Genentech's Success Story

Cancer FightersGalina Kostina, "Expert" No. 33-2010

Scientists of the world's first biotechnological American company Genentech have learned how to arm antibodies in such a way that the firing of a cancer cell was conducted in several directions at once.

In 1976, two people, a scientist and a businessman, sitting in a bar over a beer, decided to commercialize recent scientific discoveries. More precisely, Robert Swanson, a young and ambitious employee of the well-known California investment company Kleiner, Perkins, Caufield & Byers, convinced his counterpart, biochemist, professor Herbert Boyer of the University of California San Francisco to create a company. At first, the scientist, who had no such thoughts, condescendingly agreed to meet with Swanson for no more than ten minutes. But things didn't go according to plan. The professor, who was used to being listened to, listened to the guy himself for three hours, who enthusiastically drew him the prospects of creating many medicines based on the scientific discovery. In a matter of days after that evening, almost with the pocket money of two partners, the world's first biotech company Genentech was registered, in the name of which the hitherto unconnected concepts were combined: genetics-engineering-technologies.What set Swanson on fire?

In the early 1970s, biochemist Herbert Boyer and geneticist Stanley Cohen from Stanford University created recombinant DNA technology. Boyer discovered an enzyme substance that could cut DNA into pieces, and Cohen came up with a method for inserting the necessary pieces of genes into the DNA of bacteria, so that they, like living conveyors, would use these genes to produce, for example, the necessary protein. It seems to us now that the idea of the practical application of these discoveries just lay on the surface. Nevertheless, young Swanson, who saw the commercial potential in this technology, was ridiculed by everyone. However, Swanson was not only able to convince Boyer to create a firm, but also to persuade one of his bosses – Perkins – to pour initial capital into Genentech.

Already in 1977, the company received the first recombinant human protein – somatostatin, in 1978-1979, human insulin and growth hormone were cloned. And already in 1980 Genentech entered the stock exchange, and its first successes in biotech helped to attract a fantastic $ 35 million for such a company. Within an hour of trading, the stock price jumped from $35 to $88. The world's first drug produced using recombinant DNA technology entered the market in 1982. It was human insulin, which was licensed from Genentech by Eli Lilly. The license for blood clotting factor VIII was given to Cutter Biological, for interferon alpha-2 – to the Roche group. Licenses for the first drugs created by the company were sold to large pharmaceutical firms, since Genentech did not have the funds for capital-intensive clinical trials. It was only in 1985 that Genentech brought the drug protropin, a growth hormone for children, to the US Food and Drug Administration (FDA) for sale. But although the company's own sales could bring very good money, they were not enough for development, because scientists worked extremely enthusiastically and fruitfully. Therefore, in 1990, 60% of Genentech shares were sold for $ 2.1 billion to the Swiss group Roche, with which the Americans had been cooperating since the 1980s. In this transaction, Genentech bargained for the right to almost complete independence – both scientific and financial. The full merger took place in 2009, when Roche bought the remaining 40% of the shares for $ 46.8 billion. That is, in 19 years, the capitalization of the company has grown thirty times.

Since its birth, Genentech has not conceded leadership in biotech. According to analysts, it was the only biotech company that achieved such impressive success not by absorbing other players, but by its own work – outstanding scientific developments.

For twelve years in a row, including in 2010, Fortune has named Genentech one of the best companies worth working for, and last year Science named it the best employer in biotech. The unique atmosphere allowed the team to make a lot of pioneering developments, in particular in oncology. Dr. Philip Bishop, Vice President of Clinical Development at Genentech, spoke about this at the beginning of our conversation.

– Dr. Bishop, we must assume that one of the reasons for the company's long-term success was a temporary head start, because Genentech was the first in the world biotech. But what constantly supported her leadership?– The key to success were those scientists who joined the company from the very beginning.

These, without exaggeration, were the best scientists, mainly from the University of California San Francisco. Then excellent scientists from Stanford University and Berkeley joined the company. In addition, they had a constant and close connection with colleagues from these peculiar islands of concentration of California brains.

– What attracted them to a young company, where, probably, the initial salaries were unimpressive?– Oddly enough, there is a lot of freedom: in universities, scientists are still squeezed by some limits.

In many commercial companies, there may be even less freedom – there the focus shifts greatly to the area of getting the final result and profit as quickly as possible. But Genentech was originally conceived as a company in which scientists will be free enough and will be able to devote part of their working time to their scientific interests that are not directly related to current scientific projects. The literacy of business managers consisted in the fact that they provided scientists with everything they needed, stimulating the transition from scientific ideas to developments. In addition to freedom, a scientist in the company got the opportunity to touch his scientific research with his hands. The company provided the entire chain and all the specialists who could bring the development to the drug, including engineering, preclinical and clinical trials.

