Nautilus chief scientist on the power of proteomics to decode the mysteries of aging and enhance longevity drug development.
In 2003, after 15 years of concerted global research efforts and a cost of around $3 billion, the Human Genome Project achieved its goal of producing the first sequence of the human genome. Since then, the cost of DNA sequencing has fallen dramatically, and the field of genomics is now making it possible to predict, diagnose, and treat diseases more effectively than ever before.
Yet, despite its tremendous impact on modern healthcare, genomics does not provide all the answers needed to improve healthspan and longevity. The field of proteomics, which studies the role of proteins in the body, holds even greater promise to impact human health and longevity.
Longevity.Technology: By studying the interactions, function, composition, and structures of proteins and their cellular activities, proteomics can provide a much deeper understanding of human health than genomics will ever be able to. But it also an extremely complex area of study, and less than 30% of the proteome is routinely measured by researchers today. To learn more about the field and its potential in longevity, we caught up with Dr Parag Mallick, the founder and chief scientist of proteomics company Nautilus Biotechnology.
Comparing proteomics with genomics, Mallick says that the genome provides a useful picture of what might happen to you, while the proteome reveals what’s actually happening, in real-time.
“The genome doesn’t know anything about how you’ve lived your life – it doesn’t know what you ate, it doesn’t know that you smoked, it doesn’t know anything about you,” he explains. “The proteome, on the other hand, is incredibly dynamic – it changes every minute of every day in response to everything you do.”
For the most part, points out Mallick, your genome doesn’t change – from the day that you’re born to the day that you die, it remains pretty much the same.
“Of course, there are instances like cancer, for example, where there are small genome changes, but for most other diseases – Alzheimer’s, heart disease, diabetes – there are no changes in your genome, but lots of changes to the rest of your body,” he adds. “The proteome is great at both being able to observe what’s happening and to monitor it continuously to see the changes as they’re occurring. “
Proteomics and longevity
This depth and granularity of information has potentially huge implications when it comes to understanding healthspan and longevity.
“Proteomics is fundamental to understanding how life works, and in the case of longevity, how it stops working… the processes that lead to degradation over time,” says Mallick. “Proteomics can provide insight into all those biochemical changes happening every moment of every day that are consequences of aging or how we live our life. From looking at things like the effect of free radicals or telomere shortening, to the blood factors of extremely long-lived people – all these elements are captured in the proteome. The proteins are both doing the work and providing the best view of what is happening in your body right now.”
But proteomics can provide more than just insight into human aging – it can also greatly improve the chances of being able to develop successful longevity interventions.
“Think about drug development – 95% of drugs target proteins, and the vast majority of this development and understanding how drugs work is done at the protein level,” says Mallick. “When you think about wanting to increase longevity using drugs, natural products, or any other approach, you want to be able to understand what those interventions are doing and how they are changing the system.”
A complex task
However, while undeniably more powerful in terms of its potential, studying the proteome is also much more complex than the genome.
“In proteomics you have to measure your target proteins over and over again, and you may have to measure them in different places, because the proteome in your pancreas is different than the proteome that’s in your blood or in your liver, so it’s a much more complicated thing to study,” says Mallick “Also, the abundance of proteins spans a massive range – the difference between the least abundant protein and the most abundant protein spans approximately 10 orders of magnitude. To put that in visual context, that’s a poppy seed compared to the earth!”
Given that it took 13 years and $3 billion to map the human genome, does Mallick think it’s conceivable to conduct a similar initiative in proteomics?
“I do think there’s a need for us to understand the proteome in this way,” he says. “Just because there are so many proteins, and they’re changing all the time, doesn’t mean that they’re changing chaotically. It’s not random. There’s biology under the hood of each of those changes.”
“A project like the Human Genome Project in proteomics could help us understand what are the proteins that change in a systematic way as a consequence of biology. There will be proteins that have consistent understandable behavior that can be connected to aging, age-related diseases, and so on.”
While mapping the first human genome cost $3 billion in 2003, whole genome sequencing can be done for a few hundred dollars today, and any biologist who wants to study the genome or transcriptome of any sample can do it relatively easily and cost-effectively.
Of course, proteomics is now also widely used in research, but not as ubiquitously as genomic and transcriptomic methods. According to Mallick, the reason for this is twofold: the complexity of proteomic technology currently available, and the limited data produced by those technologies.
“If we look at the proteome, the tools available today are incomplete. There is no tool in the world that can measure the entire proteome in a single experiment,” he says. “And the tools that are available are complicated, so only trained proteomics research scientists can use them, which limits the range of people who can do proteomics studies.”
“Even the best technologies may be able to measure a couple of thousand proteins from blood relative to the tens of thousands that we believe exist – that’s only 10% of what’s there. So, while people are using proteomics all the time, they are subject to limitations – it’s hard to do, and it doesn’t have the range you would want.”
Mallick founded Nautilus with the aim of building a platform capable of quantifying the entire proteome in a way that is accessible to any type of researcher.
“We want proteomic technologies to come into parity with genomic technologies,” he says. “We’re democratizing proteomics so that anyone who wants to measure the proteome can do so. We need to make it so that it is just a part of how people study biology, so when they’re looking at aging and histones and telomeres, it’s as natural to get a sample’s proteome as it is to get its genome.”
Nautilus has developed a platform, expected to launch next year, which is designed to substantively analyze the entire proteome of any sample to reveal how it is affected in an unbiased way.
“We wanted to build a platform that was able to capture the scale of the proteome and that was easy to use,” says Mallick. “It also had to be fast, it had to have sensitivity down to handfuls of molecules potentially, and it had to have a dynamic range capable of measuring a few poppy seeds among planets. The genesis of Nautilus was to try to address those challenges and democratize proteomics, so that it would become as routine a part of biological inquiry as genomics is today.”
Nautilus says its modelling shows that it will be able to measure more than 95% of the proteome across a range of sample types. While he does not expect to be able to measure the entire proteome at the time of launch next year, Mallick is optimistic that the company will quickly achieve its goal.
“I expect that shortly after our launch, with additional reagents, not even changes in the instrument, our platform will make its way up to ultimately substantively measuring the entire proteome,” he says. “Think of it like this: if you took a picture of a scene and it only gave you 20% of what was going on in that scene, it would still be useful. But what if you could see 95% of what was going on in the scene? Better, right?”
The future of the proteome
Looking to the future of proteomics, Mallick expects the field to follow the path of genomics, which initially started out in the lab, but is now entering mainstream use throughout the healthcare spectrum.
“I think we’re going to see the same thing in proteomics, where it’s going to start off as a research tool, and then people are going to develop targeted panels looking at particular proteins,” he says. “Over time, it’s just going to become more efficient to measure the whole proteome, and then one day it’ll just become part of your general workup.”
When it comes to how proteomics can impact the longevity field specifically, Mallick is bullish on its potential.
“Aging processes may start with a gene mutation or a chemical that you were exposed to, and those started changing at the cellular level, at a tissue level and at a host level,” he says. “Researchers will be able to use our platform to understand those changes in a detailed manner, to find compounds or lifestyle changes that reverse those changes, and to have a readout that proves they actually worked.”