by Kirk Beebe

I hear this curious, but understandable, refrain from time-to-time in response to suggesting that metabolomics could be a useful approach for advancing research. It suggests that the respondent does not view metabolic pathways as a general feature that defines biological function – which it is. That is, they don’t view it in the same way that they do pathways involving proteins and transcription factors.

pathways.pngDo only those interested in transcriptional regulation use arrays or RNA sequencing? Are researchers interested in protein translation the only ones who use proteomics? Of course not. Tools such as expression profiling or proteomics are regarded as investigational BIOLOGY tools for monitoring gene expression or protein levels. In other words, they’re tools for “looking under the hood” to gain a greater level of understanding.

There is a comfort with molecular biology for most life scientists. Its connection and place within the function of living systems is highly intuitive. While the last few decades have focused on genes and proteins, metabolism tends to be the section in the biochemistry text books that many are happy to forget. When confronted with pathway jargon, many respond with, “I don’t do that stuff.”

I understand this perception; I was a trained biochemist who did molecular biology. Further, technologies for metabolism research (aka metabolomics) have only reached a point within the last decade where they can deliver comprehensive, accurate data. And, while some life scientists still confine tools like metabolomics to “metabolism research”, a wave of researchers are growing who recognize that metabolic pathways are a key functional layer to understanding how gene and protein expression fit into the wider biological landscape. 

The road to answers biology.png
I think it’s useful to offer a vantage-point from which to understand how metabolism inquiry relates to understanding biology. I’m going to direct you to several of the most interesting, diverse publications where metabolic pathways were a cornerstone in the results.

A quick scan through what I have summarized may identify a paper or two relevant to your interests. Upon close review of the paper, it may be become obvious how metabolism may fit into your research question. These seemingly arcane metabolic pathways are the functional basis (or play a heavy functional role) in an array of key biological themes. The contemporary biological themes should be familiar to even those of us who may initially say, “I don’t study metabolism.”

#10. Gut bacterial metabolite stimulates the production of serotonin 
Much of the body’s serotonin is produced by the gastrointestinal (GI) tract, but the mechanism was unknown. Yano and colleagues showed that the microbiota produce metabolites that regulate serotonin biosynthesis. The results are yet another example of the how the microbiome is intimately connected to our physiology and that this connection is frequently modulated by metabolites.

#9. A lipid metabolic switch for host defense and autoimmunity
T-helper 17 (Th17) cells are critical for host defense, but can also drive autoimmunity. This divergent behavior was in part explained by Wang and colleagues showing that a key metabolic switch alters the function of the master regulator of Th17 cells. This work is another example of the intimate connection of metabolism regulating various fates and functions of immune cells.

#8. Fruit sugar metabolism rewired in heart disease 
Heart failure is a leading cause of death worldwide, and consuming foods with high fructose has been associated with a significantly increased heart disease risk. Work by Mirtschink and colleagues revealed a plausible mechanistic connection showing a stress-induced metabolic rewiring of fructose metabolism in heart disease. This research reveals a potential new target for the disease and an elegant example of metabolic rewiring in pathophysiological states.

#7. Targeted destruction of gut microbes to prevent atherosclerosis
Metabolites in foods such as red meat have recently been shown to undergo conversion by gut microbes to accelerate atherosclerosis. Many strategies seek to target the microbiome for a host of diseases, but most efforts are in their infancy. Wang and colleagues show that they are able to drug a specific gut microbial enzyme to reduce the formation of atherosclerotic lesions in the mouse, demonstrating the potential to target specific gut bacterial enzymes for the prevention and treatment of diseases.

#6. Stem cell fate resides with the powerhouse of the cell
Hematopoietic stem cells (HSCs) are the source of all blood cell lineages, and many factors that regulate them are unknown. Luchsinger et al. showed that a circuit involving the mitochondria (aka the “powerhouse” of the cell) is particularly important in maintaining HSCs with extensive lymphoid potential. These findings may lead to approaches for differentiating HSCs into desired lineages after transplantation.

#5. Too many mouths to feed – the cancer and immune cell appetite
Failure of the immune system to protect against cancer is a complex, multi-faceted process. In separate work, papers by Chang et al. and Ho et al. revealed that a metabolic competition for the same substrate between immune and tumor cells is yet another aspect leading to tumor progression. This work extends the number of examples that reveal the intimate connection of metabolism and immune cell function.

#4. Workhorse organelle uses signaling lipid to control longevity
Some consider lysosomes to be boring cellular organelles for breaking down macromolecules. Folick and colleagues deciphered a key role in aging through a lysosomal metabolite’s influence on nuclear events that control longevity. This study is among a growing list of examples illustrating how metabolites from cellular organelles are often the mediators for long-range physiological effects controlled from the nucleus of the cell.

