“Keith is one of the best bioinformaticists and Molecular Geneticists I have come across. I have known him both when he was a Harvard graduate student working with George Church and as he advanced up the ladder at Millennium Pharmaceuticals Inc.”
Keith Robison
Cambridge, Massachusetts, United States
4K followers
500+ connections
About
I develop computational approaches to solve biological and chemical problems in synthetic…
Activity
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After a fulfilling two-year journey at Ansa, I’m excited to explore new challenges. I’m proud of my contributions to launching their initial product…
After a fulfilling two-year journey at Ansa, I’m excited to explore new challenges. I’m proud of my contributions to launching their initial product…
Liked by Keith Robison
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Each year WEST - Women in the Enterprise of Science and Technology selects an annual theme. This year's theme is: Grit, Growth, Gratitude. Read more…
Each year WEST - Women in the Enterprise of Science and Technology selects an annual theme. This year's theme is: Grit, Growth, Gratitude. Read more…
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The most useless line of questioning when interviewing: asking about the gap in their work history. Do you want to know a great way to destroy all…
The most useless line of questioning when interviewing: asking about the gap in their work history. Do you want to know a great way to destroy all…
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Experience
Education
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Harvard University
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Developed tools to identify genes and transcription factor sites in bacterial genomes. Worked in laboratories of Dr. Walter Gilbert (Nobel laureate) and George Church, two of the pioneers of the human genome project.
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Activities and Societies: Honors degree. Undergraduate research -- received White award. Beta Beta Beta (biology honor society). Student program association
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Publications
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The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models
Oncogene
Heat shock protein 90 (Hsp90) is an emerging target for cancer therapy due to its important role in maintaining the activity and stability of key oncogenic signaling proteins. We show here that the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion protein, presumed to be the oncogenic driver in about 5% of patients with non-small cell lung cancer (NSCLC), is associated with Hsp90 in cells and is rapidly degraded upon exposure of cells to IPI-504. We…
Heat shock protein 90 (Hsp90) is an emerging target for cancer therapy due to its important role in maintaining the activity and stability of key oncogenic signaling proteins. We show here that the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion protein, presumed to be the oncogenic driver in about 5% of patients with non-small cell lung cancer (NSCLC), is associated with Hsp90 in cells and is rapidly degraded upon exposure of cells to IPI-504. We find EML4-ALK to be more sensitive to Hsp90 inhibition than either HER2 or mutant epidermal growth factor receptor (EGFR) with an inhibitory concentration (IC)(50) for protein degradation in the low nanomolar range. This degradation leads to a potent inhibition of downstream signaling pathways and to the induction of growth arrest and apoptosis in cells carrying the EML4-ALK fusion. To generate a causative link between the expression of EML4-ALK and sensitivity to IPI-504, we introduced an EML4-ALK cDNA into HEK293 cells and show that the expression of the fusion protein sensitizes cells to IPI-504 both in vitro and in vivo. In a xenograft model of a human NSCLC cell line containing the ALK rearrangement, we observe tumor regression at clinically relevant doses of IPI-504. Finally, cells that have been selected for resistance to ALK kinase inhibitors retain their sensitivity to IPI-504. We have recently observed partial responses to administration of IPI-504 as a single agent in a phase 2 clinical trial in patients with NSCLC, specifically in patients that carry an ALK rearrangement. This study provides a molecular explanation for these clinical observations.
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Critical features for biosynthesis, stability, and functionality of a G protein-coupled receptor uncovered by all-versus-all mutations.
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The structural features determining efficient biosynthesis, stability in the membrane and, after solubilization, in detergents are not well understood for integral membrane proteins such as G protein-coupled receptors (GPCRs). Starting from the rat neurotensin receptor 1, a class A GPCR, we generated a separate library comprising all 64 codons for each amino acid position. By combining a previously developed FACS-based selection system for functional expression [Sarkar C, et al. (2009) Proc…
The structural features determining efficient biosynthesis, stability in the membrane and, after solubilization, in detergents are not well understood for integral membrane proteins such as G protein-coupled receptors (GPCRs). Starting from the rat neurotensin receptor 1, a class A GPCR, we generated a separate library comprising all 64 codons for each amino acid position. By combining a previously developed FACS-based selection system for functional expression [Sarkar C, et al. (2009) Proc Natl Acad Sci USA 105:14808-14813] with ultradeep 454 sequencing, we determined the amino acid preference in every position and identified several positions in the natural sequence that restrict functional expression. A strong accumulation of shifts, i.e., a residue preference different from wild type, is detected for helix 1, suggesting a key role in receptor biosynthesis. Furthermore, under selective pressure we observe a shift of the most conserved residues of the N-terminal helices. This unique data set allows us to compare the in vitro evolution of a GPCR to the natural evolution of the GPCR family and to observe how selective pressure shapes the sequence space covered by functional molecules. Under the applied selective pressure, several positions shift away from the wild-type sequence, and these improve the biophysical properties. We discuss possible structural reasons for conserved and shifted residues.
