Humans Have Regenerative Abilities—Scientists Just Need to Turn Them On
It's somewhat of a given that over the course of your life, you'll lose your hearing to some degree. But that doesn't necessarily have to be the case.
Christopher Loose, PhD, serves as executive director of Yale University’s Center for Biomedical and Interventional Technology (CBIT). He holds an appointment as assistant professor adjunct of urology in the Yale School of Medicine. He is also a lecturer in entrepreneurship in the School of Management and lecturer in Biomedical Engineering. Additionally, Dr. Loose is an accelerator executive at the Center for Integration of Medicine and Innovative Technology (CIMIT).
Previously, Dr. Loose co-founded Semprus BioSciences with Massachusetts Institute of Technology (MIT) Professors Robert Langer and David Lucchino, and served as chief technology officer until the company was acquired by Teleflex Incorporated in 2012 (TFX: $80M). Semprus Technology was published in Science Translational Medicine and received a Frost and Sullivan Breakthrough Technology Award in 2010. Semprus’s first product, a vascular catheter with a surface modification designed to have reduced thrombus (clot) formation, was FDA-cleared in 2012.
Dr. Loose received the prestigious Hertz Foundation Fellowship and was selected by MIT’s Technology Review as a member of the “TR35,” naming the world’s top 35 innovators under the age of 35. He was awarded the inaugural Peter Strauss Entrepreneurial Award from the Hertz Foundation in 2011 and was also named to Boston Business Journal’s 40 emerging business leaders under 40.
While earning his PhD in chemical engineering at MIT, with his Hertz Fellowship, Dr. Loose co-authored the Semprus Biosciences business plan, which won entrepreneurial competitions at MIT, Harvard University and Oxford University. Prior to his graduate work, Dr. Loose was a chemical engineer at Merck Research Labs after graduating, summa cum laude, with a BSE in chemical engineering from Princeton University.
Chris Loose: Hearing loss is a growing problem with increased prevalence, and the reason for this is because evolutionarily humans are not designed to withstand the assaults of modern society.
Interestingly if you look at places like Easter Island, people maintain normal hearing into old age, but it’s just by living the modern society where we have subways and cars and cities and iPods that we are overburdening our hearing and causing a great deal of hearing loss.
The origin of hearing loss is often the loss of what are called sensory hair cells in the cochlea. And these hair cells move in response to sound and create a signal that gets sent to your brain, and that’s really the origin of hearing.
Now what happens with hearing loss is those delicate hair cells start to die off over time due to external insults from loud noise or certain types of drugs. When that happens they are not naturally regenerated in mammals.
Interestingly, many species like birds and reptiles, if you knock out their hair cells and wait a period of time—a month—their hair cells come back naturally, and they can start hearing again.
So this process is hardwired into nature but mammals just haven’t found a way to turn on the system.
With many technologies designed to address hearing loss, they really just treat symptoms rather than the root cause of the disease, which is the loss of the hair cell.
And the way to think about this is like if you have a TV screen and you start losing the pixels on the TV screen; essentially what these aid devices do is they make the screen brighter, but they don’t fundamentally replace all the pixels that are lost.
So it does help to pick up some degree of signal, but it doesn’t in any way replace that native function of hearing, which is really our goal of re-growing hair cells and putting those pixels back in place and giving you that natural hearing.
At Frequency we’re focused on an entirely new mode of medicine and the objective of this is to make your body’s natural stem or progenitor cells regenerate damaged tissue in place.
And this could really transform medicine across a whole variety of diseases and organs. And where we’ve learned this from is actually looking at the portions of the human body that are very regenerative.
For instance, if you look at the human intestine, it re-creates itself every five days entirely. And that will actually last until you’re well over 100 years old, so your body knows how to re-create certain tissues.
Our objective is to identify what are the local signals that cells get from their niche environment that tells them to start to regrow and start to repair tissue, so we can start turning on the dormant progenitor and stem cells that exist throughout the body.
In order to make good medicines out of that, we focus on applications where those cells can be activated very selectively and very locally for a short period of time. That gives you tremendous benefits in terms of the safety and controllability of reactivating these systems.
And our first application is to do this in hearing loss, where we found that there are dormant progenitors that exist within the cochlea that in some species have the capacity to regenerate, but in mammals are locked in an off position and we are simply finding small molecule drugs, traditional drugs that can go in, turn on those progenitors and re-create hair cells, in this case in the cochlea, to restore the hearing function.
