Merry Christmas and Happy Holidays to everyone! I hope you all have a great new year :) I thought it would be fun to share my top 5 coolest studies of 2019 to round out the year! (as I did last year) This is not a list of the ‘best’ studies of the year, as that is extremely hard to quantify (although all of these are pretty stellar), so they are in no particular order. This is simply a list of papers that I thought tackled some interesting problems in a unique way, or made significant technological advances in the field. The work described in these papers makes you think ‘wow…science is really crazy!’ Many of them are from the latter half of the year as they are the freshest in my mind! I hope you enjoy checking them out as much as I did. Click the paper titles for direct access to them. (Note: these are in no particular order)
5. Glutamatergic synaptic input to glioma cells drives brain tumour progression
This paper, from Frank Winkler & Thomas Kuner’s labs, complemented another few studies in the same issue of Nature (see my journal club paper on one of them here). This series of studies demonstrated that deadly brain cancer cells (glioma) form bona fide functional synapses with neurons in the brain. Even crazier…these connections (and subsequent synaptic stimulation) potently help the cancer grow! Future studies of so called ‘neuroglioma synapses’ will prove invaluable in understanding and treating this extremely deadly disease.
A schematic representation of neuroglioma synapses. Neurons form AMPA-receptor receptor dominated glutamatergic synapses with growing glioma cells. Synaptic stimulation causes activation (depolarization) of cancer cells and large increases in intracellular calcium. This signal is propagated throughout the glioma network via gap junctions linking cancer cells together (Credit: Venkataramani et al., 2019)
4. Undulating changes in human plasma proteome profiles across the lifespan
What does ‘aging’ actually mean? If you took a blood sample from an 80 year old and a 20 year old, could you tell which sample came from each person just from the molecules in their blood? Tony Wyss-Coray’s lab was interested in understanding this question, and more generally, how we age biologically. To do this, they looked at thousands of proteins (critical molecules that do virtually everything in our bodies) in human blood, categorized them, and tracked how they changed throughout an entire lifespan (see below). They found remarkable patterns in the concentrations of blood proteins that change in non-linear ways throughout aging. This large study opens up a new area of research focused on understanding the role of many of these proteins in aging, and will likely lead to novel biomarker and drug target discovery for age-related diseases.
Waves of aging proteins across the lifespan. Thousands of proteins show age-dependent changes in expression in blood, with peaks noted at age 34, 60 and 78 (credit: Lehallier et al., 2019).
3. Deep Learning Reveals Cancer Metastasis and Therapeutic Antibody Targeting in the Entire Body
Patients with cancer usually die not due to the primary tumor, but because of metastases that cause dysfunction throughout the body. A major problem in tackling metastasis is finding where tumor cells have traveled…a problem that is an order of magnitude harder than finding a needle in a haystack. Cancer is insidious…a single or few surviving cells that a doctor may have missed due to limitations in technology can expand back into full blown cancer. So, finding these tiny metastases is critical if we want to save more people that fall victim to malignant disease.
To more accurately detect metastases, Ali Ertürk and colleagues combined a few exciting techniques to get a whole-body view of metastatic cancer spread. This technology, termed “DeepMACT” (see video abstract below) uses an artificial intelligence/machine learning approach in combination with whole-body tissue clearing to detect tiny metastases throughout the whole organism. Additionally, this technique can be used to quantify the efficacy of antibody-based therapies against cancer. This new technology will be used to make significant strides in understanding and combating metastases, and aide in high-throughput drug design and validation for the treatment of various malignancies.
2. Cortical column and whole-brain imaging with molecular contrast and nanoscale resolution
A major hurdle in neuroscience research is visualizing the brain at the resolution that neural computation occurs. This happens at the micron or sub-micron scale, which is at or below the capabilities of conventional microscopes. Several years ago, Ed Boyden’s team tackled this problem with a unique approach termed “expansion microscopy”. This technique essentially turns the brain into one of those expandable water toys (Grow Monsters), allowing researchers to isometrically ‘blow it up’ so nanoscale structures are now up to 20x bigger! This allows very fine structures like dendritic spines to be imaged with conventional microscope technology.
This solved a major problem, imaging tiny structures with molecular contrast. However, if you want to get super-resolution images, that would ‘bleach’ (damages) the sample too quickly for any sizable amount of data to be collected. To address this problem, Ed Boyden and Eric Betzig’s labs combined two technologies: expansion microscopy and lattice light sheet microscopy (LLSM). By combining these techniques, the researchers are able to image a whole brain at super-resolution (resolving structures that are < 1/200th the width of a human hair) with multiple molecular markers in as little as 2 days, with a resolution of 60 x 60 x 90 nanometers for 4× expansion! Check out the amazing video below as an example of what the technology is capable of.
1.Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones
I first heard about this research from the senior author, Holly Ingraham, at the Society for Behavioral Neuroendocrinology (SBN) meeting this past year. I thought the work was so cool that I’ve decided to include it in my list for 2019. The overarching research question was simple enough, how does estrogen signaling in the brain regulate energy expenditure, energy balance, and systemic physiology in females? This is a critical question as a major problem for postmenopausal women (with drastically reduced estrogen) is deterioration in metabolic function, bone density, among other phenomena. Prior work had pointed to a role for neurons in the hypothalamus expressing the estrogen receptor alpha (ER-alpha) in controlling whole-body physiology in females. However, the localization of these neurons and their role in bone physiology was essentially unknown.
Ingraham’s team used adeno-associated viral vectors (AAVs) to knock out ER-alpha in multiple hypothalamic nuclei, and found that doing this in the arcuate nucleus caused mice to develop very thick bones throughout their bodies! See the figure below (panel f) to see how much thicker the bones are in the ERalphaKO (arcuate) than in control mice. They further demonstrated that the neurons that govern this effect also express the neuropeptide kisspeptin, as when they knockout ER-alpha in these neurons they could recapitulate the bone-growth enhancing effect. Importantly, these effects were only found in female mice, indicating a strong sex-dependent effect of estrogen signaling in the mediobasal hypothalamus! This work reveals a previously unknown target for treatment of age-related bone disease, and suggests that sex-dependent treatment modalities may offer the best strategy for ameliorating bone loss.
ER-alpha expressing neurons in the arcuate nucleus powerfully regulate bone density only in female mice. These findings offer a previously unknown target for the treatment of age-related bone disease. (Credit: Fields et al., 2019).
BONUS: The “sewing machine” for minimally invasive neural recording
This last one is a special bonus that I did not include in the main list because it is (as of writing this) still a pre-print and has yet to be peer-reviewed. Nonetheless, I think the idea and approach that the authors devised is really cool, and worth discussion. Surgeries for minimally invasive neural recording are very hard to do, and very hard to standardize across repeated procedures. To tackle this problem, Philip Sabes and colleagues developed a neural ‘sewing machine’ to sew fine electrodes into the mouse brain (see the schematic below). The system is able to perform rapid and precise implantation of probes, each individually targeted to avoid observable vasculature and reach diverse anatomical targets. I’m keeping my eye on this one, especially with the author’s connection to Neuralink…this may be a peek into the future of brain-machine interfaces!
A schematic of the neural ‘sewing machine’ for chronic recordings of diverse neural activities (credit: Hanson et al., 2019).
Annnnndddddd….that’s it for the year! There were many more studies that I wish I could have included, but I wanted this to be a quick read…not an epic novel. With that said, I’m off to enjoy the NYE parties…see you all next year! Leave a comment below, and, as always, stay curious! —JCB.