related work experience (relevant course work may count towards experience). Additional Qualifications and Skills Bachelor’s degree in biology
neuroscience
chemistry
biomedical engineering
or other quantitative area of science or engineering. Extensive course work could in some cases be equivalent to a major. At least one year of laboratory experience. Subjective qualifications: Clear and effective in verbal and written communication. Able to critically read and discuss scientific research publications. Collaborate with a diverse group including laboratory scientists
project managers
professional staff
and academic trainees.Skills & Qualifications • Ability to work independently and efficiently. • Strong organizational and task prioritization skills. • Excellent communication skills and proficiency in performing administrative and clerical tasks. • Proficient in general laboratory procedures
techniques
and documentation. • Willingness to learn and adapt to new techniques and technologies. • Fluent in English
Spanish
French
and Catalan. • Proficient in statistical analysis and software such as SPSS
MATLAB
and Python. • Proficient in using various software programs
including Microsoft Office Suite (Word
Excel
PowerPoint). • Advanced knowledge and experience in 3D cell culture techniques. • Skilled in protein isolation
Western Blot
PCR
rt-qPCR
toxicity testing
IHC
Northern Blot
and ELISA. • Proficient in anatomical dissection studies for medical and veterinary purposes. • Experienced in static analysis of behavioral data and microarray data. • Familiarity with electrophysiology
imaging
protein purification
and optical and electron microscopy techniques. • Advanced level proficiency in conducting animal experiments
behavioral experiments
anatomical dissection
and molecular analysis. Research Human Brain Disorders and Repeated DNA The scientific teams in our lab are working to recognize the biology that underlies human brain health and illness
and the ways in which human genes
inherited genetic variation
and somatic mutations conspire to shape this biology. The biological basis for most brain disorders is unknown today: most are understood mainly in terms of collections of symptoms
neuropathological observations – such as cortical thinning
protein aggregates
or death of a specific kind of cell – and human-genetic associations. We need to deeply understand these disorders as biological entities so that we can develop new and innovative ways to monitor and treat them. Our lab is particularly focused on (i) DNA-repeat disorders and (ii) the disruptions of mental health commonly known as “psychiatric disorders”
especially schizophrenia. Our research team brings together people with experiences
approaches and insights from biology
human genetics
statistics
and computer science. Our approaches to questions tend to involve one
two or all three of the following: developing new experimental approaches that turn key aspects of brain biology into “big data” problems (for example
droplet-based single-cell RNA-seq); developing new computational and statistical ways to analyze high-volume biological data sets; and applying these approaches to reach insights about the biology that underlies human brain health and illness. Though we develop new experimental and computational approaches to answer questions
we are question-driven rather than technique-driven. Our goal is always to answer critical questions; we develop whatever experimental or computational approaches we think a biological question needs. Three current areas of focus are described below. These areas overlap
and many scientists in the lab contribute ideas and work more than one of them. We are also increasingly finding that the biology underlying diverse brain disorders is shared across many disorders; this compels us to think about clusters of brain disorders that are united by shared underlying mechanisms. DNA repeats and DNA-repeat disorders A silhouette of a head overlaid with the CAG DNA sequence repeated many times Thousands of regions within the human genome contain stretches of DNA in which a DNA sequence is repeated a substantial and variable number of times. More than 40 human diseases are known to be caused by expansions of simple DNA sequence repeats; intriguingly
most of these are primarily diseases of the brain. DNA repeats are mutable and exhibit length variation both across people (polymorphism) and within people (mosaicism). DNA repeats provide fascinating opportunities to study genetic effects on human biology
as they provide allelic series with clear quantitative relationships between DNA variation (number of repeats)
cellular phenotypes
and human phenotypes such as illness. DNA-repeat disorders are caused by inherited alleles with expansions of simple DNA sequence repeats. The classic DNA repeat disorder
Huntington’s Disease (HD)
affects people who have inherited an allele of the Huntingtin gene with at least 36 CAG repeats in its first exon. (Most people inherited alleles 15-30 CAG repeats.) Our team recently made a surprising discovery: such inherited alleles may have no inherent toxicity. Instead
they are somatically unstable: they expand in specific cell types throughout a person’s life. Only upon becoming very long (>150 repeats) do they begin to acquire toxicity
a finding which helps explain their midlife onset and their cell-type-specific pathology. We are just finishing a preprint on this work. We presented these results at CHDI’s Annual HD Therapeutics Conference in 2023: We are working to better understand this mechanism in HD
as well as in other DNA-repeat disorders that we think may share this mechanism with HD. Copy number variations (CNVs) involve tandem repeats of longer sequences
often several kilobases in length
and sometimes comprise entire genes. Students in our lab discovered that complex variation of the complement component 4 (C4) genes generate the human genome’s largest common effects on schizophrenia
lupus
and Sjogren’s syndrome
and that these help us understand the sex bias of these disorders
in which schizophrenia is more common in males
and lupus and Sjogren’s are much more common in females. Sekar et al.
