UPDATE: MECHANISM OF AGING THEORY

UPDATE: MECHANISM OF AGING THEORY

One more evidence

DKFZ The German Cancer Research Center is Germany's largest biomedical research institute with a thousand scientists. On 20th June 2018 they reported a discovery in the field of aging. I will quote some of what they report: 'Oxidative stress causes cells and entire organisms to age. If reactive oxygen species accumulate, this causes damage to the DNA as well as changes in the protein molecules and lipids in the cell. The cell ultimately loses its functionality and dies. Over time, the tissue suffers and the body ages. "The theory of oxidative stress or the accumulation of reactive oxygen species as the cause of aging has existed since the 1950s," says Peter Krammer of the German Cancer Research Center (DKFZ). "So far, however, the details of this process were unclear."

One way in which the body disposes of harmful reactive oxygen species is their conversion by the enzyme thioredoxin-1 (TRX-1). TRX-1 has been proven to play a role in protecting DNA from oxidative stress and slowing down aging processes. Its antagonist TXNIP inhibits thioredoxin-1 and thus ensures that the reactive oxygen molecules are retained.

In fact, reactive oxygen species (ROS) do more than just damage the body. For example, they are essential for the T-cells of the immune system to become active.' So ROS is also beneficial in the right proportion. The key is for excess ROS to be processed away before it can become harmful. But inversely, too much TRX-1 can impair critical immune related activity triggered by ROS. As I have stated in my earlier blog post called 'Mechanism of Aging' Nature modulates levels by using agonist and antagonists. It's like a hot water tap and a cold water tap and one can adjust their output to get water at just the right temperature. Where water represents repair pathway. Excess of either cold or hot can make it painful and harmful for us. Just the right temperature is called homeostatic state in our biology. 

When we are young the agonists Trx1 and antagonists TXNIP maintain just the right levels of ROS. But as per theory proposed in my earlier post ' Mechanism of Aging' Nature selectively increases the levels of antagonists as we age in a progressive manner. This begins to progressively increase the levels of ROS. To continue with my comparitive example it's like cold water is drowned out by increasing levels of hot water. At one point it begins to scald. That is what happens with uncontrolled ROS damaging for example DNA to a scale at which DNA's repair enzymes can't keep up. Nature by the way also modulates DNA repair systems with agonist and antagonist molecules. DNA repair is activated by PARP1 whose antagonist is DBC1 and agonist is NAD+. So can you see a pattern emerging here? TXNIP domination over TRX-1 as we age leads to rising ROS levels. One of the damage excessive ROS causes is to DNA. But as we age and just when DNA needs it most DBC1 levels also begins to dominate over NAD+ levels. So ROS causes more DNA damage just when less and less repair enzymes are available to repair it. Mounting unrepaired DNA damage then leads to rising mutations and genomic instability. 

I am excited by the DKFZ findings as it corroborates the theory proposed in mechanism of aging post on this blog of how aging program is implemented in our body. What you read above is happening in all major repair pathways and it snowballs progressively making death unavoidable. But what would happen if we selectively upregulate the dwindling agonists of repair? In the case of upregulation of NAD+ David Sinclair's lab at Harvard Medical School showed that DNA repair markers improved. Similarly the DKFZ researchers led by Krammer and Gülow wanted to know whether more TXNIP is formed in the body with increasing age, thereby undermining the protective mechanism against oxidative stress. To this end, they first compared T cells from the blood of a group of over 55-year-old volunteers with the T cells of younger blood donors, who were between 20 and 25 years old. In fact, it turned out that the cells of older subjects produce significantly more TXNIP. The DKFZ scientists have also observed similar findings in other human cell and tissue types. They also found TXNIP levels similarly much higher in older flies. Upregulation of TRX-1 would balance out the higher levels of TXNIP thereby forestalling the damaging chain reaction of rising ROS levels.
Another Evidence:
Autophagy is a very important repair and recycling pathway. With aging this too progressively goes down in efficiency leaving more and more senescent cells. It's importance can be gauged by the $307 million raised by Unity Bio based on pre-clinical data about a molecule that can clear senescent cells. One of their investors is now the world's wealthiest man Jeff Bezos founder of Amazon.
As cells die autophagy recycles the dead cells into new cells and clears debris. If this doesn't happen efficiently, aging humans are left with dead zombie cells (senescent cells) that secrete damaging cytokines harming surrounding healthy cells leading to mounting damage in tissues and organs.
Alvaro Fernandez and Salwa Sebti along with colleagues at University of Texas Southwestern Medical Center, USA published a study in Nature Journal on 30th May 2018. As per theory of mechanism of aging posted on this blog there is negative regulator of autophagy - antagonist called BCL2. It interacts with Beclin 1 a regulator of autophagy and apoptosis and blocks autophagy. As we age guess what happens. BCL2 increases it's interaction with Beclin 1. When the scientists disrupted this interaction between them it increased autophagy. Just bringing up one major repair and recycling pathway back to youthful levels not only increased healthspan but also lifespan. 

Now as promised I am sharing very good news for all who wished us luck for our pre-clinical trials mentioned in the post Mechanism of Aging: We have the results of a 2 month study where we selectively administered natural molecules and compounds that upregulate major known repair pathways. First of all safety tests cleared with flying colors histopathologist could not distinguish between young and treated old tissues. The main trial results were also spectacular: chronic inflammation of treated old rats reversed all the way back to levels of young control rats! Muscle strength - grip strength of old treated rats went up almost reaching young control rats! And cognitive skills - memory test scores of old treated rats were close to young control rats! The old treated rats lost weight despite having same amount of feed as old untreated rats! There was a wide difference between the levels of old treated rats and old untreated rats. If these are some of the key markers of aging did we reverse the age of old treated rats back to youth? It was equivalent of a 70 year old developing the metabolism, strength and memory of a 20 year old. Does it prove the theory of how Nature implements it's aging program? The anti aging benefit derived by rapamycin and metformin are limited and triggered only in a narrow range as it is a hormetic intervention. Anti aging benefits derived by resettng gene expression which has been methylated by aging changes to the epigenome theoretically may not be restricted by a narrow bandwidth. We have to find out over hundreds of studies whether this can be the fountain of youth we have been searching from thousands of years. Now on to human clinical trials. Please wish us luck.

