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Genetics

Chairman's Overview

Bruce Beutler, M.D.Bruce Beutler, M.D.

Assembled from molecular building blocks at the command of DNA, our cells in turn defend and maintain the integrity of the DNA they contain.  Before cells divide, the DNA must be copied.  Just what does this imply?  For one thing, it implies almost unbelievable speed.  Let's consider the synthesis of DNA in just a few of our cells:  the precursors that generate the red cells of the blood, which dwell within our bone marrow.  There are perhaps 100 grams of these cells in our bodies.  It has been possible to measure the life span of red cells with some precision and we know that about 2,000 new red cells are produced every second to maintain constant red cell mass.  Red cells are born when the nucleus of a normoblast is expelled.  And the DNA within each normoblast was previously made as a copy of DNA within a precursor in the erythroid line.

If gently unwound and placed end to end, the 46 chromosomes in the human normoblast with their 6.5 billion base pairs (Gbp) of DNA would be just over 2 meters in length.  We can infer that in the erythron alone, in the average human being, about 4 kilometers of DNA is synthesized every second.  By comparison, sound travels through air at only 0.34 kilometers per second.  So the erythron replicates its DNA at about Mach 12, day and night, without pause.  If circumstances require, it can accelerate synthesis by an order of magnitude.

Since there are almost 7 billion humans on the planet, we collectively synthesize DNA with a total length of 28 billion kilometers (0.003 light years) within what we might call the "global human erythron" every second.  If placed end to end, the DNA polymers formed every 1.3 seconds in the global human erythron would retrace the orbit of the planet Pluto.

Of course, this is only the DNA synthesized within one cell type, comprising about 0.15% of our total cell mass.  We are talking about only one species:  Homo sapiens, which is not the most abundant species on earth, nor the species with the greatest biomass.  Ants outweigh us by one to two orders of magnitude, I have read, and they turn over much more rapidly than we do (ashes to ashes, dust to dust).  As a single species, Antarctic krill, Euphausia superba, outweighs us by at least a factor of five, and these organisms also have a short life span and enormous reproductive capacity.  Our species is almost static by comparison.  Nor do humans have the largest genome size (Amoeba dubia currently holds the record; its 670 Gbp haploid genome is more than 200 times larger than ours).  Nor do most of our cells divide nearly as rapidly as many cells can.  Imagine how much cell division (and therefore, DNA synthesis) occurs when vast deciduous forests crowd into leaf in the spring.

What is the length of DNA synthesized per unit time by all the cells of all the organisms on the planet?  Nobody really knows, but let us make a conservative estimate.  Let us propose that the DNA synthesized in the erythroid line in human bone marrow might be about one billionth the amount of DNA synthesized on earth.  In that case, the composite length of DNA polymer synthesized by all living things on the planet would exceed the diameter of the visible universe (about 93 billion light years) about three times each day.  That wouldn't be a bad accomplishment for a tiny speck of cosmic debris like the planet earth.

Of course, a geneticist's interest in DNA is usually focused on its informational content rather than on the speed of its synthesis within the biosphere.  There is something miraculous about the economy and compactness with which DNA stores information.  The haploid human genome is only a meter in length, contains about 3 billion base pairs of DNA, and weighs approximately 3.3 pg.  Most of its informational content resides in the coding sequence of genes, which comprises only about 1.3% of genomic sequence as a whole (about 50 fg of DNA).  Yet this minute amount of linear DNA conjures the assembly of a three-dimensional organism with dynamic properties that could never be adequately described with three billion characters of text.  Where does the gain in complexity occur?  Most obviously, it occurs at the level of encoded proteins, which pursue a life of their own after they are synthesized.  Individually they can and do transiently adopt a great number of metastable conformations.   They make many thousands of intramolecular contacts, and millions of intermolecular contacts, in the latter case both with other proteins and other types of molecules.  The human genome directs the synthesis of more than 100,000 structurally distinct proteins, and these are variably modified in many different ways, both while they are being made and afterward.  But the number of molecular contacts that may occur, and hence the complexity of biological phenomena that may occur, is vast.  It is our ultimate task to understand precisely which molecular interactions, occurring alone or in temporal sequence, support the observable phenomena that interest us.