Schizophrenia risk from complex variation of complement component 4. Nature
2016. Kamitaki et al.
Complement genes contribute sex-biased vulnerability in diverse disorders. Nature
2020. We are also finding
in collaborations with Po-Ru Loh’s lab
that smaller variable-number-of-tandem-repeat (VNTR) polymorphisms – often involving individual gene exons or regulatory sequences – create some of the human genome’s largest common effects on many human phenotypes. Mukamel
Handsaker et al.
Protein-coding repeat polymorphisms strongly shape diverse human phenotypes. Science
2021. Mukamel
Handsaker et al.
Repeat polymorphisms underlie top genetic risk loci for glaucoma and colorectal cancer. Cell
2023. Somatic mosaicism and clonal expansions Schematic of brain with clonal mutations respresented by ink blots The brain and other tissues acquire somatic mutations throughout life. Our lab is interested in a specific subset of somatic mutations that appear to recur again and again in different people. These include (i) DNA-repeat expansions
which we have found expand throughout life in a cell-type-specific manner
and (ii) proliferation–promoting mutations
which we have found propel somatically expanded clones with somatic mutations in the blood and brain. DNA repeat disorders are caused by inherited alleles with expansions of simple DNA sequence repeats. The iconic DNA repeat disorder
Huntington’s Disease
is caused by alleles in which a CAG repeat in the Huntingtin gene is repeated at least 36 times (vs. normally 15-30). We have recently found that this disease is fundamentally driven by somatic mutations that cause this repeat to expand beyond 150 repeat units in specific
vulnerable cell types: Another kind of recurring somatic mutation propels clonal expansion of mitotic cells. Scientists in the lab discovered that
as we age
our blood increasingly is generated by populations of clonally expanded cells with somatic mutations. We subsequently found that inherited genetic variation conspires with somatic mutations in surprising ways to bring about somatically expanded clones. Genovese et al.
Clonal hematopoiesis and blood cancer risk inferred from blood DNA sequence. New England Journal of Medicine
2014. Loh
Genovese et al.
Insights into clonal haematopoiesis from 8
342 mosaic chromosomal alterations. Nature
2018. Loh
Genovese and McCarroll
Monogenic and polygenic inheritance become instruments for clonal selection. Nature
2020. We have recently discovered that analogous clonal dynamics occur in the human brain. Scientists in the lab are deepening our understanding of mosaicism and clonal expansions by developing new detection and and analysis methods to understand the cell-type specific dynamics and effects
and applying these new approaches to brain tissue from hundreds of human donors. Biology of mental health and illness Two head silhouettes: one with a coil in the brain representing brain health and one with a tangled rope in the brain representing mental illness Mental health and mental illness present compelling unmet need: disorders such as schizophrenia and bipolar disorder cause enormous suffering
yet are not understood as biological entities. Our goal is to reveal and understand the biology that underlies these disorders so that more effective therapies can be developed. Since human genetics provides unbiased information – unlimited by the frameworks and hypotheses of any biological field
and without the assumptions of models – we work to understand what humans and their genetics are trying to teach us about the biology of these disorders
focusing on what we can learn by analyzing human brain tissue and human genetics data in new ways. However
genetic findings on mental health disorders have been hard to interpret biologically: In contrast to the genetics of DNA-repeat disorders
the genetics of mental health disorders is far more complex
with influences from more than 100 genomic loci. Recognizing the underlying biology requires different kinds of approaches. It was for this need that we originally developed droplet-based single-cell RNA-seq
a technology that scientists in the lab are further developing to analyze single synapses
nuclear proteins
and synaptic proteins. One of our approaches is to identify the large-scale cellular and molecular systems that underlie brain health
and to identify the specific systems that are impaired in each disorder. To do this
we have been developing new ways to analyze single-cell RNA-seq data generated from hundreds of human brain donors. One of our approaches
based on machine learning
recently led us to discover that cortical neurons and astrocytes closely coordinate their gene expression
in a program we call “SNAP” – a collaboration that we find appears to be central in protection from schizophrenia and cognitive aging. Ling et al.
