All posts by pberline

Your Cells Have Antennas: Cilia’s Role in Health

We tend to think of our cells as big blobby things.

But floating around the inside of our cells, is cell cycle machinery constantly regulating growth and repair signals.

One organelle called the lysosome acts like a tiny garbage can, a small membrane bound sac containing highly acidic degradative enzymes inside the cytoplasm. Lysosomes can inform the rest of the cell of its intracellular and extracellular milieu, and trigger pathways to help the cell adapt to emerging conditions.

Outfitted with pervasive sensing cilia and microtubules, the lysosome organelles are constantly sensing the microenvironment.

Now science is discovering that far from being passive, these lysosome organelles appear to signal inside out to the surface of the cell.

In the high tech world of Silicon Valley “pervasive sensing” is a familiar concept, and driving force behind today’s trends in automation as well as the Internet of Things (IoT). Robots equipped with sensors on the factory floor can for example send signals, alerting technicians that a damaged part needs repair.

The body may also come equipped with the biological equivalent of pervasive sensing equipment.

Sitting on the cell’s surface, microscopic cilia are tiny pervasive sensors that sense growth factors and nutrients. By activating an important growth pathway called the mechanistic target of rapamycin (mTOR), these tiny microtubule signals tell the cell when to get big, and divide.

A central regulator of human metabolism and physiology, the mTOR pathway is considered to be a major axis involved in aging. mTOR helps regulate the liver, muscle, adipose tissue, and the brain, and is dysregulated in diseases such as diabetes and certain cancers.

mTOR works closely with lysosomes, the small vesicles that help our cells take out the trash. Signals travel between the mTOR growth axis and our cells via a mechanism or signaling pathway involving microtubules and cilia.

In lungs epithelial cells in the airway are ciliated with multiple motile cilia. Motile cilia make a swishing motion to move fluid or clear debris. The presence of cilia in the respiratory track is critical for normal lung function, and alterations in these motile cilia contribute to the development of pathologies such as chronic bronchitis, or Acute Respiratory Distress Syndrome (ARDS).

But there’s also another type of cilia called immobile cilium. While we may be less familiar with these cilia their signals may be important. According to Dr. Jon Lieff, author of “The Secret Language of Cells”, although first observed in 1887 these primary or immobile cilia have been difficult to study because they are ten thousand times smaller than a human cell.

Scientists believe that these immobile cilia sit on the surface of cells, and can act as nutrient-sensing antennas. When amino acids and sugars are present in the blood stream, the cilia senses the exterior environment and knows that it is safe for the cell to divide. If nutrients are scarce, the cilia can signal to the cell to switch into a quiescent mode, stop dividing and growing, and instead focus on repair.

Inside the cell, the lysosome serves as a platform to assemble signaling hubs, on its surface. An aging pathway, the hormone axis mTORC1 uses the lysosome garbage can as a docking station, to lock on to and activate growth.

If sufficiently low levels of growth signals are present, and if mTOR is deactivated and undocked, the lysosome will signal to the cell to “switch on” autophagy or self-eating. In this quiescent or standby mode, autophagy is used to repair damaged components like misfolded proteins or defective mitochondria.

The mechanistic target of rapamycin (mTOR) pathway regulates cell growth and enlargement, and has been found to be aberrant in a wide variety of malignancies.  

Scientists are now learning that more than acting as a passive blobby garbage can, the lysosome is more like a command center mTOR docking station sending signals to the cells’ surface antennae. Acting as a central processing unit of the cell, the lysosome triggers microtubules to grow.

Nutrients (proteins and sugars) are players in delivering a “go-no go” signal to the mTOR complex to be activated, and dock onto the lysosome. This cell cycle machinery can be observed in a video of fluorescent died lysosomes that move from the cytoplasm onto the lysosome or garbage can membrane wall.     

When nutrients are scarce, autophagy delivers cytoplasmic cargo to lysosomes rather than extracellular cargo. Generally, surplus organelles, damaged organelles, protein aggregates, and free bacteria that escape phagosomes are targeted for autophagy.

In a catabolic state (when nutrients are scarce) mTOR will undock itself from the lysosome’s outer membrane. mTOR is deactivated by sensing a lack of amino acids such as leucine in the bloodstream.

Once dismissed as garbage cans, these tiny organelle lysosomes appear to be integrating extracellular signaling important to healthy cell cycle, and metabolism.

