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Insulin or somatostatin

In 1869, Berlin medical student Paul Langerhans observed the pancreas through a microscope and found that there was an island composed of morphologically abnormal cells on the pancreas. These islands of cells were later called Langerhans, but no one knew Lange at that time. The physical function of Hans Island. It was not until 20 years later that Oskar Minkowski and Josef von Mering had surgically resected the pancreas of the dog to determine the function of the organ. They also discovered that the pancreas can control blood glucose by secreting insulin.

The identification of insulin function also quickly triggered the battle for purified insulin. Despite fierce competition, scientists have succeeded in extracting insulin from animals until more than 20 years later. In 1921, Banting and Best extracted several micrograms of insulin from a few tens of kilos of bovine pancreas. After injecting insulin into children with diabetes, the patient’s blood glucose quickly returned to normal levels, and symptoms of thirst and urination became more common. Also reduced. Although the efficacy of insulin is very obvious, due to the poor water solubility and thermal instability of insulin, the extraction process becomes extremely difficult.

Boyer’s plan to synthesize insulin seems to be more efficient than the cumbersome extraction process. At that time, no one had successfully obtained a DNA fragment containing an insulin gene, so he decided to synthesize two DNA molecules encoding insulin A and B chains by chemical de novo synthesis and insert the DNA into the bacterial genome to enable them to synthesize human insulin. After this, he plans to purify two peptide chains and chemically link the two chains to obtain human insulin protein.

Even if Boyer is confident again, he does not want to start this attempt from the synthesis of insulin. He hopes to first synthesize a protein that is relatively simple and easy to handle, and if successful, to challenge challenging insulin. Boyer thought about it and decided to start with somatostatin.

As with insulin, somatostatin is also a hormone, but the commercial value of somatostatin is not as large as insulin. His main advantage is its low molecular weight. Insulin has two chains of 51 amino acids, while somatostatin consists of only 14 amino acids. To de novo somatostatin synthesis, Boyer recruited two chemists, Keiichi Itakura and Art Riggs, from the City of Hope Hospital in Los Angeles. Both are experts in DNA synthesis.

However, Swanson strongly opposed Boyer’s plan. He felt that synthesizing somatostatin would only distract the company. He hoped that Boyer could directly try to synthesize insulin. For him, Genentech is a venture funded company with only a few rented offices and a microbiology laboratory at UCSF. Boyer actually wanted to hire two chemists to synthesize somatostatin genes. Made him unacceptable.

Boyer finally persuaded Swanson. In fact, Boyer and Swanson are very clear about their time is very urgent, because they have learned that two other big cattle in the field of genetics also joined the war on insulin biosynthesis. Walter Gilbert of Harvard University is an authority in the field of DNA synthesis. He and Berger and Sanger received the 1980 Nobel Prize in Chemistry. At this time he is leading a strong team using genetic cloning technology to synthesize insulin. And at UCSF, the school where Boyer is located, another team has also begun trying to use recombinant DNA technology to synthesize insulin. Boyer at the time was always worried that he was afraid every day and was afraid to hear that his opponent Gilbert had synthesized insulin first.

In the summer of 1977, Riggs and Itakura successfully synthesized somatostatin DNA. The DNA fragment was successfully inserted into the bacterial plasmid and the bacteria were successfully transformed. It seems that these bacteria are ready to synthesize somatostatin. In June, Boyer and Swanson flew to Los Angeles to witness this last moment.

That morning, the entire team gathered in the Riggs lab and everyone waited anxiously for the results of the experiment to determine if the bacteria could really produce somatostatin. Unfortunately, they did not find any traces of somatostatin. For Swanson, this was indeed unacceptable news. At that time, he was completely killed. He was sent to the emergency room the next morning because of severe indigestion.

Although the scientists suffered the same blow, they were still able to analyze the reasons for the failure of the experiment. Boyer is undoubtedly an expert in microbiology. He has decades of experimental experience in bacteria. He knew very well that bacteria might completely digest the proteins it produced. Perhaps these bacteria can produce somatostatin. Wouldn’t it be that these proteins are themselves degraded by the bacteria?

To test this hypothesis, he decided to link the gene of somatostatin with some of the bacteria’s own genes to produce a complex protein with two types of protein components, and then cut the two proteins to enable Get somatostatin. In this way, bacteria will recognize the produced hybrid protein as their own protein, but somatostatin will not be degraded.

