Aubrey de Grey at the World Stem Cell Summit in Miami on January 25, 2018.
Aging is not a mystery, says famed researcher Dr. Aubrey de Grey, perhaps the world's foremost advocate of the provocative view that medical technology will one day allow humans to control the aging process and live healthily into our hundreds—or even thousands.
"The cultural attitudes toward all of this are going to be completely turned upside down by sufficiently promising results in the lab, in mice."
He likens aging to a car wearing down over time; as the body operates normally, it accumulates damage which can be tolerated for a while, but eventually sends us into steep decline. The most promising way to escape this biological reality, he says, is to repair the damage as needed with precise scientific tools.
The bad news is that doing this groundbreaking research takes a long time and a lot of money, which has not always been readily available, in part due to a cultural phenomenon he terms "the pro-aging trance." Cultural attitudes have long been fatalistic about the inevitability of aging; many people balk at the seemingly implausible prospect of indefinite longevity.
But the good news for de Grey—and those who are cheering him on—is that his view is becoming less radical these days. Both the academic and private sectors are racing to tackle aging; his own SENS Research Foundation, for one, has spun out into five different companies. Defeating aging, he says, "is not just a future industry; it's an industry now that will be both profitable and extremely good for your health."
De Grey sat down with Editor-in-Chief Kira Peikoff at the World Stem Cell Summit in Miami to give LeapsMag the latest scoop on his work. Here is an edited and condensed version of our conversation.
Since your book Ending Aging was published a decade ago, scientific breakthroughs in stem cell research, genome editing, and other fields have taken the world by storm. Which of these have most affected your research?
They have all affected it a lot in one way, and hardly at all in another way. They have speeded it up--facilitated short cuts, ways to get where we're already trying to go. What they have not done is identified any fundamental changes to the overall strategy. In the book, we described the seven major types of damage, and particular ways of going about fixing each of them, and that hasn't changed.
"Repair at the microscopic level, one would be able to expect to do without surgery, just by injecting the right kind of stem cells."
Has any breakthrough specifically made the biggest impact?
It's not just the obvious things, like iPS (induced pluripotent stem cells) and CRISPR (a precise tool for editing genes). It's also the more esoteric things that applied specifically to certain of our areas, but most people don't really know about them. For example, the identification of how to control something called co-translational mitochondrial protein import.
How much of the future of anti-aging treatments will involve regeneration of old tissue, or wholesale growth of new organs?
The more large-scale ones, regenerating whole new organs, are probably only going to play a role in the short-term and will be phased out relatively rapidly, simply because, in order to be useful, one has to employ surgery, which is really invasive. We'll want to try to get around that, but it seems quite likely that in the very early stages, the techniques we have for repairing things at the molecular and cellular level in situ will be insufficiently comprehensive, and so we will need to do the more sledgehammer approach of building a whole new organ and sticking it in.
Every time you are in a position where you're replacing an organ, you have the option, in principle, of repairing the organ, without replacing it. And repair at the microscopic level, one would be able to expect to do without surgery, just by injecting the right kind of stem cells or whatever. That would be something one would expect to be able to apply to someone much closer to death's door and much more safely in general, and probably much more cheaply. One would expect that subsequent generations of these therapies would move in that direction.
Your foundation is working on an initiative requiring $50 million in funding—
Well, if we had $50 million per year in funding, we could go about three times faster than we are on $5 million per year.
And you're looking at a 2021 timeframe to start human trials?
That's approximate. Remember, because we accumulate in the body so many different types of damage, that means we have many different types of therapy to repair that damage. And of course, each of those types has to be developed independently. It's very much a divide and conquer therapy. The therapies interact with each other to some extent; the repair of one type of damage may slow down the creation of another type of damage, but still that's how it's going to be.
And some of these therapies are much easier to implement than others. The easier components of what we need to do are already in clinical trials—stem cell therapies especially, and immunotherapy against amyloid in the brain, for example. Even in phase III clinical trials in some cases. So when I talk about a timeframe like 2021, or early 20s shall we say, I'm really talking about the most difficult components.