We frequently get asked about the difference between stem cells and progenitor cells, and while there is debate in the field as to how to exactly define them I think what’s very important is to recognize the distinction between your body’s progenitor cells and a pluripotent stem cell. Now a pluripotent stem cell can turn into any cell in your body. It’s really powerful and really flexible.
The advantage of just activating progenitors in your body is they’re generally most of the way differentiated from that pluripotent stem cell that can become anything into the final tissue, so they’re really almost locked into their fate.
So when you activate them they generally only know how to make cells of one or two types, so this gives you a highly controlled system as opposed to if you’re working with a pluripotent system - there’s more concern about creating cell types that you don’t desire in a given application.
Throughout the body progenitor cells are often controlled by their neighboring cells, and what tends to happen is there’s a neighboring cell sitting right next to a progenitor, which is constantly sending signals over to the progenitor.
And this could be saying “continuously divide,” which is commonly going on in the intestine, or in the cochlea it could be giving a signal that is saying “stay asleep.”
Our science is really to understand: what are those signals that are being passed? What specific pathways are being activated by those signals?
And then we say, how can we go in with chemicals, inhibitors or activators to those pathways so we can selectively turn on the signals to drive growth where and when we want it?
We’re very focused on advancing our hearing loss therapy and this is part of a broader platform we think of as “progenitor cell activation,” or PCA.
And with PCA we think this can be applied to many tissues where you can understand what progenitor needs to be activated and define molecules that can activate that progenitor in the right spot.
So you can think of many skin diseases that this could address, everything from wounding to balding to burns, other types of skin pathologies where regeneration is needed.
And by being able to control the growth and differentiation in the intestinal environment also opens up opportunities to address G.I. diseases.
We see opportunities, as with the ear, in the eye, another sensory organ that’s plagued with a number of degenerative diseases where known progenitor cells have been found that could address many of these maladies as well.
It's somewhat of a given that over the course of your life, you'll lose your hearing to some degree. But that doesn't necessarily have to be the case. Your intestine can re-create itself every five days or so, and there's a science there that can (hopefully) be applied to other parts of the body. Chris Loose is a Hertz Foundation Fellow, working amongst a group of fellows and researchers who are looking at regenerative tissue and making it a reality not just for your hearing but perhaps for other parts of the body as well. We could be in for a regenerative future—and perhaps one where we can live to be well over 100 and still look like we're 22. The Hertz Foundation mission is to provide unique financial and fellowship support to the nation's most remarkable PhD students in the hard sciences. Hertz Fellowships are among the most prestigious in the world, and the foundation has invested over $200 million in Hertz Fellows since 1963 (present value) and supported over 1,100 brilliant and creative young scientists, who have gone on to become Nobel laureates, high-ranking military personnel, astronauts, inventors, Silicon Valley leaders, and tenured university professors. For more information, visit hertzfoundation.org.
Young people could even end up less anxiety-ridden, thanks to newfound confidence
- The coronavirus pandemic may have a silver lining: It shows how insanely resourceful kids really are.
- Let Grow, a non-profit promoting independence as a critical part of childhood, ran an "Independence Challenge" essay contest for kids. Here are a few of the amazing essays that came in.
- Download Let Grow's free Independence Kit with ideas for kids.
New research establishes an unexpected connection.
- A study provides further confirmation that a prolonged lack of sleep can result in early mortality.
- Surprisingly, the direct cause seems to be a buildup of Reactive Oxygen Species in the gut produced by sleeplessness.
- When the buildup is neutralized, a normal lifespan is restored.
We don't have to tell you what it feels like when you don't get enough sleep. A night or two of that can be miserable; long-term sleeplessness is out-and-out debilitating. Though we know from personal experience that we need sleep — our cognitive, metabolic, cardiovascular, and immune functioning depend on it — a lack of it does more than just make you feel like you want to die. It can actually kill you, according to study of rats published in 1989. But why?
A new study answers that question, and in an unexpected way. It appears that the sleeplessness/death connection has nothing to do with the brain or nervous system as many have assumed — it happens in your gut. Equally amazing, the study's authors were able to reverse the ill effects with antioxidants.
The study, from researchers at Harvard Medical School (HMS), is published in the journal Cell.
An unexpected culprit
The new research examines the mechanisms at play in sleep-deprived fruit flies and in mice — long-term sleep-deprivation experiments with humans are considered ethically iffy.