Autophagy, ketogenic diets, and measuring telomeres has grabbed headlines as a way to maintain health.

But the lysosome acting as a central processing unit coordinating healthy cilia signals may play an underlying role, regulated by nutrition.

Something as innocuous as protein and type of protein consumed in the diet could control when mTOR finds the “off” switch, to signal the body to switch to repair.

“Pile on the protein” is popular nutrition advice given to patients.

Eating to maintain muscle keeps the body strong and yet the molecular science cells a different story.

Scientists studying the mTOR complex point out that nutrient-sensing cilia vital to regulating homeostasis appear to be highly attuned to levels of protein in the bloodstream. Acting as tiny antennae cilia signals are constantly sensing the microenvironment and use nutrition (especially certain proteins) as an”on” and “off” switch for repair.

Like motile cilia in the lung that constantly clear out debris, these immobile cilia appear to be active players in health. How to keep cell cycle machinery working and protein’s role, may warrant further investigation.

       

Even Without Steroids, Cancer Patients Experience Less Chemo Side Effects on Fasting Mimicking Diet

In 1971 President Nixon declared a “War on Cancer”, and signed the National Cancer Act on December 23, 1971. Since the early 70s the focus in cancer research has been on drug development, as well as early preventative screenings.

But a somewhat eyebrow raising trend in cancer treatment, is exploring ways to treat certain cancers by combining standard of care therapies and nutritional intervention. Based on decades of aging research, nutritional pathways in the body are used in a targeted way to impact the cancer patient microenvironment and oncogenes. Early human pilot studies are testing whether a few days of fasting with food, followed by refeeding can make chemotherapy more targeted and less toxic.

A recent study investigated whether the fasting mimicking diet (FMD) influenced the toxicity or effectiveness of chemotherapy in women with early-stage breast cancer. The fasting mimicking diet is a four-day meal replacement designed to provide vital nutrients. The FMD triggers the body to switch from an anabolic (growth state) to catabolic (repair state) metabolism, and for cells to enter into a protected state.

The authors of the randomized controlled study assigned 131 women with stage II/III breast cancer to receive either a low calorie fasting mimicking diet or their regular diet three days before and throughout neoadjuvant chemotherapy.

Chemotherapy administered to shrink a tumor prior to surgery is known as neoadjuvant chemotherapy.

Researchers observed that women on the FMD were more likely to experience a 90 to 100 percent tumor cell loss as compared to women on a regular diet. Patients on the FMD had less DNA damage in T-lymphocytes from chemotherapy than those on the regular diet.

A fasting-mimicking diet (FMD) combined with chemotherapy resulted in a 300-400% increase in the chance of killing 90-100% of cancer cells in women with breast cancer. DNA damage in T-cells was less in patients who received the FMD with chemotherapy.

Interestingly, a steroid Dexamethasone was not given to the FMD group. But there was no difference in toxicity between both groups.

Dexamethasone is an antiemetic drug, belonging to a class of drugs that is effective against vomiting and nausea. Antimetics are typically used to treat motion sickness and the side effects of general anaesthetics and chemotherapy directed against cancer. Administering steroids is a standard practice to help chemotherapy patients stave off naseau and handle chemo side effects.

According to the study: “This suggests that the FMD may obviate the need for dexamethasone in the prevention of the side effects of chemotherapy. Importantly, DNA damage in T-lymphocytes was less in patients who received the FMD in combination with chemotherapy compared to those receiving chemotherapy while on a regular diet, suggesting that the FMD protected these cells against the induction of DNA damage by chemotherapy.”

Steroids like dexamethasone are routinely given to cancer patients directly following chemotherapy, but also can trigger serious spikes in insulin.

Typical cancer dietary guidelines encourage chemo patients to consume a high protein diet to combat malnutrition or muscle wasting.

Only normal weight patients were involved in this study to guard against cachexia or muscle wasting. Fasting faces the challenge of going against nutritional guidelines in cancer therapy that are deeply entrenched. And patient compliance in this study was problematic, indicating that patients may need to be followed carefully or supported by a dietician in future larger mult-site studies still in the planning stage.

For now, this cutting edge pilot trial suggests that for certain cancers at least new nutritional, and even steroid administration options, could be on the horizon.