HORMESIS: CAN BOOST YOUR HEALTHSPAN TODAY

Hormesis is evolutionarily conserved stress response. No other anti aging therapy has shown beneficial results in humans so far except Hormetic interventions like Calorie Restriction, prolonged fasting, intermittent low dose rapamycin and metformin. 
We come across all kinds of stress on a daily basis like UV radiation, very hot or cold exposure, prolonged hunger, high intensity exercise, etc. Our body has adaptive genes that activate boosters to cope with these minor stress events and minimize damage to the system. At a sweet spot of the amount of stress Hormesis leads to house cleaning with activation of autophagy and mitophagy. This recycles senescent cells and leads to mitogenesis. It also activates Nrf2 which releases enzymes that reduce the burden of reactive oxygen species ROS amongst 200 other beneficial gene expressions. It protects against age related chronic disorders including diabetes, middle aged obesity, cardiovascular disease, cancer and neurodegenerative diseases (Mattson, 2008). This post is not a detailed study of hormesis but a layman's update about benefits of hormesis and how one can take advantage today. So there are many other beneficial hormetic actions but the above examples illustrate their purpose. It launches a cascade of renewal including stem cell renewal, release of beneficial enzymes and hormones (for example an oxytocin bath) and clean up of wastes which allows the system to use it's full resources to recover from the stress. For a more comprehensive understanding of hormesis please read posts on the blog 'Anti Aging Firewalls' by Vincent Giuliano. You can also read 'Hormesis, Adaptive Epigenetic Reorganization, And Implications For Human Health and Longevity' by Alexander Vaiserman published in 2010 in Dose Response. Hormetic response is only available against stress up to a certain threshold with regards to intensity and time. It has a sweet spot or narrow  range where it leads to an over compensation. The beneficial cascade not only helps recover from the stress but also then goes ahead and delivers system wide improvements. This over compensation is what provides all the anti aging benefits of hormesis.  Hormesis can also be seen in plants. For example when we boil raw peanuts or tomatoes their nutritive value increases in multiples. Although limited the benefits can be potent. All system wide anti aging successes seen so far in humans use hormesis. For example Calorie Restriction at identified levels creates a stress which triggers a hormetic response leading to all its studied benefits. Valter Longo director of University of Southern California Longevity Institute has published an amazing study which concludes that prolonged fasting of 7 days triggers a stem cell based repair and regeneration of our hematopoietic system. Similarly rapamycin is a poison which targets mTOR. Its inhibition due to a low intermittent dose leads to partial reversal of the damage caused by aging. mTOR is inversely related to many pathways involved in renewal and repair like Nrf2, AMPK, etc. From a different path Metformin also generates hormetic benefits. Diabetic patients on Metformin it has been found in large studies tend to outlive patients on other medicines and also non diabetics. Even the most popular health intervention exercise provides it's most powerful benefits due to hormesis. 
So can hormesis stop aging and increase lifespan. No. As we age our repair and renewal machinery begins to lose its efficiency gradually in a progressive manner. Hormesis provides boost to the repair and renewal systems. Regular use of it would slow down the loss of efficiency thereby reducing unrepaired damage and build up of senescent cells, cancer causing mutations and protein aggregates. This has shown to improve healthspan and help prevent diseases like middle age obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer, neurodegenerative disease, etc. This in turn may lead to reaching longer lifespan.  
I have started on rapamycin (Sirolimus) thanks to Dr. Alan Green (please web search for his name and rapamycin and it will lead to his website). On his website he has given his experience with rapamycin along with some very useful information about dosage, half life, strategy to avoid side effects, etc. He suggests 2 options conservative could be 3mg per 10 days. Aggressive would be 6mg per week. FDA states a elimination half life of 62 hours +/- 16 hours. So in a week it would be 2.7 half lives. If we take a shorter interval than it may lead to accumulation of the toxin which is not a good idea. Dr. Green as he says on his website ran a marathon in 4 hours at age 40 but by the time he reached 70 his physical activity was restricted to walking his dog. At age 72 he experienced angina and shortness of breath - his fasting blood sugar was high, creatinine was high and he could not fit in any of his pants. He discovered rapamycin and Koschei through Blagosklonny. He decided to take the aggressive approach. He shared that the results in 4 months were miraculous: he lost  20 pounds, his waist line went from 38 to 33 inches. He could walk 5 miles a day and ride bike over hills without angina. His blood sugar and creatinine went back to normal. He reported no side effects (no mouth sores). He felt from feeling old to feeling young. He has called rapamycin the world's greatest medicine. I have had a few exchange of messages with Dr. Green on an anti aging forum and can vouch that he is skeptical of all science unless it has shown replicable evidence. Someone younger may want to consider the conservative approach. Of course rapamycin and metformin both are prescription drugs and must be taken only after consulting your doctor. I personally started with 1mg and after 9 days taken 2mg and have now stabilized at 3mg. Also space weights training and other heavy exercise away from rapamycin days. It is important to do exercise as that too produces hormesis and allows us to make the most of taking rapamycin. Let me give you an example. In our middle age rogue macrophages block signal from our brain to our visceral fat cells to burn fat when we need energy for example during exercise. But when rapamycin benefits reconnect the signal it will not do any good unless we create an energy demand by doing intense exercise. With regards to Metformin one can create a hormetic effect every day whereas in the case of rapamycin there would be a tapering off between doses as part of the cycle. Not yet come across a study comparing the hormetic benefits between the two. Life Extension foundation has a good web page discussing metformin dosage for non diabetics at:
 http://www.lifeextension.com/Featured%20Articles/2003/8/Metformin%20Dosage/Page%2001 
They mention 500 mg twice a day for anti aging benefits for non diabetics but some scientists believe such benefits start only at 1,500 mg a day divided in 3 doses. To be noted that anyone having liver, kidney or congestive heart failure should not take this. One must also consider that no human trials have been done in either specifically for their anti aging benefits. That doesn't mean hormetic benefits are speculative but it leaves a gap with regards to ideal dosage for optimum benefits and safety. My personal opinion is not to take both rapamycin and metformin as too much of mTOR inhibition too is not good. When one does weights training one needs the growth with an activated mTOR. An article by Blagosklonny published in Aging 2010 cites two studies that show that inhibition of mTOR beyond a certain level causes depletion of male hormones which would adversely affect ones sex life. Therefore it may be better to have a cyclic intervention like rapamycin with a 10 day interval rather daily dose of metformin. One can investigate whether cyclic dosing of metformin provides similar benefits. I do take DHEA about 4 days away from rapamycin to make up for any deficiency in testosterone.  People as young as 35 are starting on one of the two to protect their future from age related diseases but one must avoid such mTOR inhibition in younger than 35. Many scientists wrongly believe that chronic inhibition of mTOR during aging leads to sustained anti aging benefits. Even when we are young mTOR swings between activation and inhibition based on its role as an important sensor. Insulin, cytokines, nutrients, and tesosterone stimulate cellular growth in part by activating the mTOR pathway. At puberty there seems to be optimum balance between mTOR activation for growth and mTOR inhibition for repair. As we age due to falling levels of repair the balance is lost which leads to over activation of mTOR. All we need is either intermittent activation of repair (a strategy my venture is pursuing) or intermittent inhibition of mTOR. Either action should lead to reduction of their imbalance. Which in turn should slow down the epigenetic drift - and in turn aging itself.
With regards to hormesis what is exciting though is that for the aging this system wide benefit is available today! One could begin to benefit immediately.
This is not a cure for aging or death but is still the most significant recourse available today for humans to improve old age. If we can slow down aging we may be alive when the cure for aging is discovered. In the future people will see old movies just to find out about the disease of old age and gasp at how horrible it made us look and feel. My venture to hunt for the cure just progressed further - We have a CTO who is a Professor of Natural Sciences from 23 years of a highly reputed USA University and we just signed a research collaboration agreement with a very highly reputed University for pre-clinical trials - 14 in all. We are awaiting Ethical Committee approval and hope to launch by first week of December. Wish us luck. We are developing nature or endogenous derived interventions that also inhibit mTOR like rapamycin and metformin but indirectly by upregulating or activating key repair pathways. It seems that Repair and activated mTOR are inversely related. Our interventions are expected to have amongst the highest upregulation of beneficial gene expressions available. On a separate note I was asked what will you look for if you were able to live longer. I said: Purity. The most prized human trait after unsolicited acts of kindness.

