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Biological Complexity and the Myth of the Low-Hanging Fruit

Two events persuaded FDA Matters to write another column on biological complexity and its implications for medical research, drug discovery, and personalized medicine. First was the release of a remarkable study on gene mutations in cancer tumors. It is a stellar and sobering example of how biological complexity confounds our expectations that rapid advances in science will quickly lead to cures. 

Second was the multiple comments from readers of last week’s columnsuggesting that drug discovery (and biomedical advances generally) are so hard because “the low-hanging fruit has been picked.” This is a persistent and dangerous myth that devalues past breakthroughs and distorts the challenges bio-medicine faces over the next decade. 

This past week’s New England Journal of Medicine contained an original article on cancer tumor heterogeneity. According to Reuters, the study showed:

 “about two-thirds of genetic mutations in samples from primary tumors of kidney cancer patients were different from one another, even if they were taken from the same tumor…Researchers also found even more genetic differentiation in biopsies of secondary tumors. The findings suggest that using samples from a primary tumor as a basis for treatment decisions may not be good enough, researchers said.”

An accompanying NEJM editorial, as well as a Wall Street Journal article and comments,  both pointed to this as a setback for matching treatments to the genetic make-up of a person’s tumors (i.e. personalized medicine). Their comments didn’t surprise me.

Over 2 ½ years ago, I put personalized medicine in perspectiveby comparing it to the long history of biotechnology. I didn't predict the cancer gene mutation discovery. I just pointed out what history tells us: biological complexity is greater than we imagine, making promising areas of discovery appear closer to maturity than they really are. The truth of this was on prominent display in these new research results on cancer tumors.

This provides a near-perfect context to respond to those who thought the answer to last week’s column, “Why is Drug Discovery So Hard (and Expensive)?is “because the low-hanging fruit has been taken.” They suggested: what remains to be accomplished in human biology and drug discovery is incredibly difficult because all the easy questions have been answered and the easy drugs and biologics have already been developed.*

As near as I can tell, a great many very smart people believe this. And they could not be more wrong. The challenges ahead are, indeed, quite difficult….but so were yesterday’s challenges before we solved them.

The “low-hanging fruit theory” is truly insulting to a generation of bioscientists whose record of accomplishments over the last 50 years was achieved by their hard work and dedication, as well as their brilliance. If anything, they might argue that it is easier now—given the new knowledge and the new tools that researchers have to work with.

Beyond that, the view of the past as low-hanging fruit–“easy and less expensive”–distorts our view of the future…that somehow we face challenges greater than other people have faced before us. We don’t.

Human biology is complex and biomedical research is slow and time-consuming. Most new knowledge raises as many questions as it answers (as is certainly true with the new cancer tumor research). None of this is new.  And it is true no matter where you stand in the continuum of biological knowledge, whether you are Pasteur or one of today’s biotechnology “rock stars”.

I am not pessimistic or discouraged about biomedical discovery or opposed to personalized medicine, just concerned we see them in a realistic light. I conclude that:

·         More biological knowledge is always better than less.

·         Having more knowledge doesn’t tell you whether the next task is easier or harder (and often it is both).

·         Having more knowledge doesn’t tell you whether success is near or far.


These three observations are controlling principles in biomedical research’s quest to lessen the burden of disease and provide all of us with a higher quality of life.


Since this is FDA Matters blog, how does FDA fit in? The agency works closely with companies developing drugs and devices and is one of the final arbiters in whether biological knowledge has, indeed, been turned into benefit for mankind.


The agency needs the tools, the resources and the top scientific minds to stay ahead of the ongoing flood of new biomedical knowledge. It needs to be ready to stimulate, then evaluate, what we hope will be a torrent of new, ground-breaking drugs and devices that will, over time, arrive.


* Dr. John LaMattina, former President of Pfizer R&D, examines this same question in his recent column in Forbes. We agree that “low-hanging fruit” is a myth, but articulate the reasons differently. His perspective complements my own and I recommend reading it along with this column.

5 Responses to “Biological Complexity and the Myth of the Low-Hanging Fruit”

  1. gordida says:

    Just when we think we got it figured out, it turns out we are just beginning. The more we learn, the more we realize just how much more there is to learn. The mysteries of the human body remains so we search, search, and research.

  2. Mark McCarty says:

    As the author of the “easy cures” comment, I’d like to point out that I amended my remarks to clarify that the medical advances of the past dealt with matters that are relatively (repeat, relatively) easier than those encountered today. Can we correct the record on that point?

