insight
工程技术，地产投资，信仰家园，时尚生活
- PHOTO: YEN MENG JIIN
'If I had to pick between great management or great science, I would pick great management. If there is great management but the science is wrong, you can change the science'
- Prof Sharp when asked if a system of state-directed capitalism like Singapore's can produce results for research companies
THE most exhilarating thing about the life sciences, to hear Nobel laureate and genetics pioneer Phillip Sharp tell it, is that there are still so many discoveries to be made.
His own prize-winning discovery of the split structure of genes in 1977 laid the foundation for his student to make a discovery in 1998 with commercial applications: RNA interference, where disease-causing genes can be shut down by certain molecules. Nasdaq-listed Alnylam Pharmaceuticals, the company he co-founded in 2002, is a market leader in the race to find a commercial application for this discovery.
"There are other companies in the field but they are a tenth of our size. We started earlier than the others, got the intellectual property and the financing, and are pushing the technology as hard as we can," Prof Sharp tells The Business Times.
Alnylam is approaching the final clinical trial stages of testing a drug that, if successful, has implications beyond just treating the ill.
If the drug is successful, it will have implications for the entire biopharmaceutical industry. For one, the lengthy drug development process will be sped up, cutting costs and bringing in bigger profits for pharmaceutical companies which will be protected by drug patents for longer.
The market has recognised the potential. Alnylam has rocketed from about US$15 a share a year ago to well over US$60 a share in September.
"The big challenge in pharmaceuticals is how to invest and recover your research. It takes typically 10 years of investment before you begin selling the product and capturing the return before you lose the exclusivity of the patent," he says.
If Alnylam's technology works, "give me the target gene sequence and I can design the target-silencing RNA within two months".
RNA, like the more well-known DNA, is a strand of chemicals that make up the genetic code explaining how living organisms and viruses function. RNAs were known previously as messenger boys for DNA, carrying a coded set of instructions from DNA to tell cells what proteins to make.
But in 1998, Prof Sharp's student Andrew Fire and fellow scientist Craig Mello discovered that tiny double strands of RNA, known as small interfering RNA or siRNA, can silence, or shut down, the function of any gene.
The discovery, called RNA interference, won the pair the 2006 Nobel Prize in Physiology or Medicine. It also led Prof Sharp, who also co-founded drug giant Biogen (now Biogen-Idec) in 1978, to set up Alnylam in 2002. Alnylam began working on a way to use the knowledge to treat diseases, which were often caused by faulty genes that induced the production of disease-causing proteins.
After 10 years and US$1 billion spent, Alnylam is within two to three years of a breakthrough, he says. By the end of the year, it is aiming to begin Phase III trials, the final, large-scale testing of drugs, on patients affected by an inherited mutation in the gene TTR (transthyretin) that causes damage to nerves and heart problems and is fatal within 10 years without a liver transplant.
In this case, RNA has been designed to target the TTR gene and delivered via drip, and positive results on patient trials were announced in June. Another way to deliver the silencing RNA through an injection was announced in July. Researchers have found a way to move large, water-loving RNA molecules across cell membranes without getting dissolved, by encasing the molecules in water-repellent fats in a tiny particle measuring billionths of a metre, called a nanoparticle. A successful clinical trial addressing TTR problems will benefit patient numbers to the thousands to tens of thousands. Many more diseases can also be addressed. "We have to show to the world that it works. This hasn't been done before," Prof Sharp says.
Revolutionising drug design
Prof Sharp believes the ability to design a gene-silencing molecule to tackle a disease is part of a new revolution in drug therapy, which he coins "modular therapeutics". This refers to how one known entity can be combined with another to make a drug, just like how electronic components are assembled together in an iPhone. Traditional drug research does not work this way. The chemical compound that will finally form the drug is not known at the beginning.
Researchers have to figure out what kinds of cells or proteins diseases target and test new molecular compounds to see what might interact with the target. Once a promising compound is found, it is modified for safe use in humans, before the trial stage. This process takes many years.
By contrast, the modular approach to discovering drugs assembles known tiny fragments of a molecule and links them together, much like how interfering RNA is paired with a nanoparticle to form a drug. This method is faster and circumvents the need to screen a large number of compounds.
Hype about similar methods in the field of nanomedicine has been around for years, but momentum is building this year. In February, Kadcyla, an antibody and drug mix developed by Swiss healthcare firm Roche, won US approval in February as a way to treat an aggressive type of breast cancer. Kadcyla moves the drug directly to the cancer cell, minimising damage to healthy cells.
Since January, privately held nanomedicine company Bind Therapeutics struck deals with drug giants Amgen, Pfizer, and AstraZeneca to fund the development costs of nanoparticles that target tumours.