FDA APPROVED PROSCILLARIDIN A CAN BE USED AGAINST CANCER TODAY!

FDA APPROVED PROSCILLARIDIN A CAN BE USED AGAINST CANCER TODAY!

Reversing Epigenetic Silencing of Tumor Suppressor Genes

FDA approved Cardiac Glycosides for heart related ailments have turned out to be novel and exciting therapy for cancers which can be prescribed to you today by a knowledgeable and confident oncologist. 

I have recently become a fan of Dr. Jean-Pierre Issa of Temple University, USA. His recent paper on 'Caloric Restriction delays age related methylation drift' in Nature published on 14th September 2017 explains how the rate of changes in our epigenome as we age impacts our lifespan. Caloric Restriction slows that drift and so does rapamycin explaining their life extension benefits in humans.

In his earlier study published in Cancer Research in March 2016 called 'Targeting Calcium Signalling To Induce Epigenetic Reactivation Of Tumor Suppressor Genes in Cancer' Dr. Issa and his colleagues uncover the mechanism by which Cardiac Glycosides reverse epigenetic Silencing of Tumor Suppressor Genes. Dr. Issa screened 1,100 FDA approved drugs to find the ones that reversed the Tumor Suppressor Gene Silencing. They found 11 out of which Proscillaridin A a Cardiac Glycoside was the most potent. Surprisingly the action is effected through the calcium signalling pathway. When calcium levels rise above a certain threshold they activate a very interesting protein called Calmodulin. Calcium-Calmodulin Kinase activity leads to nuclear exclusion of MeCP2. Basically unlocking the promoter of Tumor Suppressor Genes and thereby increasing it's expression. As we age for unknown reasons certain beneficial gene expressions are silenced by methylation of their promoter region. Cells mutate every day and can turn into cancerous cells but Tumor Suppressor Genes eliminate them before cancers are formed.

Calmodulin

Interestingly Calmodulin also activates DNA repair and so does tumor suppressor genes. DNA mutation caused by unrepaired lesions is one of root causes of many age related dysfunctions and diseases. This just goes to show how cancer and aging are closely related in many ways. Finding such agents which can reverse detrimental epigenetic changes as we age can lead to the next wave of anti aging therapies that actually work in humans.

There are many studies that confirm the ability of Cardiac Glycosides to send cancers into remission. One example: published in Oncotarget 2014 'Proscillaridin A is cytotoxic for glioblastoma cell lines and controls tumor xenograft growth in vivo' by Figarella Branger and colleagues demonstrates that even at low intravenous doses Proscillaridin A a FDA approved Cardiac Glycoside resulted in cancer cell death, self-renewal blockade in all glioblastoma cell lines. Glioblastoma is difficult to treat and usually has relapses so these results are significant. Such results have been seen in breast and colon cancers as well in separate studies.

Proscillaridin A is plant derived. There are other natural herbs and spices which also have shown reverse silencing of Tumor Suppressor Genes. A Review Article by
Kitagashi, Kobayashi and Matsuda published in the Journal of Oncology in 2012 titled 'Protection Against Cancer With Medicinal Herbs via Activation of Tumor Suppressor' lists many herbs and spices like Honokiol, Curcumin, Klangaite, Thymoquinone,  Triptolide, Bsicalin and Trycosanthin which reactivate Tumor Suppressor Genes. As a reader pointed out these can be taken as preventive remedies as we age.

What is very exciting for cancer patients and the reason for my post is that Cardiac Glycosides like Proscillaridin A are approved by FDA (for heart related ailments) which means they have passed safety and efficacy standards. This means cancer patients can get this benefit today under medical supervision of their oncologist! 

CANCER & AGING: II. AGING STARTS AT 15 AND NOT 50!

CANCER & AGING: II. Aging Starts at 15 and not 50!

AGING: Two clues have emerged that shocked me with the realisation that aging starts just after puberty! These two studies also add two more evidences that aging is not due to accumulation of errors or wear and tear over time but due to direct missiles fired by pre-installed instructions just after the formation of reproductive organs. One of them collapses the support system to the protein formation machinery and the other attacks the heart cells. These are just two that have been discovered but there must many more such secret attacks that begin the process of deterioration of our biology.
After water proteins have the second highest weight in our body. There are probably more than 30,000 types of proteins that are manufactured from our DNA and the proteasome machinery that do multiple tasks including transcribing and translating instructions from our genes to our cells, act as hormones, enzymes and part of immune system. Proteins are born in long strips which are then folded into a particular shape. This shape decides it’s function. If there is misfolding it can become damaging. So nature has added multiple chaperones to help it fold correctly and if any still slip by then to avoid damage they are degraded by ubiquitin protease system and autophagy. Soon after puberty Germline Stem Cells GSCs send a signal to this important support machinery to collapse it’s efficiency by as much as 70%. This seems to be the first identified assault of aging. From then onwards more and more proteins come out misfolded and worst are not degraded so clump together to create sticky aggregates which disturb many cellular functions leading to damage and disease.

