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BIO, TECHNOLOGY

HOW CAN WE REVERSEPROTEONOMICS AND SYNTHETIC RIBOSOMES

 

Will death remain inevitable, or can we live forever? What if life had no end ? The greeks believed in healing water, aqua vitae, water that could make a person young again, a legend that may have spawned ponce de Leon’s belief in the fountain of youth. But what if the fountain of youth could be found within our proteins? We used to think aging was a passive process where you randomly fall apart, with nothing complicated going on, no common mechanism. But a decade ago we started to question that idea, wondering if it might just be protein regulation that’s responsible for aging. That our genes initiate biomolecular processes to accelerate death for evolutionary reasons. Natural selection wants us to reproduce when we’re young, and then die off when we get older. Your body cares about slowing aging at first, but then it loses interest so it can make room for the next generation. When your body starts to age is also a matter of what species you are. There are fish and turtles that live to 200, and they have very similar organs to us, yet we die after 80 years while they get to live. Biochemists try to explaain these phenomena using proteonomics, the large-scale experimental analysis of proteins. Through protein purification and mass spectrometry, we can find out the role that the thousands of different types of proteins in our bodies play in aging. There are 5 main different types of proteins in our body. There are Hormones, like insulin. Receptors, like the famous IGF-1. Structural proteins, like collagen. Enzymes, like Telomerase. Antibodies, like IgM. But for now we’ll mostly just focus on enzymes. Proteonomics offers us a way of measuring the aging process by overexpressing or underexpressing specific enzymes, and understanding the human proteome could yield unparalled possibilities. The Human Proteome Project, or HPP, has spent the entire decade pooling computational resources to make a list of all these proteins and figure out how they work. It includes critical enzymes like “AMP activated protein kinase”, which helps get rid of cellular garbage by promoting autophagy and destroying damaged cells.  Researchers from UCLA showed that by turning on the gene for this protein in flies they could extend their lives by 30%, since the accumulation of broken cells is one of the leading causes of aging. In addition to human aging research, we’ve come even closer to completing the proteomes for animals. Geneticist Dr. Cynthia Kenyon found that another gene called DAF-2, also known as “the grim reaper pathway”, keeps C Elegans worms from living twice as long as they could potentially but altering the gene radically extends their lifespan. The Gene DAF-16 has the opposite effect, and overexpressing it could even triple the worm’s lifespan. So it means you could potentially have a worm that lives 6 times as long by just making 2 genetic changes. Mammal geneticists have even found a counterparts to that nematod aging gene called IGF-1. Altering the gene can extend lifespan in mice by up to 33% and also plays a role in the anti-aging effects of caloric restriction. In addition to all these findings, Dr. Kenyon also uncovered a master-control gene called FOXO, regulating hundreds of other genes making proteins that keep the worms freakishly youthful. FOXO protects and repairs the worm’s tissues, kills invading microorganisms, and produces antioxidants. While worms and flies may look very different from humans, the basic processes of life are still very similar at the molecular level. For example, the equivalent of the FOXO pathway was also confirmed in humans through a study done on japanese american men in Hawaii. The Hawaii study showed that the protective varient of the FOXO gene was more likely to be found in centennarians, people who have lived to over 100. News of the study spread around the world, and dr. Nil Barzilai of the Albert Einstein college confirmed the results in a new york study of Ashkenazi Jewish centennarians, where he also demonstrated the analog pathway. The fundamental processes in life take place in the exact same way in worms as they do in humans. After all, a human muscle cell looks just like a worm muscle cell, it has the same proteins, generates force the same way, and develops from a stem cell the exact same way human cells do. We are much more similar than we are different thanks to evolution, so there’s a good chance that whatever you learn in these worms will also apply in humans to some degree. Just as with worms, if you take  the proteins millions of old people and the proteins from millions of young people, then subtract, you can track down the genes responsible for aging. With methods like this, we’ve already identified over 60 genes involved in the aging process, now there’s just the question of which ones are the biggest culprits. Potentially, tweaking just a few important genes could help us reprogram a human who only lives 100 years into a 2-300 year old person. If we were to treat the human body like a broken car, it would help to look where things go wrong the most, the engine. Every cell in our body has small engines called Mitochondria, double membrane powerhouses who’s job is to provide energy. But when these powerhouses wear down from oxidative stress, our bodies begin to decay. But now we can reverse this process, for example, we’ve extended the lifespan of mice twofold, the equivalent of 160 human years, all simply by removing the genes for proteins ras-2 and SCH-9 from their DNA. Mice and humans share 90% of their genes, so  a similar radical extension in life would likely apply to us. Given this premise, we’ve recently discovered 3 very important proteins in humans that have shown to play a crucial role in aging, they are: Number 1, carbonic anhydrase, number 2, PAI-1, and number 3, DRP-1.

