The birth of Gleevec is legendary and very touching. To understand the birth of a drug, we must first understand the disease that this drug treats.
Gleevec is a medicine for the treatment of chronic myeloid leukemia, but not many people understand it in the early stages.
We all know that we have white blood cells to help us defend against disease, which is equivalent to the guards of our bodies.
But what’s wrong if the guard itself has a problem?
If the guards themselves are not effective, they will also fight each other and ruin many of our functions, such as blood.
This is chronic myeloid leukemia.
But we didn’t know what it was like before.
First back to 130 years ago.
In 1889, a surgeon, Stephen Paget, completed an essay.
For the first time, research on cancer has been raised to the molecular level to study the spread of cancer.
He suggested that blood is the soil of cancer cells, the Seed and soil hypothesis.
You should know that everyone’s understanding of cancer in that era is still stuck in viruses and bacteria. It is believed that tumors and cancers must be caused by certain cancer cells like viruses and bacteria.
And this Stephen Paget said that cancer should start from ourselves, his most classic sentence: “You will never grow breast cancer on your legs.”
Let us come to know the great Stephen Paget, which is elegant and unique.
His theory was rejected by the mainstream society at the time.
why? He believes that our tissue organs themselves affect the occurrence of cancer.
What is the theory of mainstream society at that time? It is believed that all cancer cells are born one or a few, but only in the lungs, the mutation turns into lung cancer. In the breast, the mutation turns into breast cancer.
It has little to do with our own cell organization itself, and this idea is very easy to understand.
The most famous among the opponents is James Ewin, who is also an expert.
One type of cancer, Ewing’s sarcoma, is named after him.
He believes that cancer research itself organizes cells is wrong, and the relationship between passive and active is wrong.
He even said that Stephen Paget was completely wrong, and we are still studying the cancer cells that are swimming around.
After nearly 100 years, the experiments of mice by Ian Hart and Isaiah Fidler in 1980 proved:
Stephen Paget’s statement is correct, and the century-old theory is proven!
What a wonderful 100-year showdown, the collision of human science!
At the time, Stephen Paget’s theory influenced one person: David Paul von Hansemann, a German pathologist.
Because Stephen Paget mentioned his own tissue cells, he felt very reasonable and was enlightened.
Based on Stephen Paget’s theory, the first time human put cancer into the perspective of genetics, and opened a new door for the first time!
Not only opened the door to Gleevec, but also opened a new era of cancer research.
He studied the etiology of cancer from the genetics of cell division to chromatin, opening the door to cancer genetic cell division chromosomes.
Then the sea urchin gourmet further laid the theoretical foundation of Gleevec.
Theodor Boveri, a German biologist.
Why is he called a sea urchin gourmet, because it is said that he not only loves sea urchins, but also obtains many research results of cell division from sea urchins.
It is him who first proposed a shocking view: cancer tumors are caused by their own cell division, which may cause problems in the chromosome of a certain cell.
Why is there a problem, he has two judgments:
1. Congenital, your father, this cell of your grandfather has problems, and this cell in your body also has problems.
2. Acquired, environment and radiation cause mutations in the original normal cell chromosome
What happens after the chromosome has a problem? Uncontrollable crazy growth.
It eventually leads to the production of cancer and even the inheritance of cancer.
What a terrible theory!
Is this completely consistent with everyone’s understanding of cancer now?
And Theodore proposed this theory in 1902, 116 years ago!
But at the time of the technical limitations, the study of chromosomes was too lacking, and the sea urchin gourmet could not prove his theory.
The study of chromosomes is not in place, and there is no way to actually argue. Even at that time, even humans have several pairs of chromosomes.
It was not until 1921 that the discovery of the chromosome “pressing plate method” turned around.
In 1923, an American cytogeneticist named Payett published a paper on tableting to prove that humans have 48 chromosomes.
How many chromosomes do people have?
Is this a common sense? The answer is 23 pairs of 46.
So is his paper correct? Obviously it is wrong.
However, this result was not opposed by the academic circles at that time and has been maintained for 32 years!
For 32 years, the world believes that people have 48 chromosomes.
Until 1956, a Chinese scientist, Jiang Youxing, was not afraid of authority. He believed that the American legendary geneticist’s point of view was wrong.
He was not studying for a long time at the time. He was locked up in concentration camps for more than three years during World War II, but he never gave up on cytogenetics.
In January 1956, Jiang Youxing published a paper.
To overthrow the US authority, it is determined that humans have 46 chromosomes, creating a history of human cytogenetics!
In fact, some people have observed 46 before, but they are afraid of authority. They think they are wrong.
Jiang Youxing not only re-corrected the chromosomes, but also showed the world the challenge of authority.
If science does not question how it will develop?
If there is no doubt about the study of leukemia, how can Gleevec appear?
At this time, the most important person in the Gleevec treatment of leukemia appeared.
His name is Peter Nowell, American, Philadelphia, Pennsylvania, and is the pride of Philadelphia.
He is a person who likes to discuss with others and especially likes to discuss with young researchers and scientists.
At the University of Pennsylvania, his main focus is leukemia and lymphoma.
