The First Cell - On Why Questions, Data And Future Treatments (Part 3 of 3)

We all are going to die one day. Eventually, Max too would have died of old age. But why he has to suffer from cancer even after spending trillions of dollars for half a century with no understanding of the root causes nor cure? Why? 

Judea Pearl, father of causal inference in his book The Book of Why: The New Science of Cause and Effect instills a meditative-mental anchor in our minds: 

Ironically, the need for a theory of causation began to surface at the same time that statistics came into being. In fact, modern statistics hatched from the causal questions that Galton and Pearson asked about heredity and their ingenious attempts to answer them using cross-generational data. Unfortunately, they failed in this endeavor, and rather than pause to ask why, they declared those questions off-limits and turned to developing a thriving, causality-free enterprise called statistics.

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My emphasis on language also comes from a deep conviction that language shapes our thoughts. You cannot answer a question that you cannot ask, and you cannot ask a question that you have no words for. 

Not only statistics but multi-disciplines failed in this endeavor by working in silos, parochialism - lack of collaboration across disciplines, funding, and more importantly no incentive for bright students to get into the field. 

This is part 3 of my lessons from Russ's latest episode with Dr. Azra Raza, author of the new book The First Cell: And the Human Costs of Pursuing Cancer to the Last.

Part 1 of my lessons are here, part 2 here,  and you can listen to the full interview here:

Azra Raza: And, by the way Russ, let me stop here and tell you one other thing. We are talking a lot about immune therapies these days, and there are multiple kinds of immune therapies. But, the most dramatic ones are those that use bodies' own immune cells to activate them and attack the cancer. You might have heard of CAR-Ts [Chimeric Antigen Receptor Therapy]. Nowhere do investigators point out that while CAR-T cellular therapies, the most dramatically effective form of killing every last cancer cell in the body. I acknowledge all of that. It is a fabulous feat of scientific achievement.

Incredible achievement to take the body's own T-cells, which are a kind of immune cells, and engineer them in such a way that they are now carrying part of a B-cell, which is another lymphoid immune cell. And it's activated to kill any cell it means that is expressing a B-cell receptor, CD-19. This is the most common CAR-T therapy used for B-cell lymphoma or leukemia.

But, nowhere do investigators point out that these T-Cells also cannot differentiate between a normal cell and a cancer cell.

So, what they actually do is kill the whole organ. But specifically that organ. Still there are off-target effects, which means other cells in the brain or somewhere else which are expressing the same marker. These engineered cells are so effective they will seek out and kill every cell that even has a molecule of that receptor being expressed.

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Azra Raza: Russ, one of the big problems we have faced in cancer is that, despite looking for 60 years, we have not been able to find molecules that are expressed only by cancer cells and not by normal cells.

In other words, we can't find the address, the unique zip code, of a cancer cell so far.

So, at best what we are trying to do is basically kill cells more effectively irrespective of whether their cancers are normal. When you ask me that, 'Will this immune therapy be applicable to other cancers?' Absolutely. It should be applicable.

But, right now it is not so because if we try to kill liver cancer cells with this kind of CAR-T therapy it will destroy the whole liver, not just liver cancer cells. Or, it will destroy the whole GI [Gastro-Intestinal] tract, the whole colon. So, the entire organ would be killed because normal cells are expressing the same markers as the cancer cells.

However, when we learn to identify by means of whatever biomarkers we develop, in the future as technology is evolving, then not only would we be able to specifically target cancer cells, but the other thing is that we would be able to use these therapies in earlier stages.

So, that right now, when we give these therapies, the only patients who respond are the ones who experience the most severe side effects, called the cytokine storm, which basically puts the patient's life at stake. That, if they survive it, they will enter remission. Those patients who don't experience this horrendous cytokine storm, they don't even eventually respond to this kind of therapy.

