Research, Books & Scientific Contributions

Abstract

Independent replication of the SM(42:3) sphingomyelin elevation signal identified in the ALS-SLI derivation cohort. Demonstrates that the targeted sphingomyelin/ceramide biomarker signal is reproducible across independent sample sets, supporting the prospective validation roadmap for the ALS Serum Lipid Index (ALS-SLI).

Abstract

Cancer genomes carry many inactivating events at once, raising the possibility of higher-order vulnerabilities: a gene that becomes essential only after two others are lost. We screened the cancer dependency map for such third-gene targets by defining the cell lines that have lost a pair of tumor suppressors and asking which gene each background can no longer spare. The screen recovers textbook biology, the PRMT5 axis in CDKN2A and MTAP-deleted cells and the E2F machinery in TP53 and RB1-deleted cells, and nominates targets in real cancers, including VPS4A in SMAD4-deleted pancreatic cancer and, in its original form, ENO2 in ENO1-deleted glioma. But these copy-number-based collateral targets share a limitation: they require homozygous deletion of the partner, whereas many clinically defining events, such as the 1p/19q co-deletion of oligodendroglioma, are heterozygous and halve a gene’s dosage rather than remove it. Pushing the higher-order logic further, we show that a dosage-sensitive, expression-based approach fits the heterozygous genotype: scanning 1p and 19q for paralogs that become essential as their partner’s expression falls returns ATP1A1, which cells come to require as the 19q-encoded neuronal pump subunit ATP1A3 is reduced. ATP1A1 is a dangerous target for a small-molecule drug, which cannot avoid the closely related neuronal subunit ATP1A3. An antisense oligonucleotide sidesteps this: it is selective by sequence, so it lowers ATP1A1 while sparing ATP1A3, and because it is too large to cross the blood-brain barrier, delivery into the spinal fluid keeps its action confined to the nervous system. Throughout, the discipline is the same: separate a driver from a passenger, a marker from a mechanism, and the depth of a deletion from its dosage.

Abstract

TDP-43 loss of function drives cryptic exon inclusion in hundreds of neuronal transcripts, and restoring TDP-43 activity or blocking individual cryptic splice sites are leading therapeutic strategies for ALS and related TDP-43 proteinopathies. Rational design of antisense oligonucleotides (ASOs) that block cryptic splice sites requires knowing precisely where TDP-43 binds along each pre-mRNA. We trained a deep-learning model on eCLIP binding data to predict TDP-43 footprints at single-nucleotide resolution across the transcriptome, then applied it genome-wide to score candidate ASO target windows in 86 high-confidence cryptic-splicing genes. The model recovers known UG-repeat binding motifs and generalizes to held-out genes with high accuracy (AUC 0.91). Nominated target sites cluster in the deep intronic regions flanking cryptic exons, consistent with a steric-blocking mechanism. For the top-ranked genes, including STMN2, UNC13A, and HDGFL2, we report ranked ASO target coordinates, predicted binding scores, and estimated off-target profiles. This pipeline provides a systematic, data-driven framework for prioritizing ASO designs in TDP-43 proteinopathies and is released as open-source software.

Abstract

Profile of Jeff Milton, CMU chemistry alumnus (2004) and co-founder of La Jolla Labs, describing his work developing RNA therapeutics for rare and complex neurological diseases. Covers his use of AI, next-generation sequencing, and RNA biology to reduce drug discovery costs and timelines, his executive fellowship at St. Jude Children's Research Hospital, and his ongoing engagement with CMU's Department of Chemistry to build a research-grade synthesis lab.

Abstract

Proposes a novel framework called the Exploratory Genetic Research Project (EGRP) to align a clinical trial sponsor's need for broad whole-genome sequencing (WGS) research with study participants' rights to data access and control. The EGRP is structured as a separate umbrella protocol to streamline consenting and delineate clinical endpoints from exploratory research, establishing participant autonomy over genomic data and the disclosure of actionable incidental findings.

Abstract

Introduces the HELM biopolymer notation standard for representing complex macromolecules including oligonucleotides, peptides, and antibody-drug conjugates in cheminformatics systems.

Abstract

Proposes the ALS Serum Lipid Index (ALS-SLI), a transparent targeted-lipidomics algorithm over four sphingomyelin and ceramide species derived from reanalysis of MetaboLights study MTBLS13295 (36 ALS vs 32 healthy first-degree relatives). The algorithm sum-normalizes and log2-transforms serum LC-MS data, extracts four analytes by accurate mass and retention time, enforces explicit QC/confound guards, and returns a probability from a standardized logistic model. In repeated cross-validation on the derivation cohort it achieves AUC 0.84 ± 0.09. Presented as a candidate for prospective validation, not a validated clinical diagnostic, with a full specification, fitted constants, mandatory confound guards, and a validation roadmap.

Abstract

Reanalysis of MetaboLights study MTBLS13295 (36 ALS patients vs 32 healthy first-degree relatives; 8,579 features, dual-polarity reverse-phase LC-MS). A single feature separates cases from controls with nested-CV AUC 1.000, surviving stress-tests for positional, normalization, and technical confounds. A coherent set of sphingomyelin and ceramide species is elevated in ALS, robust to normalization, and concordant with independent ALS cohorts at the species level, anchored mechanistically by the monogenic SPTLC1 form of ALS. Elevated serum SM/Cer is framed as a pre-registerable hypothesis for a future validation cohort.