At that time, in 1956, the society at the time did not think that leukemia and chromosomes would be related.
There is still no improvement in this area, and then wonderful!
On that day, he routinely completed the observation of chronic myeloid leukemia samples and prepared to clean the slides after work.
At this time he may be tired and made a mistake.
It stands to reason that cleaning the slides requires special solvents, but he forgot to take the tap under the tap.
When he was half washed, he found that he was not washing his hands.
This is over, and see what it looks like.
He put the slide back under the microscope and found that the chromosome of the original sample had a huge change!
How could he not think that impurities in tap water would cause chromosome expansion?
Because before that everyone thought that the chromosomes would not change.
He felt that things had changed qualitatively and began to focus on the study of chromosomes.
No one would have thought that tap water would change the course of human treatment of leukemia.
In 1960, he used the advanced colchicine solution chromosome preparation technology to successfully find the same chromosomal variation in two patients with chronic leukemia.
It is the chromosome 22 in the figure below.
There is a problem with the apparent length of the 22nd. Will this be the cause of chronic leukemia?
He immediately tested the other five patients and found the same variation!
He finally concluded that chronic leukemia is most likely caused by genetic variation and is most likely to be derived from a single variant cell.
More than 50 years later, the theory of crazy sea urchin foodies has been verified!
The whole world is crazy, and for the first time someone has identified the possible cause.
Bringing the treatment of chronic leukemia to a new era of practical operation!
To commemorate this discovery, the name was named “Philadelphia chromosome.”
A city is famous for its genetic discoveries, and movies can’t reproduce it!
However, subject to the development of chromosome technology at the time, he could only find that there was a problem on the 22nd, but could not find the cause of the problem.
After 1960, it took 10 years to complete.
A great old lady found out why in 1970.
Her name is Janet Davison Rowley, and her outstanding achievements in genetics have earned the highest level of Presidential Medal of Freedom in the United States.
In 2009, Obama personally presented her awards.
She studied the chromosome 22 on the basis of his research and improved the most advanced quinacrine fluorescence method and Giemsa staining method at that time.
Finally, the cause of chromosome 22 mutation was found to be related to chromosome 9.
The part of the 9th break, the 22nd part of the shortage.
That is to say, the chromosome 9 break caused the long arm displacement to cause the 22nd mutation, and the 22nd mutation caused the chronic leukemia.
In 1973, she proposed two unprecedented ideas:
1. A chromosome breaks and is linked to another chromosome.
2. Two chromosomes exchange material when two chromosomes break.
Based on this theory, she also discovered the possible causes of other leukemias:
Chronic leukemia is the cause of No. 9 and No. 22, acute myeloid leukemia is the cause of No. 8 and No. 21, and promyelocytic leukemia is a problem with No. 15 and No. 17.
This discovery is so great, and many people even call her the mother of leukemia.
The whole United States is cheering for her, an unprecedented discovery.
After all, the technology is limited. Although she narrowed the problem further, she could not find the cause of the problems with these chromosomes.
Then the world continued to wait for 10 years until 1983.
On the basis of Janet, Gerard Grosveld focused on the fracture between the 9th and the 22nd and found that the c-abl cancer gene on the 9th was transferred to the 22nd.
Then, on the 22nd, the breakpoint cluster area bcr was found, and this c-abl+bcr was combined into bcr-abl.
The reason for Philadelphia chromosome formation was found!
The whole world was sensational and finally found the process of formation.
But what prompted this process to form?
Four years later, David Baltimore made a major discovery based on Gerard Grosveld.
In 1987, he embodied the pathogenic bcr-abl and developed a protein with a size of 210kd.
On his basis, George Daley hit the protein on the mouse, and the mouse actually developed leukemia!
They finally confirmed that this damn bcr-abl protein is actually an activated form of tyrosine kinase!
This damn mutant protein has been constantly signaling the cells, as if a mad battlefield commander gave the soldiers a command, which eventually led to a series of cancers.
At this point, the truth is clear.
From the 1960 model, the male found that there was a problem on the 22nd, and in 1990, it was finally confirmed that the tyrosine kinase was in trouble.
For 30 years, the cause of chronic myeloid leukemia has finally been determined!
The cause is determined, and the rest is the study drug.
The goal is clear, that is, this damn crazy mutant protein is destroying.
It is imperative to suppress this mutant protein.
This is very difficult because there are many kinds of kinases in the human body.
Most types of kinases are similar, and there has been no mechanism to study kinases before.
Because no one thinks that kinases and cancer are also related.
And the kinases are mostly similar, and it is difficult to get rid of a certain kinase by a single drug.
At this time, one of Gleevec’s five heroes appeared!
Brian J. Druker found through long-term studies that although the kinases are similar to each other, the ATP binding pockets between different kinases are not the same.
We can simply understand the synthetic container for kinases.
This container is not the same, there is a difference.
Can the container destroy the damn mutant protein?
Let’s do it!
Alex Matter was the head of Ciba-Geigy (now part of Novartis Pharmaceuticals) and he thought Druker’s theory was correct.
But at the time, the study of kinases had no market at all and did not make money.