5 Mind-Blowing Medical Breakthroughs You Might’ve Missed During Covid

These days the media focus is on all things virus, catching a virus, and how to treat a virus. So you’d be forgiven if you missed some important news in science. But here’s five exciting breakthroughs that went under the radar:

ONE – No “Blood Boys” or Younger Donors Required for Healthy Aging

In the hit TV series HBO’s Silicon Valley, tech oligarch Gavin Belson receives blood transfusions from a young donor. “Blood boys” is both a biohack and social meme, a slightly creepy way to defy aging.

Back in 2005, a UC California, Berkeley research lab made conjoined twins by sewing together an old and a young mouse – each mouse shared blood and organs. The blood from the young mice seemed to rejuvenate tissues in the old mice.

The 2005 study sparked the idea of parabiosis that young blood might contain special proteins that could act as a “fountain of youth’. San Francisco based startup Ambrosia began offering an $8,000 procedure involving transfusion of blood plasma from a young donor.

Now according to lead researcher Irina Conboy, her lab has upended the idea that young blood slows aging. In a new experiment, simply diluting blood plasma in old mice reversed aging in the brain, liver, and muscle.

In this new experiment, the breakthrough came from testing out a new mini dollhouse-size plasma exchange device, specially built for the mice. Old mice had half of their plasma replaced with a saline and albumin mixture.

According to Conboy, the study suggests there’re proteins in old blood that are responsible for accelerating aging.

The plasma exchange lowers the concentrations of many pro-inflammatory proteins which increase with age while enabling a rebound in beneficial proteins which improve new blood vessel growth.

Today plasma exchange can be done by Therapeutic Plasma Exchange (TPE) a well-established medical procedure and FDA-approved.

TWO – Forget Light, Dark – Liver Clock Tied to Disease Risk Factors

There’s a circadian clock in your brain, regulated by light and dark cycles. But the body also has a circadian clock in the liver and when we eat may drive risk factors for cardiometabolic disease.

Time restricted eating in a ten hour window (7am to 7pm for example) in a pilot study, was found to be an effective adjuvant treatment to treat metabolic syndrome. In the clinical trial, patients were put on medication to treat hypertension or statins for cholesterol, but were still eating in a 14 hour window.

After switching to a ten hour eating window, patients’ metabolic markers and disease risk factors improved. Time restricted eating (TRE) is now being tested in the clinical setting as an “add-on” to pharmacological treatment for diseases like hypertension and diabetes.

THREE –  Cytokine Storms When Exercise-Induced, Improve Fitness

Interleukin 6 (IL-6) is used as a biomarker of inflammation and to guage disease progression in Covid patients. But sports science is now learning that IL-6 acts as a double-agent cytokine.

IL-6 had previously been classified as a proinflammatory cytokine. But now researchers are learning that in the context of exercise IL-6 can also serve an anti-inflammatory role through rapid activation of an anti-inflammatory cytokine know as IL-10.

Exercise turns on the body’s own anti-oxidant system. Our body’s anti-oxidant pathway is a hundred times more powerful than any antioxidant that you could take in a pill.

We’ve all been told to megadose antioxidants to boost our immune system, but this health myth is now getting upended by sports science researchers. According to early pilot studies involving elite athletes, taking a pre-workout (especially Vitamin E) before a gym session may blunt some of the benefits of exercise.

FOUR – Fasting and Cancer Clinical Trials Expand from Mice to Humans

In a recent study, a fasting-mimicking diet (FMD) combined with chemotherapy resulted in a 300-400% increase in the chance of killing 90-100% of cancer cells in women with breast cancer. DNA damage in T-cells was less in patients who received the FMD with chemotherapy.

Fasting may impact the same genes that control cancer. Proto-oncogenes function as key negative regulators of the protective changes induced by fasting. Scientists’s hypothesis is that cells expressing oncogenes, and therefore the great majority of cancer cells, can’t respond to the protective signals generated by fasting.

Normal healthy cells can switch to maintenance pathways, and stop trying to grow during fasting. But some cancer cells may be addicted to consuming sugar. Cancer cells will continue trying to divide as much as possible, even when nutrients are scarce.

In the 1930s Otto Warburg proposed that damaged mitochondria and an altered metabolism are a hallmark of cancer. Human clinical trials are now hoping to find if for certain cancers, lowering sugars and proteins can make cancer more vulnerable to chemotherapy treatments.