In other words, what I am saying is that we are going in the right direction. We have made some significant, dramatic advances in these kinds of immune therapies, but the way they are talked about, the hyperbolic language that is used minimizing not just the financial toxicity but actual physical toxicity of immune therapies.  

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So, now it comes to two issues. One is that we have patients today for whom we need treatments and we need to invest resources to try and improve those treatments and find better ones. I'm saying that the other half of resources need to go to improve the technology we have for earlier detection, which means a really serious, thorough, overall analysis of cells, RNA, DNA, proteins, metabolites from serially, sequentially studied actual human samples, not animal models.

And, the last thing I want to say about this is that this is where real and large-scale studies will have to evolve to provide the sample size for machine learning and artificial intelligence.

Since 1984 when I turned my attention towards studying pre-leukemia and following these patients as they are either died of MDS or developed leukemia, I started banking bone marrow and blood samples of my patients.

Today, Russ, this may sound like a very ordinary thing; but I have now collected over 60,000 samples from thousands of patients. Not one cell in my tissue bank has come from another investigator. All of these patients mean something to me because I've personally taken care of them. Most of them I have done with my own hands. This is a tissue repository where, today, I can go in, look at the cells, look at RNA, DNA, proteins, and metabolites in a serial fashion--as the patient progressed from pre-leukemia to acute leukemia.

This is how we can work our way back and then ask the question, why did some patients get pre-leukemia? What were the risk factors that made this individual or these people susceptible to getting pre-leukemia, even? And, this will take us then to identify a group who is at high risk of developing pre-leukemia and then we can start monitoring those individuals, healthy individuals who are at high risk, in a targeted fashion.

So, I can do this for pre-leukemia and acute myeloid leukemia. The resources are needed. I'm making this appeal to everybody that we should not rely on any one test done annually which was developed 50 years ago. Rather, we need to develop using the latest scanning, imaging, biomarking, genomic, proteomic, metabolomic technologies to find maybe 500 different tests that can be amassed in a bar code fashion or can be done rapidly, quickly, to identify individuals in the earliest stages of cancer.

The resources, half the resources, go to treating current cancer patients and developing and improving treatments for them. The other half must be invested towards early detection through the latest technology and prevention and nipping the cancer in the bud.

This is very depressing news... even targeted gene therapy doesn't differentiate between good and cancer cells. It does make sense since we never found the root causes of cancer. 
I am not as optimistic as Dr. Azra is when it comes to AI and Machine Learning. Nevertheless, AI can help us go from zero to 60 or even 80 easily. But the key here is we need data. 

The data needs to come from people like you and me in the form of samples. For the last two decades, Max and I have donated our genes, microbiome, and other samples from home for research. 

Trust me, there is no "John Corner" version of Max and me from the future came nor coming. We self-immolate ourselves by refusing to give out samples. Free samples from each one are more precious than donating billions and science cannot provide an alternative to samples. A piece of great news for animals is that a lot of animal testing in cancer and current medical research doesn't work - which means non-human animal samples don't go too far. 

People believe in magic and assume "they" are working on a cure. One of the biggest lessons I learned as I am getting older is that there is no "they". 

"They" is nothing but collective humanity. So if you want to find the root causes of cancer and cure for cancer - volunteer to give samples. Wearing a yellow bracelet and walking for "pink" in NYC doesn't move mountains expect feeding one's virtue signaling or self-deception. These help to raise money but money will do no good without good samples via your blood, DNA, microbiome, and other samples. 

This is exactly what I said the day Max was cremated. You can check out the responses I got in part 1. I cannot comprehend the idiocy of this without thinking most of us are deluding ourselves that "magically" we will escape cancer or we will be cured. Humans do baffle me. 

We as a society lost the art of asking questions. I cannot think of a better person than Richard Feynman who taught the art of asking the proper "Why" questions:. 