A concerted neuron-astrocyte program declines in ageing and schizophrenia. Nature
2024. We are currently working to more deeply understand SNAP at the molecular and cellular levels by using animal models
cellular models
and deeper analyses of human brain tissue. In earlier work
students in the lab showed that the human genome’s largest common influence on risk of schizophrenia – the Major Histocompatibility Complex (MHC) locus – surprisingly does not arise
as previously thought
from HLA genes
but rather from many different alleles of the complement component 4 (C4) genes. We also found that C4 protein localizes to synapses. These results demonstrated that molecular events at synapses – rather than an infection or autoimmune response – are the likely explanation for this genetic effect on schizophrenia. Sekar et al.
Schizophrenia risk from complex variation of complement component 4. Nature
2016. Kamitaki et al.
Complement genes contribute sex-biased vulnerability in diverse disorders. Nature
2020.
By Melike Cansel EREN
Melike Cansel EREN
[Your Address]
[City, State ZIP Code]
[Email Address]
[Today’s Date]
Steve McCarroll, Dorothy and Milton Flier Professor of Biomedical Science and Genetics
Director of Genomic Neurobiology, Stanley Center for Psychiatric Research
Department of Genetics, Blavatnik Institute, Harvard Medical School
Broad Institute of MIT and Harvard
[Department Address]
Dear Professor McCarroll,
I am writing to express my enthusiasm for the Research Assistant position at The McCarroll Lab - Harvard Medical School. As a highly motivated and dedicated individual with a strong passion for genetics and neuroscience, I am confident that my skills, experience, and educational background make me a perfect fit for this role.
I am particularly impressed by the multidisciplinary and innovative research being conducted at The McCarroll Lab. The opportunity to contribute to an interdisciplinary team and work towards understanding the genetic and cellular basis of human brain function and disorders is truly exciting to me. Having closely followed the groundbreaking work of the lab, I am enthusiastic about the prospect of being a part of it and making meaningful contributions to the field of genetics and neuroscience.
I have a Bachelor’s degree in Neuroscience and have completed extensive coursework in biology, chemistry, and biomedical engineering. My passion for quantitative science has led me to take courses in statistics, data science, and computer science, which I believe will be valuable in contributing to the cutting-edge research at The McCarroll Lab.
During my two years of laboratory experience, I have developed strong skills in experimental workflows, including planning and executing experiments, creating DNA-barcoding reagents, extracting nuclei from human brain tissue, preparing molecular libraries, and conducting high-throughput sequencing. My proficiency in molecular-biological reactions such as PCR and DNA extraction has been further honed through independent troubleshooting and optimization of techniques and technologies. I am also skilled in maintaining detailed experimental notes and reporting results in lab meetings.
In addition to my technical skills, I possess strong organizational and task prioritization skills, excellent communication skills, and proficiency in performing administrative and clerical tasks. I am fluent in English, Spanish, French, and Catalan, which I believe will be an asset in collaborating with a diverse group of individuals.
What I find most appealing about this particular position is the opportunity to work with state-of-the-art technologies and techniques, such as droplet-based single-cell RNA-seq, which I find fascinating. I am also drawn to the collaborative and question-driven approach of The McCarroll Lab, which aligns with my own research philosophy. I am eager to learn and adapt to new techniques and technologies, and I am confident that my strong work ethic and ability to work independently and efficiently will make me a valuable addition to the team.
Furthermore, I am highly interested in the research areas of DNA repeats and DNA-repeat disorders, somatic mosaicism and clonal expansions, and the biology of mental health and illness. I have extensive experience in conducting animal experiments, behavioral experiments, anatomical dissection, and molecular analysis, which I believe will be beneficial in studying these areas. I have also worked on projects involving static analysis of behavioral data and microarray data, as well as 3D cell culture techniques and protein isolation. My experience in conducting anatomical dissection studies for medical and veterinary purposes, as well as my proficiency in using various software programs, including Microsoft Office Suite, SPSS, MATLAB, and Python, will also be valuable in my work at The McCarroll Lab.
Lastly, I am passionate about making a meaningful impact in the field of genetics and neuroscience, and I am confident that my skills and qualifications make me a strong candidate for the Research Assistant position at The McCarroll Lab. I am eager to contribute to the mission of the lab and work towards understanding the biology that underlies human brain health and illness.
Thank you for considering my application. I look forward to the opportunity to discuss my qualifications further.
Sincerely,
Melike Cansel EREN