The ribosome makes mistakes in as many as 1 in every 7 proteins! Even under normal conditions, up to 30% of all cell proteins fail to fold properly, and are immediately degraded. Protein folding is a very sensitive process that is influenced by several external factors including electric and magnetic fields, temperature, pH, chemicals, space limitation and molecular crowding. These factors influence the ability of proteins to fold into their correct functional forms.
Scientists have pinpointed the start of aging and discovered it is not a slow series of random events. Two Northwestern University scientists have identified a molecular switch in the transparent roundworm C. elegans, that abruptly begins cell aging just as the animal reaches reproductive maturity.
A genetic switch starts the aging process by turning off the cell's ability to respond to stress. Responding to stress would otherwise protect a cell by keeping essential proteins folded as well as functioning. The switch is thrown by germline [sperm and egg] stem cells in early adulthood, after reproduction begins.
While the studies were conducted in worms, the genetic switch and other components identified by scientists as part of aging, are conserved in all animals — including humans. And as C. elegans has a biochemical environment similar to our own, it is a popular animal model for human disease and for human aging.
"Wouldn't it be better for society if people could be healthy and productive for a longer period of their lifetime? I am very interested in keeping the quality control systems optimal as long as we can, and now we have a target. Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress." said Richard Morimoto PhD, the Bill and Gayle Cook Professor of Molecular Biosciences, director of the Rice Institute for Biomedical Research, Weinberg College of Arts and Sciences, Northwestern University.
Once the germline has completed its job and 1) produced eggs and sperm needed to create the next generation, it 2) sends a signal to cell tissues to turn off protective mechanisms and begin the decline of the adult.
In one experiment, researchers blocked the germline from sending the signal to turn off cellular quality control, and found the somatic tissues remained robust and stress resistant.
Morimoto: "This was fascinating to see. We had, in a sense, a super stress-resistant animal that is robust against all kinds of cell stress and protein damage. This genetic switch gives us a target for future research."
Study’s finding that the loss of stress protection responsiveness in C. elegans is a result of failure to clear a single repressive chromatin modification, which interferes with a heat shock factor (HSF-1) binding event, which in turn suppresses transcription initiation in response to stress.
The molecular mechanism is particularly intriguing, as it involves a signal from germline stem cells that decreases expression of a specific demethylase enzyme, resulting in elevated levels of a repressive class of histones targeted to the genes for cell stress responses.  The consequence: a rapid, coordinated inhibition of stress survival mechanisms.”
Here again we see what I pointed out in my last post Mechanism of Aging - Nature's calibration happens through tuning of activators and inhibitors.
They demonstrate that HSF1-promoter accessibility sharply declines on the second day of adulthood. This is strongly associated with sharply increased levels of H3K27me3 marks at the promoters of heat shock genes, a hallmark of transcriptional repression [that results in dysfunctional protein production]. This demonstrates, for the first time, that the repression of the heat shock response is regulated, and that epigenetic changes modulate the animals’ ability to respond to stress after reproduction onset.” “discovered that enhancing this demethylase (jmjd3.1), which is conserved to humans, prevents this decline in stress resilience, and results in animals both robust and long-lived.”
In a separate study Lead author Dr Sean Byars from the University of Melbourne says the team wanted to understand more about how CAD (coronary artery disease) has been inherited in our evolutionary past, in order to better understand why it is so common presently. "CAD is often thought of as modern disease, but actually atherosclerosis, or thickening of the artery walls, has been detected in Egyptian mummies, so we suspect it has been in our genes for thousands of years."
CAD currently affects 110 million people and causes 8.9 million deaths annually, from 2015 figures.
"According to the theory of natural selection, as proposed by Charles Darwin, genes for traits that improve individual survival or reproduction will increase or be maintained in populations, whereas those that reduce these will be selected against and gradually removed or reduced over time. "So it is unclear why CAD is so common in modern humans and this is important to understand given the global health burden it represents," explains Dr Byars.
Associate Professor Michael Inouye, who also led the study, said the findings showed that many genes associated with CAD have actually been positively selected for through evolution.
"After further research, we found CAD genes are also important for reproduction and that these genes are involved in important functions in male and female fertility being expressed in the testes, ovaries and endometrium, for example," said Assoc Prof Inouye, based at the Baker Heart and Diabetes Institute.
So in this case too same genes which were important and beneficial during reproduction biology later flip a switch and become very harmful by causing CAD – the leading killer in humans.
These studies show that for Nature once the primary function of reproduction is done the body becomes only a competition for resources for the new born and is to be bumped off. What is shocking is that aging begins its damage just after we reach reproductive maturity – puberty. By the time we begin to see the effects of this build up of damage around 50 years of age it is already too late and a lot of the damage is done. Although this shows how complex is aging disheartening the anti aging crusaders, a clue also emerges: the changes that initiate the damage are actuated by new epigenetic marks. A permanent cure for aging may lurk in the corridor of the epigenome and the transcription factors.

CANCER & AGING: I. COMBINATION THERAPY - A COMPLETE CURE FOR CANCER?

CANCER & AGING: I. Combination Therapy – a complete cure for Cancer?

When I started deep research I used to regret not being a PhD because almost all scientists seem to be PhDs. But now I feel that it has been a blessing as it has allowed me to be able to view a research topic in 3D. Almost all PhDs specialise and narrow focus to create expertise in a particular niche. Nothing wrong with that and great discoveries have resulted from such an approach. But for working towards curing a disease ability to learn and analyze on a multifactorial basis it seems improves the chances of finding a cure rather than incremental benefit.
My thirst for knowledge and research continues to rise by every passing day it seems. In my leisure time if I have an option to either watch a movie, read a book or discover new music I end up choosing to research. Either thats where I get my highest pleasure or I have probably become a scientist in heat. Probably entering the last mile of a scheduled jump in clinical validation of my scientific discoveries.
In my research journey I continue to evolve my knowledge about a target and my own conclusions about it. So there are studies and there are studies but some become milestones after which we view the subject with new eyes like Sinclair’s NAD+, Conboy's parabiosis, Katcher's HPE and Hayashi's reversal of aging cells with glycine. Today I want to share two posts which cover studies which should have been ranked as major breakthroughs but may have been missed in the clutter.
My spotlight is on the two subjects I have done the most posts on this blog: cancer and aging. The irony is that both are highly related and are in fact two sides of the same coin. Unchecked growth can lead to cancer and systemic decay is a hallmark of aging. Let’s first look at cancer:
CANCER: Cure for cancer may emerge from a combination therapy of immunotherapy and blocking proteins that help cancer metastasis. Metastasis is behind 90% of cancer deaths. I have covered immunotherapy in my earlier post. Today I want to share a remarkable study:
Hasini Jayatilika a post doctoral researcher at John Hopkins came out with a brilliant conclusion: Metastasis occurs not after the tumour reaches a certain size as it is believed but due to tumour density. During a lecture while she was still studying at John Hopkins she saw a similar diagram regarding how bacteria proliferate. She tried to find some study in cancer showing that. Couldn’t find it so she took up that hunt herself. 7 years of research and she  demonstrated how after reaching a certain density tumour cells begin to release two proteins Interleukin 6 and Interleukin 8. They tell the new cancer cells that it is getting too crowded separate out and build your own nest at some other site. She observed this after studying the communications between cancer cells.

