Structural elucidation: to ensure that drug products can dock at a specific point in the body, scientists have to understand the precise structure of the target. They can then develop an active substance that binds at this exact site. Bayer colleagues from Structural Biology like Tina Stromeyer therefore support the scientists by investigating crystal structures under the microscope.
All around the world, pharmaceutical researchers and patients are united by a huge mission: the search for powerful treatments capable of prolonging life and offering completely new therapeutic options. Bayer’s experts are therefore cooperating with top scientists from around the globe, for example the United States and China. They want to jointly develop creative approaches for new drug products to treat, for example, cancer, cardiovascular diseases and lung diseases. Bayer’s scientists hope that this combined innovative strength will be able to enhance people’s lives.
Challenge: Powerful treatments need real innovations, so that they can improve and extend the lives of patients.
Solution: Bayer experts are therefore cooperating with top scientists in China and the United States among others. Together they are developing new approaches for diseases such as cancer, cardiovascular disease and lung diseases.
Benefits: This is to lead to the development of innovative treatments even for patients who previously had few or no therapeutic options.
Pharmaceutical research is a risky business: innovative ideas can crash and burn on their way to becoming a new drug - but they might just hit the bullseye and enable patients to live a better life. The latter include individualized cancer treatments, for example, or innovative active ingredients for patients with hemophilia that might no longer have to be injected. Bayer’s scientists are among the researchers searching for these innovations, in many cases arising on the very fringes of our constantly expanding medical knowledge. "To really set new therapeutic standards or help patients for whom we don’t yet have treatments, we need medical breakthroughs,” explains Professor Andreas Busch, Head of Global Drug Discovery at Bayer HealthCare.
The search for new paths to the limits of the known world – in the most varied of disciplines – is best traveled together in a network with top scientists from all over the world. The need is great. Take lung cancer, for example: "Some lung cancer patients have a mutation in a specific gene, and we can help these patients. But for others, however, there’s not much we can do. It depends on where precisely the gene is mutated,” explains Dr. Matthew Meyerson, a pathologist at the Dana-Farber Cancer Institute in Boston, USA. Meyerson played a leading role in the development of two therapies for lung cancer patients, and is now collaborating with Bayer researchers to find new approaches. "Our knowledge of the specific characteristics of many tumor cells is now so extensive that we can transform it into breakthrough innovations for patients with different types of cancer if we join forces to work together,” explains Dr. James E. Bradner, an oncologist at the Dana-Farber Cancer Institute. He and Meyerson are also each in charge of their own research laboratories at the globally renowned Broad Institute, Boston, USA. Bayer recently began collaborating with this important cooperation partner in the search for new cancer treatments.
To help patients for whom we don’t yet have treatments, we need medical breakthroughs.
Prof. Dr. Andreas Busch, Head of Global Drug Discovery at Bayer HealthCare
Our knowledge of the specific characteristics of many tumor cells is now so extensive that we can transform it into breakthrough innovations for patients with different types of cancer if we join forces to work together.
Dr. James E. Bradner, Oncologist at the Dana-Farber Cancer Institute
Cooperation for New Cancer Treatments: Intensive Dialog with Researchers from the Broad Institute
The Broad Institute unites scientists from Harvard, the Massachusetts Institute of Technology (MIT) and several hospitals under one roof and is a pioneer in the field of oncogenomics. For example, the scientists are searching for gene mutations that are typical for various types of cancer and could therefore offer targets for new treatments. To find such genes, the researchers employ state-of-the-art technology to analyze multiple tumor genomes from patients and then compare them with genomes from healthy cells of the same patients. "That allows us to identify precisely the points at which the cancer cells differ from normal cells,” explains Dr. Barbara Nicke, a biologist at Bayer HealthCare. Many of the pathological cells in genetic material can be divided into two groups – mutations in oncogenes that promote cell reproduction and mutations in what are called tumor suppressor genes which are then no longer able to halt cell growth.