Moreover, the costs of DNA sequencing to work out the precise order of chemicals within a DNA molecule have fallen significantly over the years.
"Now, we can sequence DNA from every plant, microbe, lifeform, hundreds of thousands of different genes with structures we've never seen before. Every one of them provides material to make new biological entities that we've never made," Prof Sharp says.
Combining engineering and biology
More advances in technology will be made in the future as the life sciences are integrated with the physical sciences, engineering, mathematics or computational science. Researchers are tapping the ability to store and process large sets of data, make materials on the nanoscopic scale and blend them together, and measure, image and control things at that level.
Institutes have sprung up to bring people from different disciplines together.
Prof Sharp is a professor in one of them, the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT), together with another nanotechnology pioneer, Robert Langer.
The institute's work includes exploring how white blood cells in the human immune system can be engineered to fight cancer and designing nanotubes to monitor tumours after surgery, or using them to guide surgery.
"We have a beer party every Friday afternoon, bringing together graduate students with postdocs. If an engineer and a biologist work together on a project, we can support it with funds," he says.
The institute is supported by a hub of businesses and start-up companies that have sprung up around Kendall Square by MIT and includes drug and biotech companies Novartis, Genzyme, Pfizer, Amgen, and tech giants Microsoft and Google.
At a conference in Singapore at the end of October, Prof Sharp spoke about his work at an event organised by Exploit Technologies, the technology transfer arm of A*Star, the Agency for Science, Technology and Research. He was asked by Nanyang Technological University (NTU) president and noted plant biochemist Bertil Andersson about how long it will take for Singapore's own Biopolis biomedical research hub to achieve similar success.
While Biopolis has only been around for 10 years, there is "some impatience... when will the deliveries come, when will the KPIs (key performance indicators) be fulfilled," Prof Andersson said, to knowing laughter from the audience of researchers, administrators and students.
Prof Sharp replied that even with the breakthrough discovery of the double helix structure of DNA in 1953 and the establishment of a research community in Harvard and MIT in the late 1950s, it was not until the 1970s that any impact was made. Moreover, private capital is needed to take some of the risk of research, he says.
Can a system of state-directed capitalism like Singapore's work, then, Prof Andersson asked. "It can work if you have the commitment to the endeavour," Prof Sharp replied. "If I had to pick between great management or great science, I would pick great management. If there is great management but the science is wrong, you can change the science."
Role of bioscience
But picking winners, especially among small biomedical startups, is tough.
"If you're only investing in one, you're taking on a great deal of risk. So you find typically that most investors will invest in a lot of them in a venture fund or hedge fund," he says.
"You look for people who've had experience, new ideas, something not developed yet, with leadership who... really think about their market targets and in terms of translating the technology."
The life sciences are only around 40 years old and unimaginable advances will be made in the next 40 years, he says. Bioscience can figure out how to increase food production in plants to accommodate more people in the world, how to get sustainable energy from plants, how to tackle climate change. The final challenge for biomedical science is to discover what has eluded kings, physicians and the wealthy for millennia: stopping the ravaging effects of age and thwarting the grim reaper himself.
As people age, the chance of getting cancer increases exponentially, along with the incidence of degenerative diseases like Alzheimer's and diabetes.
To Prof Sharp, there is hope. "In the next 20 years, we will have remarkable insights into the ageing process. There is very innovative research going on in that area...
"You can be sceptical, people have tried for thousands of years. But they don't have what we have now. We understand what genes are. There might not be an answer... we will still age, but we may be able to control some of the degenerative processes related to it."
While he says he might not live to see some of these advances, there is plenty of work ahead.
"I can't think about a more exciting frontier... There is so much to do. I haven't had trouble getting up for the last 40 years and going to work. I've had trouble going home, as my wife would tell you."
PHILLIP ALLEN SHARP
Institute Professor, Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology
1944: Born in rural Kentucky
1966: BA, Chemistry & Mathematics, Union College
1969: PhD, Chemistry, University of Illinois. Became Postdoctoral Fellow, California Institute of Technology
1972: Senior Research Investigator, Cold Spring Harbor Laboratory
1974: Associate Professor, MIT
1978: Co-founded Biogen, now Fortune 500 company Biogen-Idec; chairman of scientific board till 2002; member of board of directors till 2009
1979: Professor, MIT
1985: Director, Center for Cancer Research, MIT
1991: Head, Dept of Biology, MIT
1993: Awarded the Nobel Prize in Physiology or Medicine
1999 to date: Institute Professor, MIT
2002: Co-founded Alnylam Pharmaceuticals, chairman of scientific board, member of board of directors
2013: President, American Association for the Advancement of Sciences
