Ronald J. Konopka is a former American geneticist who studied chronobiology

Chronobiology

Chronobiology is a field of biology that examines periodic phenomena in living organisms and their adaptation to solar- and lunar-related rhythms. These cycles are known as biological rhythms. Chronobiology comes from the ancient Greek χρόνος , and biology, which pertains to the study, or science,...

. He made his most notable contribution to the field while working with Drosophila

Drosophila melanogaster

Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...

in the lab of Seymour Benzer

Seymour Benzer

Seymour Benzer was an American physicist, molecular biologist and behavioral geneticist. His career began during the molecular biology revolution of the 1950s, and he eventually rose to prominence in the fields of molecular and behavioral genetics. He led a productive genetics research lab both at...

 at the California Institute of Technology

California Institute of Technology

The California Institute of Technology is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering...

. During this work, Konopka discovered the period

Period (gene)

Period is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving...

(per) gene, which controls the period of circadian rhythms.

Academic career

Ron Konopka received his Ph.D. in Biology from the California Institute of Technology in 1972. In 1975, following his discovery of the period mutants, Konopka was awarded a faculty position at the California Institute of Technology. While there, Konopka's colleagues were critical of his reluctance to publish his work on the period gene, and Konopka was denied tenure

Tenure

Tenure commonly refers to life tenure in a job and specifically to a senior academic's contractual right not to have his or her position terminated without just cause.-19th century:...

. After his stay at Caltech, Konopka accepted a position at Clarkson College

Clarkson College

Clarkson College is a private college located in Omaha, Nebraska that offers undergraduate and graduate degrees in the health sciences. Areas of study include nursing, medical imaging, imaging informatics, radiologic technology, health care business, physical therapist assistant and professional...

 but was again denied tenure and subsequently exited the field of science. Konopka's career, interwoven with the work of his mentor, Seymour Benzer, and the other scientists working in Benzer's lab is narrated in Time, Love, Memory by Jonathan Weiner

Jonathan Weiner

Jonathan Weiner is a Pulitzer Prize-winning author of non-fiction books on his biology observations, in particular evolution in the Galápagos Islands, genetics, and the environment....

.

Discovery of Period

As a graduate student in Seymour Benzer's lab, Konopka sought to use Benzer's method of behavioral genetics to unravel the mysteries of the "master clock" that existed in every organism. He used ethyl methanesulfonate (EMS) to induce point mutations in the Drosophila melanogaster genome, and eventually isolated three mutants with abnormal rhythms in eclosion. He mapped the mutations to the same location on the far left of the X chromosome

X chromosome

The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...

, less than 1 centimorgan

Centimorgan

In genetics, a centimorgan or map unit is a unit of recombinant frequency for measuring genetic linkage, defined as that distance between chromosome positions for which the expected average number of intervening chromosomal crossovers in a single generation is 0.01. It is often used to infer...

 away from the white gene locus

White (mutation)

White, abbreviated w, was the first sex-linked mutation ever discovered in the fruit fly Drosophila melanogaster. In 1910 Thomas Hunt Morgan, collected a single male white-eyed mutant from a population of Drosophila melanogaster fruit flies, which usually have bright red eyes...

. These mutations were alternative alleles of a gene that Konopka subsequently named period. While wild type flies have a circadian period around 24 hours, Konopka found the per⁰¹ mutant was arrhythmic, the per^S mutant had a period of 19 hours, and the per^L had a period of 29 hours.

Neurobiology of per mutants

In 1979 and a 1980, Konopka and Dominic Orr tested whether mutations in per mutations effected the period of the entire circadian cycle or just a portion of it. By comparing the light responses of per^S eclosion rhythm to that of wild type flies, Konopka and Orr found that light pulses reset the mutant clock to a greater extent than the wild type clock (about 10 hours for per^S compared to 3 hours for wild type flies). They also observed that the while duration of the light-sensitive part of the day (subjective night) was found to be similar between per^S and wild type flies, the duration of the light-insensitive part of the cycle (subjective day) was 5 hours shorter in mutant flies than in wild type flies. They concluded that differences in period length between mutant and wild type flies could be accounted for by a shortening of the subjective day, or the active part of the circadian cycle, in per^S mutants. From this, Konopka concluded that separate molecular processes correspond to the subjective night and subjective day and that the per^S allele acts by shortening the subjective day while leaving the subjective night unchanged. Based on these findings, Konopka and Orr constructed a model for the action of the per gene. The oscillation is interpreted in terms of a membrane gradient that is established during the subjective day and dissipates during the subjective night. The model predicts that the per gene product is active during the subjective day and functions like a pump to establish the gradient. Once a high threshold is reached, the pump shuts off and light-sensitive channels open to dissipate the gradient. A light pulse during the subjective night closes the channels and starts the pump; the value of the gradient when the channels close is the same as the value when the pump starts, and thus a reset in the cycle is produced and an oscillation results. This model has been replaced with a transcription translation negative feedback model involving timeless

Timeless (gene)

Timeless is a gene in Drosophila which encodes TIM, an essential protein that regulates circadian rhythms. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation [negative feedback] loop involving the period gene and its protein.-Discovery:Timeless was...