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Thirteen years after defending my PhD and after a decade with Oxford Nanopore Technologies, I had the incredible opportunity to bring both…
Thirteen years after defending my PhD and after a decade with Oxford Nanopore Technologies, I had the incredible opportunity to bring both…
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Nice writeup in Nature Biotech about our work with Wisconsin Alumni Research Foundation (WARF) to demonstrate Ginkgo Bioworks, Inc.'s technology for…
Nice writeup in Nature Biotech about our work with Wisconsin Alumni Research Foundation (WARF) to demonstrate Ginkgo Bioworks, Inc.'s technology for…
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New post on the evolution of Illumina sequencers. This one’s also free, hopefully nobody copies it uncredited this time. But if you feel like…
New post on the evolution of Illumina sequencers. This one’s also free, hopefully nobody copies it uncredited this time. But if you feel like…
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Othram Inc. is honored to have assisted the Mississippi State Medical Examiner's Office in identifying a 2023 John Doe as Daniel Grantham. Thank you…
Othram Inc. is honored to have assisted the Mississippi State Medical Examiner's Office in identifying a 2023 John Doe as Daniel Grantham. Thank you…
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What’s a biotech role that is undervalued today but will be critical tomorrow? I’ll start: one that we often work with is who we call a ‘data…
What’s a biotech role that is undervalued today but will be critical tomorrow? I’ll start: one that we often work with is who we call a ‘data…
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Today we launched NVIDIA’s virtual screening for drug discovery implemented via inference microservices or NIMs. Leading biotechnology software…
Today we launched NVIDIA’s virtual screening for drug discovery implemented via inference microservices or NIMs. Leading biotechnology software…
Liked by Keith Robison
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Happy International Dog Day for everybody! May these lil' furry ones bring you as much joy in life as they do for us! 🐶 🐾 ❤️ #InternationalDogDay
Happy International Dog Day for everybody! May these lil' furry ones bring you as much joy in life as they do for us! 🐶 🐾 ❤️ #InternationalDogDay
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I have a new publication on creating large scale Neo4j knowledge graphs for genomics and natural product drug discovery. Using hundreds of…
I have a new publication on creating large scale Neo4j knowledge graphs for genomics and natural product drug discovery. Using hundreds of…
Liked by Keith Robison
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We all know more cells and more samples are needed to unlock the understanding of disease. Scale Biosciences is working to break this barrier. What…
We all know more cells and more samples are needed to unlock the understanding of disease. Scale Biosciences is working to break this barrier. What…
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🚀 Get ready for Beyond! Mark your calendars to attend our inaugural virtual event featuring interactive sessions with the Element team and our…
🚀 Get ready for Beyond! Mark your calendars to attend our inaugural virtual event featuring interactive sessions with the Element team and our…
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The two gels below spawned a multi-billion dollar industry that didn't exist prior to their publication in 1997. While it may seem obvious today…
The two gels below spawned a multi-billion dollar industry that didn't exist prior to their publication in 1997. While it may seem obvious today…
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Campus was filled with excitement as over 3,900 new first-year students unpacked in UD's residence halls. Welcome to the flock, Class of 2028!…
Campus was filled with excitement as over 3,900 new first-year students unpacked in UD's residence halls. Welcome to the flock, Class of 2028!…
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Very interesting story in today’s Modern Healthcare focusing on innovation around urgent care and ED services. Notes the role of Intuitive where our…
Very interesting story in today’s Modern Healthcare focusing on innovation around urgent care and ED services. Notes the role of Intuitive where our…
Liked by Keith Robison
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