The foregoing narrative had much to do with parallel processing.  The rate of extension of a single strand of DNA can't even approach, let alone exceed the speed of light.  But the composite extension of all DNA strands does indeed exceed the speed of light, by many orders of magnitude, even if we are only speaking of speed in a virtual sense.  And a vast number of chemical interactions and transformations occur in parallel to make a living organism.  One can begin to grasp evolution as an exercise in parallel processing as well.  A vast number of mistakes occur when one is synthesizing and transmitting DNA with a length measured in light years per second in the "collective germ line" of all living species on earth, and doing so for billions of years.  And selection is applied in parallel at every step of the life cycle of every organism, also over billions of years.

In the laboratory we can't operate on a cosmic scale.  But scientific inquiry is a fairly large-scale example of parallel processing all the same.  Around the world, many labs operate independently of one another, and quite commonly, discoveries made in one lab light the way to discoveries in others.  A department ideally fosters synergy of this type.  In the Department of Genetics, our attention is drawn to DNA, how it behaves, and the consequences of mutations (programming errors) when they occur.  The labs of the Department of Genetics work on different problems, but in broad outline, pursue related goals and share a similar philosophy.  All use unbiased genetic methods to study nature.  And each works in parallel with the others toward a common goal whenever possible.

Eros Lazzerini Denchi wishes to understand precisely how the ends of chromosomes are protected within the shelterin complex, so they aren't recognized as broken DNA, which ordinarily triggers a specific type of damage response within the cell.  This response entails a cascade of events that can lead either to cell death, or to repair of the damage that has occurred.  The molecular details of the shelterin complex, and its ability to suppress the DNA damage response, have implications for many biological phenomena that interest us, including aging, cancer, and host defense.

Nathalie Franc wishes to understand how dead cells are recognized and engulfed by other cells in the body:  an essential process that occurs throughout life in many species.  To do so she uses genetic tools, and a favorite model organism:  the fruit fly.  The failure of systems for recognizing and managing cells that have died can, in mammals, lead to autoimmune diseases such as systemic lupus erythematosus (SLE), which cause a great deal of human suffering.  Moreover, the management of dying cells during embryogenesis is necessary for the formation of a normal animal.

The Beutler lab is concerned with innate and adaptive immunity and the interface between them; also with defects that cause inflammatory or autoimmune diseases.  The mouse is the genetic tool of choice in this lab, and hundreds of mutations that cause aberrant immune phenotypes have been created using the germline mutagen ethylnitrosourea (ENU).  Many of these have been identified through positional cloning.  Not only immune phenomena, but development, behavior, and metabolism are polled in phenotypic screens.  And the rate at which phenotypically interesting mutations are found will soon be enhanced by new and powerful sequencing methods.

Dr. Xin Du, currently a Senior Staff Scientist in the Beutler lab, will soon be appointed Assistant Professor of Genetics.  Her lab will be devoted principally to the genetic analysis of iron deficiency.  Among her greatest successes of recent years, Dr. Du found three ENU-induced mutations within a single gene, which disrupt iron absorption by destroying the normal mechanism for sensing iron attenuation.  In humans, mutations in the orthologous gene, TMPRSS6, were subsequently found to cause iron deficiency anemia, refractory to oral iron supplementation.

The outlook for the Department is bright.  Despite the austerity of the times, we have grown substantially in size and funding this past year.  The Department of Genetics now includes a total of 35 people, including 4 faculty members and 20 individuals with doctoral degrees.  The quality of the faculty is outstanding.  And parallel processing makes us more than the sum of our parts.