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For decades, biology has spoken three main languages: DNA, RNA, and proteins. These fields – genomics, transcriptomics, and proteomics – are now deeply integrated into both research and the clinic. But there’s a fourth language that remains largely unexplored: metabolites, the study of which is called metabolomics.
This field is only beginning to catch up. “We’re just on the verge of understanding all sorts of interesting things in that space,” said Andrea Choe, chief executive officer (CEO) of Holoclara. Often referred to as the “dark matter” of biology, metabolites reflect the actual physiological state of a cell or organism.
As the tools finally catch up to the complexity, metabolomics is emerging as a powerful new source of insight.
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What is metabolomics?
Metabolomics is the study of metabolites which are the products of metabolism. “Metabolism happens in every biological organism, and metabolites are the sum of all biochemical reactions, whether it’s to generate energy or build essential blocks and sometimes remove waste,” explained Choe.
Metabolites can be thought of as the fourth language of biology. However, unlike DNA, RNA, and proteins, which are composed of a limited set of blocks – nucleotides and amino acids – metabolites have an immense structural diversity. This is because metabolites are not confined to a set of monomers, instead, they can be any small molecule resulting from metabolic reactions.
“If genomics, transcriptomics, and proteomics are Lego kits, with metabolites you are now outside these kits and building blocks with more different and unpredictable pieces.”
Analyzing the metabolome – the set of metabolites in a cell, tissue, or organism – gives real-time insights into physiological states and biochemical activities. This level of understanding is like observing the actual outcomes of genetic and protein interactions, offering a direct window into the functional state of biological systems.
Why is now the time for metabolomics?
Despite being one of the four biology languages, metabolites have long remained under the radar. “That’s really intriguing to me. Similarly to how people thought that the space between DNA was junk DNA, I think the same shift is about to happen in metabolomics allowing us to understand the field more deeply,” said Choe.
While Choe thinks it’s intriguing that metabolites have been overlooked all this time, she does admit the complexity of the field might explain the setback.
“They call it dark matter, for a reason. It’s an infinite space compared to the unseen corners of the universe. When you look at the other classes of biological molecules, DNA is made up of four letters, and RNA is made up of four letters and proteins come from a library of 500 possible amino acids. It is comprised, so you can quickly screen it in a library. It’s a yes/no question. But for the metabolome, there’s just an infinite ability to make all sorts of molecular structures.”
Today, a convergence of technological progress is finally allowing researchers to explore the metabolome with depth. High-resolution mass spectrometry now makes it possible to detect and analyze metabolites with far greater sensitivity and speed than before. At the same time, artificial intelligence (AI) and machine learning are helping make sense of the vast and messier datasets metabolomics tends to produce.
Andrea Choe sees it as part of a broader shift. “We’ve had all of these revolutions – CRISPR in genetics, AAVs in neuroscience – and now organic chemistry is quietly having its moment,” she said. “The tools have been developing in the background, and now we’re starting to turn toward them to see what could come from that.”
That shift isn’t just technical. It’s also driven by medical needs, according to Choe. Chronic diseases like allergies, autoimmune disorders, and obesity are all rising, despite decades of progress in biotech. “These are diseases that impact both quality of life and lifespan,” Choe said. “Regardless of all the technology we’ve been developing as humans for the last 50 to 100 years, we haven’t yet delivered on being able to get our arms around that.”
Metabolomics, she believes, offers an untapped route forward – a way to move past traditional drug discovery models and uncover new mechanisms of disease and coincidently, treatments. “If you wanted to go out there and look for something new, where would you go? You’d go to wells that have been untapped. You’d go to mines that have been unmined. That’s metabolomics.”
Where could metabolomics make a difference?
According to Choe, metabolomics could contribute to research in a very broad range of diseases, in two different ways.
“One aspect is measuring metabolites and ultimately using them as biomarkers. Can we get out of this way of tracking disease by one cell type or cell surface antigen? Now, we understand that biology is much richer than a couple of readouts. Historically, there are a lot of drugs that work but die on the vine because they hit their clinical readout. Metabolomics can help as a diagnostic tool in fields where the readout is just not as rich, like Parkinson’s or autism,” said Choe.
The second aspect is using metabolites as drugs, explained Choe. “Metabolites have already proven their therapeutic value – just look at aspirin, Taxol, and countless antibiotics, all of which originated as natural metabolites,” said Choe. “An entire field of medicine has been built on these molecules, yet we’ve barely scratched the surface. There’s no reason to think we won’t find whole new classes of therapies if we start looking more closely.”
Indeed, many effective therapies, such as the anticancer agent paclitaxel (Taxol) and the analgesic aspirin, are derived from plant metabolites. Paclitaxel was originally isolated from the Pacific yew tree and has become a drug in oncology. Similarly, aspirin’s active ingredient, salicylic acid, was first identified in willow bark.
The challenges and the path forward
Unlike genomics, metabolomics involves significantly more small molecules with varying chemical properties, making it challenging to reach consistent and reproducible results.
According to the Center for Open Science, the challenges in metabolomics reproducibility stem from issues in compound identification, methodology, data processing, and statistical analysis. The lack of standardized protocols in sample preparation, data acquisition, and analysis contributes to this issue.
Choe draws an analogy to the film Contact, where decoding an extraterrestrial message necessitated worldwide scientific collaboration. “There have to be people all over the world interested in pouring in their efforts to this sort of global database where we can expand upon what’s known, not just from man-made compounds. We’ve been doing this for 50 to 100 years – organisms have been doing this for hundreds of millions of years.”
The core nature of metabolomics drives companies to experiment with diversified approaches. Choe’s company, for instance, takes inspiration from co-evolution. Holoclara mines metabolites produced by gut-dwelling worms – organisms that have lived in symbiosis with humans for millions of years. These parasites have evolved complex biochemical tools to modulate their host’s immune system, making them a source of potential therapeutics.
There is still a lot of work to be done to reach metabolomics’ full potential. According to Choe, we’ve only scratched the surface of metabolomics. “The 2015 Nobel Prize went to scientists who discovered metabolites that had a major impact on diseases like malaria. If you read their stories, there’s always some element of chance involved — moments where unexpected findings led to breakthroughs. But then, how do we not stop there?”
What we’ve achieved so far in metabolomics is just the tip of the iceberg, and according to Choe, the rest is just a matter of time and effort.
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