She and her Professor Denis Wirtz found out that all the cancer therapeutics were being built to target the primary tumour and no one was working drugs that could block the metastasis. They then themselves set out to test two already approved drugs which were known to work on the Interleukin receptors called Tocilizumab a rheumatoid arthritis treatment and Reparixin a potential cancer drug. When combined they seemed to significantly slow down the metastasis. Hasini feels that some tuning or another combination could potentially stop all proliferation completely. The amazing thing is that this may be applicable to all solid tumours. This is very good news for cancer patients as 90% of cancer deaths are caused by metastasis. My blog post “Goodbye Chemotherapy” already discussed how immunotherapy can attack only the cancer cells. But as I had pointed out in a following post about metastasis and mother cells – the cancer stem cells causing the lethal proliferation which may not be addressed by immunotherapy alone. With this combination therapy of immunotherapy and blocking of interleukin 6 and 8 proteins there might be complete cure which may prevent a relapse after clearance. All patients with solid tumours should talk to their doctors about the feasibility of prescribing this combination to put a break to any event of metastasis. Of course keep in mind that although both are approved drugs a combination therapy for metastasis has still not been approved by FDA. Another good news is that these drugs do not cause the horrible side effects of  chemotherapies. So a doctor may make their own decision based on patients parameters and each drugs safety profile. I rate this as a major breakthrough for cancer survival making Hasini a rock star hero for cancer patients worldwide.

MECHANISM OF AGING

                    MECHANISM OF AGING

                  Can we grow young again?                            Trials that can change the lives of billions

                            
I have formed a view regarding the mechanism of aging, not the switches that turn it on, only the mechanism. In our body DNA damage is very frequent, occurring on average about 60,000 times a day per cell of the human body but this is not the cause of aging. The rate of damage is the same for the young and the old - what changes as we age is the rate and efficiency of repair. At any given moment, there's competition in your body between cellular damage and repair. As the damage becomes greater than your body's ability to repair and regenerate, deterioration sets in. "If we could repair damage as fast as it occurs, we could live forever," says Dr. Rosedale. Another competition is between growth and repair. When one is dominant the other is muted. Too much repair beyond what is needed can become harmful to healthy cells and so is too little. So Nature has created activators and inhibitors and sensors. In our prime the opposing forces move the steering wheel left and right efficiently so that the repair car remains in the middle of its lane but as we age one begins to dominate the other (for example inhibitors overpower the activators) causing the snowballing feedback loops and dysfunctions which slacken the pace of repair, on a sliding basis, leaving unrepaired damage. Their dysfunction increases systemic damage including to the organs. What would happen if the steering wheel is pulled only on one side more and more? The repair car will soon veer off road and sooner or later is destined for a fatal accident. Yin and Yang a 3rd century BC gift of Taoism figured out Nature's system of opposing forces maintaining an equilibrium - agonists and antagonists, push and pull - how seemingly opposite or contrary forces may actually be complementary, interconnected and interdependent in the natural world and how they may give rise to each other as they interrelate to one another - as described in Wiki. Multiple reactions with intricate networks of activators and inhibitors are involved in biological homeostasis. Homeostasis is maintained by a series of control mechanisms functioning at the organ, tissue or cellular level. These control mechanisms include substrate supply, activation or inhibition of individual enzymes and receptors, synthesis and degradation of enzymes and compartmentalization. Despite its complexity biological systems are after all finite. And all finite problems can be solved. Restoring the equilibrium found in our prime between damage and repair can cure aging. When young blood is transfused in old it temporarily rejuvenates the equilibrium of the repair systems by the circulating young factors. But the transcriptional program resumes destabilizing the balance between the opposite forces to ensure repair gets weaker again and progressively. Clearing senescent cells or lengthening telomeres or upregulation of NAD+ are resurrecting some parts of the dysfunction. Only restoration of full equilibrium in the repair machinery vis-a-vis damage can cure aging as a whole. 
 An example: A recent exciting development in the field of anti aging has been the discovery of a molecule called FOXO4-DRI by
Cell biologist Peter de Keizer of Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues. When the cells face damage, repair machinery remedies the damage and revives the cell. Sometimes the damage is beyond repair. At such time cell adopts a process called Apoptosis and dies or is recycled by a process called Autophagy. If for any reason a severely damaged cell misses both, the cell becomes a zombie - senescent cell. Senescent cells secrete poisons which affect surrounding healthy cells. As we age and the forces inhibiting our repair systems begin to dominate over repair activators it begins to reduce our repair efficiency.  This creates more and more senescent cells. They tend to clog our tissues and organs and cause progressive damage to them. But Nature has made a cure for them to keep a check on how many senescent cells remain. P53 is a tumour suppressor protein that binds to senescent cells and helps them achieve apoptosis. But as we read above Nature keeps a inhibitor to ensure there is not too much of P53. This is another protein called FOXO4. It binds to P53 and blocks it's ability to help senescent cells achieve apoptosis. In our prime the opposing forces of P53 and FOXO4 balance at levels to create optimum clearance of senescent cells. As some amount senescent cells are needed for wound healing and they are also a valuable raw material in the genesis of new cells. But as we age this balance too is disturbed wherein too many of the P53 inhibitor FOXO4 are produced which in turn multiplies the numbers of senescent cells which continue to multiply the damage in the system, tissues and organs. This is a classic example of the Yin and Yang losing its optimal balance. FOXO4-DRI is a synthetic molecule that has higher affinity for P53 - it wins the competition with FOXO4 in binding with P53. This allows P53 to complete it's task of enabling senescent cells achieve apoptosis. It has shown remarkable reversal in certain aging markers on mice. Old mice regained thick coat of fur seen in young mice and were able to do tasks that they did when they were young. An intervention that restores the optimum balance between inhibitors and activators can potentially undo damage and reverse aging helping us regain our youth.
Another Example: PARP1 is an enzyme that is essential in initiating various forms of DNA repair. DBC1 binds to PARP1 and prevents it from executing DNA repair. So it becomes a inhibitor. Each inhibitor should have a corresponding activator - in this case NAD+ plays that role. NAD+ prevents DBC1 from binding with PARP1 and thus ensures DNA repair. As we age the levels of NAD+ decreases by which increases the binding of DBC1 with PARP1 the result: DNA breaks go unrepaired and as these breaks accumulate over time, precipitate cell damage, cell mutations, cell death, and loss of organ function. David Sinclair’s lab at Harvard Medical School observed that when NAD+ levels were restored the markers showed improved DNA repair. Thus here too we see that restoring the optimum balance of inhibitors and activators brings back youthful levels of repair. 
As we age we see our body shape, fitness, skin, hair and our face change gradually but visibly. When we compare our photos of age 25 and age 75 we look so dramatically different - we find our 25 year old self better looking and more attractive. The difference between the two is the damage that slips by the repair machinery. One can see how mercilessly it chisels away the radiant beauty of youth. Since we have seen others also suffer this damage without question we too accept this trauma and tragedy as normal. A few tweaks may be all that may be required to not only avoid these debilitating changes but potentially reverse them. We assume that all of us is as old as our age but except for neurons of the cerebral cortex we are not more than 15 years old. As everything inside us renews and recycles itself. Sperms life is only 3 days, taste buds 10 days, lungs 3 weeks, skin which carries our outward appearance just 2-4 weeks, liver 150 days, bones 10 years, etc. We always look at reversal of age very sceptically but now that you have this perspective it brings it back in the realms of possibilities. So my question is: if damage caused by aging is reversible (as confirmed by recent studies Hayashi Tsukuba University) and if we are able to bring back the optimum balance between repair system inhibitors and activators why would a 75 year old not begin to look and feel like his 25 year old self again??? My venture is hoping for that to happen. In collaboration with a reputed University we are launching pre-clinical trials on old lab mice where my proprietary protocol of interventions (a fruit of many years of research and analysis) may bring back the optimum performance of their repair systems. Hopefully this in turn may make the old mice young again. There have been many anti-aging experiments around the world which have been able to extend the life of lab mice by 5% to 50%. Our quest is to maintain repair system biochemical homeostasis and keep the reversal to youth sustainable. I will be able to update you with the results within a few months. The tests are for safety, dosage, bioavailability and efficacy. If we are successful we plan to conduct human clinical trials next in collaboration with a reputed hospital. Wish us luck and success