What recent strides are you most excited about?
Looking back over the past couple of years, I'm particularly proud of the successes we've had in the very most difficult areas. If you go through the 7 components of SENS, there are two that have absolutely been stuck in a rut and have gotten nowhere for 15 to 20 years, and we basically fixed that in both cases. We published two years ago in Science magazine that essentially showed a way forward against the stiffening of the extracellular matrix, which is responsible for things like wrinkles and hypertension. And then a year ago, we published a real breakthrough paper with regard to placing copies of the mitochondria DNA in the nuclear DNA modified in such a way that they still work, which is an idea that had been around for 30 years; everyone had given up on it, some a long time ago, and we basically revived it.
A slide presented by Aubrey de Grey, referencing his collaboration with Mike West at AgeX, showing the 7 types of damage that he believes must be repaired to end aging.
(Courtesy Kira Peikoff)
That's exciting. What do you think are the biggest barriers to defeating aging today: the technological challenges, the regulatory framework, the cost, or the cultural attitude of the "pro-aging" trance?
One can't really address those independently of each other. The technological side is one thing; it's hard, but we know where we're going, we've got a plan. The other ones are very intertwined with each other. A lot of people are inclined to say, the regulatory hurdle will be completely insurmountable, plus people don't recognize aging as a disease, so it's going to be a complete nonstarter. I think that's nonsense. And the reason is because the cultural attitudes toward all of this are going to be completely turned upside down before we have to worry about the regulatory hurdles. In other words, they're going to be turned upside down by sufficiently promising results in the lab, in mice. Once we get to be able to rejuvenate actually old mice really well so they live substantially longer than they otherwise would have done, in a healthy state, everyone's going to know about it and everyone's going to demand – it's not going to be possible to get re-elected unless you have a manifesto commitment to turn the FDA completely upside down and make sure this happens without any kind of regulatory obstacle.
I've been struggling away all these years trying to bring little bits of money in the door, and the reason I have is because of the skepticism as to regards whether this could actually work, combined with the pro-aging trance, which is a product of the skepticism – people not wanting to get their hopes up, so finding excuses about aging being a blessing in disguise, so they don't have to think about it. All of that will literally disintegrate pretty much overnight when we have the right kind of sufficiently impressive progress in the lab. Therefore, the availability of money will also [open up]. It's already cracking: we're already seeing the beginnings of the actual rejuvenation biotechnology industry that I've been talking about with a twinkle in my eye for some years.
"For humans, a 50-50 chance would be twenty years at this point, and there's a 10 percent chance that we won't get there for a hundred years."
Why do you think the culture is starting to shift?
There's no one thing yet. There will be that tipping point I mentioned, perhaps five years from now when we get a real breakthrough, decisive results in mice that make it simply impossible to carry on being fatalistic about all this. Prior to that, what we're already seeing is the impact of sheer old-school repeat advertising—me going out there, banging away and saying the same fucking thing again and again, and nobody saying anything that persuasively knocks me down. … And it's also the fact that we are making incremental amounts of progress, not just ourselves, but the scientific community generally. It has become incrementally more plausible that what I say might be true.
I'm sure you hate getting the timeline question, but if we're five years away from this breakthrough in mice, it's hard to resist asking—how far is that in terms of a human cure?
When I give any kind of timeframes, the only real care I have to take is to emphasize the variance. In this case I think we have got a 50-50 chance of getting to that tipping point in mice within five years from now, certainly it could be 10 or 15 years if we get unlucky. Similarly, for humans, a 50-50 chance would be twenty years at this point, and there's a 10 percent chance that we won't get there for a hundred years.
"I don't get people coming to me saying, well I don't think medicine for the elderly should be done because if it worked it would be a bad thing. People like to ignore this contradiction."
What would you tell skeptical people are the biggest benefits of a very long-lived population?
