Watching Wolfson

Two years ago, Clive Stanway was strolling around the ornately tiled, 19th century corridors of London's Wolfson Institute for Biomedical Research (WIBR) when he caught sight of a poster that described work on a molecule called geminin.

Geminin represses DNA replication licensing by shutting down the DNA prereplication complex. Research has shown that if you inhibit a cancer cell's replication-licensing machinery with a nondegradable form of geminin, the cell undergoes apoptosis.

Stanway, chief scientific officer at Cancer Research Technology (CRT), a technology transfer company that had recently moved into the WIBR building, saw an opportunity to turn fundamental research into a drug candidate. He talked with Kai Stöber, one of the lead investigators on the project, who was standing by the poster. "He told me he thought it was a great target, and that they were working on a novel approach to developing an inhibitor," Stanway remembers. He suggested his team might be able to screen CRT's compound library for an inhibitor of the licensing machinery. Stöber and his colleagues were enthusiastic, so a collaboration was born. The project is still underway, but has yet to produce results they're willing to discuss publicly.

At WIBR, that's how collaborations work. The institute's goals are to blur the borders between traditional disciplines, encourage groups with different interests to informally cross paths, and develop drug candidates. There are signs that the approach is working: In the 12 years it has been around, researchers at WIBR have produced more than 600 papers (collectively cited nearly 13,000 times according to ISI), six spinoffs, and 31 patents listed on the World Intellectual Property Organization database. Recent research highlights have included the use of recombinant methods to permanently label single cells to map the neural crest origins of the neck and shoulder,¹ and new details on how a nitric oxide-cGMP-dependent pathway controls mitochondrial biogenesis and the body's energy balance.^2,3

The standout feature of the institute is the way it has managed to achieve genuine interaction among researchers of different disciplines, says WIBR collaborator Mary Collins, a researcher based at University College London (UCL). "The interdisciplinary thing is fantastic," she says. "Getting medicinal chemists alongside biologists is quite hard to do in academia."

Jim Smith, director of the Gurdon Institute at the University of Cambridge, agrees. "It's a terrific idea to bring together groups in fields that normally don't speak to one another," he says. "That sort of interaction is where you get new ideas."

The WIBR is the brainchild of Salvador Moncada, a Honduras-born investigator and 40-year UK resident, who achieved notoriety when he discovered the cardiovascular effects of nitric oxide.⁴ In the 1990s, Moncada had a vision: Create a research environment that was better funded than the average academic institute but with greater freedom from the bottom line than a pharmaceutical company. The phrase "bench to bedside" may now be one of the most threadbare clichés in science, but when the Wolfson was getting off the ground, translational research was a novel idea in British academia, says Moncada.

His model was the UK's Wellcome Foundation, where he had been research director for 10 years in the 1980s and 1990s. Remembering those days, Moncada, who keeps his grey hair and beard trimmed short, leans back on his office chair: "Wellcome was without any doubt a very special place," he says. "It combined fundamental research and drug discovery in a very successful way. The idea I had was to recreate Wellcome. I wanted to put the best of academia and the best of industry in the same place ... without direct industry funding of researchers."

When Glaxo bought Wellcome, he decided the writing was on the wall. A new era was emerging in the pharmaceutical industry, in which companies would focus on marketing, and outsource their research endeavors to biotech firms. "When I saw what was happening to the pharmaceutical industry, I knew that such a place [as Wellcome] would not survive."

In 1995, Moncada was looking for a potential home for his new institute, and he began talking to academic centers about his vision. Early discussions with the government-funded Medical Research Council did not progress, but then he heard that the Cruciform building at University College London was available.

As its name suggests, the Cruciform building is a gothic, red-brick edifice shaped like a cross. Designed in 1896 to house a hospital, this 5-story building is situated in the center of London. The wrought-iron balustrades, mosaic floors, and hand-painted illustrated tiling that decorate the building's interior are a long way from the kind of open plan, steel and glass architecture favored by most research institutes these days. But in Moncada's eyes it was perfect, so he made a proposal to the university. The then-provost Derek Roberts quickly accepted, and WIBR was established as part of UCL. Indeed, every WIBR employee has an appointment at UCL.

The next challenge was raising funds. Moncada, together with Roberts and other UCL administrators, set about gathering the cash needed to renovate the building and establish their center. Some £11.5 million came from the Wellcome Trust, another £14.5 million from the UK government, and £10 million from the Wolfson Foundation - a charity that businessman and research philanthropist Isaac Wolfson founded in 1955.

The remainder of the funding came from private finance, and Glaxo Wellcome provided a crucial £7 million toward operating costs in exchange for the rights to any intellectual property that emerged in the institute's first seven years.