IS OUR DEATH CAUSED BY A CODE?

IS OUR DEATH CAUSED BY A CODE?

2nd of the two biggest debates of biomedical world: Are we programmed to die?

DEBATE II: Do we die because we succumb to wear and tear of our biology over the years or due to a DNA code programmed in us before we were born? Longevity has a good explanation for this theory: The wear and tear theory of aging believes that the effects of aging are caused by damage done to cells and body systems over time. Essentially, these systems "wear out" due to use. Once they wear out, they can no longer function correctly. It was first expressed in science by German biologist Dr. August Weismann in 1882. We simply expect that the body, as a mechanical system, is going to break down with use over the years. 

A range of things can damage body systems. Exposure to radiation, toxins, and ultraviolet light can damage our genes. The effects of our body's own functioning can also cause damage. When the body metabolizes oxygen, free radicals are produced that can cause damage to cells and tissues. There are some cellular systems that don't replace themselves throughout life, such as the nerve cells of the brain. As these cells are lost, function eventually will be lost. Within cells that continue to divide, the DNA can sustain damage errors can accumulate. Simply the act of dividing again and again shortens the telomeres of the chromosomes, eventually resulting in a senescent cell that can no longer divide. Oxidative damage in cells results in cross-linking of proteins, which prevents them from doing the jobs they are intended to do in the cells. Free radicals inside mitochondria, the powerhouses of our cells, injures their cell membranes so they can't function as well. 

Not all damage can be repaired fully, and mistakes in repairs may accumulate over time leading to our death.

Whereas
Programmed aging and death theory is based on aging related slow decline of cellular functions being caused by a epigenetic clock programmed into our DNA. One major development in a Japanese lab of Jun-ichi Hayashi from Tsukuba University may tilt the scales towards this theory. The Tsukuba team has performed some compelling research that has led them to propose that age-associated mitochondrial defects are not controlled by the accumulation of mutations in the mitochondrial DNA but by another form of genetic regulation. The research, published this month in the prestigious journal Nature’s ‘Scientific Reports’, looked at the function of the mitochondria in human fibroblast cell lines derived from young people (ranging in age from a fetus to a 12 year old) and elderly people (ranging in age from 80-97 years old). The researchers compared the mitochondrial respiration and the amount of DNA damage in the mitochondria of the two groups, expecting respiration to be reduced and DNA damage to be increased in the cells from the elderly group. While the elderly group had reduced respiration, in accordance with the current theory, there was, however, no difference in the amount of DNA damage between the elderly and young groups of cells.

This led the researchers to propose that another form of genetic regulation, epigenetic regulation, may be responsible for the age-associated effects seen in the mitochondria. Epigenetic regulation refers to changes, such as the addition of chemical structures or proteins, which alter the physical structure of the DNA, resulting in genes turning on or off. Unlike mutations, these changes do not affect the DNA sequence itself. If this theory is correct, then genetically reprogramming the cells to an embryonic stem cell–like state would remove any epigenetic changes associated with the mitochondrial DNA. In order to test this theory, the researchers reprogrammed human fibroblast cell lines derived from young and elderly people to an embryonic stem cell-like state. These cells were then turned back into fibroblasts and their mitochondrial respiratory function examined. Incredibly, the age-associated defects had been reversed – all of the fibroblasts had respiration rates comparable to those of the fetal fibroblast cell line, irrespective of whether they were derived from young or elderly people. This indicates that the aging process in the mitochondrion is controlled by epigenetic regulation, not by mutations. The researchers then looked for genes that might be controlled epigenetically resulting in these age-associated mitochondrial defects. Two genes that regulate glycine production in mitochondria, CGAT and SHMT2, were found. The researchers showed that by changing the regulation of these genes, they could induce defects or restore mitochondrial function in the fibroblast cell lines. In a compelling finding, the addition of glycine for 10 days to the culture medium of the 97 year old fibroblast cell line restored its respiratory function. This suggests that glycine treatment can reverse the age-associated respiration defects in the elderly human fibroblasts. These findings reveal that, contrary to the mitochondrial theory of aging, epigenetic regulation controls age-associated respiration defects in human fibroblast cell lines. Can epigenetic regulation also control aging in humans? That theory remains to be tested, and if proven, could result in glycine supplements giving our older population a new lease of life.
Similarly David Sinclair's lab at Harvard showed that by upregulating NAD+ in the mitochondria the musculosketal infrastructure of the body rejuvennated to youthful peak levels.