Any question about the longevity of people is the wrong question. Because the longevity that people fixate about so much will only ever occur as a side effect of health. However long ago you were born or however recently, if you're sick, you're likely to die fairly soon unless we can stop you being sick. Whereas if you're healthy, you're not. So if we do as well as we think we can do in terms of keeping people healthy and youthful however long ago they were born, then the side effect in terms of longevity and life expectancy is likely to be very large. But it's still a side effect, so the way that people actually ought to be—in fact have a requirement to be—thinking, is about whether they want people to be healthy.
Now I don't get people coming to me saying, well I don't think medicine for the elderly should be done because if it worked it would be a bad thing. People like to ignore this contradiction, they like to sweep it under the carpet and say, oh yeah, aging is totally a good thing.
People will never actually admit to the fact that what they are fundamentally saying is medicine for the elderly, if it actually works, would be bad, but still that is what they are saying.
Shifting gears a bit, I'm curious to find out which other radical visionaries in science and tech today you most admire?
Fair question. One is Mike West. I have the great privilege that I now work for him part-time with Age X. I have looked up to him very much for the past ten years, because what he did over the past 20 years starting with Geron is unimaginable today. He was working in an environment where I would not have dreamt of the possibility of getting any private money, any actual investment, in something that far out, that far ahead of its time, and he did it, again and again. It's insane what he managed to do.
What about someone like Elon Musk?
Sure, he's another one. He is totally impervious to the caution and criticism and conservatism that pervades humanity, and he's getting on making these bloody self-driving cars, space tourism, and so on, making them happen. He's thinking just the way I'm thinking really.
"You can just choose how frequently and how thoroughly you repair the damage. And you can make a different choice next time."
You famously said ten years ago that you think the first person to live to 1000 is already alive. Do you think that's still the case?
Definitely, yeah. I can't see how it could not be. Again, it's a probabilistic thing. I said there's at least a 10 percent chance that we won't get to what I call Longevity Escape Velocity for 100 years and if that's true, then the statement about 1000 years being alive already is not going to be the case. But for sure, I believe that the beneficiaries of what we may as well call SENS 1.0, the point where we get to LEV, those people are exceptionally unlikely ever to suffer from any kind of ill health correlated with their age. Because we will never fall below Longevity Escape Velocity once we attain it.
Could someone who was just born today expect—
I would say people in middle age now have a fair chance. Remember – a 50/50 chance of getting to LEV within 20 years, and when you get there, you don't just stay at biologically 70 or 80, you are rejuvenated back to biologically 30 or 40 and you stay there, so your risk of death each year is not related to how long ago you were born, it's the same as a young adult. Today, that's less than 1 in 1000 per year, and that number is going to go down as we get self-driving cars and all that, so actually 1000 is a very conservative number.
So you would be able to choose what age you wanted to go back to?
Oh sure, of course, it's just like a car. What you're doing is you're repairing damage, and the damage is still being created by the body's metabolism, so you can just choose how frequently and how thoroughly you repair the damage. And you can make a different choice next time.
What would be your perfect age?
I have no idea. That's something I don't have an opinion about, because I could change it whenever I like.
A movie still from the 1966 film "Fantastic Voyage"
"Chemotherapy is delivered systemically," Bionaut-founder and CEO Michael Shpigelmacher says. "Often only a small percentage arrives at the location where it is actually needed."
But what if it was possible to send a tiny robot through the body to attack a tumor or deliver a drug at exactly the right location?
Several startups and academic institutes worldwide are working to develop such a solution but Bionaut Labs seems the furthest along in advancing its invention. "You can think of the Bionaut as a tiny screw that moves through the veins as if steered by an invisible screwdriver until it arrives at the tumor," Shpigelmacher explains. Via Zoom, he shares the screen of an X-ray machine in his Culver City lab to demonstrate how the half-transparent, yellowish device winds its way along the spine in the body. The nanobot contains a tiny but powerful magnet. The "invisible screwdriver" is an external magnetic field that rotates that magnet inside the device and gets it to move and change directions.
