Aminopterin was the first ever drug that led to remission of cancer in children with leukemia (blood cancer). Dr. Sidney Farber, hence the father of chemotherapy tested it in children in 1948 at Boston Children’s Hospital in Boston, Massachusetts.
By today’s “safety” standards, what Sidney did to solve cancer would be considered unethical (no children knew that toxins were going to be injected in them - and many died). But his ways, mainly the ability to record failure and conclusion fast and take the next corrective actions is what led to the first battle humanity won against cancer.
The only other attempt of injecting humans with toxins - chemotherapy - to treat cancer was post WW2 when mustard gas was used to reduce the size of solid tumors. However, these secret experiments did not lead to remission cases.
I first got to know about the story of Aminopterin from the book I am reading right now called “The Emperor of All Maladies” - which is a biography of cancer. Getting to know this led me to a thought trail where I wanted to know what led to this ground breaking discovery - the first ever win against cancer in 1000s of years. Are there any lessons we can draw.
One of the lessons I am seeking is to understand what 'Safety' should mean. In an earlier paragraph, I double quoted the word - because I do have a feeling that we have institutionalised safety and often used it against growth.
What do I mean by “institutionalising safety”?
Firstly, I believe, safety means there has to be enough confidence on a solution to work out positively. Humans should not be guinea pigs (well, neither should guinea pigs) - the one and only goal when dealing with humans in medical context should be to save them.
Second, the patient should know every nook and corner of what’s happening with them and what options/treatments are available. They should be the only one choosing the options they wish to go ahead with (exception made, if they mentally cannot). Government, regulations, babus should have no say - they can opt to be a catalyst for a particular option but not have the final say.
So - I am not suggesting going full Sidney Farber mode.
Institutionalising safety means using it to specifically stop growth - either by having policies that are not thought for. Creating hierarchies of people where not required, separating people and decision making deliberately for power and control. You know this happens. I know this happens. And it specifically happens a lot in India.
Hence we need to redefine Safety and keep it separate from Medical Research, Innovation and Growth aspects.
The immediate impacts that I see are,
- The Turnaround Time for conducting clinical trials will be faster. Policies simplified. Decision making made faster.
- The sharing of results plus amongst different research departments would be faster. Scientists, Researches, Chemists, Biologists, Botanist, Zoologist, Doctors, Engineers, Investors - all networked under one roof.
- Research and medical infrastructure available to all technicians who need them. Small startups should not be required to spend millions in dollars and months or years in time to start their research.
- 90% + failures converted to success conversions and in record iteration times. Iterations should be fast - productivity improved by modern tools.
- Personalised healthcare journeys - patients are able to choose their treatments (including research driven new methods not entirely proven) and faith
When millions of humans are working on the same planet within same ecosystems - there's always something that someone knows or is capable of finding out, that leads to breakthroughs or faster decisions or faster execution plans being made. We need to network humans effectively.
And this is not something I am making up, this is historically proven. Consider the timeline that led to discovery of Aminopterin itself.
Imagine, WW2 era - science is expected to be fast. Different groups of technicians and intellectuals highly networked. Diseases that we have no understanding about. And a lot of curiosity, faith, courage to keep going.
It’s time we replicate these with a new well suited definition to safety.
The Events that led to Aminopterin
Early 1900s. The story starts with a different disease Anemia.
Anemia is a condition where the body does not produce enough hemoglobin which is the protein that transports oxygen from the lungs to across the body. So the Red Blood Cells (RBCs) which holds the hemoglobin as well as the protein itself are in shortage.
No oxygen to tissues and muscles mean they would not be able to breakdown carbohydrates to create energy. Which leads to symptoms of feeling week and exhausted.
So the root cause of Anemia is:
- The body is not able to produce RBCs or hemoglobin
- The body is destroying the cells or the cells are suiciding at higher rates
- Their is considerable blood loss through leakage
Pernicious Anemia was one such type that led to most fatalities. This anemia was the kind where the RBCs were deformed.
- 1926: George Minot and William Murphy discovered that feeding patients with half a pound (~250 grams) Liver every day cured pernicious anemia. This led to the start of efforts to singulate the nutrient within Liver that resulted in the cure.
- 1931: Lucy Wills discovered that Marmite (a yeast extract) cured a similar type of anemia. Now the nutrient got dubbed Wills Factor.
- Trivia: Lucy Wills visited Mumbai textile factory owners, this was the best ecosystem for anemia given low salaries, colonialism, shortage of quality food.
- 1941: It was known that leafy vegetables contain the Wills Factor based on observations that certain bacteria required the same Wills Factor to grow, which was tested by artificially providing them extracts from different sources.
- Since Spinach was easy to process and available. The researchers at University of Texas, Austin isolated the compound and named it Folic Acid.
- Not a Trivia: I searched, this is not the reason for the cartoon markers Popeye to make spinach the superfood of their universe. However it was another research that led to it.
- 1945–1946: Yellapragada Subbarow who was Research Director at Lederle Laboratories used the isolated compound to make a synthetic variation of Folic Acid that can be packages as a medicine.
- Note: We can see some good impacts of capitalism here, a lab wanting to isolate a nutrient to provide it as a medicine - and funding research for that reason.
- 1947: Sidney Farber had the idea of using Folic Acid to attempt treating leukemia due to the similarly deformed RBCs in both diseases. However the effects were completely opposite and led to accelerating the cancer instead (more RBCs - more means to spread).
- Note: Quite a simple observation that led to this. Evidence that even pre internet there was very strong sharing of results and ideas. Sidney was not restricted by any regulations to attempt his trials, his hospital did however object his methods and only wanted last-resort cases to go through him.
- 1947-1948: Subbarow’s team prepared an antagonist to folic acid on Farber’s request which then led to aminopterin.
- Note: No evidence of corporate or government politics. Farber and Subbarow knew each other and had an open collaboration.
- 1948: Farber treated children with aminopterin which led to the first ever remission cases of cancer.
The Ecosystem we need
Here’s the summary of things that came into place resulting in this breakthrough. Let’s consider these as lessons and augment them with better safety definitions - and it might lead us back on faster medical breakthroughs.
- The Courage for Trial and Errors: Knowing that liver solves anemia.
- Access to Niche Ecosystems: Lucy’s ability to visit India and do trials and gather evidence there.
- The Pursuit supported by Capitalism: The races that led to isolation of folic acid, initially by synthesising it through spinach and later Lederle Labs
- Interpersonal Networks and Open Research: Farber knowing Subbarow. Subbrow collaboration. And Farber being able to compare Anemia with Leukemia.
- No Bureaucracy through Institutions or Governments: Safety concern were prevalent in Farber’s hospital, but it did not restrict the discovery.
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