Why teamwork is better than attempting lone heroism in science

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Why teamwork is better than attempting lone heroism in science

A story of failure, collaboration, and incredibly tiny medicine

The best way for scientists – or anybody, really – to address shortcomings after experiencing failure is teamwork. And never has that been more clearly apparent than in the story of Doxil, the first nanomedicine, which failed multiple times before a resourceful team cracked the code.

Nanomedicine is the application of nanoscale technologies (think about it as really, really tiny pieces of matter – 10,000 times smaller than a strand of hair or 100 times smaller than a red blood cell) for the prevention, diagnosis, treatment, and study of disease and human health. It’s pretty successful at getting funded as well – privately held nanomedicine companies (such as Nanobiotix) are getting a lot of money – in the tens of millions of dollars – from pharmaceutical giants such as Pfizer and Merck.

Not unlike research

Arxiu Ismael Latorre Mendoza

But nanomedicine wasn’t always such a buzzworthy topic – it really hit the scene in the 1990s when an anti-cancer drug called Doxil became the first FDA-approved nanomedicine-based therapy thanks to a multinational team headed by biochemist Yechezkel Barenholz at Hebrew University in Jerusalem.

Decades in the making

Barenholz believed as far back as the late 1970s that chemotherapy could be improved by placing anti-cancer drugs in nanoscaled carriers made of lipids – the stuff that forms the membranes of all the cells in our body. Placing the free-floating drug molecules into carriers takes advantage of the enhanced permeability and retention (EPR) effect, in which nanosized particles in the blood stream should enter and accumulate in solid tumors more easily than in healthy tissue.

One of the characteristics of tumors is their rapid growth, causing blood vessels to grow abnormally, which results in tiny gaps in the vessel walls that nanoparticles can pass through easily. Another consequence of rapid growth is the suppression of "lymphatic drainage," meaning that the lymph fluid in tumors can't clear out waste products and nanoparticles as effectively as in healthy tissues, causing more accumulation in tumors than in the rest of the body. Ideally, placing the drugs in nanocarriers would cause fewer side effects and require smaller doses as a result.

Barenholz began to develop early prototypes of such a drug in 1979 with oncologist Alberto Gabizon. But in 1987, that trial drug, called OLV-DOX, failed its clinical trial. The carriers were too large; they didn’t have enough of the drug inside of them to be effective, and they were readily destroyed by the body’s immune system.

In the interim, though, Barenholz started a parallel project as part of a team. In 1984, after chatting with an old colleague from UC–San Francisco, Dimitri Papahadjopoulos, Barenholz was convinced to take a sabbatical at Papahadjopoulos's startup, Liposome Technology Inc. (LTI) in California, on the condition that LTI would support the ongoing Doxil research at Hebrew University at the same time.

Second time's the charm

In the 1990s, Barenholz and his team at LTI worked together on what they called “stealth liposomes.” An outer layer of a polymer called polyethylene glycol (commonly called PEG) was added to the lipid carrier to extend the circulation time of the liposomes. This polymer is very hydrophilic – it interacts well with water, so that the closely packed water molecules at the surface of the liposome will prevent the liposomes from interacting with any proteins or cells in the blood stream, allowing them to reach their intended target.

At the same time, Barenholz was working in his lab in Israel to figure out a way to make the nanocarriers smaller while still being able to put enough of the drug inside to make the treatment effective. These teams patented these new technologies by 1989, and the new and improved OLV-DOX, now called Doxil, began clinical trials in Jerusalem in 1991.

The rest is history. FDA approved in 1995, the team was excited to have brought the first nanomedicine to market. Even though another research and development company approached Barenholz with a large sum of money and royalties for the rights to the early Doxil prototypes, he stuck with LTI, believing that he would have more control and success with the team there. (LTI is part of Johnson & Johnson today.)

In some of the last words of his reflective and personal review, Barenholz wrote that he wants to transfer his experience with Doxil development and eventual approval to researchers worldwide. He leaves us with an overarching lesson that anyone can learn from: collaboration is an essential part of successful science and is undervalued most of the time in the pursuit of great personal discoveries.

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Josh Peters

Biological Engineering

Massachusetts Institute of Technology

Barenholz's situation nicely highlights the strength of collaboration between public/private companies and academic labs. This collaboration helped drive translation from Barenholz's academic lab to patients. I would expect this model is becoming more prevalent as funding competition increases and translational impact is increasingly scrutinized, as highlighted by recent proposed legislation. Labs provide a nimbleness and quick proof-of-concept, whereas these companies offer the infrastructure to test and scale – both parties reap big benefits.

Danbee Kim

Comparative Neuroscience

Champalimaud Foundation

As someone with family members who have gone through chemotherapy, how accessible are current nanomedical treatments for the average cancer patient? I'm wary of collaborations between research labs and commercial companies, because it can be hard to overcome the financial interests of companies. While I agree that such collaborations can help research projects progress from proof-of-concept to scalable production, research is at its essence a common enterprise, and the principles of research integrity can often clash with the principles of good business. I do appreciate the pro-collaboration message, and I'm curious now to learn more about the many people who contributed to this breakthrough research.

Samantha McWhirter responds:

I can't make a definitive comment on the accessibility of nanomedicines for cancer patients - I am not knowledgeable enough on that side of the equation to make a general statement. However, I know that there are currently more than 10 nanomedicines (I want to say 13?) that are approved for clinical use in the US/Canada at this time. An interesting comment that was made during a panel discussion at a nanomedicine conference I was at recently was that it is apparently much easier to get new nanomedicines approved in Europe than over here in North America; these therapies may be more accessible there.

I also think that your comment on collaborations is also very interesting, because this is a conversation that happens a lot within the nanomedicine field. I can only speak for funding in Canada, but there is a lot of funding for proof-of-concept studies in academia and not a whole lot for researchers to do more translational stuff, like making the nanomedicines/diagnostic methods more user-friendly to really make a difference in the clinic. 

I think this is the reason a lot of academics who are truly trying to get their innovations into the clinic will collaborate with companies or start their own and raise the money for it from investors. But it is true that companies and academics do have very different goals (innovative, good science vs profitability) and this causes a lot of frustration between the two groups. But I do believe that both are necessary in order to advance these nanomedicines. There are a lot of hoops to go through for a nanomedicine to be FDA-approved, so hopefully this means that research integrity can't be ignored by nanomed companies.

Danbee Kim responds:

It's a truly paradoxical situation -- on the one hand, getting this research translated into clinical methods is obviously good and desirable; on the other, how does research integrity play well with business goals? I'm curious to know how nanomedicine deals with the resulting frustrations, as many other fields of science research face a similar dilemma (neuroscience for sure faces this dilemma). I feel like these fields could learn from any progress made in insuring research integrity when collaborating with companies.