Once these cancer drivers have been identified, Nicke and her colleagues get working to experimentally investigate the significance of these genes in the laboratory. Bayer scientists are now able to exchange notes with the experts at the Broad Institute and thus benefit from their experiences. And their combined knowledge is also useful when it comes to selecting potential development candidates later on: "Our substance libraries complement each other well and open up completely new opportunities for patients who currently have no treatments available,” says Dr. Florian Pühler, Alliance Manager at Bayer HealthCare, who is based in Boston to support the collaboration locally.
While many of the biological mechanisms involved in cancer research are already understood in great detail, the mechanisms in other areas have still to be discovered. "That’s why we often collaborate with outstanding scientists from academic research institutions,” explains Dr. Chris Haskell, Head of the Bayer HealtCare Science Hub in San Francisco, USA. An expert group headed by Bayer scientist Dr. Ye Jin and Professor Charles Craik from the Department of Pharmaceutical Chemistry at the University of California San Francisco (UCSF) has investigated a mechanism used by the innate human immune system to protect the body against foreign objects and intruders: NETosis. In the event of an infection, specific cells in the immune system called neutrophil granulocytes release a sort of spider’s web of DNA that becomes loaded with antimicrobials. This net traps microorganisms and is capable of destroying them.
It takes up to
to develop a drug product from drug discovery to approval.
Bayer CoLaborator: Inspiring Environment
The CoLaborator concept shows how individual companies can benefit from a scientific network: the start-up company Xcell Biosciences, for example, rented premises on Bayer’s Mission Bay site in California close to Bayer HealthCare’s own research labs. "Their technology looks very promising to us,” explains Dr. Chris Haskell, Head of the U.S. Science Hub. The "Avatar” platform developed by Xcell Biosciences aims to very specifically analyze a patient’s cancer cells: the cancer specialists plan to use blood samples to determine which drug products would be appropriate for a specific tumor. "We’ve already built up and consolidated our scientific network in these innovative surroundings,” confirms Brian Feth, founder of Xcell Biosciences. There are also opportunities for young life science companies to rent laboratory and office space in the immediate vicinity of Bayer research departments in Berlin. The aim is to promote scientific dialog above and beyond company boundaries.
But as useful as this mechanism is, "an increasing number of inflammatory and autoimmune disorders are known to trigger an excessive NETosis response, destroying adjacent cells or even causing thrombosis,” says Jin, explaining the unwanted side effects. Such disorders have also been observed in rheumatoid arthritis and lung diseases such as cystic fibrosis or allergic asthma. With the help of the expertise of Craik’s team, Jin and her colleagues have identified and analyzed the neutrophil granulocytes’ main weapons: "Certain enzymes known as proteases appear to play a key role in the NETosis function and could therefore be attractive diagnostic markers as well as a potential target for new therapies,” says Jin. NETosis may also be significant in a variety of cardiovascular diseases. img Active ingredient purification at laboratory scale: new drug products manufactured using biotechnology are produced in... Bayer scientists are therefore working together with their experienced colleagues from UCSF in the search for approaches to regulate NETosis. They have already identified four key proteases that are now being further investigated. "The project shows how knowledge can be gained if top scientists from both academia and industry cooperate closely,” says Busch. After all, without the joint efforts and knowledge contributed by both sides – UCSF and Bayer – the project probably would not have been so successful: "We have a lot of experience and the appropriate technologies for analyzing proteases and their activities,” explains Craik. His team was able to learn from Bayer how this knowledge can ultimately be used in pharmaceutical research and integrated into a project plan.
New projects like NETosis research can be risky for all involved parties. On the one hand, they could generate an innovative therapeutic approach, but they could just as likely lead to a dead end. "But if you want to achieve breakthroughs, you mustn’t be afraid of failure. Innovations always involve some risk - that’s something we can and have to consciously factor in,” explains Busch. The NETosis project was likewise divided into different risk stages. After an initial experimental phase, the results were evaluated by both sides and the decision was taken to continue the project.