FIVE – Using Stem Cells To Transport Mitochondria

In the movie Replica a genetic scientist played by Keanu Reeves, uses embryonic stem cells to re-grow his family in the garage.

But not all stem cells are about regenerating tissue. With Covid19 a different type of stem cell is coming into focus, the mesenchymal stem cell.

Mesenchymal stem cells (MSCs) can secrete growth and repair factors. But it’s now been observed using electron microscopy, that an MSC can make cell-to-cell contact with a damaged lung cell, project a small microtubule out of its cell wall, and via this microscopic tube transport healthy mitochondria to rescue damaged lung cells via cell to cell contact and tiny nanotubes.

This isn’t the first time nanotubes have been observed transporting materials in between cells, in cell to cell contact. Science has known that natural killer Tcells dock on to cancer cells to use tiny tubes to insert killer toxins, and kill them. And now a nanotubule has been observed extending from a mesenchymal stem cell, and transporting stemy new mitochondria into a damaged lung cell.

MSC stem cells reside in the niche in bone marrow. Normally, these stem cells lie in a dormant state.  When the body has been injured, the mesenchymal stem cell “homes” to the site of injury and secrets growth factors to help injuries heal.

A study headed by Dr. Bhattacharya at Columbia University, observed MSCs injected into lungs attached directly to alveolar epithelium. Scientists observed a delivery of mitochondria from MSCs to the injured alveolar epithelium. The MSCs fix mitochondria and restore normal ATP levels, surfactant release, and fluid transport in the lungs.

In the clinic setting, MSCs are typically used to repair orthopedic injuries like a torn rotator cuff. Using MSCS to do cell-to-cell contact is fairly new.

A Phase 1/11 Trial of MSC for Severe ARDs, is currently underway to test the safety of giving Covid19 ARDS patients three different doses of mesenchymal stem cells, to repair lungs and mitochondria damage.

Why This Chemotherapy Ward Includes a Gym

Putting a gym in a chemo ward at first blush, may sound out there.

But in a groundbreaking move, at the Edith Cowan University Cancer Clinic in Perth, Australia researchers located the gym (exercise medicine care clinic) directly next to the chemotherapy suites.

On chemo or radiation days, patients book into the exercise clinic and then go directly from hospital to workout.

And patients aren’t doing just gentle walking, but intense short bursts of weight lifting or jumping, following radiation or chemotherapy. Each cancer patient meets with an exercise physiologist to go through exercises, specifically customized to their tumor or cancer type.

One of the ideas behind exercise medicine for cancer patients is based on tumorogenisis. Tumors grow rapidly, sometimes developing pockets with no functional blood vessels.

By increasing blood flow to tumors, exercise is thought to help drive chemo into the tumors. Working out might also make it easier for our own immune system, to move in and destroy cancer cells.

Typically a cancer patient will lose 10% to 15% of lean body mass during chemo or radiation treatment.

Exercise as medicine had previously been used only after chemotherapy to rehabilitate patients. Oncologists were wary about asking patients to workout directly before or after chemo and radiation treatments.

But science is now learning that precision exercise can help the body maintain muscle, if highly personalized to the cancer, tumor type, and stage of treatment.

“What’s quite astounding is that a patient [with stage three breast cancer] increased her muscle mass during chemotherapy,” explains Professor Robert Newton of Edith Cowan University.

“Bodyweight squats or step ups can have a very large impact on the body,” says Newton. Even ten minutes of intense effort counts and could help make chemotherapy treatment targeted in two important steps:

Step One: Stimulate Immunosurveillance

Science has known that among our white blood cells killer T-Cells are hunting down and killing cancer cells floating around in the body. T-Cells are immunotherapy anti-cancer medicine as evidenced in this microscopic video showing a T-cell in action, hunting down a cancer cell.

According to Professor Newton dovetailing off the way immunosurveillance seems to kill cancer, exercise for cancer patients aims at recruiting the help of the Natural Killer (NK) cell.

Natural killer (NK) cells are the most responsive immune cells to exercise, and seem to mobilize during physical exertion. Exercise-dependent mobilization of NK cells might improve NK recruitment and infiltration in solid tumors.

Step Two: Increase blood flow to Hypoxic Tumors

Tumor cells divide rapidly, and this can create a messy blood supply system with areas of hypoxia. Hypoxia, or low oxygen condition, is a normal physiological response to certain body stressors such as high altitudes. Tumor cell hypoxia results from an imbalance between the oxygen supply available and the oxygen consumption of the rapidly dividing cells.

