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Will proteomics provide answers to questions of ageing and longevity?

Dr Parag Mallick is founder and chief scientist of Nautilus Biotechnology.

The lead scientist of Nautilus on the potential of proteomics to unlock the secrets of ageing and improve the development of longevity drugs.

In 2003, after 15 years of concerted global research efforts and a cost of around 3 billion dollars, the Human Genome Project achieved its goal of creating the first sequence of the human genome. Since then, the cost of DNA sequencing has fallen dramatically and the field of genomics now makes it possible to predict, diagnose and treat diseases better than ever before.

However, despite its enormous impact on modern healthcare, genomics does not provide all the answers needed to improve health and longevity. The field of proteomics, which studies the role of proteins in the body, promises even greater impact on 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 ever will. However, it is also an extremely complex field of research and less than 30% of the proteome is routinely measured by researchers today. To find out more about this field and its potential for longevity, we spoke to Dr Parag Mallick, founder and chief scientist of proteomics company Nautilus Biotechnology.

Mallick compares proteomics to genomics, saying that the genome provides a useful picture of what might happen to you, while the proteome shows what is actually happening in real time.

"The genome doesn't know anything about how you've lived your life - it doesn't know what you've eaten, it doesn't know that you've 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.

By and large, Mallick says, the genome doesn't change - from the day you're born to the day you die, it stays pretty much the same.

"Of course, there are cases like cancer where there are small changes in the genome, but in most other diseases - Alzheimer's, heart disease, diabetes - there are no changes in the genome but lots of changes in the rest of the body," he adds. "The proteome is great for observing what's happening and continuously monitoring it to see the changes as they happen. "

Proteomics and longevity

This depth and granularity of information has potentially major implications for understanding health and longevity.

"Proteomics is fundamental to understanding how life functions, and in the case of longevity, how it ceases to function - the processes that lead to degradation over time," says Mallick. "Proteomics can provide insights into all the biochemical changes that take place every moment of the day that are consequences of aging or the way we live our lives. From studying the effects of free radicals or the shortening of telomeres to the blood factors of extremely long-lived people, all of these elements are captured in the proteome. Proteins do both the work and provide the best insight into what's going on in your body."

However, proteomics can do more than just provide insights into human ageing - it can also significantly improve the chances of developing successful longevity interventions.

"Think about drug development - 95% of drugs target proteins, and most of the development and understanding of how drugs work happens at the protein level," says Mallick. "If you want to increase longevity using drugs, natural products or other approaches, you need to understand what these actions do and how they change the system.

A complex task

Whilst studying the proteome is undeniably more powerful, it is also much more complex than studying the genome.

"In proteomics, you have to measure the target proteins over and over again, and at different sites, because the proteome in the pancreas is different from the proteome in the blood or liver, so the study is much more complicated," says Mallick. "Also, the abundance of proteins covers a huge range - the difference between the least abundant protein and the most abundant protein is about ten orders of magnitude. To put that into a visual context: That's a poppy seed compared to the Earth!"

Considering that it took 13 years and 3 billion dollars to decode the human genome, does Mallick think a similar initiative in the field of proteomics is conceivable?

"I do think it's necessary to understand the proteome in this way," he says. "Just because there are so many proteins and they are constantly changing doesn't mean they change chaotically. It's not random. There is a biological basis behind each of these changes."

"A project like the Human Genome Project in proteomics could help us understand which proteins change systematically as a result of biology. There will be proteins that show consistent, understandable behaviour that can be linked to ageing, age-related diseases and so on.

On the trail of genomics

While mapping the first human genome cost $3 billion in 2003, whole genome sequencing can now be done for a few hundred dollars, and any biologist who wants to analyse the genome or transcriptome of any sample can do so relatively easily and inexpensively.

Of course, proteomics is now also used in research, but not as frequently as genomic and transcriptomic methods. According to Mallick, there are two reasons for this: the complexity of the proteomic technology currently available and the limited data that these technologies provide.

"When we look at the proteome, the tools available today are incomplete. There is no instrument in the world that can measure the entire proteome in a single experiment," he says. "And the tools that are available are complicated, so they can only be used by trained proteomics researchers, which limits who can do proteomic studies.

"Even with the best technologies, maybe a few thousand proteins can be measured from the blood, compared to the tens of thousands we think exist - that's only 10 per cent of what's out there. So although proteomics is used all the time, there are limits to it - it's difficult and it doesn't have the reach that you would want."

Democratisation of proteomics

Mallick founded Nautilus with the goal of developing a platform capable of quantifying the entire proteome in a way that is accessible to any type of researcher.

"We want proteomics technologies to be on par with genomics technologies," he says. "We are democratising proteomics so that anyone who wants to measure the proteome can do so. We need to ensure that proteomics becomes an integral part of biological research, so that when studying ageing, histones and telomeres, it is as natural to determine the proteome of a sample as its genome."

Nautilus has developed a platform, due to be launched next year, that can analyse the entire proteome of any sample to determine how it is affected in an unbiased way.

"We wanted to develop a platform that could capture the scope of the proteome and be easy to use," says Mallick. "It also needed to be fast, have sensitivity down to a handful of molecules, and have a dynamic range that would allow it to measure a few poppy seeds among planets. Nautilus was developed to overcome these challenges and democratise proteomics so that it becomes as routine a part of biological research 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 doesn't expect to be able to measure the entire proteome by the time it launches next year, Mallick is optimistic that the company will reach its goal quickly.

"I expect our platform to be able to measure the entire proteome shortly after launch with additional reagents, not even changes to the device," he says. "Imagine the following: If you took a picture of a scene and could only recognise 20% of what was happening in that scene, it would still be useful. But what if you could see 95% of what was happening in the scene? Better, isn't it?"

The future of the proteome

Looking to the future of proteomics, Mallick expects the field to follow the path of genomics, which originally started in the lab but is now being applied across the healthcare spectrum.

"I think we'll see the same thing happen with proteomics: It will start as a research tool, and then you will develop targeted panels for specific proteins," he says. "Over time, it will become more and more efficient to measure the whole proteome, and one day it will simply be part of general investigation.

As for the impact of proteomics on the field of longevity, Mallick is optimistic about its potential.

"Aging processes can start with a gene mutation or a chemical you've been exposed to, and these start to change at the cellular level, at the tissue level and at the host level," he says. "Researchers can use our platform to understand these changes in detail, to find agents or lifestyle changes that reverse these changes, and to have a readout that proves they actually worked."

Dr Parag Mallick is the founder and chief scientist of Nautilus Biotechnology.


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