In 1969, one of the more memorable incidents in the public advocacy of science took place. The American physicist Robert Wilson was asked to testify before Congress in support of the construction of the Fermi National Accelerator Laboratory, known as Fermilab. For Wilson, building this huge machine had been a labor of love and nobody had a better background for it. He had worked on the Manhattan Project where he was the youngest group leader in the experimental division, and after the war he had become a professor at Cornell University.
Wilson
was a first-rate amateur architect who saw accelerators as works of
art. He lovingly designed Fermilab with his own hands and, in order to
add to the aesthetic appeal of the place, turned the surrounding acres
into a wilderness housing bison and geese. His efforts paid off; Fermilab would become the largest accelerator in the United States and CERN's primary competitor. In 1969 Wilson was asked to
justify the expenditure for the multi-million dollar laboratory in front
of Congress. The Cold War was raging, most research and especially
physics research was being viewed in the context of national security,
and Wilson was specifically asked what contribution the new laboratory
would make to national defense. He replied in words that should be
etched on the foundation stone of every center of basic research. The
research, he said, had no direct bearing on national defense. Instead,
It
has only to do with the respect with which we regard one another, the
dignity of men, our love of culture. It has to do with: Are we good
painters, good sculptors, great poets? I mean all the things we really
venerate in our country and are patriotic about. It has nothing to do
directly with defending our country except to make it worth defending.
It has nothing to do directly with defending our country except to make it worth defending. In
saying these words, Wilson was appealing to the heart of what makes any
country great. It is not the fancy cars, the shiny malls, the great
financial houses and the cornucopia of industrial food that truly
contribute to a country's progress. At one point or another in history,
Athens, Florence, Takshashila, Baghdad, Oxford, Gottingen, Copenhagen
and Philadelphia were primarily known not for their wealth and the
splendor of their monuments but for the unmatched wealth of ideas about
science, art, economics, politics, freedom and human dignity that their
citizens generated. These ideas are now the bedrock of much of modern
civilization. Many of these ideas were solutions to practical problems,
but most only sought to explore and push the boundaries of human
creativity, curiosity, passion and tolerance. The creators and dreamers
of these ideas were less concerned about their practical application and
more concerned about their ability to answer questions about human
origins and nature, our place in the cosmos and our relationship to
other human beings.
Why
am I retelling the story of Robert Wilson? Because I believe it strikes
at the heart of what these days is fashionably called "translational
research". Just like physics research was being viewed through the lens
of national defense in the 60s, basic biomedical studies run the risk of
being viewed through the lens of translational research in the 2010s.
The approach is clearly not popular among leading researchers. In 2009, Nobel Laureate Martin Chalfie gave a talk at Lindau in which he described the great satisfaction he had had from doing non-translational research (in fact Chalifie was going to give a talk about this very topic this year at Lindau but unfortunately could not attend). Chalfie is not alone; as
just another example, a few months ago I attended a lecture by another Nobel Laureate,
Thomas Steitz, also at Lindau this year. Steitz who won the prize for
his exploration of the structure and function of the ribosome proudly
announced at the beginning of the talk that "the only kind of
translation I have worked on is that orchestrated by the ribosome".
So what is translational research? Many definitions seem to abound and Wikipedia seems to be as good a guide as any: "Translational
research is a way of thinking about and conducting scientific research
to make the results of research applicable to the population under study
and is practised in the natural and biological, behavioural, and social
sciences". The goal of translational research especially in
medicine seems to transform basic biomedical research discoveries from
"bench to bedside".
In
the last few years this kind of thinking has has swamped the public
discourse on science. New centers are being founded and funded whose
mandate is to translate basic research into products directly benefiting
humanity. The NIH, the largest biomedical research agency in the world,
has also embraced a new National Center for Advancing Translational
Research. The director of the NIH, Francis Collins, has not tired of
pointing out the exciting advances in discovering new drugs which would
be made possible by harnessing data from the human genome project. Not
surprisingly, the press has eagerly jumped on the bandwagon, with
reports pitching translational research and personalized medicine
regularly appearing in the nation's leading papers. Echoing leading
scientists, the press seems to be telling us that we should all look
forward to supporting translational research in its various guises.