Good Mix: High-risk Projects Involving New Technologies and Concrete Research Projects
Collaborations between universities and industry can be extremely successful, which is also being demonstrated by the strategic partnerships with top scientists on the other side of the planet - in China. "We’re relying on a good mix of more high-risk start-up projects involving new technologies, for example, and concrete research projects,” explains Dr. Jing-Shan Jennifer Hu, Head of the Bayer HealthCare Innovation Center China in Beijing. Here, a group headed by Professor Hilmar Weinmann, Division Head of Medicinal Chemistry at Bayer HealthCare in Berlin, Germany, is working together with Professor Xiaoyu Li from Peking University on setting up DNA-encoded substance libraries. Bayer researchers will then be able to use these in the future to search for new starting points for therapeutic molecules thanks to a highly efficient technology.
What is special about this technology is that each tiny molecule is labeled with a kind of barcode – a DNA fragment. "That means that we will require less effort in substance logistics and will be able to test extremely large substance libraries with great efficiency,” explains Weinmann. If the pilot project continues in such a promising fashion, the technology could also be applied elsewhere, and could become an important additional method in the future, both in the search for new molecules in cancer therapy and for other diseases. However, the project would not have been viable without the chemical expertise from Peking University: Li’s team generated both the DNA codes and the final molecule library. "This dialog with other experts and renowned institutions strengthens the spirit of invention in our teams, inspires lateral thinking and thus paves the way for new technologies and treatments,” says Busch.
Defense with Different Strategies
Our immune system is responsible for defending the body against bacteria, viruses, fungi, parasites and other harmful environmental factors and preventing infections. The human body has developed two mechanisms for this: one is the innate immune system, which reacts quickly and has a relatively non-specific action. It triggers inflammation reactions, for example, including NETosis. The other mechanism is more specific and specifically targets substances that the body considers foreign. This system requires a little more time to react and is known as the adaptive immune system. It can identify intruders and recognize them again in the case of a second infection. The two mechanisms complement one each other.
Search in High-throughput Screening
Once the molecular target for a new therapy has been discovered, scientists have to find a substance that can capture or influence this protein molecule. They do this by developing a chemical compound that fits particularly well - like a key in a lock. The scientists find a suitable key by looking in substance libraries. These contain millions of chemical compounds that have already been manufactured by scientists. The challenge is to comb through these huge quantities to find the most promising candidates. This is done by means of high-throughput screening, which is capable of quickly and above all completely automatically testing the effect of numerous substances in the lab. Robots mix tiny quantities of the biological target proteins with the individual compounds from the substance library to produce small samples.
The value of this approach has also been demonstrated in the work to develop a new active ingredient for hemophilia patients; here too, cooperative input from experienced experts has proved its worth. "We’re looking for a substance that prevents excessive blood loss and can be taken in tablet form,” explains Dr. Martina Schäfer, a structural biologist at Bayer HealthCare. The researchers’ idea is to block a specific enzyme that plays a key role in fibrinolysis, the process involved in dissolving blood clots. "If we can successfully inhibit this enzyme, we will be able to promote wound healing, a mechanism which no longer works correctly in many hemophilia patients,” explains Schäfer. The substance is currently in the development phase and could mean that patients suffering from hemophilia no longer have to inject coagulation factors in the future.
But the enzyme – a protease – is tricky. "To inhibit the targeted function, we need a molecule that fits perfectly into its 3D structure – and nowhere else,” says Dr. Ursula Egner, Head of Structural Biology at Bayer HealthCare. Once a potential drug candidate has been found, it has to be further optimized. For this, Schäfer and her team produce 3D models of crystal structures on the computer. First, however, the Bayer experts have to understand the structures of the two molecules and how they bind to one another. "We get this information from the crystal structures of the respective molecular complexes,” says Schäfer.