Although WIBR researchers generated intellectual property during the Glaxo Wellcome funding period, it was not taken up by the company, which by then had become GlaxoSmithKline. "The collaboration involved good science, but at the end of the seven-year agreement there was nothing of commercial interest to GSK and the collaboration came to an end," says Pauline Page, spokesperson at GlaxoSmithKline, which stopped funding the WIBR in 2002.

Now, the Wolfson Institute for Biomedical Research houses 220 research staff, postgraduate researchers, and related personnel who work in the top four floors of the building. Their research, funded by grants and industry to the tune of £10 million per year, covers cancer and stem cell biology, neuroscience, developmental biology, and mitochondrial and cardiovascular research. This years' income is £10.96 million, of which £1.75 million comes from central UK government coffers. The remainder of the research funding comes from the Wellcome Trust (49%), the Medical Research Council (26%), Cancer Research UK (10%), industry (5%), and other charities (10%).

WIBR also employs a group of medicinal chemists, whose goal is to work with their colleagues to develop drug candidates. Their presence was a key focus for the small team Moncada brought with him from Wellcome. They wanted the institute to offer freedom for researchers to explore their interests, while maximizing the chance that drugs could be developed from their discoveries. "We've always seen drug discovery as being a major part of our niche," says Tony Dunne, one of the core group of founders.

A short walk from Stanway's office, another WIBR group is taking a different approach to geminin, in which they focus on getting the molecule into cells. This collaboration uses a molecular system that Dave Selwood, head of the WIBR medicinal chemistry group, designed to transport proteins. As a shuttle, the researchers use a small peptide constructed to mimic an alpha-helix peptide protein transduction domain. These transporter molecules are designed to be small and easily attached to proteins and other cargo, which they can transport into cells in its native form. Preliminary results show that delivering geminin in this way induces an antiproliferative effect in human cancer cells in vitro.⁵

Today about 25 researchers work in WIBR's fourth-floor chemistry department, many of them trying to identify small-molecule inhibitors of disease pathways identified in labs on other floors. "At the end of the day, we need to get products out," says medicinal chemist John Roffey, a tall Englishman with spiky hair and glasses. Turning from his work at a cluttered fume hood, Roffey explains that he is busy screening potential inhibitors to a cancer-linked lipid kinase, which his WIBR colleagues recently discovered. "For us, success would be defined as getting something into clinical trials," says Roffey. With only 18 months at WIBR, though, Roffey has yet to reach that goal.

Moncada had strong ideas about how he wanted the institute to operate. Part of that plan was to not force connections between medicinal chemist Selwood's team and the rest of the institute. "It just works on a personal interaction level," says Selwood. "Someone might give a seminar or I'll meet someone in the tea room and we'll start to talk about what they're doing and whether we can help with it."

Still, Moncada's intentions are clear. "All of us are encouraged by Salvador to foster links with the medicinal chemistry group," says cancer researcher Chris Boshoff. "Most of the groups at the Wolfson keep that in the back of their minds."

Boshoff, a viral oncologist originally from South Africa, is young, sharply dressed, and busy. He's been at UCL for five years, and Moncada and others recently nominated him to head a new cancer institute that will have close ties to the Wolfson - even physically, in the form of a Victorian-era subterranean tunnel that joins the new cancer institute to WIBR.

Boshoff's reserve gives way to enthusiasm as he leads a guided tour of the new facility, a spanking new building of glass, wood, and formed concrete that sits in stark contrast to the century-old Cruciform next door. Boshoff and other research staff were not due to move into the new building for another few weeks, so its labs are still pristine. Looking out across rooms filled with furniture still wrapped in plastic, he points out sound-dampening ceilings (apparently designed by the architects to mimic the shape of cell structures) and the louvers positioned outside the windows to create a comfortable working environment that excludes exactly 50% of the potentially bright London light.

To encourage connections between the two institutes, scientists will share some core facilities such as electron microscopes, cell sorters, and genome analyzers. Indeed, shared facilities have always been another part of Moncada's strategy to encourage interaction between scientists. "I deliberately arranged the space so that central services were distributed unevenly between groups, to force people to move around," he says.

Some might find such an arrangement frustrating, but it's a strategy that works, Boshoff says. "I think the big thing here is the variety. People are so mixed together, you develop collaborations with them just because you get talking." In 2003, Boshoff saw the benefits of this arrangement in his field, which focuses on the Kaposi's sarcoma-associated herpesvirus. A PhD student, whose time he shared with UCL's Mary Collins, showed how a viral oncoprotein known as vFLIP activates NFκ-B, a transcription factor that plays a key role in regulating the immune response to infection.

