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June 3, 2002
Volume 80, Number 22
CENEAR 80 22 pp. 22-26
ISSN 0009-2347

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Serono Researchers Expect The Unexpected

From the time Serono was founded in 1906, research has played a crucial role in its growth. Research, of course, is an absolutely essential ingredient in the success of pharmaceutical and biotechnology companies. But everyone at Serono agrees that a critical turning point for research and the future of the company occurred on Oct. 1, 1997. That's the day that Glaxo Wellcome announced its intention to close the Geneva Biomedical Research Institute.

Ph.D. chemists Timothy Wells and Eric Kawashima were Glaxo Wellcome employees back then. It was not a happy time. "GBRI was built to bring Glaxo into the molecular biology era," says Kawashima, now assistant head of discovery at Serono. "Then Glaxo fired almost everyone. We were all very depressed."

Serono Chief Executive Officer Ernesto Bertarelli read about the closure on a plane en route to a business meeting. Six weeks later, he bought virtually the entire operation--130 people and the facility. "We reset our attitude and said, 'Let's do this for Serono,'" Kawashima says.

"This" was establishing a counterpart to Serono's Reproductive Biology Research Institute, which is based in Boston and focuses on reproductive biology and endocrinology. The counterpart would be an institute aimed at discovering new therapeutic solutions in immunological, autoimmune, and neurological diseases and developing them as far as the preclinical phase. The vision for what became the Serono Pharmaceutical Research Institute was provided by Silvano Fumero, Serono's head of research and pharmaceutical development, and Wells, now vice president of research and head of discovery.

Fumero notes that Serono has moved in the past two decades from a company whose products came primarily from extraction of biological fluids to one whose products result from understanding the human genome. "Our mission is to understand our molecules and the pathway from the gene to the disease," he explains.

This involves eight steps, all of which are carried out at Serono or in collaborations with universities, research institutes, and other companies: mining the genome for novel secreted proteins, using selective gene-splicing technology, applying protein conformation remodeling technology, creating computational lead prediction technology, synthesizing rationally designed small molecules, developing genetically engineered pharmacological models, using expression technologies and multiple processing, and designing drug-release formulation technologies.

"In 1998, everything began taking off," Wells says. "Serono had one major therapeutic area: infertility." It did not have a particularly strong drug pipeline, but it had a lot of enthusiasm. "We had to deliver molecules that were active in year two of the research program. In a big company, you focus on barriers, what will stop you. But at Serono, we have a culture of trying to make everything happen.

"At SPRI," Wells adds, "we attract the best scientists because we create an atmosphere that allows them to excel. We have an open, informal management style that emphasizes teamwork. We look for the right balance between encouraging individual initiative and achieving our common goals as one of the world's leading biotechnology companies. These goals include discovering novel targets in key diseases and finding proteins and small molecules as therapeutic agents that will act on these targets."

SPRI has 170 people and as many as 30 visiting students and scientists who work in five major divisions. Wells describes the departments: "The molecular biology department uses genomic technologies to discover new therapeutic proteins and to identify new drug targets. DNA sequencing, differential gene expression, proteomics, and functional genomics are combined to decipher the function of new genes in health and disease. The cellular biochemistry department focuses on identifying the key points that control disease mechanisms and their targeting by proteins, peptides, and low-molecular-weight compounds to modify disease progression.

"The biotechnology department," Wells continues, "provides a state-of-the-art drug discovery platform with high-throughout screening for the discovery of biologically active small molecules." Dennis Church, trained as a chemist and biochemical pharmacologist, has developed novel small molecule substructure searching algorithms that are based on the concept that pharmacological action is dictated by chemical determinants that are contained in the 2-D structures of molecules. Using these methods, his team has mapped the chemical determinants associated with over 800 biological outcomes. It uses the information to design compound libraries for screening against selected drug targets using different robotic systems, thereby delivering the first starting points for the drug discovery process.