But the problem, you see, when you ask why something happens, how does a person answer why something happens? For example, Aunt Minnie is in the hospital. Why? Because she went out, slipped on the ice, and broke her hip. That satisfies people. It satisfies, but it wouldn’t satisfy someone who came from another planet and knew nothing about why when you break your hip do you go to the hospital. How do you get to the hospital when the hip is broken? Well, because her husband, seeing that her hip was broken, called the hospital up and sent somebody to get her. All that is understood by people. And when you explain a why, you have to be in some framework that you allow something to be true. Otherwise, you’re perpetually asking why. Why did the husband call up the hospital? Because the husband is interested in his wife’s welfare. Not always, some husbands aren’t interested in their wives’ welfare when they’re drunk, and they’re angry.

And you begin to get a very interesting understanding of the world and all its complications. If you try to follow anything up, you go deeper and deeper in various directions. For example, if you go, “Why did she slip on the ice?” Well, ice is slippery. Everybody knows that, no problem. But you ask why is ice slippery? That’s kinda curious. Ice is extremely slippery. It’s very interesting. You say, how does it work? You could either say, “I’m satisfied that you’ve answered me. Ice is slippery; that explains it,” or you could go on and say, “Why is ice slippery?” and then you’re involved with something because there aren’t many things as slippery as ice.

We outsource some of the precious things in life such as our food (by letting corporations cook for it), our thoughts (letting the morons on TV and Radio implant an ideological virus in our heads). 

In the end, what then is precious to humans? 

Crazy as it sounds, we think our "choices" we make while outsourcing is what we think is precious! 

These choices become our habits, "culture", part of our vocabulary, and endowment effect sets in. Yes, we defend the "precious" bullshit we eat and the morons we watch. That pretty much sums up our life outside of our work life and super cuddly family! 

Democracy cannot operate and sustain with such attitudes leave alone giving samples to find the root cause of cancer and finding a cure. 

The worst part of all of it is when you have a personal conversation with a meat-eater or someone refusing to understand the importance of giving samples - they will in ways gaslight you by using your passion against you. They are smart enough to turn the personal conversation into general one by using phrases like people, belief, goodness, busy, work, and such filler bullshit. And the final straw which usually ends the conversation would be acting the victim game. Not sure how they are victims while they are funding animal sufferings and not giving out samples that would help cancer research. They will maintain an unbelievable calmness and soft-spoken the entire conversation but their passions would flare for 10 min traffic job or being a helicopter parent, drop in a few dollars in the stocks. 

These attitudes make me sad. Even after watching Max suffer, the bond we had - they cannot comprehend nor think outside of their ideological walls and habits. This is just a dog and a guy who loved the dog because of lack of relationships he had while he was a kid. This the story they tell themselves and probably would live and die in that belief. 

My Max had to suffer and die of cancer because of collective choices we make every day by voting with our dollars and refusing to give any samples when we are healthy nor when we are unhealthy nor when we are dead - all because of some abstract concept of liberty, individualism and in most cases by lack of caring until shit hits their home. With omnipresent bad luck, you and I might die suffering for the same reason. 

Distilling all my noisy rant and to summarize what can a good person do:

• Always ask the why question. Why we haven't made any progress in finding the root causes of cancer? 
• Never settle for the status quo when it comes to science and answers regarding the world around us. 
• Open up your heart and mind to give out samples of your DNA and microbiome. 
• Data on your eating habits, daily activities (workout, walking, etc.), diversity of life inside your house, your ecological choices (laundry detergent, soap, etc.) 
• Cook your own food with no ingredients made from corporations. They don't understand complex systems nor will they attend your funeral. 
• Don't outsource your thinking to morons on TV and Radio. 
• Vote. Elect representatives who talk less and do more. They are not our leaders but they are our workers. Elect representatives who have a sense of gratitude, are humble,  understand the complexities of science, and don't believe in magic. 
• Make time to read all the bill's that matter to you which are due in the senate. Read the bills which have already passed as well. 
• Understand and follow all the nuances FDA does. 
• There is a brand new "field" named Exposome - We think about all health and illness as a combination of genes and the environment, and now it really is time to fill out the environment side of that equation. Limit and eliminate chemicals in your life. You need to bring to the surface the invisible choices you make in everyday life. 
• Every school, every university, every office, and every household should learn about complex systems. You do too. 
• Repeat all of the above. Understand - democracy, civilization and the life of earth depend on that. If that doesn't convince you - this will help minimize suffering during your final months and days. 