However, it took more than two months to synthesize this hybrid DNA. In August 1977, Boyer’s team reunited in Riggs’s lab to wait for the final result. Swanson looked anxiously at the monitor. He was nervous and could not breathe. He turned to not see the final results. But this time they succeeded, Itakura told Swanson that they detected somatostatin.

Genentech scientists did not have time to celebrate. They immediately started a project to synthesize insulin. Obviously, the competition for synthetic insulin at that time was already fierce. Boyer at this time often heard various rumors, some people say that Gilbert’s research team has cloned the insulin gene from human cells and is ready to synthesize insulin. Others said that the UCSF task force has already synthesized a few milligrams of insulin and is planning to conduct human trials.

Does somatostatin really distract the attention of Genentech? Boyer and Swanson feel very sorry, they think that the first choice for the synthesis of somatostatin is a wrong choice, so that they fall out of the competition in insulin synthesis. At this time, Swanson had serious dyspepsia due to excessive anxiety.

What everyone did not expect was that it was the Asilomar meeting that was extremely despised by Boyer and saved them. Berg and Mertz met with strong questions after the first synthesis of chimeric DNA. These questions included not only the fear of the SV40 virus’s harmfulness, but also concerns about the ethical issues arising from the recombinant DNA technology itself.

In 1975, Berg organized an influential meeting at a conference center in Asilomar Beach to discuss the dangers of biotechnology and how to formulate regulations in this area. Although Cohen and Boyer also participated in the meeting, Cohen was very disgusted with the meeting. Cohen also refused to sign the Asilomar meeting after the meeting (but due to NIH’s request, Cohen must comply with the requirements of the deal).

Like Cohen Laboratories and most academic institutions funded by the federal government, Gilbert Laboratories at Harvard University must also abide by the Asilomar Treaty. These treaties impose great restrictions on Gilbert because, according to the provisions of the treaty, he cannot isolate human genes and insert them into the bacterial genome.

After successfully synthesizing somatostatin, Riggs and Itakura decided to use chemical synthesis to obtain insulin DNA. Chemical synthesis of DNA is not limited by the Asilomar Treaty. Moreover, Genentech is financially supported by venture capital companies. It has not received federal government funding and is naturally not bound by these regulations. These restrictive treaties for Gilbert are simply a magic weapon for Genentech to win the battle for insulin synthesis.

At this time, San Francisco’s cubicle office could no longer meet the needs of Genentech’s development, and Swanson began looking for new laboratories in the city. In the spring of 1978, after traveling through the Bay Area, Swanson finally found a suitable office and experimental site. Boyer recruited several scientists and purchased new equipment.

Boyer and Swanson did not find insulin traces successfully, and Gilbert was not willing to be subject to the Asilomar Treaty and sent a professional team to the United Kingdom to continue project research. The UCSF task force also sent a student to a pharmaceutical company in Strasbourg, France, to be able to synthesize insulin as quickly as possible.

In the summer of 1978, Boyer heard that Gilbert was about to announce the successful separation of human insulin genes by their research group. Swanson, who learned of this news, once again collapsed. Gilbert at the time did not know that their experiments had gone awry. Instead of the human insulin gene, the mouse insulin gene was cloned.

In the gap between Gilbert’s mistakes, Genentech got up. This is a contest between academic institutions and pharmaceutical companies. One of them has a strong academic background and has top-notch teams. However, it is bound by various restrictions. While the other party has relatively few personnel, it has responded quickly and has been very effective. Between various complicated regulations.

In May 1978, Genentech’s team of scientists finally synthesized two peptide chains of insulin in bacteria; in July, they purified proteins containing two insulin peptide chains from bacteria. In early August, they cut off the linked bacterial proteins and successfully separated the two peptide chains of insulin. On the night of August 21, 1978, Goeddel successfully linked two peptide chains and obtained recombinant human insulin for the first time.

What kind of power has made Genentech? Is it a venture capital investment by Swanson or a recombinant DNA technology by Cohen and Boyer? Is it a coincidence with Gilbert’s battle, or is it inevitable that the technology has developed to a certain extent? Is Swanson’s keen sense of business or Boyer’s strength as a professional background scientist?

I think everyone has their own answer.

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