A cell is a vibrating bag of molecules, densely packed with DNA, proteins, RNAs, and lipids. The ratios of these molecules are not balanced, though. A typical HeLa cell, widely used as a model to study cancer in the laboratory, has about 20 times more protein than DNA by mass.
Such imbalances are pervasive across the tree of life, but proteins are always the heaviest and most diverse group of molecules within a cell. A single human cell encodes more than 20,000 proteins, each built from 20 standard amino acids. But those amino acids can be arranged in a staggering number of combinations to make everything from small, spindly structures like insulin (51 amino acids) to globular giants such as titin (34,350 amino acids).
A protein’s structure is not fixed, either. Chemical tags can modify it. Adding a sugar molecule to certain antibody proteins can flip whether they activate or suppress inflammation. And when an enzyme called glycogen phosphorylase is tagged with phosphate, it begins chewing up glycogen to release the glucose molecules that feed hungry muscle cells.
So, while human cells make thousands of different proteins, the forms of those proteins shift according to a cell’s needs. This vast chemical diversity is what makes proteins so adaptable. Despite their importance, however, molecular biologists rarely study proteins directly because the technology to do so is limited and does not easily scale to a large quantity of cells.
The cost to sequence a human genome fell from about $100,000 in 2009 to a few hundred dollars today. Massive sequencing machines can study thousands of genomes each day. The costs to analyze a cell’s proteome have likewise fallen over time; it now costs anywhere from $2 to $50 to study the proteins in a single mammalian cell.
However, that low cost can be misleading. Unlike genomes, which are mostly identical across all the cells in an organism, the proteins within each cell can vary considerably. To get a clear picture of what's happening in a sample, then, researchers must look at each proteome individually. Ideally, scientists would study thousands of cells in each experiment, but existing proteomics technologies can only be used to analyze about a dozen cells at once — a paltry amount.
A mass spectrometry machine at Parallel Squared Technology Institute in Watertown, MA.
This limitation stymies biology research, especially for diseases like Alzheimer’s, which are heavily influenced by post-translational modifications. Protein alterations, including phosphorylation and ubiquitination, can alter a protein’s function in ways that are invisible at the level of DNA or RNA. And, furthermore, it is exceptionally difficult to study the brain, with its billions of cells, by looking at just a few cells each day.
This bottleneck is what Parallel Squared Technology Institute, a non-profit research organization, is trying to solve. On a brisk day in March, I visited their laboratories in Watertown, Massachusetts, to learn about their efforts to make proteomics as easy and affordable as DNA sequencing.
Lackluster Experiments
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