Cancer Fighting Protein Kills Tumors and Boosts the Body’s Immunity

Tumor cells typically alter their energy metabolism and increase glucose uptake to support their rapid division and spread. This limits glucose availability for immune cells and therefore dampens the body’s anti-cancer immune responseBy searching for proteins that both regulate the metabolism of cancer cells and affect immune cells in tumors, a team led by investigators at Massachusetts General Hospital (MGH) recently identified a potential target for therapies that could simultaneously drain tumors of energy and boost the immune response against them.

For the research, which is published in Cancer Discovery, Keith T. Flaherty, MD, the director of Clinical Research at the MGH Cancer Center and a professor of medicine at Harvard Medical School, and his colleagues developed a new computational tool called BipotentR that can identify targets that block immune activation and also stimulate a second user-defined pathway (in this case, metabolism). When applied to gene expression data from patients with cancer who were treated with immunotherapy, as well as from cell lines and animal models, the tool identified 38 cancer cellspecific immune-metabolic regulators.

Artificial intelligence techniques showed that the activity level of these regulators in tumors predicted patients’ outcomes after receiving immunotherapyThe topmost identified regulator, ESRRA (Estrogen Related Receptor Alpha), was activated in immunotherapy-resistant tumors of many types. Inhibiting ESRAA killed tumors by suppressing energy metabolism and activating two immune mechanisms involving different types of immune cells.The scientists also demonstrated that BipotentR can be applied to other survival mechanisms used by cancer cells, such as their ability to promote blood vessel formation to increase their blood supply. Therefore, BipotentR, available at, provides a resource for discovering single drugs that can act through one cancer-related pathway while simultaneously stimulating an immune response.


What is the Human Cortex?

The cerebral cortex is the thin surface layer of the brain found in vertebrate animals that has evolved most recently, showing the greatest variation in size among different mammals (it is especially large in humans). Each part of the cerebral cortex is six layered (e.g., L2), with different kinds of nerve cells (e.g., spiny stellate) in each layer. The cerebral cortex plays a crucial role in most higher level cognitive functions, such as thinking, memory, planning, perception, language, and attention. Although there has been some progress in understanding the macroscopic organization of this very complicated tissue, its organization at the level of individual nerve cells and their interconnecting synapses is largely unknown.

Petabyte connectomic reconstruction of a volume of human neocortex. Left: Small subvolume of the dataset. Right: A subgraph of 5000 neurons and excitatory (green) and inhibitory (red) connections in the dataset. The full graph (connectome) would be far too dense to visualize.

Mapping the structure of the brain at the resolution of individual synapses requires high-resolution microscopy techniques that can image biochemically stabilized (fixed) tissue. We collaborated with brain surgeons at Massachusetts General Hospital in Boston (MGH) who sometimes remove pieces of normal human cerebral cortex when performing a surgery to cure epilepsy in order to gain access to a site in the deeper brain where an epileptic seizure is being initiated. Patients anonymously donated this tissue, which is normally discarded, to our colleagues in the Lichtman lab. The Harvard researchers cut the tissue into ~5300 individual 30 nanometer sections using an automated tape collecting ultra-microtome, mounted those sections onto silicon wafers, and then imaged the brain tissue at 4 nm resolution in a customized 61-beam parallelized scanning electron microscope for rapid image acquisition.

Imaging the ~5300 physical sections produced 225 million individual 2D images. The team then computationally stitched and aligned this data to produce a single 3D volume. While the quality of the data was generally excellent, these alignment pipelines had to robustly handle a number of challenges, including imaging artifacts, missing sections, variation in microscope parameters, and physical stretching and compression of the tissue. Once aligned, a multiscale flood-filling network pipeline was applied (using thousands of Google Cloud TPUs) to produce a 3D segmentation of each individual cell in the tissue. Additional machine learning pipelines were applied to identify and characterize 130 million synapses, classify each 3D fragment into various “subcompartments” (e.g., axon, dendrite, or cell body), and identify other structures of interest such as myelin and cilia. Automated reconstruction results were imperfect, so manual efforts were used to “proofread” roughly one hundred cells in the data. Over time, the scientists expect to add additional cells to this verified set through additional manual efforts and further advances in automation.


General Cognitive Assessment Of The Brain In Seven Minutes

React Neuro, a startup founded three years ago by veterans of Harvard Medical School (HMS) and Massachusetts General Hospital (MGH), wants to analyze how healthy your brain is.

Rudy Tanzi, a well-known Alzheimer’s disease researcher and professor of neurology at HMS and MGH, started the company in 2017 with Brian Nahed, a neurosurgical oncologist specializing in brain tumors and associate program director of neurosurgery at MGH and HMS. The two had worked with the NFL for years — Tanzi as a brain-health advisor to the New England Patriots, Nahed as a neurotrauma consultant for the league — and wanted to focus on the issue of concussions in football players. Specifically, they wanted to take a scientific approach to figuring out when a player could safely return to the sport following a concussion. The startup has evolved since then to take a holistic look at brain health through AI software and a VR headset.

From a consumer health standpoint, the idea is essentially [that by] using software, we can assess people’s brain health and provide feedback on what’s working and what’s not working,” said React Neuro CEO Shahid Azim, who joined the company in early 2019. “What really got me interested was not so much the concussion use case, but the more fundamental question that the team was looking to ask, which was, ‘Is there a better way to measure your brain health?’”

React Neuro answers that question with digital exams administered through a custom VR headset, which is developed by Pico Interactive in San Francisco. Designed based on the tools, techniques and exams traditionally used to assess neurological conditions, the tests return results that the startup’s AI software turns into actionable insights for physicians.

Azim, a 2009 MIT Sloan School of Management grad, calls the brain assessments via headsetdigital exams,” or “experiences on screen.” The exams, he said, can last anywhere from two and a half minutes to 10 minutes, depending on the use case. A general cognitive assessment typically lasts seven minutes.

We’re using eye tracking and voice analysis [for the exams],” Azim said. “In some cases, they’re voice-based, so you’re asked to repeat something that you see on the screen.