All
this makes the idea of translational research sound promising. And yet
there must be a good reason why distinguished Nobel Prize winners like
Chalfie and Steitz bristle at the mention of translational research. The
reason is actually not too hard to discern. The problem is not with
applied research per se. Nobody can doubt that applied research
especially done by the pharmaceutical and biotechnology industries has
saved innumerable lives in the last one hundred years. As Pasteur said,
"there is science and the applications of science", and he saw them
lying on a continuum. No, there is nothing wrong with trying to turn
basic ideas into applied products.
What is
wrong is that translational research is being seen as a panacea that
will address the flagging rate of new biomedical advances. The thinking
seems to declare that if only more people were given more money and
deliberately focused on direct application, we would suddenly see a
windfall of new therapies against disease. This thinking suffers from
two major problems.
The
first problem is that history is not really on the side of
translational research. Most inventions and practical applications of
science and technology which we take for granted have come not from
people sitting in a room trying to invent new things but as fortuitous
offshoots of curiosity-driven research- the kind that Chalfie and Steitz
have dedicated their lives to. Penicillin was discovered through
serendipity by a most alert Alexander Fleming who was trying to plate
bacterial cultures, not one trying to actually discover the next
breakthrough antibiotic. Nuclear Magnetic Resonance was discovered by
physicists who were tinkering with atoms in magnetic fields, not ones
who were trying to find a method for determining the structures of
organic and biological molecules. The discovery of most drugs built upon
basic discoveries about human physiology and anatomy made by physicians
and researchers who were simply trying to find more about how the body
works. The new class of drugs inhibiting protein kinases for instance
ultimately owe their development to the discovery of phosphorylation, a
fundamental discovery by this year's Lindau attendee Edmond Fischer that
was a result of purely basic scientific thinking about how chemical
signals are communicated by cells. Similarly, Steitz's ribosome and
Chalfie's green fluorescent protein are lending themselves to drug
discovery and medical advances in ways which they never planned.
If
the history of science teaches us anything, it is that curiosity-driven
basic research has paid the highest dividends in terms of practical
inventions and advances. Tinkering, somewhat aimless but enthusiastic
exploration of biological and physical systems and following one's nose
have been the ingredients for some of the key inventions that have
transformed our lives. Radar, computers, drugs, detergents, plastics and
microwave ovens were all made possible not because someone sat down and
tried to discover them but because they arose as fortuitous
consequences of
elemental, pure research. The hype of translational research not only
deflects attention from curiosity-driven basic research but also creates
the illusion that asking people to discover new things is the best way
to generate new ideas. In fact, trying to discover new things by forcing
people to discover them will only siphon off funds from those who have
the actual capability of discovering these things.
The
second more practical but equally important problem with translational
research is that it puts the cart before the horse. First come the
ideas, then come the applications. There is nothing fundamentally wrong
with trying to build a focused institute to discover a drug, say, for
schizophrenia. But doing this when most of the basic neuropharmacology,
biochemistry and genetics of schizophrenia is unknown is a great
diversion of focus and funds. Before we can apply basic knowledge, let's
first make sure that the knowledge exists. Efforts based on incomplete
knowledge would only result in a great squandering of manpower,
intellectual and financial resources. Such misapplication of resources
seems to be the major problem for instance with a new center for drug
discovery that the NIH plans to establish. The NIH seeks to channel the
new-found data on the human genome to discover new drugs for
personalized medicine. This is a laudable goal, but the problem is that
we still have miles to go before we truly understand the basic
implications of genomic data. It is only recently that we have started
to become aware of the "post-genomic" universe of epigenetics and signal
transduction. We have barely started to scratch the surface of the
myriad ways in which genomic sequences are massaged and manipulated to
produce the complex set of physiological events involved in disease and
health.
