By David Grainger, Ph.D.
When Disraeli supposedly said "The only two certainties in life are death and taxes," he could not have imagined that a little over a century later, such rock-solid logic could be under threat. If a team of Croatian scientists, led by Professor Miroslav Radman, is correct, death need be no certainty.
I was fortunate to spend several days with Professor Radman and his team earlier this year and hear about his research into proteome instability and the insights that has given him into the mechanism of aging. Most intriguingly, these insights have the potential to underpin a whole pipeline of novel therapeutics for a wide range of degenerative diseases, and perhaps, ultimately, for aging itself.
Swimming in the sea along the beautiful Adriatic coast around Split, home to the Mediterranean Institute for Life Sciences, you can find a tiny marine creature, a medusa, that potentially carries the secret to eternal life.
"For humans, death seems inevitable," says Professor Radman, "but that's not true for all creatures. The medusa Turritopsis seemingly lives forever."
It's easy to imagine living forever in the temperate blue waters of the Adriatic, but other creatures take this indestructibility to whole new levels: An unassuming small pink bacterium called Deinococcus can survive doses of radioactivity 10 times higher than those used to sterilize food and medical instruments, while the caterpillar-like tardigrades can survive two weeks on the outside of spacecraft at -270ºC in a vacuum.
"Studying these indestructible species promises to teach us why humans degenerate and die," smiles Professor Radman, "and maybe show us how to stop that process," he continues with a gleam in his eye. Is the fabled Elixir of Life about to become a reality in the Mediterranean sunshine?
Asked why we age, most scientists will tell you that DNA, which carries the blueprint for making every protein in the body, accumulates mutations during your lifetime, causing cells to make faulty protein building blocks. Eventually, enough damage accumulates to make the plans unreadable or the building blocks so shaky that everything falls apart.
"Our studies of radiation-resistant bacteria tell us that is completely the wrong way round," explains Anita Krisko, who together with Professor Radman is compiling an entirely different explanation for aging. "Even a low dose of radiation shatters the DNA, both in normal bacteria and the radiation-resistant ones. The difference is that the resistant ones can repair the DNA and so avoid death."
We have known for 40 years how special proteins can repair DNA damage--thanks again to Professor Radman, who discovered the SOS repair pathway in bacteria in 1975, for which he has received numerous international prizes. "It's the loss of these repair proteins that triggers death--the radiation damages the proteins as well as the DNA, but as long as the proteins still function to repair DNA the organism survives."
The key difference between the radiation-resistant bacteria and normal, everyday bacteria, then, has nothing to do with DNA--the proteins in the resistant bacteria are somehow protected from damage.
In fact, it is not the proteins themselves that are inherently more resistant to damage. Instead, the radiation-resistant bacteria produce high levels of a protector molecule that chaperones its proteins. And Professor Radman and his team have identified this protein guardian. "If we give normal bacteria this factor, we give them the indestructible properties," he notes.
So if we can make immortal bacteria, can we pull off the same trick in humans?
"There is clear evidence that the same processes drive human aging," says Dr. Krisko. "If we look in cells from older people, there is much more protein damage." But the strongest evidence comes from the rare disease progeria, in which young children age so rapidly that by their teenage years they appear as old as a pensioner. In progeria, protein damage accumulates much faster than in healthy people.
This new understanding offers a real opportunity to treat progeria and the milder premature aging disease called Werner syndrome. The protein guardian Radman's team identified in the radiation-resistant bacteria can protect human proteins too. "If we can find a way to deliver it as a drug, we can give these people real hope of a cure," says the professor.
And what about the rest of us, who age more slowly, but age nonetheless? Can this same factor halt the aging process in all of us?
The gleam in Professor Radman's eye is back: "Probably not. Healthy people most likely already have plenty of their own proteome-protector molecules, made by their own metabolism. But the same insight--that accumulation of protein modifications rather than DNA mutations underpins aging--reveals a whole new approach to treating degenerative diseases associated with aging.
"These degenerative diseases, like Alzheimer's disease or Parkinson's disease, are caused by damage to particular proteins (rather than accelerated damage to all proteins that we see in progeria). Evolution has optimized long-lived proteins not just for function but for resistance to damage, such as oxidation, as well. As a result, any change in the sequence (due to a single-nucleotide polymorphism, for example) makes the protein less robust. For each of us, therefore, depending on our unique genomic sequence, there is a particular protein that is more vulnerable than the rest--and the function of the protein that's lost determines the particular disease you develop."
And it's not just a hypothesis. Professor Radman and his team are accumulating new evidence, showing the damage that occurs when the sequence is altered. This understanding of how protein damage occurs allows us to design specific protein guardians for these vulnerable proteins--a whole pipeline of high-value drug product candidates invisible to conventional discovery approaches.
For Professor Radman, whose youthful twinkle belies his 60 years, it will almost certainly take too long to turn these ideas into drugs to secure his own immortality. But if he is right, he will surely secure a place in science history alongside Europe's other geniuses such as Newton, Einstein and Pasteur, as the man who cured aging--another kind of immortality.
David Grainger, Ph.D., who is the author of DrugBaron, serves as a biopharma consultant and venture partner at Index Ventures. Read his blog.