He rallied and supported Druker’s research.
At the same time he pulled Nick Lydon into the drug synthesis.
Lydon has endlessly synthesized hundreds of small molecular structures, and Druker is responsible for detecting which compounds work.
The research process was very difficult and failed again and again.
What is the most difficult? Be aware that patients with chronic leukemia are still a minority.
There are 1 or 2 chronic leukemia patients in 100,000 people.
A few represent the market is not big, almost no company is willing to invest.
This is definitely a loss, but they persisted.
At this time, the other two scientists were also moved by their deeds and joined the research team that was not profitable at the time.
Dr. Juerg Zimmerman, he eventually synthesized a kinase inhibitor.
Dr. Elisabeth Buchdunger completed the initial screening of the inhibitor.
The five heroes arrived, and the war is on the verge!
In an experiment in 1992, Zimmerman discovered that the inhibitor numbered STI751 successfully killed the mutant protein and did not affect other cells.
Yes, this STI751 is the later Gleevec!
Finally made a major breakthrough!
However, due to the small number of chronic leukemias, clinical trials are very difficult and can only be performed between individual patients.
But the effect is very good, Gleevec’s effect is 100%! It is a miracle.
However, everyone does not know how much the human body should be dosed. If the dose is wrong, it is likely to become murder.
No one dared to come to the trial. At this time, a woman named Suzan Mcnamara came forward.
After she learned the news from her patients, she launched an initiative around the world, calling on everyone to participate in the trial, not to be afraid of death!
At that time, chronic leukemia was actually treated with drugs, called hydroxyurea and interferon combination therapy.
But the curative effect is very poor, hair loss, fatigue, depression, and skinny, very painful.
She was the first to encourage scientists to test different doses on her.
Scientists say this is too dangerous, and if the dose is too large you will die.
Because STI751 showed toxicity in previous toxicological tests, the 600 mg dose of STI751 caused liver failure in dogs.
She firmly said: If my death can bring life to other patients, then my death is worthwhile!
She also collected the signatures of more than 4,000 patients, and in 1999 wrote to Novartis CEO Daniel Vasella to request an expansion of production.
In fact, Novartis was not optimistic about this project because the audience is too small and the profit is too small.
But he was moved by Susan’s affairs and stood in the office for a long time.
In the end, he made up his mind: Up yours, I will do this thing even if I don’t make money!
He convinced the board and increased the production of the STI751 formulation.
A large area of testing has begun!
In 2000, a patient named Lopossa was equally moved. Her white blood cell index exceeded 200,000, and almost no cure was possible.
She resolutely participated in the test with the support of her family.
She told the scientists, come on, let my death bring more people to life.
“Don’t worry, I have my own gravestones ready.”
Three weeks later, her spleen returned to normal with STI751, and she eventually escaped from the hands of death.
Even she took a photo next to the empty tombstone she had prepared for herself.
The board of directors was also moved and started testing globally.
At the 43rd Annual American Blood Conference in 2001, the paper reached 110 articles, which is a miracle in the history of drugs!
At this time, it is more effective for the US drug approval agency FDA. This drug is too effective. The FDA has made an exception to the drug organization to ensure that it is not sleepy.
After extensive and extensive testing, Novartis submitted the report.
“For the life of leukemia people around the world, request a quick approval of imatinib!”
STI751 has since had a resounding name: Imatinib!
Just after 10 weeks! It was not available for 3 months. After the second phase of clinical testing, the FDA approved the drug with a record-breaking rate.
The final product name after the listing: Gleevec!
On May 10, 2001, Gleevec was born!
This small unremarkable tablet has reduced the 5-year survival rate of leukemia patients from less than 30% to nearly 90%!
And nearly five percent of patients received blood remission five years later, and Gleevec was even called “silver bullets for cancer” by Time magazine.
Everyone knows that the silver bullets are shooting werewolves.
The werewolf represents viciousness and cannot be eliminated. Gleevec’s status is evident.
Almost equal to saving the lives of patients with chronic leukemia worldwide!
Gleevec is now listed by the World Health Organization as a list of essential medicines.
(Standard therapy before the third phase of efficacy)
This medicine is not only a life-saving, but also a new history of cancer-targeted drug treatment!
From the 1960 Philadelphia chromosome to the FDA approval, it took 41 years to develop a drug for the treatment of chronic leukemia.
In the 130 years, how many scientists have worked hard for it, and many people have not even seen the birth of this drug until their death.
The development of a drug has been unimaginable for so many years. So many scientists are sticking to it, so many patients have the medicine to get the present.
Let us pay a high tribute to these great people!
Gleevec’s invention has been around for more than a decade, and scientists have not stopped the pace of research and development.
Gleevec developed certain resistance after more than a decade, and Bristol-Myers Squibb developed the Dasatinib tablets that replaced Gleevec.
Novartis has also developed Dahina to replace Gleevec.
More new anticancer drugs are still under development.
It can be seen that in the corner we don’t know, science has never stopped!
Thanks to the tireless research of these scientists, thanks to the persistence of researchers for decades!
The history of the struggle between humans and diseases is also a history of scientific struggle, come on, all humans!