– Many companies, including large pharmaceutical companies, tried to attract good scientists. How did yours differ?– The fact that they were really elite.

Among our scientists, and there are now more than a thousand of them, there are members of the National Academy of Sciences, many have received prestigious awards. One of them was nominated for the Nobel Prize. A strong proof of the level of our scientists is the fact that up to a dozen of their publications appear in the most famous scientific publications – Nature, Science, Cell. No pharmaceutical or biotech company can boast of this. Another indicator is the number of patents in the biotechnology industry. Last year, the Roche Group, where Genentech makes a significant contribution on patents, was the leader among pharmaceutical companies and was twice ahead of its next competitor.

– What was the reason for the focus on oncology – the competencies of scientists?– No, at first no one thought about cancer at all.

The company's first drugs are growth hormone, insulin and other products obtained by recombinant DNA. The motto of our scientists is: following not the market, but science. Of course, it was possible to follow the market and come up with some popular medicines, but they could be better or worse than what others are doing. At Genentech, the team aimed to do something that no one else has done, something that has just hatched in fundamental science. And therefore, not only oncological drugs appeared in the company. Our focus is on such areas as neurology, immunology, viral diseases and others. We have certainly made a great contribution to world oncology, since the revolution in modern cancer therapy is associated with the appearance of targeted antibody-based drugs that Genentech began to create. I want to give an example of the history of one of our cancer drugs, which is indicative for the Genentech team. We are talking about avastin.

– I know that this drug has had a long and difficult path…– That's right.

To begin with, more than eighty years have passed since the moment of the fundamental discovery, which subsequently served as the impetus for the creation of avastin, before the drug entered the market. In 1927, it became known that the tumor indirectly affects the vessels. In 1939, vascular growth around the tumor was observed in vivo. It was only in the seventies that the term "angiogenesis" was introduced – it means provoking the growth of blood vessels by a tumor. And in 1989, Genentech scientist Richard Foreva discovered vascular endothelial growth factor in his laboratory – the key to triggering cancer angiogenesis. This factor is released by tumor cells to initiate the growth of the vascular network, which will feed the growing tumor. I will note that Foreva made this discovery just in the time allotted for his scientific "hobbies", most of the time he was working on a completely different project. The scientist immediately saw the practical prospect of his discovery – the possibility of creating a drug that would block the work of this vascular growth factor. In the company, it has always been customary to collectively discuss everything interesting that scientists discover. And after such a discussion, the project was immediately launched. So-called monoclonal antibodies were created, which were supposed to serve as an obstacle to the harmful action of vascular growth factors. The beginning of the experiments was simply a failure. There were continuous failures. In another company, this project would probably have been quickly shut down. But the scientists were so confident in the correctness of the main direction that this conviction did not allow them to throw the project into the trash, although this path took a long fifteen years until the moment of registration. More than five hundred clinical trials have been conducted – just an unprecedented number for the pharmaceutical business. No one has done so much research before. But each test allowed us to gain new experience and answered the company's motto – to approach the problem of cancer globally. We have seen the effectiveness of the drug in several types of cancer. The drug entered the market in 2004. At the same time, we continue to test it in new areas: very good results have recently been shown in the treatment of ovarian cancer.

– But avastin wasn't the company's first anti-cancer drug?– We can say that we started oncology closely in the mid-nineties.

And this was due to the development of one small biotech company – IDEC Pharmaceutical. They had a good idea, but they didn't have enough strength of their own, they needed help. As a result of our partnership, the drug rituxan appeared, which was aimed at specific blood cells that were subjected to malignancy and caused lymphoma. It was approved in 1997.

– It was a time of great hopes for antibodies – a revolutionary idea for oncology…– Yes, because antibodies made it possible to switch from therapy, which oppressed not only tumor, but also healthy cells of the body, to a targeted effect on tumor cells.

And it really was a coup, giving great hopes. Our scientists have also been working on other antibodies. In particular, the following year after the approval of rituxan, the company released herceptin antibodies against specific breast cancer receptors (HER2). Scientists have found out that these receptors are present in large numbers on the surface of cells in a special type of breast cancer. Therefore, the antibodies created against these receptors were not a universal drug for any breast cancer, but they effectively "closed" HER2. By the way, when I was still a student, I knew that there is simply breast cancer, now we know at least seven types of breast cancer, each of which requires its own approach.