, clock

CLOCK

Clock is a gene encoding a basic-helix-loop-helix-PAS transcription factor that affects both the persistence and period of circadian rhythms...

, and cycle

Cycle

Cycle, and in some cases cyclic, may refer to:* A process that returns to its beginning and repeats itself in the same sequence. Such processes are seen in many fields, such as physics, mathematics, biology, astronomy, economics, audio frequency, etc....

.

Also in 1980, Konopka and Steven Wells reported an abnormality in the morphology of a neurosecretory cell group associated with the arrhythmic per⁰¹ mutation and with 2 arrhythmic mutants of another fly strain, Drosophila pseudoobscura

Drosophila pseudoobscura

Drosophila pseudoobscura is a species of fruit fly, used extensively in lab studies of speciation.In 2005, D. pseudoobscura was the second Drosophila species to have its genome sequenced, after the model organism Drosophila melanogaster....

. This cell group normally consists of four clustered cells in either side of the brain, roughly halfway between the top and bottom edge, in the posterior area of the brain. Cells in this cluster are occasionally located abnormally near the top edge, rather than the middle, of the brain at a rate of about 17% of cells in wild-type D. melanogaster. The per⁰¹ mutation significantly increases the percentage of abnormally located cells to about 40%. In two aperiodic strains of D. pseudoobscura, the percentages of abnormally located cells are likewise significantly increased over those in the wild type. Konopka inferred from the results that neurosecretory cells may be part of the Drosophila circadian system and that per gene product may influence the development of these cells.

Pacemaker signalling

In 1979 Konopka worked with Alfred Handler to discover the nature behind pacemaker signalling by transplanting brains of donor flies into abdomens of arrhythmic host flies. They found that circadian rhythms in host flies were restored with the period of the donor; for example, short period (per^S) adult brains implanted into the abdomens of arrhythmic (per⁰¹) hosts could confer a short period rhythm on the activity of some hosts for at least 4 cycles. Since the transplanted brains were unable to create new neuronal connections to locomotor activity centers, Konopka and Handler concluded that pacemaker signalling for locomotion must be humoral and not neuronal.

Reciprocal behavior of per mutants

While at Clarkson College, Konopka continued his work with Orr and also collaborated with chronobiologist Colin Pittendrigh

Colin Pittendrigh

Colin Pittendrigh was a US-American biologist of English parentage. He is a co-founder of modern chronobiology along with Jürgen Aschoff and Erwin Bünning.-Life:...

. During the collaboration, Konopka worked to understand behaviors of Drosophila per mutants beyond their abnormal period lengths. Konopka was primarily interested in how these mutants behaved in constant light or constant darkness and whether they conformed to the rules established by chronobiologist Jurgen Aschoff

Jürgen Aschoff

Jürgen Walther Ludwig Aschoff was a German physician, biologist and behavioral physiologist. Together with Erwin Bünning and Colin Pittendrigh, he is considered to be a co-founder of the field of chronobiology.-Life:...

. In addition, Konopka also observed behavior of the flies under varying light intensities and over a range of temperatures. Konopka found that the per^S and per^L flies showed reciprocal behaviors under the experimental conditions. For example per^S period shortened, while per^L period lengthened in response to decreasing temperature. Konopka hypothesized that these reciprocal behaviors were a manifestation of two coupled oscillators, a model proposed in 1976 by Pittendrigh and Daan.

Clock mutants

In 1990, Konopka collaborated with Mitchell S. Dushay and Jeffery C. Hall to further investigate the effects of the clock gene in D. melanogaster. Konopka had noted in 1987 that the Clock (Clk) mutant, induced via chemical mutation, was a semidominant mutation that shortened the rhythm of locomotor activity in flies by around 1.5hr. Dushay, Konopka and Hall noted that Clk mutants had phase response curve that was shortened from 24hr to 22.5hr, and that the short period was also observable in the eclosion rhythm of the mutant flies. Clk was mapped close enough to the per⁰¹ mutation such that it could be considered a per allele, but due to the presence normal courtship song rhythms in Clk males and the lack of coverage of its effects via duplications, Dushay and Konopka determined that Clock was a novel circadian mutation.

Andante mutants

By working with Randall F. Smith and Dominic Orr of Caltech, Konopka discovered a new circadian mutant, named Andante, in 1990. In contrast to Clock, Andante lengthens the period of eclosion, and locomotor activity by 1.5–2 hours, and was also shown to lengthen the periods of other circadian mutants. Andante is a semi-dominant mutation, temperature compensated, and unaffected by the sine oculis mutation, which eliminates the outer visual system of flies. It was mapped to the OE-2 to OF region of the D. melanogaster X chromosome, close to the miniature-dusky locus.

External links

• 2000 Brief Interview with Konopka on period gene