Unknowns, yes, but are there unknowables in biology?

The old Rumsfeld jokes about the knowns and unknowns are pretty stale by now, so we won't really indulge in beating that dead horse.  But in fact his statement made a lot of sense.  There are things we think we know (like our age), things we think we don't know but might know (like whether there will be a new message in our inbox when we sign onto email), and things we don't know but don't know we don't know (such as how many undiscovered marine species there are). Rumsfeld is the subject of ridicule not for this pronouncement per se (at least to those who think about it), because it is actually reasonable, but for other things that he is said to have done or said (or failed to say) in regard to American politics.

Explaining what we don't know is a problem!  Source: Google images

The unknowns may be problems, but they are not Big problems.  What we don't know but might know are at least within the realm of learning.  We may eventually stumble across facts we don't know but don't yet even know are there.  The job of science is to learn what we know we don't know and even to discover what we don't yet know that we don't know.  We think there is nothing 'inside' an electron or photon, but there may be if we some day realize that possibility.  Then the guts of a photon will become a known unknown.

However, there's another, even more problematic, one may say truly problematic kind of mystery: things that are actually unknowable.  They present a Really Big problem.  For example, based on our understanding of the current understanding of cosmology, there are parts of the universe that are so far away that energy (light etc.) from them simply has not, and can never, reach us.  We know that the details of this part of space are literally unknowable, but because we have reasonably rigorous physical theory we think we can at least reliably extrapolate from what we can see to the general contents (density of matter and galaxies etc.) of what we know must exist but cannot see.  That is, it's literally unknowable but theoretically known.

However, things like whether life exists out there are in principle unknowable.  But at least we know very specifically why that is so.  In the future, most of what we can see in the sky today is, according to current cosmological theories, going to become invisible as the universe expands so that the light from these visible but distant parts will no longer be able to reach us.  If there are any living descendants, they will know what was there to see and its dynamics and we will at least be able to make reasonable extrapolations of what it's like out there even though it can no longer be seen.

There are also 'multiverse' theories of various sorts (a book discussing these ideas is Our Mathematical Universe, by Mark Tegmark).  At present, the various sorts of parallel universes are simply inaccessible, even in principle, so we can't really know anything about them (or, perhaps, even whether they exist).  Not only is electromagnetic radiation not able to reach us so we can't observe, even indirectly, what was going on when that light was emitted from these objects, but our universe is self-contained relative to these other universes (if they exist).

Again, all of this is because of the kind of rigorous theory that we have, and the belief that if that theory is wrong, there is at least a correct theory to be discovered--Nature does work by fixed 'laws', and while our current understanding may have flaws the regularities we are finding are not imaginary even if they are approximations to something deeper (but comparably regular). In that sense, the theory we have tells us quite a lot about what seems likely to be the case even if unobserved. It was on such a basis that the Higgs boson was discovered (assuming the inferences from the LHC experiments are correct).

What about biology?
Biology has been rather incredibly successful in the last century and more.  The discoveries of evolution and genetics are as great as those in any other science.  But there remain plenty of unknowns about biological evolution and its genomic basis that are far deeper than questions about undiscovered species.  We know that these things are unknown, but we presume they are knowable and will be understood some day.

One example is the way that homologous chromosomes (one inherited each of a person's parents) line up with each other in the first stage of meiosis (formation of sperm and egg cells).  How do they find each other?  We know they do line up when sex cells are produced, and there are some hypotheses and bits of relevant information about the process, but we're aware of the fact that we don't yet really know how it works.

Homologous chromosomes pair up...somehow.  Wikimedia, public domain.

Chromosomes also are arranged in a very different 3-dimensional way during the normal life of every cell.  They form a spaghetti-like ball in the nucleus, with different parts of our 23 pairs of chromosomes very near to each other.  This 'chromosome conformation', the specific spaghetti ball, shown schematically in the figure, varies among cell types, and even within a cell as it does different things.  The reason seems to be at least in part that the juxtaposed bits of chromosomes contain DNA that is being transcribed (such as into messenger RNA to be translated into protein) in that particular cell under its particular circumstances.

Chromosomes arrange themselves systematically in the nucleus.  Source: image by Cutkosky, Tarazi, and Lieberman-Aiden from Manoharan, BioTechniques, 2011

It is easy to discuss what we don't know in evolution and genetics and we do that a lot here on MT. Often we critique current practice for claiming to know far more than is actually known, or, equally seriously, making promises to the supporting public that suggest we know things that in truth (and in private) we know very well that we don't know.  In fact, we even know why some things that we promise are either unknown or known not to be correct (for example, causation of biological and behavioral traits is far more complex than is widely claimed).

There are pragmatic reasons why our current system of science does this, which we and many others have often discussed, but here we want to ask a different sort of question:  Are there things in biology that are unknowable, even in principle, and if so how do we know that?  The answer at least in part is 'yes', though that fact is routinely conveniently ignored.

Biological causation involves genetic and environmental factors.  That is clearly known, in part because DNA is largely an inert molecule so any given bit of DNA 'does' something only in a particular context in the cell and related to whatever external factors affect the cell.  But we know that the future environmental exposures are unknown, and we know that they are unknowable.  What we will eat or do cannot be predicted even in principle, and indeed will be affected by what science learns but hasn't yet learned (if we find that some dietary factor is harmful, we will stop eating it and eat something else).  There is no way to predict such knowledge or the response to it.

What else may there be of this sort?
A human has hundreds of billions of cells, a number which changes and varies among and within each of us.  Each cell has a slightly different genotype and is exposed to slightly different aspects of the physical environment as well.   One thing we know that we cannot now know is the genotype and environment of every cell at every time.  We can make some statistical approximations, based on guessing about the countless unknowns of these details, but the numbers of variables will exceed that of stars on the universe and even in theory cannot be known with knowable precision.

Unlike much of physics, the use of statistical analytic techniques is inapt, also to an unknowable degree.  We know that not all cells are identical observational units, for example, so that aggregate statistics that are used for decision-making (e.g., significance tests) are simply guesses or gross assumptions whose accuracy is unknowable.  This is in principle because each cell, each individual is always changing.  We might call these 'numerical unknowables', because they are a matter of practicality rather than theoretical limits about the phenomena themselves.

So are there theoretical aspects of biology that in some way we know are unknowable and not just unknown?  We have no reason, based on current biological theory, to suspect the kinds of truly unknowables, analogous to cosmology's parallel universes.  One can speculate about all sorts of things, such as parallel yous, and we can make up stories about how quantum uncertainty may affect us. But these are far from having the kind of cogency found in current physics.

Our lack of comparably rigorous theory relative to what physics and chemistry enjoy leaves open the possibility that life has its own knowably unknowables. If so, we would like at least to know what those limits may be, because much of biology relates to practical prediction (e.g., causes of disease). The state of knowledge in biology, no matter how advanced it has become, is still far from adequate to address the question of the levels of knowable things that may eventually be knowable, but also what the limits to knowability are.  In a sense, unlike physics and cosmology, in biology we have no theory that tells us what we cannot know.

And unlike physics and cosmology, where some of these sorts of issues really are philosophical rather than of any practical relevance to daily life, we in biology have very strong reasons to want to know what we can know, and what we can promise....but perhaps also unlike physics, because people expect benefits from biological research, strong incentives not to acknowledge limits to our knowledge.