"Mary had been interested in the immune response to the virus in cells, and we worked on the virus in my lab," Boshoff says. "Once we found how the pathway works, we started thinking that if we wanted to make drugs to block it, we'd need to start looking at the crystal structure of vFLIP interacting with IKK." The enzyme IKK, otherwise known as IkB kinase, is central to the mechanisms of action of NFκ-B.⁶ Now, WIBR's medicinal chemists are designing small molecules that can interrupt the interaction between vFLIP and IKK, with an eye to potential clinical applications in treating Kaposi's sarcoma.

Collins says the institute has gone from strength to strength during its 12 years. However, she says she wonders if there is a downside to being so multidisciplinary - namely, whether it prevents the WIBR from building visibility in any particular field.

Because WIBR's researchers are divided among several research areas, it may be that they lack the critical mass to attract attention in those specific fields, Collins suggests. "I work in the virology building, and everyone knows that's what we do here," she says. "Being multidisciplinary may make it difficult to build that kind of profile." As evidence for WIBR's relatively low profile, several UK researchers say they are aware of the WIBR but do not know enough about its research to be able to comment in detail.

In a cramped, dark room in a quiet corner of the institute, Matteo Rizzi and Alanna Watt watch a small black and white monitor that displays an image from a nearby two-photon laser-scanning microscope. They are looking at a single mouse neuron that Rizzi has just pumped full of fluorescent red dye. "It looks really nice, Matteo," Watt says with a smile. "Well done."

A couple of minutes earlier, Rizzi, a PhD student from Italy, had spent tense moments delicately guiding a glass capillary into close proximity with the neuron (a Purkinje cell from the cerebellar cortex), while gently blowing through a mouth-piece to create a faint positive air pressure. Once the capillary and cell were touching, Rizzi stopped blowing, allowing the glass to penetrate the cell wall so the dye could be delicately pushed in, filling the branches of dendrites extending from the cell soma. "It's kind of like kissing," he laughs. "You have to be gentle."

The cell Rizzi is working with came from the brain of a mouse expressing channelrhodopsin-2, a light-gated ion channel that allows neurons to be switched on or off by pulses of light. It's a molecule that only recently made a splash in the media, and Watt, a postdoc, is impressed. "I didn't realize you already had the channelrhodopsin," she says. "It's fun to see."

Rizzi and Watt, both members of a research group that Michael Häusser heads, are primarily interested in the refinement of neural circuits during mammalian development. Their channelrhodopsin experiment is mostly about fine-tuning techniques to that end, says Rizzi. Nevertheless, as he turns his attention from the screen to describe the implications of what he is doing, his thoughts immediately shift to how the light-sensitive ion channel could be used in a more clinical setting. "I could imagine using it to look at the role of electrical activity in directing the differentiation of stem cells," he says.

In Moncada's own labs, Alexander Galkin, a Russian postdoc who came to London a year ago from Frankfurt, is studying the change in activity of mitochondrial complex I in the presence of nitrosating agents. Sitting in the cubicle next to Galkin is David Unitt, a former physicist from Cambridge University who is using spectroscopy to measure the effect of cellular nitric oxide concentrations on cytochrome functions.

Neither Galkin nor Unitt have been at WIBR much more than a year, but they are both quick to praise its atmosphere. "There are a lot of very committed, clever people who are quite passionate about the work," Unitt says. "Also, it's a big enough institute so you don't feel like you're stuck in a small group."

It's also clear that Moncada himself is content with the way the institute has developed. "My conclusion after the experience of the past 12 years is that it is possible to have an environment that allows the interface between academia and industry without letting money interfere. I would say in general we have been very successful."

I read in the paper: ?Geminin represses DNA replication licensing by shutting down the DNA prereplication complex. Research has shown that if you inhibit a cancer cell's replication-licensing machinery with a nondegradable form of geminin, the cell undergoes apoptosis?. And soon thereafter it sounds: ?The institute's goals are to blur the borders between traditional disciplines, encourage groups with different interests to informally cross paths, and develop drug candidates?. One has to agree with such noble statements.
Than, only few advices: Since birth, individuals, who will develop a cancer, show both Oncological Terrain ?and? Inherited Oncological Real Risk in one (or more rearly some) biological system, detected bedside in a few minutes with a stethoscope as you can realize asking Google.com! Well. In my opinion, beside Coniugated-Melatonin plus NIR-LED application cicles on diseased biological system, that proved to be very efficacious in treating these dangerous condititons, also Geminin could play a central role, so I forsee, since forecasting is scientific in nature? . Here it?s a paramount example of aiming ?to the goal to blur the borders between traditional disciplines, encourage groups with different interests to informally cross paths, and develop drug candidates?. Is it true, isn?t it?
Above-referred consideration accounts for the reason I am now awaiting Moncada's answer via The Scientist!