    Characterizing my remarks as insulting to previous efforts is quite distortive. I’d appreciate it if my words aren’t deliberately twisted in this manner. It’s really quite dishonest.

  3. Mark—-I apologize if you felt that my column–and particularly the comments about insulting a generation of scientists–was intended as a response or rebuttal to your earlier comments (both the initial one and your revised second reply). It was not addressed to you at all, except in the most general sense that you (and many others who wrote to me directly or responded to the column in linked-in groups) suggested that low-hanging fruit was the answer to the question of why drug discovery was hard.

    Even then, I probably would not have taken on the topic if I didn’t believe a great many smart people believe in this also (which I mention in this column). Thus, the column is about what’s wrong with low-hanging fruit, why it is a myth, not about any individual or their prior comments.

    It never occurred to me that the comment about the generational insult was directed at you (because, we agree, you never suggested that point and besides I wasn’t addressing anybody in particular anyway). I actually don’t think ANY advocates of the low-hanging fruit theory realize how insulting it is to bioscience pioneers, who were in many cases also their mentors; it is totally unconscious on their part. Far from being about anything you said, I consider the point to be a unique contribution to the dialogue on low-hanging fruit. I am hoping it has the effect of pushing some people to reconsider why they believe in low-hanging fruit and the consequences of interpreting the past in that way.

    Again, I certainly apologize for any misunderstanding that somehow this was a personal response or rebuttal to something you wrote and I am happy to re-affirm on the record that it was not.

    Now that (I hope) we have clarified the origins and intent of the column, I would point out that we probably still disagree on the substance. My position (which may seem extreme to you) is that, in general, the medical advances of the past were not–even on a relative basis–any easier than the challenges we face today. I say “in general” because we can always point then (and now) to things that we believe are easier and some harder than average. As I point out in the column: “If anything, they [scientists of the past 50 years] might argue that it is easier now—given the new knowledge and the new tools that researchers have to work with.”

  4. Ray Perkins says:

    Hi Steven,

    Perhaps the strongest argument against the “low-hanging fruit” rationale is that the decline in drug development has been progressing for decades. Do today’s problems get harder the more we work on them? Still, the grab-an-apple-on-your-way-home argument is understandably appealing – who wants to acknowledge failure and all its attendant ramifications? However, if we’re to climb our way out of this hole, everything must be on the table. Everything.

    You introduce the posting with the incredible report of significant genetic variation within a single tumor. This should be fascinating news (if true) and would be, except that it flies in the face of our perception of biology as reflected in cancer tumor genetics. It also rides rough over targeting drugs or biomarkers at a single defect. A great deal of how we approach both basic research and drug development arises not from conclusions based on empirical evidence, but from designing work to accord with prior work. More than one renowned scientist has bemoaned our collective unwillingness to fund truly new ideas.

    Biology is messy, a fact well known to any young man or woman who grew up following farm animals to put food on the family table. Some of the more sophisticated thinking rightly sees biology as a complex of interconnected networks (One imagines the image of a butterfly flapping its wings in Japan setting off a tornado in Kansas). In like manner, tweaking one equilibrium may produce significant bio-events at apparently unrelated locations. This is a great opportunity, but also a great challenge – a challenge for which we have few tools. Even a quick conversation with in silico researchers reveals complaints about a lack of hard data – especially confirmed data – to fill their algorithms. And, it can be a little disturbing for some to realize that a given biological state may arise from dissimilar initial conditions.

    Biology doesn’t have to make sense, it just has to work. My grandson knows this truism and, I suspect, so did Darwin.

  5. Ray has written a short piece on drug discovery that I recommend. It is called “The Saga of Molly” and is at http://www.newlibertyproteomics.com/molecule-to-drug.html.

    As a complement from my own writing, I suggest “Is the Human Body Just an Equisitely Intricate Machine” at http://www.fdamatters.com/?p=1428. What I write there is: “The human body as a machine” is a metaphor, not a fact. There is no clock-work biology just waiting for us to discover all the mechanisms, processes and parts. Some complex biological responses may prove to be “explainable” only through unpredictable, random, counterintuitive activity.

    This is not biological nihilism. Complexity, to use my term, is not the same as unknowable. Messy, to use Ray’s term, is not the same as undiscoverable. FDA is right to expect better products from the bio and pharma industries when they seek approvals. In turn, FDA needs to integrate into its thinking that better products are a function of “it works and its safe” and that, in some situation, approvals should be possible even though we aren’t yet sure why the product works and why it is safe.

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