And all this does not even consider the actual workings of proteins and small molecules in mediating key biological events, something which is underlined by genetics but which constitutes a whole new level of emergent complexity. In the absence of all this basic knowledge which is just emerging, how pertinent is it to launch a concerted effort to discover new drugs based on this vastly incomplete knowledge? It would be like trying to construct a skyscraper without fully understanding the properties of bricks and cement.
Chalfie, Steitz and others like them are also right to criticize the frenzy that translational research generates in the popular press. We live in an age when buzzwords are eagerly generated and lapped up by the media. These buzzwords usually run roughshod over subtleties and ambiguities and the press seldom has a taste for indulging these in the first place. Needless to say, committing national resources and public attention to translational research when most of the basics are still to be understood is an endeavor fraught with great risk and uncertainty. It would be far wiser to bolster basic research that can bring us to the brink of real application. There are places where such research is conducted. They are called universities.
Ultimately, the importance of basic research goes back to what Robert Wilson said to Congress. It has to do with the same reasons that we created the Mona Lisa, painted the Sistine Chapel, built Chartres Cathedral, wrote The Love Song of J. Alfred Prufrock and composed the Goldberg Variations. Da Vinci, Michelangelo, T. S. Eliot and Bach were all trying to find the essence of man's soul and his relationship with the universe and with his fellow men. So were Einstein, Newton, Faraday and Darwin. They were not trying to invent a better mousetrap, but the world did beat a path to their door. Similarly, once our basic understanding of biological systems is firmly in place, translation will willingly follow.
The next researcher, when asked to comment on the relevance of his or her basic studies in cell biology to translational research, should echo Wilson: "It has nothing to do directly with translational research, except to enable it".
And all this does not even consider the actual workings of proteins and small molecules in mediating key biological events, something which is underlined by genetics but which constitutes a whole new level of emergent complexity. In the absence of all this basic knowledge which is just emerging, how pertinent is it to launch a concerted effort to discover new drugs based on this vastly incomplete knowledge? It would be like trying to construct a skyscraper without fully understanding the properties of bricks and cement.
Chalfie, Steitz and others like them are also right to criticize the frenzy that translational research generates in the popular press. We live in an age when buzzwords are eagerly generated and lapped up by the media. These buzzwords usually run roughshod over subtleties and ambiguities and the press seldom has a taste for indulging these in the first place. Needless to say, committing national resources and public attention to translational research when most of the basics are still to be understood is an endeavor fraught with great risk and uncertainty. It would be far wiser to bolster basic research that can bring us to the brink of real application. There are places where such research is conducted. They are called universities.
Ultimately, the importance of basic research goes back to what Robert Wilson said to Congress. It has to do with the same reasons that we created the Mona Lisa, painted the Sistine Chapel, built Chartres Cathedral, wrote The Love Song of J. Alfred Prufrock and composed the Goldberg Variations. Da Vinci, Michelangelo, T. S. Eliot and Bach were all trying to find the essence of man's soul and his relationship with the universe and with his fellow men. So were Einstein, Newton, Faraday and Darwin. They were not trying to invent a better mousetrap, but the world did beat a path to their door. Similarly, once our basic understanding of biological systems is firmly in place, translation will willingly follow.
The next researcher, when asked to comment on the relevance of his or her basic studies in cell biology to translational research, should echo Wilson: "It has nothing to do directly with translational research, except to enable it".
Frank Wappler 12.07.2011 | 13:19
Ashutosh Jogalekar wrote (08. July 2011, 12:34):
> The next researcher, when asked to comment on the relevance of his or her basic studies in cell biology to translational research, should echo Wilson: "It has nothing to do directly with translational research, except to enable it".
Thanks for recalling Bob Wilson's thoughts;
but I'm afraid your punchline doesn't have quite the same ring.
Given plenty of proposals for funding of actual "translational research" it might be best enabled by granting as much requested funds as can be afforded.
Rather, it seems, what basic research has to do with translational research is to secure its foundation and to enrich its stock of what may be worth translating.