What the scientists found is that death from sleep deprivation is always preceded by a buildup of Reactive Oxygen Species (ROS) in the gut. These are not, as their name implies, living organisms. ROS are reactive molecules that are part of the immune system's response to invading microbes, and recent research suggests they're paradoxically key players in normal cell signal transduction and cell cycling as well. However, having an excess of ROS leads to oxidative stress, which is linked to "macromolecular damage and is implicated in various disease states such as atherosclerosis, diabetes, cancer, neurodegeneration, and aging." To prevent this, cellular defenses typically maintain a balance between ROS production and removal.
"We took an unbiased approach and searched throughout the body for indicators of damage from sleep deprivation," says senior study author Dragana Rogulja, admitting, "We were surprised to find it was the gut that plays a key role in causing death." The accumulation occurred in both sleep-deprived fruit flies and mice.
"Even more surprising," Rogulja recalls, "we found that premature death could be prevented. Each morning, we would all gather around to look at the flies, with disbelief to be honest. What we saw is that every time we could neutralize ROS in the gut, we could rescue the flies." Fruit flies given any of 11 antioxidant compounds — including melatonin, lipoic acid and NAD — that neutralize ROS buildups remained active and lived a normal length of time in spite of sleep deprivation. (The researchers note that these antioxidants did not extend the lifespans of non-sleep deprived control subjects.)
Image source: Tomasz Klejdysz/Shutterstock/Big Think
The study's tests were managed by co-first authors Alexandra Vaccaro and Yosef Kaplan Dor, both research fellows at HMS.
You may wonder how you compel a fruit fly to sleep, or for that matter, how you keep one awake. The researchers ascertained that fruit flies doze off in response to being shaken, and thus were the control subjects induced to snooze in their individual, warmed tubes. Each subject occupied its own 29 °C (84F) tube.
For their sleepless cohort, fruit flies were genetically manipulated to express a heat-sensitive protein in specific neurons. These neurons are known to suppress sleep, and did so — the fruit flies' activity levels, or lack thereof, were tracked using infrared beams.
Starting at Day 10 of sleep deprivation, fruit flies began dying, with all of them dead by Day 20. Control flies lived up to 40 days.
The scientists sought out markers that would indicate cell damage in their sleepless subjects. They saw no difference in brain tissue and elsewhere between the well-rested and sleep-deprived fruit flies, with the exception of one fruit fly.
However, in the guts of sleep-deprived fruit flies was a massive accumulation of ROS, which peaked around Day 10. Says Vaccaro, "We found that sleep-deprived flies were dying at the same pace, every time, and when we looked at markers of cell damage and death, the one tissue that really stood out was the gut." She adds, "I remember when we did the first experiment, you could immediately tell under the microscope that there was a striking difference. That almost never happens in lab research."
The experiments were repeated with mice who were gently kept awake for five days. Again, ROS built up over time in their small and large intestines but nowhere else.
As noted above, the administering of antioxidants alleviated the effect of the ROS buildup. In addition, flies that were modified to overproduce gut antioxidant enzymes were found to be immune to the damaging effects of sleep deprivation.
The research leaves some important questions unanswered. Says Kaplan Dor, "We still don't know why sleep loss causes ROS accumulation in the gut, and why this is lethal." He hypothesizes, "Sleep deprivation could directly affect the gut, but the trigger may also originate in the brain. Similarly, death could be due to damage in the gut or because high levels of ROS have systemic effects, or some combination of these."
The HMS researchers are now investigating the chemical pathways by which sleep-deprivation triggers the ROS buildup, and the means by which the ROS wreak cell havoc.
"We need to understand the biology of how sleep deprivation damages the body so that we can find ways to prevent this harm," says Rogulja.
Referring to the value of this study to humans, she notes,"So many of us are chronically sleep deprived. Even if we know staying up late every night is bad, we still do it. We believe we've identified a central issue that, when eliminated, allows for survival without sleep, at least in fruit flies."
We must rethink the "chemical imbalance" theory of mental health.
- A new review found that withdrawal symptoms from antidepressants and antipsychotics can last for over a year.
- Side effects from SSRIs, SNRIs, and antipsychotics last longer than benzodiazepines like Valium or Prozac.
- The global antidepressant market is expected to reach $28.6 billion this year.
Philosophers like to present their works as if everything before it was wrong. Sometimes, they even say they have ended the need for more philosophy. So, what happens when somebody realizes they were mistaken?
Sometimes philosophers are wrong and admitting that you could be wrong is a big part of being a real philosopher. While most philosophers make minor adjustments to their arguments to correct for mistakes, others make large shifts in their thinking. Here, we have four philosophers who went back on what they said earlier in often radical ways.
Or is doubt a self-fulfilling prophecy?