"The experimental biology and pharmacology department focuses on understanding fundamental mechanisms underlying healthy immune responses and immunopathologies," Wells says. "This knowledge is then applied to areas of strategic interest for Serono in order to validate novel targets and test hypotheses leading to the generation of new therapeutics."

Chemistry is the fifth department. "'Chemistry creates its object,'" Wells says, quoting the 19th-century French chemist Marcellin Berthelot. "We harness the creative power of chemistry for design and synthesis of 'objects' in order to find new drugs."

Immediately after Serono took over the institute, Wells realized that Serono was lacking in the small-molecule side of the drug discovery process and that it was very important to have biology and chemistry in one place. Chemists have a different world, a different way of understanding, he believes. Biologists understand the disease function, and chemists make the target molecules that can interact in the disease process. "So we built a chemistry department in Geneva from scratch," he says.

Serge Halazy, who is now worldwide head of chemistry at Serono, was the first hire in the chemistry area; he now has 59 chemists reporting to him (43 in Geneva, 16 in Boston). He has worked at Marion Merrell Dow and the Centre de Recherche Pierre Fabre in France.

"Building a department is fantastic--you choose excited, enthusiastic people who are problem solvers," Halazy says. In his group, chemists work on projects from start to finish: taking a hit--a molecule active against a protein involved in a disease process--and modifying it until it is a lead, that is, a molecule active in an in vivo model with acceptable toxicity and potency.

In parallel with this process, they look at the druglike profiles of the molecule--solubility, stability, and so forth. The goal is to optimize the lead to get it into preclinical trials. "The price you pay is that each chemist will need to learn new technologies and new specialties all the time," he says, "but we've been able to do that." Halazy's group works on molecules for each of Serono's major therapeutic areas with strong support from "design technologies" experts including protein crystallographers, computational chemists, and cheminformaticians.

Work in one relatively new area for Serono, neurodegenerative diseases, takes place in the team headed by Claudio Soto. His researchers are studying the process of protein folding and how to prevent the formation of amyloid plaques found in such neurodegenerative diseases as Alzheimer's and new-variant Creutzfeldt-Jakob disease, the human equivalent of bovine spongiform encephalopathy ("mad cow" disease). Soto points out that plaque formation is also important in 90% of type 2 diabetes patients, who have amyloid plaques in their pancreas.

Mad cow disease is caused by prions, a modified form of a normal protein. In prion-caused diseases, the normal protein adopts an abnormal shape known as the beta sheet. Serono's researchers developed an engineered peptide called a "beta-sheet breaker" that reverses the process, causing the prion to revert to a normal shape that is no longer infectious. The ultimate goal is to get a drug into Phase I trials with human volunteers in the near future.

Soto's group also made another breakthrough in detecting prions. Using cyclic amplification (C&EN, June 18, 2001, page 9), Soto's team developed a simple technique for converting the normal form of prion protein into the abnormal form. The technique is called protein-misfolding cyclic amplification and is like a polymerase chain reaction for prions. PMCA could result in the possibility of more sensitive diagnostic tests.

In its traditional area of reproductive health, Serono scientists also discovered a small-molecule antagonist of the oxytocin receptor that is being tested for the prevention of premature childbirth. Oxytocin is a hormone that triggers labor contractions leading to delivery of the baby; in about 10% of all pregnancies--more than 600,000 cases in Europe and the U.S. every year--the hormone is secreted too early in the pregnancy. Currently, there is no effective treatment to counter the effects. Serono's lead compound, which was optimized in the chemistry department, is in the preclinical phase and is expected to enter Phase I trials in 2003.

Other research at Serono takes place at facilities in Ivrea and Ardea, Italy (preclinical research and regulatory safety studies as well as formulation and analytical development), and in Corsier-sur-Vevey, Switzerland (biotech process development).

"In R&D," Fumero concludes, "we have discovered that small, interdisciplinary teams are the best way to make real breakthroughs. These teams share insights, challenge individual assumptions, and pursue the unexpected. The result is a working environment that fosters creativity, the source of our success and the engine of our future."

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Serono Researchers Expect The Unexpected


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