The current model has a diameter of less than a millimeter. Shpigelmacher's engineers could build the miniature vehicle even smaller but the current size has the advantage of being big enough to see with bare eyes. It can also deliver more medicine than a tinier version. In the Zoom demonstration, the micorobot is injected into the spine, not unlike an epidural, and pulled along the spine through an outside magnet until the Bionaut reaches the brainstem. Depending which organ it needs to reach, it could be inserted elsewhere, for instance through a catheter.
"The hope is that we can develop a vehicle to transport medication deep into the body," says Max Planck scientist Tian Qiu.
Imagine moving a screw through a steak with a magnet — that's essentially how the device works. But of course, the Bionaut is considerably different from an ordinary screw: "At the right location, we give a magnetic signal, and it unloads its medicine package," Shpigelmacher says.
To start, Bionaut Labs wants to use its device to treat Parkinson's disease and brain stem gliomas, a type of cancer that largely affects children and teenagers. About 300 to 400 young people a year are diagnosed with this type of tumor. Radiation and brain surgery risk damaging sensitive brain tissue, and chemotherapy often doesn't work. Most children with these tumors live less than 18 months. A nanobot delivering targeted chemotherapy could be a gamechanger. "These patients really don't have any other hope," Shpigelmacher says.
Of course, the main challenge of the developing such a device is guaranteeing that it's safe. Because tissue is so sensitive, any mistake could risk disastrous results. In recent years, Bionaut has tested its technology in dozens of healthy sheep and pigs with no major adverse effects. Sheep make a good stand-in for humans because their brains and spines are similar to ours.
The Bionaut device is about the size of a grain of rice.
Bionaut Labs
"As the Bionaut moves through brain tissue, it creates a transient track that heals within a few weeks," Shpigelmacher says. The company is hoping to be the first to test a nanobot in humans. In December 2022, it announced that a recent round of funding drew $43.2 million, for a total of 63.2 million, enabling more research and, if all goes smoothly, human clinical trials by early next year.
Once the technique has been perfected, further applications could include addressing other kinds of brain disorders that are considered incurable now, such as Alzheimer's or Huntington's disease. "Microrobots could serve as a bridgehead, opening the gateway to the brain and facilitating precise access of deep brain structure – either to deliver medication, take cell samples or stimulate specific brain regions," Shpigelmacher says.
Robot-assisted hybrid surgery with artificial intelligence is already used in state-of-the-art surgery centers, and many medical experts believe that nanorobotics will be the instrument of the future. In 2016, three scientists were awarded the Nobel Prize in Chemistry for their development of "the world's smallest machines," nano "elevators" and minuscule motors. Since then, the scientific experiments have progressed to the point where applicable devices are moving closer to actually being implemented.
Bionaut's technology was initially developed by a research team lead by Peer Fischer, head of the independent Micro Nano and Molecular Systems Lab at the Max Planck Institute for Intelligent Systems in Stuttgart, Germany. Fischer is considered a pioneer in the research of nano systems, which he began at Harvard University more than a decade ago. He and his team are advising Bionaut Labs and have licensed their technology to the company.
"The hope is that we can develop a vehicle to transport medication deep into the body," says Max Planck scientist Tian Qiu, who leads the cooperation with Bionaut Labs. He agrees with Shpigelmacher that the Bionaut's size is perfect for transporting medication loads and is researching potential applications for even smaller nanorobots, especially in the eye, where the tissue is extremely sensitive. "Nanorobots can sneak through very fine tissue without causing damage."
In "Fantastic Voyage," Raquel Welch's adventures inside the body of a dissident scientist let her swim through his veins into his brain, but her shrunken miniature submarine is attacked by antibodies; she has to flee through the nerves into the scientist's eye where she escapes into freedom on a tear drop. In reality, the exit in the lab is much more mundane. The Bionaut simply leaves the body through the same port where it entered. But apart from the dramatization, the "Fantastic Voyage" was almost prophetic, or, as Shpigelmacher says, "Science fiction becomes science reality."
This article was first published by Leaps.org on April 12, 2021.