– Are antibodies the main fighters in cancer therapy?– Perhaps they thought so at the very beginning, when the antibodies only began to appear.

Now we believe that the range of funds should be quite wide. This is due to the biology of tumors. There are a lot of mechanisms involved. Depending on which mechanism we are targeting, we are looking for the right tool. These can be small molecules and large molecules, like antibodies. And if at first we created simple, or naked, antibodies that "sat down" on certain receptors of tumor cells and thus blocked some mechanisms, now we are creating more complex, or armed, antibodies. In particular, at a fairly advanced stage there is a drug in which an antibody and a toxic agent are combined: the antibody finds a cancer cell, attaches to it, and the toxic agent penetrates and destroys it. Another drug created using our glycoengineering technology increases the ability of complex monoclonal antibodies to stimulate the body's immune response against malignant cells.

– Probably, healthy people and cancer patients perceive information about new products differently: healthy people say that the drug prolongs life for only five months, patients - that for as long as five… Why is it not possible to create more radical means? Does it not inspire pessimism that a cancerous tumor still remains something like a black box, from which new details fall out from time to time?– You are right that we still know very little about the nature of tumors.

I would say that scientists are at the tip of the iceberg in their knowledge, if they try to estimate, no more than ten percent of the total knowledge about cancer is available to them. But we are by no means pessimistic about this. On the contrary, it gives us confidence. Look at what was in the arsenal of oncologists just thirty years ago: the bombardment of all the cells of the body. Look at what has happened over the past ten years: we have made very significant progress in understanding the biology of cancer. This understanding led to a revolution in the approach to creating new tools. Now we know that most tumors have, as a rule, several mechanisms, or signaling pathways, which we must act on in order to defeat them. Therefore, we must act globally – on several targets at once. This can be achieved by a combination of drugs aimed at a specific target or complex molecules being created now that can hit several hot spots.

– So it all depends on how quickly scientists will discover new mechanisms of tumor development? Then, as they say, it's a matter of technique?– We see that now the rate of discoveries in this area is quite high.

We sort of immediately grab every new knowledge and try to simulate the transition from scientific discovery to the clinic as quickly as possible. At the current ASCO Congress (American Society of Clinical Oncology), held in Chicago in June, we heard a lot about the transmission of various signals inside a cancer cell. And we are proud that we already have drugs in development using these discoveries. For example, one of the drugs is designed to block the hyperactivation of one of the signaling pathways responsible for controlling the growth of a cancer cell. In the first phase of clinical trials, there is another drug designed to block the mutated BRAF protein, which is found in almost half of melanoma patients. This is our joint development with a small biotech company Plexxicon.

It seems to me that the exciting time is coming right now when we can create more and more effective tools with the help of new knowledge and new technologies. Now we have twenty-two molecules at different stages of development. Five of them are planned to be submitted for regulatory approval in 2013. I cannot say that the creation of the drug today is a matter of technique. It's very difficult. I have already given an example of the history of the creation of avastin. But the conviction and passion of our scientists and the whole company allow us to expect that patients will receive this help.

– Once upon a time, mankind dreamed of a universal remedy that could defeat cancer. Now we understand that we need to hit the cancer cell with several weapons at once. Is it possible that in the future, with the help of new technologies, some kind of universal tool will still be created?– I don't think so yet.

Cancer is one word, but even every type of cancer, whether it's breast cancer, colorectal cancer or lung cancer and so on, includes quite a few varieties. And they all behave differently, have different mechanisms, different markers, which are targets for us. It is no coincidence that there is so much talk about personalized medicine today. We must look for approaches not only to different types of tumors, but also to different patients.

– You have always focused on the unique structure of Genentech, unique scientists and the atmosphere in the company, which were the key to its success in the global biotech. Will entering Big Pharma, which is currently experiencing a crisis in development and development strategies (R&D), break this atmosphere?– Genentech has very long-standing ties with the Roche group of companies, which arose even before our company became a member of this group.

Already at the time of the first merger of the two companies, there was an initial agreement that Roche would preserve the unique culture of Genentech, which allows for the effective production of pioneering molecules in highly sought-after areas. We are confident that combining two companies with strong corporate principles and a culture focused on pioneering developments will give our cooperation greater freedom, greater openness and flexibility – both inside and outside the company. I think this cannot but affect the appearance of breakthrough drugs.

Portal "Eternal youth" http://vechnayamolodost.ru23.08.2010