Harvard's David Sinclair's Formula to Reverse Aging 

Parallely the Conboys and Wager demonstrated the rejuventation of muscles, brain, liver and other organs and systems by parabosis in two linked mice circulating young blood in old mice. Which proved that when signal proteins from young plasma circulated in an already age ravaged body were still able to reverse aging on the old mice.

The above two have been covered in my earlier post called 'Can we cure aging?' in more detail.
All the three put together provides clear evidence that aging does not create permanent damage or is not caused by wear and tear.


My Conclusion: There is a code that has been planted in the DNA of ALL living things on this planet which is triggered by a epigenetic clock and leads to decline and death of the host. Steve Horvath of UCLA has not recieved the fame and appreciation he deserves for discovering the DNA methylation clock that accurately measures human age. Various strips of DNA has codes that make us grow to adulthood from babies and later, on reproductive maturity, trigger a slow decline leading to death. I don't expect these strips to be in one long chain but in different locations. What is remarkable is zero error rate - we do not see anyone due to DNA mutations cheating death. There are errors which cause various handicaps and deformities but never ever since record of humanity have we observed an error in code regulating aging and death. This shows that Nature gives a lot of importance to death and must have programmed multiple pathways to ensure decline and death in all living things. When we upregulate NAD+ or glycine or AMPK or whatever else has been shown to prolong life in lab animals we are only trying to cure the symptoms. Which can not lead to cure of aging and avoidance of death. There are only two ways it seems that one can aim to achieve this:

1. By disrupting the epigenetic clock by infusion of plasma of a young donor into the patient wanting to reverse aging. The noch protein signals of a donor whose epigenetic clock is signaling body to works at its peak is expected to do the same for the new recipients body as seen in parabiosis models in lab mice pairs. The question is will it do the same in human parabiosis or plasma exchange? Also if it does would the new signals flooding the body in sufficient numbers be able to reset the epigenetic clock of the old human to the age of its young donor or will the benefitial rejuvenation last only up to the life of the signal proteins? If it is the former the parabiosis or plasma exhange would be needed only once every 10 years to reset the epigenetic clock back to the age of 25 (from 35) and if it is the latter then the parabiosis or plasma exchange would need to be done every 4 months.


2. The other way would be identifying which section or sections of the human DNA has the triggers for decline messages to be relayed linked to the progress of the epigenetic clock. DNA does not need to have a message for effecting death. The total body decline ensures that it leads to death. This would be quite a challenge compared to the first option which can be implemented today by any qualified physician using the plasmapheresis machine. Identifying from the 20,000 to 25,000 protein coding genes - it may be a single one that triggers a cascade or it may be multiple ones that work independently or in synergy - too many permutations and combinations to evaluate. It may also be from the huge amount of non coding genes which now are no longer considered junk but also seem to be having some biological function. Needle in a haystack type of situation. But we have already mapped the entire human genome and have invented incredibly powerful gene editing tools like CRISPR - The importance of CRISPR - We are Nature's Robots with a software that dictates everything that happens to us - CRISPR is a tool that allows us to edit this software. We still don't know what to edit but when we do CRISPR will help us execute it.
Once the genes are identified we would need specific binding agents to block it from triggering the functional decline messages. Assuming that the identified genes also do not have other needed functions. Testing which genes play a role in triggering aging decline is very difficult to do as we can not try editing out genes on a living human. So is it impossible to eventually identify the genes triggering aging decline? Of course not. We will achieve this - it is only a matter of time.

Half a Million DVDs of Data Stored in Gram of DNA

CANCER STEM CELLS CAUSE OF METASTASIS?

CANCER STEM CELLS CAUSE OF METASTASIS?

One of two biggest debates of the biomedical world (second debate covered in separate blog post)

DEBATE I: Are all cancer cells mutagenic and proliferative or only the core mother stem cells? 

Dr John Dick sparked this debate in 1994 when he isolated the first cancer stem cell, and showed that these rare cells cause leukemia to grow in mice. Researchers at the University of Michigan made the case in 2003 that the same was true in breast cancer. In 2004  Dr Dirk a scientist and neurosurgeon at Toronto's Hospital for Sick Children discovered cancer-causing stem cells in the brain tumours of mice. The idea began gaining wider acceptance that a tiny number of cancer stem cells cause cancers to grow. As reported in Wkipedia under Cancer Stem Cells (CSCs): CSCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are hypothesized to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. The theory suggests that conventional chemotherapies kill differentiated or differentiating cells, which form the bulk of the tumor but do not generate new cells. A population of CSCs, which gave rise to it, could remain untouched and cause relapse. The debate over the existence of a minority of CSCs at the root of all cancers or not has been continuing since the last 12 years. Both sides have been citing lab and murine studies to validate their argument. One example for each:

Evidence for Refuting the CSC theory: Sean Morrison director of the University of Michigan Center for Stem Cell Biology and his team of researchers  have determined in Nov 2010 that most types of melanoma cells can form malignant tumors, providing new evidence that the deadliest form of skin cancer does not conform to the increasingly popular cancer stem cell model. In addition, the researchers found that melanoma tumor cells can change their appearance by switching various genes on and off, making the malignant cells a stealthy, shape-shifting target for researchers seeking new treatments. As reported in Michigan News Both findings fly in the face of the cancer stem cell model, which states that a handful of rare stem cells drive the formation, growth and progression of malignant tumors in many cancers. Some supporters of the model have suggested that melanoma might be more effectively treated by taking aim specifically at these rare cancer stems cells, rather than attempting to eliminate all melanoma cells. But after conducting an exhaustive search for this elusive sub-population of tumor-forming melanoma cell, the U-M team concluded that it probably does not exist. The researchers analyzed 44 sub-populations of human melanoma cells, and all 44 had a similar ability to form tumors when transplanted into mice. "Some have suggested that melanoma follows a cancer stem cell model in which only rare cells are able to proliferate extensively and form new tumors. Our results suggest that most melanoma cells are capable of driving disease progression and that it won't be possible to cure patients by targeting rare sub-populations of cells," Morrison said. "We think you need to kill all the cells."