Firstly, in addition to being the “powerhouse of the cell,” the mitochondria could also be home to a certain protein that’s directly in charge of longevity. According to a new study  published in the journal Aging , biochemists at Nottingham University have now  discovered a protein in human cells that could help them withstand the effects of the aging process. It’s called carbonic anhydrase, and it’s found in the mitochondria of brain cells. The team leaders, Dr. Lisa Chakrabarti and dr. Amelia Pollard studied brain and muscle cells of both young and middle-aged mice with varying levels of neurodegeneration and noted that higher levels of a protein called carbonic anhydrase were found in those of the older mice, suggesting that an increased concentration of the protein could be linked to the aging process. The researchers hope that the study will provide a good starting point for drug development that targets carbonic anhydrase in human cells. While it’s still in the early stages of development, their research could even lead to treatments for diseases like Alzheimer’s and Parkinson’s. To further test the theory, the scientists fed carbonic anhydrase to tiny nematode worms and found that their lifespans were shortened as well. Knowing that carbonic anhydrase has this effect could help us unlock future treatments to mitigate neurodegenerative disease and give us a very promising start for slowing down aging. Though the team’s work is promising, we are still quite a long way from fully understanding the causes of cellular degeneration. There’s a big leap from mice to men, so further testing will need to be done before their research can be applied to human subjects. References: The SunThe University of Nottingham

Overall, we don’t know if any of these proteins will work for sure, but if they don’t, we could always create our own custom proteins. In my video on Xenobiology I’ve already talked about creating synthetic ribosomes to build unnatural proteins, and amazingly enough, scientists have finally managed to create one in the lab. To create these synthetic ribosomes, scientists from the University of Illinois at Chicago and Northwestern University built a synthetic protein building nanofactory that worked inside living cells at a molecular level, without interfering with the cell’s native protein-making machinery.  Additionally, it did a remarkably good job functioning as well as the real thing. This could mean that in the future, scientists might be able to use these designer machines to create molecules of interest, such as therapeutic enzynmes, anti-aging proteins, or antibodies for viruses. Here’s how it works. Normally, when cells need to make a protein, DNA first gets transcribed into a blueprint called messenger RNA (mRNA). This is then fed through the ribosome to translate the instructions into strings of protein building blocks. But this was a problem for biologists trying to get artificial ribosomes to work inside living cells, because when the ribosome broke up into subunits, the synthetic versions would partner up with the natural counterparts and interfering with cell’s native protein synthesis, eventually killing it. To get around this problem, researchers created anew type of synthetic ribosome dubbed “Ribo-T,” where the ribosomal subunits are tethered together and never break up into subunits. The scientists were actually skeptical that this would work, since it was long believed that ribosomal subunit separation was pivotal for the process of protein synthesis. Remarkably, it seems that this assumption was wrong: because Ribo-T still had the functionality of a natural ribosome and could create proteins in a test tube, no subunit seperation needed (the scientists report in Nature). Moreover, it was even able to act in place of the real thing when put into bacteria lacking natural ribosomes, churning out the basic enzymes needed to keep the microbes alive. Of course, it isn’t as efficient as its natural counterpart, but unlike nature, we haven’t had billions of years of evolution to perfect it. Although synthetic ribosomes have actually been made before, they had a limited spectrum of use because they were only restricted to a small selection of mRNA sequences. But Ribo-T holds the potential to work on an array of sequences, allowing the synthesis of never before seen proteins and thus, opening up applications in medicine and biomaterials. On top of that, scientists could use them to enhance our understanding of protein synthesis, possibly taking us a step closer to artificial life.

 

Overall, proteonomics and synthetic ribosomes together could potentially offer us a new way to fight aging and synthesizing the proteins we need to slow it down. Through this technology we have now left the age of scientific discovery and entered the age of scientific mastery (add pic of michio kaku). The pace of biotechnology is accelerating very rapidly in this decade, and in the future, we may even have the God like power to affect human evolution and create a transhuman species. However, we will still have to vigilently stop the technology from being abused, misused, and overused to the point of creating extreme genetic apartheid. Because as it would seem, Humans are now the first software that writes its own hardware, and with great power, comes great responsibility.

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