This interactive quiz from the BBC on how much of your body is your own? is a good place to understand the complexities inside "I" and how little of "I" is actually in "I".

One might feel overwhelmed by the little list above. But our brains love when we unleash them on things that matter. The hard part is to get started and persists. Garret Hardin comes to our rescue.

Garret Hardin in his book Filters Against Folly: How To Survive Despite Economists, Ecologists and the Merely Eloquent identifies three major filters against the folly that we citizens can use against blindness, short-sightedness, and sheer idiocy that so often comes disguised as eloquence or expertise.

Hardin contends that most of the major controversies of our time can be better understood as the result of the participants relying too much on any single one of these three filters. Since no one filter by itself is adequate for understanding reality and predicting the consequences of our actions, Hardin devotes the rest of the book to a discussion of the strengths and weaknesses of each of the three filters (my notes here)

• The first filter is literacy - "the ability to understand what words really mean."
• The second is numeracy - "the ability not only to quantify information but also to interpret it intelligently."
• Hardin calls the last filter ecolacy - "the ability to take into account the effects of complex interactions of systems over time." 

Hardin goes on to explain more on his ecolacy concept: 

More comprehensive development of ecolacy - the ability to ask and answer the question: and then what? so that the effects of the interactions of systems over time can be taken into account - is necessary if we are not to fall victim to the forces we unleash and are unwilling or unable to control. 

Some ecologists have tried to draw attention to the interrelatedness of our world by stating that everything is related to everything else (sometimes called Barry Commoner's first law of ecology).  This statement has been criticized by many scholars because while it is valuable as a warning it is useless as a guide to action. 

While all things in the environment interact they interact in different ways. The ecologist Garrett Hardin restated this important ecological understanding in the following language so that it can serve as a guide to action: WE CAN NEVER DO MERELY ONE THING which is now known as Hardin's Law. The language that we have used to describe the effects of our actions demonstrates the reality that Hardin's Law draws our attention to. We talk about the effects and side effects, products, and wastes. Hardin contends that since we cannot do just one thing we must always ask and answer the question and then what? 

When we try to ascertain the benefits and costs of proposed courses of action on both the individual as well as social levels. The ecological systems' way of thinking employs modern scientific theories and knowledge to study a world of interlocking processes characterized by many reciprocal cause-effect pathways. The ecological systems' way of thinking has to become an integral part of the thinking of the well-educated person if we are to adequately control technology rather than fall victim to the forces we generate and are unable or unwilling to control. Ecological systems thinking provides well-educated persons with the opportunity to act more rationally because they have learned a more comprehensive and more accurate way of estimating the probable costs and benefits of their actions.

We as individuals need to develop an ecolacy way of thinking. A habit of ecolacy thinking helps one not to get lost in a myriad of details and it helps develop meta-level thinking. Nurturing meta-level thinking helps detect bullshit a mile away and helps decipher the essence of progress in any domain without getting lost in details.

I will close with a brilliant philosophical Tamil song from 1964 - the essence of the song might get lost in English translation but it's worth pondering. 

There is no life without asking the why question 

No human with me, me, and me attitude lived a good life 

General knowledge was born only because of asking questions

All the liberties were earned only because of having emotions

Let thousand years pass until the meaning of our patience is understood

Let future generations sing that we are not salves 

There is no life without asking the why question 

No human with me, me, and me attitude lived a good life 

Progress happens only because all the work of those who work 

All the duties are followed because of the wants for freedom