by Friedrich Miescher, a Swiss physician who extracted and isolated a previously unknown substance from pus-soaked bandages at the hospital where he worked. White blood cells, a major constituent of pus, have very large nuclei, and Miescher correctly concluded that the substance came from those nuclei. He called it “nuclein.” Today we call it DNA.
How many chromosomes in a human cell?
Although the fine points of cell division were still unexplained, scientists in the early 1900s were eager to learn the number of chromosomes in human cells. However, counting the number of human chromosomes during cell division turned out to be quite a challenge. Even when chromosomes were lined up on the “midline” of a cell, scientists’ counts ranged from 16 to 36.
Evidently, Hans von Winiwarter got tired of these wide-ranging approximations. Using the best microscopes available to him in 1912, he produced early karyotypes by capturing and fixing human cells at the moment of cell division. Despite his best efforts, Winiwarter’s counts ranged from 46 to 49; and while noting correctly that women have two X chromosomes, he mistakenly concluded that males had only one X and no Y. For the next 40+ years, students were generally taught that human cells contained 48 chromosomes.
Finally, in 1956, the correct value of “46” was confirmed – 22 pairs of autosomes and 1 pair of sex chromosomes in human cells other than eggs or sperm. It’s surprising to learn that Watson & Crick had published their model of DNA’s structure, opening the world of modern genetics, several years before the number of human chromosomes was firmly established!
Good things come in small packages
By the end of the 20th century, knowledge of DNA structure and the mechanisms of cell division had advanced dramatically. Yet, based on their school textbooks, most people still tended to picture chromosomes as the condensed “X-shaped” bodies seen in karyotypes. DNA was known to uncoil between cell divisions, but it was hard to imagine how such long straggling threads (more than 2 meters, or 6 feet, per cell) could pack into a nucleus only 6/1,000,000 of a meter in diameter (smaller than the diameter of a human hair).
Eventually, studies showed that DNA decreases in length when regions of about 166 base pairs wrap like twine around small proteins to form complexes known as nucleosomes . A short stretch of non-wound DNA falls between each nucleosomal unit, the result looking a bit like a string of beads. In such a configuration, a 1-meter (3-foot) strand of DNA is reduced to 14 cm (about 6 inches). This shortened strand then coils even more, until an X-shaped chromosome in a dividing cell measures roughly 1/10,000 the length of the DNA strand it contains!
The “fractal globule” (aka ramen noodles)
So what does the 3-dimensional model of the nucleus, as seen in the Genome Ball, have to do with all this?
One of the most important discoveries in genome biology has been the demonstration that genomes are non-randomly organized in the nucleus.
Even though chromatin looks like long straggly threads, it is amazingly well organized: Thanks to the organized coiling of chromatin, genes are able to interact with the DNA regions that regulate them.
The genome is organized into “distinct regions of open and closed chromatin regulatory domains,” explains Dr. Laura Elnitski, senior investigator at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health. Put more simply, chromatin that is less active in a given cell type, or chromosomes containing few genes, are located just inside the nuclear membrane; but more active chromatin (for example, a gene coding for insulin in healthy pancreatic cells), and chromosomes carrying many genes, occupy the center of the nucleus. Overall, the nuclear location of specific genes correlates with their activity in a given cell.
Erez Aiden (who spearheaded the Genome Ball project) also discussed chromatin organization in his prize-winning essay in Science: “Loci on the same chromosome – even at opposite ends – interact more than loci on