In 2013, the Human Brain Project set out to build a realistic computer model of the brain over ten years. Now, experts are reflecting on HBP's achievements with an eye toward the future.
Scholars have found that the project did help advance neuroscience more than some detractors initially expected, specifically in the area of brain simulations and virtual models. Using an interdisciplinary approach of combining technology, such as AI and digital simulations, with neuroscience, the HBP worked to gain a deeper understanding of the human brain’s complicated structure and functions, which in some cases led to novel treatments for brain disorders. Lastly, through online platforms, the HBP spearheaded a previously unmatched level of global neuroscience collaborations.
Simulating a human brain stirs up controversy
Right from the start, the project was plagued with controversy and condemnation. One of its prominent critics was Yves Fregnac, a professor in cognitive science at the Polytechnic Institute of Paris and research director at the French National Centre for Scientific Research. Fregnac argued in numerous articles that the HBP was overfunded based on proposals with unrealistic goals. “This new way of over-selling scientific targets, deeply aligned with what modern society expects from mega-sciences in the broad sense (big investment, big return), has been observed on several occasions in different scientific sub-fields,” he wrote in one of his articles, “before invading the field of brain sciences and neuromarketing.”
"A human brain model can simulate an experiment a million times for many different conditions, but the actual human experiment can be performed only once or a few times," said Viktor Jirsa, a professor at Aix-Marseille University.
Responding to such critiques, the HBP worked to restructure the effort in its early days with new leadership, organization, and goals that were more flexible and attainable. “The HBP got a more versatile, pluralistic approach,” said Viktor Jirsa, a professor at Aix-Marseille University and one of the HBP lead scientists. He believes that these changes fixed at least some of HBP’s issues. “The project has been on a very productive and scientifically fruitful course since then.”
After restructuring, the HBP became a European hub on brain research, with hundreds of scientists joining its growing network. The HBP created projects focused on various brain topics, from consciousness to neurodegenerative diseases. HBP scientists worked on complex subjects, such as mapping out the brain, combining neuroscience and robotics, and experimenting with neuromorphic computing, a computational technique inspired by the human brain structure and function—to name just a few.
Simulations advance knowledge and treatment options
In 2013, it seemed that bringing neuroscience into a digital age would be farfetched, but research within the HBP has made this achievable. The virtual maps and simulations various HBP teams create through brain imaging data make it easier for neuroscientists to understand brain developments and functions. The teams publish these models on the HBP’s EBRAINS online platform—one of the first to offer access to such data to neuroscientists worldwide via an open-source online site. “This digital infrastructure is backed by high-performance computers, with large datasets and various computational tools,” said Lucy Xiaolu Wang, an assistant professor in the Resource Economics Department at the University of Massachusetts Amherst, who studies the economics of the HBP. That means it can be used in place of many different types of human experimentation.
Jirsa’s team is one of many within the project that works on virtual brain models and brain simulations. Compiling patient data, Jirsa and his team can create digital simulations of different brain activities—and repeat these experiments many times, which isn’t often possible in surgeries on real brains. “A human brain model can simulate an experiment a million times for many different conditions,” Jirsa explained, “but the actual human experiment can be performed only once or a few times.” Using simulations also saves scientists and doctors time and money when looking at ways to diagnose and treat patients with brain disorders.
Compiling patient data, scientists can create digital simulations of different brain activities—and repeat these experiments many times.
The Human Brain Project
Simulations can help scientists get a full picture that otherwise is unattainable. “Another benefit is data completion,” added Jirsa, “in which incomplete data can be complemented by the model. In clinical settings, we can often measure only certain brain areas, but when linked to the brain model, we can enlarge the range of accessible brain regions and make better diagnostic predictions.”