Are all Melanoma cells are cancer stem cells in disguise? Melanoma cells under an elctron microscope

The study found that tumor-forming melanoma cells have the ability to throw a genetic switch that changes the types of proteins expressed on the cells' surface. The study is the first to present evidence for this type of pervasive "phenotypic plasticity" among melanoma cells from patients. Patterns of surface proteins are used to identify different cell types and are commonly called cell surface markers. "The fact that these markers are turned on and off by melanoma cells raises the possibility that melanoma cells may also turn on and off genes that regulate clinically important characteristics like drug resistance and metastatic ability," Morrison said. "The ability to transition between various states may make melanoma more difficult to treat." The authors stress that while their results argue against a cancer stem cell model for melanoma, their findings do not invalidate the model. In fact, certain leukemias and other cancers appear to follow the model.
"It will be critical to determine which cancers follow a stem cell model and which do not, so therapies designed to target rare sub-populations of cells are not inappropriately tested in patients whose disease is driven by many diverse cancer cells," Quintana also from the UM Stem Cell Center said. "The cancer stem cell model says that tumor cells are organized hierarchically, and that only the cells at the top of the hierarchy form tumors. Cells at the bottom of the hierarchy can't," Morrison said. "In our model, all these cells can form tumors," he said. "And they're phenotypically different from each other not because they're hierarchically organized but because they're just turning these surface markers on and off." The U-M team found that all tumor-forming melanoma cells gave rise to progeny with a variety of marker patterns, and that all of those sub-populations retained the ability to form tumors. The marker changes appeared to be reversible, rather than being associated with a transition from tumor-forming to non-tumor-forming states, as the cancer stem cell model would predict.

Evidence for existence of CSCs and their role in cancer: In a study published in the journal Cancer Cell in 2014, researchers at Oxford University and Sweden’s Karolinska Institutet said they had tracked gene mutations responsible for a form of blood cancer back to a distinct set of cells which they say are at the root of the cancer’s spread. 'It's like having dandelions in your lawn. You can pull out as many as you want, but if you don't get the roots they’ll come back,' explains first author Dr Petter Woll of the MRC Weatherall Institute for Molecular Medicine at the University of Oxford. The 15 patients involved in the study had myelodysplastic syndrome (MDS), a blood disorder which causes a drop in the number of healthy blood cells, and develops into acute myeloid leukaemia in around half of all cases.

Genetic tracking identifies cancer stem cells in patients. Photo: University of Oxford

Researchers investigated malignant cells in the bone marrow of the patients and tracked them over time. Using genetic analysis, they were able to isolate a small and distinct group of MDS cells which were the origin of the cancer-driving DNA changes which were causing the disease to progress. 'This is conclusive evidence for the existence of cancer stem cells in myelodysplastic syndromes,' says Dr Woll. 'We have identified a subset of cancer cells, shown that these rare cells are invariably the cells in which the cancer originates, and also are the only cancer-propagating cells in the patients. It is a vitally important step because it suggests that if you want to cure patients, you would need to target and remove these cells at the root of the cancer – but that would be sufficient, that would do it.'Dr Peter Woll, first author, said that it did give future researchers “a target” for development of more efficient “cancer stem cell-specific” therapies. However, even if cancer stem cells were eliminated, Dr Woll added, there would still be a chance that genetic mutations could lead to other stem cells later becoming cancer stem cells. Professor Kamil Kranc, a Cancer Research UK stem cell expert based at the University of Edinburgh, said that the findings were a “a huge leap towards understanding the roots of blood cancers”. Dr Neil Rodrigues, of the European Cancer Stem Cell Research Institute at Cardiff University, said that the new study was “very important”, as it “precisely defines the provenance and biological composition of the cancer stem cell in MDS.”

Leader of the Pack: There are more than a dozen companies that have reached clinical trials in patients specifically targetting cancer stem cells including Boston BIomedical which was acquired by Dainippon Sumitomo Pharma Co. for US$ 2.63 billion and Oncomed at US$ 300 million valuation on NASDAQ.
The leader of he pack of cancer stem cell tergetting biotech companies is Stemcentrix. It has achieved an astounding valuation of US$ 5 billion without any sales and has raised half a billion dollars. This Californian start up is backed by heave weight investors Fidelity Investments, Artis Ventures, Silicon Valley Bank, Sequoia Capital, Elon Musk,  and a US$ 200 million investment from one of the most successful investors in the world Peter Thiel and his Founders Fund (earlier co-founder of Paypal, dscovered Facebook and invested in AirBnB and Palantir).

Scott Dylla co-founder Stemcentrix

Brian Slingerland co-founder Stemcentrix

Peter Thiel The backer with the midas touch

Stemcentrx, formed in 2008, is developing a small-cell lung cancer therapy that homes in on a target, DLL3. The product, which uses an antibody to guide a cell-killing drug to its target, appears to be effective in some small-cell lung cancer patients. In a recent trial of 80 small-cell lung cancer patients, which was testing safe dosage, tumors shrank more often than they did in response to the only approved drug to treat the cancer, topotecan. For patients whose cancer exhibits the stem-cell marker the drug aims at, benefits were larger. It’s one of three drugs the company is already testing in human trials. Why do top investors put in so much money at such crazy valuations in such early stage highly risky venture? Probably based on the success of Pharmacyclics Inc., a cancer drug developer that was acquired by AbbVie Inc., for $21 billion in May 2015. Scott Dylla an ex Stanford stem cell targetting researcher and ex tech banker Brian Slingerland co-founded Stemcentrix. All this smart money is betting that CSCs are present in cancer biology and play the role of the mother bee in a beehive.

My conclusion: Both sides are showing evidence in this debate. It is finally irrefutable results in human clinicals of stem cell targetting drugs that will put in the last word. It may be that both are right. Different cancers may have different biologies some with CSCs and some without. Or cancer may be the most scary shape shifter of them all constantly changing its avatar. But if the CSCs are the cause of all recurrences of resistant cancers and we can kill the CSCs with allopathic and natural drugs then we may be able to save millions of lives.

I leave you with some useful information from European Cancer Stem Cell Research Institute at Cardiff University:

This shows how a normal stem cell creates a new stem cell and a progenitor cell. The normal progenitor cell then matures into differentiated (specialised) cell required by the body. An event such as a direct genetic mutation or effect from external factors could make these cells mutate or de-differentiate i.e. lose their specialisation at any stage. These affected cells could then produce a cancer stem cell. (With inspiration from Therese Winslow’s artwork)

his shows the initial theory of how cancer stem cells can maintain a tumour. Even with conventional cancer therapy the cancer stem cells survive and the cancer can relapse but if we can identify cancer stem cells and develop specific treatment the patient outcome could be improved as the tumour would regress or enter remission.

This shows another theory of how cancer stem cells can conserve a tumour. There may in fact be more than one type of cancer stem cell so with conventional cancer therapy the tumour mass is maintained. But again if we can identify cancer stem cells treatment could be improved.

Pictures from Dr Richard Clarkson (Cardiff University) showing how Cancer Stem Cells grown in the laboratory can be killed over time – a model of tumour regression.