The Dawn of Molecular Genetics: A Glimpse of History in a Textbook from 1952

The email from my former neighbor Shaun Kuczek was unexpected.

“Hi Ricki! My Dad passed in July, and we’re cleaning out his house. He was a biology teacher for 35 years and I have 40 or so old biology textbooks. I remember that you write biology textbooks, and maybe you have an idea of a way to pass them along? They’re all old, 1950s, 1960s. If you think of anything, please let me know.”

Bernie Kuczek had been 91. In addition to teaching high school biology and chemistry and coaching baseball, Bernie’s claim to fame was being drafted by the Brooklyn Dodgers and sitting alongside Jackie Robinson in the dugout. Alas, a broken leg ended his baseball career. Bernie served in the Korean War and worked summers as a fisheries biologist.

Treasure from 1952, Just Before Watson and Crick’s Paper

A pile of old biology books to me is like a toy store to a child. I went to Shaun’s the next morning, flipped through a few books, and without hesitation loaded them all into the trunk of my car.

Once in my office, I moved aside the dozing cats and gently stacked the books on their bench. I recognized the covers of a few tomes that had competed with my own intro biology textbook Life. I zeroed in on the oldest-appearing books that I’d been hoping to find. One, missing a back cover, was tattered and looked particularly ancient.

I was thrilled to discover that it was a genetics textbook – I’m the author of such a book recently published in its 14th edition, Human Genetics, Concepts and Applications, from McGraw-Hill. The textbook I’d just inherited from Shaun was a first edition of General Genetics, with two rock stars of biology as co-authors.

Cornell molecular geneticist Adrian M. Srb is known for the “one gene-one enzyme” hypothesis. He worked with the bread mold Neurospora crassa. Ray D. Owen, professor of biology at CalTech, discovered immunological tolerance with experiments that attached twin cattle through their bloodstreams. His work lead to the practice of immune suppression in transplant medicine. (One of the things I love about genetics is how vastly different species reveal the same underlying principles of heredity – I worked with fruit flies.)

Inside the front cover of Srb and Owen – textbooks tend to become known by author surnames – is a short list of “professional associates.” It includes a scientist who trained my own mentor, as well as one who worked at my grad school lab bench at Indiana University, Noble prizewinner Hermann Muller.

Published by W.H. Freeman and Company, the book has torn and missing pages and notes penciled along the margins from Bernie. Beautiful black and white sketches adorn the pages. In the early days of my career, illustrations for my books would come, via UPS, directly from artists. Today, of course, all are created digitally. The charm is gone.

In fishing out General Genetics from the pile of books, I’d happened upon what has been called “the most widely used genetics textbook of its time” and “the primary university genetics text from the publication of the first edition in 1952 until well after the 1965 publication of the second edition.”

1952!!!

That’s what got my attention, for 1953 was when James Watson and Francis Crick published their iconic one-page paper in Nature, “Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid.”

The structure revealed how the molecule can both encode information and copy itself. “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material,” read Watson and Crick’s famous final sentence. Their names are notably not in the index of General Genetics. Their time had yet to come.

Amazingly, the authors wrote their bestselling book without knowing the chemical nature of a unit of heredity, a gene. The text is a snapshot in time, brilliantly written on the brink of perhaps the most important paper in genetics, if not all of biology.

How did they do it? They posed questions, evaluated clues and evidence, and drew tentative conclusions that provoked further, more nuanced questions. The popular view of science consisting of breakthroughs and proofs is not accurate.

Vague Definitions and Examples from Nature

All genetics textbooks, including mine, relate the convergence of experimental evidence that led Watson and Crick to deduce DNA’s structure. Srb and Owen’s account is perhaps even more exciting, because they told the tale without knowing the ending, only guessing at it – correctly, it turned out. I chronicled the experiments that inspired Watson and Crick on the 70th anniversary of publication of their famous paper, this past April 20, 2023.

The 1952 textbook calls genes “a rather heterogeneous collection of things … that generally constitute the unexplained, Mendelizing residue,” referring to the telling ratios of pea plant offspring in Gregor Mendel’s famous experiments. “Probably a part of this heterogeneous class represents true chemical changes in genes. There is no way of knowing how large a part this is.”

Danish botanist W. Johannsen coined the term “gene” in 1909, but he credited Hippocrates, “who suggested that the different parts of the body may produce substances which join in the sexual organs, where reproductive matter is formed.” That’s an amazingly prescient description of how meiosis distributes genes as sperm and egg form.

I love the old textbook’s less-than-precise definition of the field: “Genetics is … concerned with increasing our knowledge of why organisms are the way they are.“

The opening chapter then considers what species share, yet how they differ, establishing the “unity and diversity of life” theme that’s popped up in many a biology textbook title. Srb and Owen cite an example: humans, mice, guinea pigs, and bread mold use the same biochemical pathway to make the amino acid arginine. But species also illustrate diversity. “How can a cat beget another cat, and a radish another radish?”

The 1952 textbook explains heredity through trait variations, which have long been observed without knowing the role of DNA.

