Illuminating the Immune System with Silicon Photonics
The human immune system is able to respond to an astonishing number of possible threats by first recognizing the protein fragments (antigens) that correspond to these threats and then targeting the antigen-presenting cells for death.
Determining their sequences, and correlating these structures with their immune-celltriggering activity, could unlock advances in treatments for cancer, autoimmune diseases, neurodegeneration, and more. However, existing technologies can only identify an extremely small fraction of the antigens that drive disease.
With a new method that uses tightly focused beams of light to illuminate molecules, the startup Pumpkinseed may soon be able to far surpass traditional protein sequencing methods like mass spectrometry, while also linking these sequences to their immune cell activity. The pairing of antigen sequences and immune cell activation state could enable entirely new immune-modulating medicines.
Pumpkinseed’s innovation relies on improvements to a technique called Raman spectroscopy that involves bouncing beams of light off of individual molecules and cells and reading the unique signatures encoded by each biomarker’s vibrations. The interactions between the light and the molecules are typically very weak, but Pumpkinseed Co-Founder Jack Hu created a nanophotonic chip capable of focusing light in very precise ways, greatly boosting the signal.
“We can shrink the light down to the scale of the antigen, and read thousands of antigens nearly simultaneously,” he said. “We have one technology, called deSIPHR (de-novo sequencing of immunopeptides with high resolution), that tells us the antigen sequence.” A related technology, cell-MAPP (single-cell monitoring against the presented peptides), dynamically determines the immune cell activation state corresponding to each antigen.
The startup signed a license for a part of the underlying technology with Stanford in 2024.
Pumpkinseed’s approach comes with a number of advantages, including freeing researchers from the need for individual fluorescent “labels” typically used to detect proteins and cell activation states, and allowing billions of sensors to fit on a silicon wafer produced in the foundries that make computer chips.
One important application for Pumpkinseed’s device is in designing better cancer vaccines, said Professor JeOnJGFS Dionne, a Pumpkinseed Co-Founder. One group collaborating with Pumpkinseed is using their platform to find antigens on the surface of cancer cells that differ from those on healthy cells, and to determine their ability to boost T cell responses. That information would allow for therapies that help the immune system recognize and respond to tumor cells, preventing metastatic disease.
Pumpkinseed has a distinct advantage when it comes to this kind of work, said the startup’s third Co-Founder, Nhat Vu. They can pair their immune-triggering peptide detection with machine learning to study and characterize the vast array of immune responses far faster than previously possible. “We’re mining novel biological data at a pace that exceeds current methods by many orders of magnitude,” he said. “From this data, we can develop better AI models to create medicines that tailor immune responses.”
The trio founded Pumpkinseed in 2021 with the goal of accelerating the development of their technology to develop an “immunogenicity AI oracle.” They are working with a chip foundry to make their nanophotonic chips at scale, and working with biotech collaborators on various therapeutic pipelines, something Prof. Dionne said has helped them to evolve their technology in unique ways.
Vu said the future of Pumpkinseed includes gathering large amounts of data to help train AI systems that enable immune-modulating medicines. Beyond cancer, these could include new peptides or proteins for autoimmunity and inflammation not found in nature. Such proteins could let T cells recognize the body’s cells from intruders more effectively. Designing proteins that modulate the immune system very precisely has its challenges, but Pumpkinseed has an end-to-end system encompassing protein detection and functional cell analysis that can speed the work considerably.
Hu puts it perfectly: “The platforms we have provide a new light into the inner workings of the immune system.”