Each Molecular Complex Involves Different Challenges – and Necessitates New Partners
Investigating the chemical compounds requires a great deal of skill and experience with different solvents and other chemicals, because every molecular complex is different and involves new challenges. The Bayer experts are therefore constantly searching for different partners with exceptional expertise. In the hemophilia project, they found the ideal partner in Professor Haitao Li from Tsinghua University in Beijing. "Li’s team generated valuable crystal structures for us, and used a substance for protein purification that we now use routinely ourselves,” says Dr. Naomi Barak, Alliance Manager at the Bayer HealthCare Innovation Center China and responsible for the collaboration with Tsinghua University. But Li also learned a lot from the colleagues at Bayer as well: "I’ve gained a valuable insight into active substance development and learned a lot about new hemophilia treatments,” says Li, who has been working mainly in structural epigenetics research.
Enhancing the Quality of Life for Hemophiliacs
Hemophilia is a condition that mainly affects men. Sufferers lack a specific factor in their blood coagulation and therefore have a tendency to bleed severely, which can have dangerous consequences. Approximately 400,000 people around the world suffer from hemophilia A. The condition cannot be cured but it is now possible to administer the missing factor intravenously. However, the relevant protein breaks down in blood over time, so it has to be administered at regular intervals, several times a week. Bayer scientists are currently working on extending the duration of action of the coagulation factor in blood to improve the quality of life for patients.
Focus on Benefits for the Patients: Further Strengthening the Global Innovative Power in Fringe Areas as well
Regardless of which research area the cooperation partners are operating in – "the focus is always on the direct benefit for the patients,” says Busch. Particularly important for the future for him will be to make sure that the company does not concentrate too closely on individual projects. "We have to keep an eye on the fringe areas as well so that we can find spaces for potential new treatments,” explains Busch. The hemophilia project likewise has potential that extends far beyond a drug product only for hemophilia patients: "A second feasible application, for example, could be a tablet for women who have heavy menstrual bleeding,” says Bayer scientist Schäfer. Yet another indication could be the prevention of heavy blood loss during organ transplantation.
So innovative power is not something that is going to run out at Bayer any time soon. To reach patients all over the world, Bayer scientists are committed to collaborating with renowned partners all around the globe, venturing together with them into new scientific terrain.
Interview: Dr. Stuart Schreiber
"Research for Patients"
Dr. Stuart Schreiber is one of the four founding members of the Broad Institute, Boston, USA. The renowned non-profit research institute unites outstanding scientists and oncologists under one roof and has comprehensive expertise in tumor biology and cancer medicine.
Which projects in the area of cancer research do you regard as particularly promising?
Cancer cells are robust and extremely hardy. We are gradually learning that tumors can develop like organs. Precisely this cell differentiation process is a target for cancer treatments, which makes it very interesting. There are also a number of new targets in tumor therapy known as epigenetic targets that I believe are very promising.
What does the collaboration between Bayer and the Broad Institute mean to you?
We at the Broad Institute are primarily focused on early biomedical research. Bayer is the first partner we have had that has a lot of experience in transforming early-stage developments into medications that are approved for patients. There are many new aspects here for us, and it’s very exciting to be traveling down this road together with Bayer.
How will patients benefit from the research being conducted at the Broad Institute in future?
Our therapy development is strongly focused on patient needs and is closely linked to human biology and the individual characteristics of the cancer patients themselves. We believe that we can develop new and efficient drug products much more quickly.
Interview: Dr. Karl Max Einhäupl
Professor Karl Max Einhäupl is a neurologist and Chairman of the Executive Board of Europe’s largest university hospital: the Charité in Berlin employs 16,000 nurses, carers, doctors and scientists who attend closely to their patients’ needs.
Which treatments are patients pinning their hopes on in particular at present?
Patients want to be able to benefit from new treatments as quickly as possible and they should be available at affordable prices.
How do patients judge whether new treatments are a success or not?
They assess the success of their treatment on the basis of the ratio of its efficacy to its side effects. Patients are increasingly well informed, and in more and more cases they consider whether they wish to expose themselves to the potential risks before undergoing treatment.
In your opinion, in which clinical picture has the greatest progress been achieved in recent years?
As a neurologist, I can confirm that my field has developed from a relatively limited discipline into one in which therapeutic options are now available. We are seeing considerable progress in diseases such as Parkinson’s disease, dystonia, epilepsy, multiple sclerosis and other severe infections of the central nervous system.
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