With time, Jirsa’s team was able to move into patient-specific simulations. “We advanced from generic brain models to the ability to use a specific patient’s brain data, from measurements like MRI and others, to create individualized predictive models and simulations,” Jirsa explained. He and his team are working on this personalization technique to treat patients with epilepsy. According to the World Health Organization, about 50 million people worldwide suffer from epilepsy, a disorder that causes recurring seizures. While some epilepsy causes are known others remain an enigma, and many are hard to treat. For some patients whose epilepsy doesn’t respond to medications, removing part of the brain where seizures occur may be the only option. Understanding where in the patients’ brains seizures arise can give scientists a better idea of how to treat them and whether to use surgery versus medications.
“We apply such personalized models…to precisely identify where in a patient’s brain seizures emerge,” Jirsa explained. “This guides individual surgery decisions for patients for which surgery is the only treatment option.” He credits the HBP for the opportunity to develop this novel approach. “The personalization of our epilepsy models was only made possible by the Human Brain Project, in which all the necessary tools have been developed. Without the HBP, the technology would not be in clinical trials today.”
Personalized simulations can significantly advance treatments, predict the outcome of specific medical procedures and optimize them before actually treating patients. Jirsa is watching this happen firsthand in his ongoing research. “Our technology for creating personalized brain models is now used in a large clinical trial for epilepsy, funded by the French state, where we collaborate with clinicians in hospitals,” he explained. “We have also founded a spinoff company called VB Tech (Virtual Brain Technologies) to commercialize our personalized brain model technology and make it available to all patients.”
The Human Brain Project created a level of interconnectedness within the neuroscience research community that never existed before—a network not unlike the brain’s own.
Other experts believe it’s too soon to tell whether brain simulations could change epilepsy treatments. “The life cycle of developing treatments applicable to patients often runs over a decade,” Wang stated. “It is still too early to draw a clear link between HBP’s various project areas with patient care.” However, she admits that some studies built on the HBP-collected knowledge are already showing promise. “Researchers have used neuroscientific atlases and computational tools to develop activity-specific stimulation programs that enabled paraplegic patients to move again in a small-size clinical trial,” Wang said. Another intriguing study looked at simulations of Alzheimer’s in the brain to understand how it evolves over time.
Some challenges remain hard to overcome even with computer simulations. “The major challenge has always been the parameter explosion, which means that many different model parameters can lead to the same result,” Jirsa explained. An example of this parameter explosion could be two different types of neurodegenerative conditions, such as Parkinson’s and Huntington’s diseases. Both afflict the same area of the brain, the basal ganglia, which can affect movement, but are caused by two different underlying mechanisms. “We face the same situation in the living brain, in which a large range of diverse mechanisms can produce the same behavior,” Jirsa said. The simulations still have to overcome the same challenge.
Understanding where in the patients’ brains seizures arise can give scientists a better idea of how to treat them and whether to use surgery versus medications.
The Human Brain Project
A network not unlike the brain’s own
Though the HBP will be closing this year, its legacy continues in various studies, spin-off companies, and its online platform, EBRAINS. “The HBP is one of the earliest brain initiatives in the world, and the 10-year long-term goal has united many researchers to collaborate on brain sciences with advanced computational tools,” Wang said. “Beyond the many research articles and projects collaborated on during the HBP, the online neuroscience research infrastructure EBRAINS will be left as a legacy even after the project ends.”
Those who worked within the HBP see the end of this project as the next step in neuroscience research. “Neuroscience has come closer to very meaningful applications through the systematic link with new digital technologies and collaborative work,” Jirsa stated. “In that way, the project really had a pioneering role.” It also created a level of interconnectedness within the neuroscience research community that never existed before—a network not unlike the brain’s own. “Interconnectedness is an important advance and prerequisite for progress,” Jirsa said. “The neuroscience community has in the past been rather fragmented and this has dramatically changed in recent years thanks to the Human Brain Project.”
According to its website, by 2023 HBP’s network counted over 500 scientists from over 123 institutions and 16 different countries, creating one of the largest multi-national research groups in the world. Even though the project hasn’t produced the in-silico brain as Markram envisioned it, the HBP created a communal mind with immense potential. “It has challenged us to think beyond the boundaries of our own laboratories,” Jirsa said, “and enabled us to go much further together than we could have ever conceived going by ourselves.”