 “One of the biggest issues with improving delivery of chemotherapy to solid tumors is that only about half of the blood vessels are functional and mature enough to deliver the drugs,” explains Keri Schadler, Ph.D., an expert in cancer tumors at MD Anderson.

By increasing blood flow in the body, the hypothesis is that precision exercise can help get chemotherapy to the places that need it most. Chemo is a blunt instrument, but exercise administered by an exercise physiologist in coordination with the oncologist is precisely tailored. And cytokines or other growth factors released by exercise may help the body’s natural immunosurveillance system find tumors.

Although the exact mechanisms aren’t well understood, early clinical trial data indicates that exercise is doing more than helping cancer patients ward off nausea. Pilot studies in Australia and Sweden and a few early clinical trials are just beginning in the U.S.

Recently Newton told Australia’s ABC news radio, other than in Australia and Sweden, cancer management is behind where the research is.

The problem according to Professor Newton is the way oncologists are currently prescribing exercise to their patients. What type of cancer and where tumors are located matters. He sees little benefit from telling a cancer patient to simply “get out there and move”.

Diluting Plasma Slows Aging, New Mouse Study Suggests

University of California, Berkeley researchers have recently published a mouse model study that shows age-reversing effects can be achieved by diluting the blood plasma of old mice.

In 2005, University of California, Berkeley, researchers made a surprising discovery by stitching together a young and and old mouse like conjoined twins. Sharing blood and organs between the mice, scientists rejuvenated tissues and reverse the signs of aging in the old mice.

This conjoined twin mouse model study led to the idea that young blood contains special proteins, which deliver a ‘fountain of youth’ effect. And biohackers got the idea that getting transfusions from young donors aka “blood boys” could slow aging.

Problem is mouse studies are not a strong signal and exploratory. A follow on mouse model study conducted by the same research team, now shows simply diluting the blood plasma of old mice achieves age reversing effects.

Here’s how parabiosis became a thing:

Early 2000s – Senior researcher and professor of bioengineering Irina Conboy and Michael Conboy have a hunch that our body’s ability to regenerate damaged tissue remains with us into old age in the form of stem cells. But that somehow these cells get turned off through changes in our biochemistry as we age.

2005 – Conboy lab publishes study showing that making conjoined twins from the old mouse and a young mouse reversed many signs of aging in the older mouse. Many researchers seized on the idea that specific proteins in young blood could be the key to unlocking the body’s latent regeneration abilities.

2016 – a second follow-up study finds young blood does not reverse aging in old mice. Tissue health and repair dramatically decline in young mice when half of their blood is replaced with blood from old mice.

The study suggests to Irina Conboy that young blood by itself will not work as effective medicine. Rather the idea that emerges is that inhibitors in old blood could be a target to reverse aging.

In this 2016 study, Conboy and colleagues developed an experimental technique to exchange blood between mice without joining them so that scientists can control blood circulation and conduct precise measurements on how old mice respond to young blood, and vice versa.

In the new system, mice are connected and disconnected at will, removing the influence of shared organs or of any adaptation to being joined. One of the more surprising discoveries of this study was the very quick (within 24 hours) onset of the effects of blood on the health and repair of multiple tissues, including muscle, liver and brain.

June, 2020 – A new study finds that diluting blood in old mice by replacing half of the plasma with a saline and albumin mixture was able to reverse aging in the brain, liver, and muscle.

In a press release statement Irina Conboy, a professor of bioengineering at UC Berkeley who is the first author of the 2005 mouse-conjoined twins paper and senior author of the new study explains the results:

“There are two main interpretations of our original experiments: The first is that, in the mouse joining experiments, rejuvenation was due to young blood and young proteins or factors that become diminished with aging. But an equally possible alternative is that, with age, you have an elevation of certain proteins in the blood that become detrimental, and these were removed or neutralized by the young partners.”

In the years since the exploratory 2005 study, scientists have spent millions to investigate the potential medical properties of youthful blood with enterprises emerging to infuse old people with young blood.

“What we showed in 2005 was evidence that aging is reversible and is not set in stone,” Irena Conboy said in a UC Berkeley press release. “Under no circumstances were we saying that infusions of young blood into elderly is medicine.”