A black fox is black because of “discrete granules of a compound called melanin,” Srb and Owen write. The fox’s parents have “genes for blackness,” whereas a red fox makes a different version of an enzyme needed to make melanin. Sketches of “frizzled fowls” offer other examples. “Genetics is concerned with the manner and extent of hereditary control of these primary differences in function.”

With the book’s agricultural underpinnings, effects of inbreeding arise –applicable to all sexually reproducing species. Inbreeding can lead to “unfortunate biological consequences.” In corn, continual self-fertilization leads to puny ears festooning a dwindling crop, versus the succulent ears demonstrating “hybrid vigor.” Similarly, animal breeders note “weaknesses” when parents are related. And in humans “a disproportionate number of cousin marriages is found among the parents of albinos.”

Inbreeding is “biologically undesirable,” but not always. Srb and Owen cite the health of highly inbred lab rats and the Ptolemy dynasty of ancient Egypt with its brother-sister pairings. In genetics, luck is part of the picture.

Zeroing in on the Nature of the Gene

Srb and Owen readily admit what they don’t know, using the example of hairy fingers. “The trail of events leading from gene to mid-digital hair appears to be so tenuous that no one knows as yet how to back-track from phenotype to gene in order to find out just what is the primary chemical action of the gene.”

Health conditions are inherited traits too. The authors mention sickle cell disease (then called anemia), alkaptonuria and its unmistakable black urine, and phenylketonuria.

Srb and Owen state the two “primary properties” of “the particles of heredity,” whatever they may turn out to be:

1. “Specific self-duplication.” Genes must be copied to transmit info while maintaining it in the original cell (DNA replicates).

2. The ability to produce something vital to the cell’s biochemistry, called “primary gene action.”

How the two processes are linked wasn’t yet known, but “in some way, their interaction organizes materials inside cells into “a highly specific molecular pattern.”

Growth of crystals isn’t the same, the authors argue, because it doesn’t impart information. Still, genetic material circa 1952 was not “a mysterious vital principle that must remain forever intangible.” Science would explain it, Srb and Owen write.

Many researchers suspected that DNA was the genetic material, based on knowing that chromosomes are composed of DNA and protein. The four building blocks of DNA could carry a simpler code than the 20 building blocks of protein. Srb and Owen describe DNA as “probably stacks of nucleotides (base-sugar-phosphate).” That statement was the recipe for a gene, without direct biochemical evidence. Genes mutate and are “units of biochemical action.” Overall, DNA best fit the criteria for the genetic material.

From Idiocy to DEI: How Textbook Language Has Evolved

When I was revising my human genetics textbook last year, a company was hired to analyze every word to be sure I was cognizant of Diversity, Equity, and Inclusion. I recounted that experience here. With DEI in mind, reading through General Genetics from 1952 was an eye-opener.

Sexism is rampant: “Man is not a particularly favorable object for genetic investigation. He has a long life cycle and comparatively small individual progenies.” Do men birth those progeny?

The word “normal” is pervasive. “Single genes can affect intelligence, but among normal individuals, intelligence varies widely.” I was only permitted to use “normal” in describing chromosomes, which apparently cannot be offended as people can.

But the authors weren’t entirely tone deaf. They contrast “relatively inconsequential departures from the normal” – colorblindness, extra fingers, albinism – with more serious conditions like “hemophilia, Huntington’s chorea, juvenile amaurotic idiocy (aka Tay-Sachs disease), and eye tumor” (retinoblastoma).

The discussion of race circa 1952 is too offensive for me to repeat any of it.

Predicting the Future of Genetic Medicine with Astounding Prescience

General Genetics was written at a time when diagnosis and sometimes prevention were possible, but treatments not. Diagnoses were clinical, based on recognizing telltale groups of symptoms. Consider ectodermal dysplasia. A child with scant hair, undeveloped teeth, dry skin, fevers, and poor thyroid function has a parent and other relatives with the same symptoms. Absence of sweat glands leads to fever and poor development of hair and teeth.

The book’s example of prevention is xanthoma tuberosum (aka hyperlipoproteinemia), in which cholesterol clumps at the elbows, knees, fingers, heels, buttocks, and sometimes heart. Srb and Owen suggest testing healthy relatives for high cholesterol, so dietary intervention can begin before the lumps appear. This observation presages pre-symptomatic detection of genetic disease, as is now done routinely for breast cancer and Huntington disease. But the authors look ahead:

“When this type of procedure can be applied in many instead of only a few kinds of disease, medical men will be able to forego certain ‘shotgun’ methods of prevention in favor of ‘sharpshooting’ methods. The consequent advantages to precision and effectiveness of treatment are obvious.”

The authors also predict genetic counseling:

“The physician should … advise a father affected with dominant ectodermal dysplasia that half his offspring can be expected to suffer from the same difficulties.” (Not exactly. Each child has a 1 in 2 chance.)

“He should be able to explain to two normal parents who have had an albino child that the expectancy of another of their offspring being albino is one in four.” I can forgive the assumption that doctors are men and the “normal” and “albino.” Finally, Srb and Owen “hope that ‘clinics of human heredity’ will be established to handle such situations.”

It is indeed hard to believe that today, a human genome can be sequenced in under a day, and that we can carry such information on our smartphones. I can’t wait to find more treasures in my book pile. Thank you Bernie and Shaun Kuczek!