#3. NOTCHing out a new strategy for leukemia
A majority of T cell acute lymphoblastic leukemia (T-ALL) cases are accompanied by activating mutations in the NOTCH1 receptor. But, anti-NOTCH1 clinical development has had limited success. Herranz and colleagues revealed synergistic activity in cell and animal models when the metabolic inhibitor glutaminase and a NOTCH1 inhibitor were combined. This result illustrates how metabolic traits may be a key way to target specific cancers.

#2. Genes hard-wiring metabolic adaptations for eating blubber
One clear concept that has emerged the last few years is that genetic data is far more powerful when combined with the metabolic output. A seminal example of this is work by Fumagalli and colleagues who uncovered a metabolic adaptation within Greenlandic Inuit populations. Their work revealed a clear picture of how adaptations within this population arose in response to the lipid-rich diet provided by marine mammal hunting.

#1. (tie) Aspartate: a key to a 35-year cellular mystery 
In the late 70s, an unexplained observation emerged about cells that had ceased proliferation due to electron transport chain (ETC) inhibition. Despite ETC inhibition, cells could resume proliferation upon supplementation with pyruvate. Why this single metabolite could restore proliferation remained a mystery.

Like many observations scattered throughout the literature that, on the surface, seem inconsequential or boring, these observations were left to scientific mystery for several decades. That is until the Vander Heiden and Sabatini labs solved the mystery and revealed what elegance lay beneath it. In separate work published in the same issue of Cell, they showed that the primary role of respiration in proliferating cells is to provide electron acceptors for aspartate synthesis (pyruvate, as it turns-out, can supply electron acceptors for aspartate synthesis).

I’m not going to detail a lot of scenarios for why this could be important therapeutically. I’ll let this rest on its merits as an elegant collective example of exceptional basic science by these labs. 

#1. (tie)  The Trojan-horse of vitamin C efficacy in cancer cells revealed
For decades, high-dose vitamin C has been examined for its efficacy in anti-cancer therapy, but has yet to demonstrate significant benefit. In contrast, when used alone in in vitro and animal tests it has exhibited beneficial effects. 

Work by Yun and colleagues provided a precise, clear rationale for these discrepancies. Their work is a beautiful example of scientific logic, revealing a detailed mechanism of how vitamin C may work in a precision oncology scenario. Working with human colorectal cancer cells with the commonly mutated BRAF and KRAS genes, the authors surmised that although these cell rewire glucose metabolism, in part by up-regulating GLUT1 expression, GLUT1 also transports the oxidized form of vitamin C, dehydroascorbate (DHA). Thus, they reasoned that vitamin C may be effective in cells that overexpressed GLUT1 by taking up DHA. Indeed, these cells preferentially took-up DHA on their way to cell death.

This finding alone could offer insight into the elusive clinical response to vitamin C in cancers and which tumors may be more responsive (i.e. those overexpressing GLUT1). The authors did not stop there, as they then went on to uncover an elaborate chain of intracellular events that explained the efficacy of DHA. This outstanding series of experiments and logic provides a clear, compelling rationale for how vitamin C may someday find a home in cancer therapy.  

Discoveries just ahead
Whether you embrace metabolism research and metabolomics, or may have been in the “we don’t study metabolism” camp, hopefully these highlights offer a glimpse into some really exciting research where metabolism adds key mechanistic insight into diverse areas of biology. We’ve just begun to scratch the surface using metabolomics, but it’s clear that this is valuable technology and will continue to lead scientists to discoveries and answers we never thought possible. 

For the complete papers see:

  1. Luchsinger, L.L., de Almeida, M.J., Corrigan, D.J., Mumau, M. & Snoeck, H.W. Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature 529, 528-531 (2016).
  2. Birsoy, K. et al. An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. Cell 162, 540-551 (2015).
  3. Chang, C.H. et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell 162, 1229-1241 (2015).
  4. Folick, A. et al. Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans. Science 347, 83-86 (2015).
  5. Fumagalli, M. et al. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science 349, 1343-1347 (2015).
  6. Ho, P.C. et al. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell 162, 1217-1228 (2015).
  7. Mirtschink, P. et al. HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease. Nature 522, 444-449 (2015).
  8. Sullivan, L.B. et al. Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. Cell 162, 552-563 (2015).
  9. Wang, C. et al. CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity. Cell 163, 1413-1427 (2015).
  10. Wang, Z. et al. Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis. Cell 163, 1585-1595 (2015).
  11. Yano, J.M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264-276 (2015).
  12. Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391-1396 (2015).