overall: 47 cm x 64.8 cm x 112.4 cm; 18 1/2 in x 25 1/2 in x 44 1/4 in
This robot was constructed in 1987 by Dr. Kenneth Kinzler and his colleagues at the Johns Hopkins Oncology Center's Molecular Genetics Lab run by Dr. Bert Vogelstein. It was used to conduct PCR in research on the p53 gene, which is linked to 50 percent of human cancers. Polymerase chain reaction, or PCR, is a chemical reaction that can create a huge number of copies of sections of DNA from a very small sample.
Kinzler and his fellow researchers started using PCR immediately after the technique was published in Science in 1985. The technique revolutionized their ability to do research, but it was time-consuming, requiring continuous, repeated changes in temperature. (For this reason, PCR is also known as thermal cycling.) Automated commercial PCR machines were not available until 1987, and were hard to come by due to high demand and a hefty price tag.
Low on funding and unwilling to wait, the researchers at Hopkins decided to make their own PCR machine. Over the course of two days, they constructed this robot out of parts found around their lab and objects available at Radio Shack and hardware stores. The robot has a moving arm that transfers the DNA sample between two water baths of different temperatures. A programmable lab timer from another piece of lab equipment makes up the “brains” of the robot. A TV antenna rotator from Radio Shack moves the arm (a long wooden dowel) back and forth, and a solenoid from a dishwasher door lock lowers the arm into the bath.
To give the robot a bit of personality, the scientists added a styrofoam head, sunglasses, and a navy baseball cap with a gold star and gold braid detailing. One part of the object has been painted with a red “BV,” likely for “Bert Vogelstein.” All of these parts are assembled on a two-tiered wood frame.
Thanks to help from the robot, the researchers were able to determine the function of the p53 gene. Prior to their work, p53 was known to be linked to cancer, but its function was not understood. The Hopkins team’s research determined that p53 is a tumor suppressor gene, regulating cells whose DNA is damaged. Mutations in the gene destroy this regulatory function and result in cancer. The team published their results on April 14, 1989 in a Science article entitled “Chromosome 17 Deletions and p53 Gene Mutations in Colorectal Carcinomas.”
Kary Mullis drew this diagram of the polymerase chain reaction process during an interview for a video history conducted on May 15, 1992, by former National Museum of American History curator Ray Kondratas. The video history is available at the Smithsonian Archives under record number SIA RU009577. Mullis invented the polymerase chain reaction (PCR) in 1983 as a method to copy specific portions of DNA. He won the 1993 Nobel Prize in Chemistry for his invention.
The drawing’s purple and red horizontal lines represent strands of DNA being copied. The letters “dNTPs” at the top of the page refer to deoxyribonucleotides, the individual units of DNA that are assembled into the longer continuous chain. A supply of dNTPs (which come in four types: dATP, dCTP, dGTP, and dTTP) are necessary for PCR to occur.
To learn more about PCR see object 1993.0166.01, Mr. Cycle.
average spatial: 36.2 cm x 26 cm x 38.1 cm; 14 1/4 in x 10 1/4 in x 15 in
This object is a prototype liquid-handling machine developed at Cetus Corporation in Emeryville, California, in the early 1980s. It was designed to facilitate bioactivity assays by automatically performing dilution series. It has the ability to manipulate small volumes of liquid on a microtiter plate. The Pro/pette was later adapted to become part of the first PCR machine, “Mr. Cycle” (see object 1993.0166.01).
average spatial: 33.6 cm x 33 cm x 45.7 cm; 13 1/4 in x 13 in x 18 in
This object, nicknamed “Son of Son of Cycle,” was the third prototype automated PCR machine developed by engineers at Cetus.
PCR, short for polymerase chain reaction, was a revolutionary laboratory technique developed by Kary Mullis at Cetus Corporation in 1983. PCR acts like a photocopier for genetic material, working on principals similar to nature’s own method for replicating DNA. With the reaction, scientists can take a single portion of DNA they wish to study and amplify it into millions of copies in only a few hours. This simple technique for creating large amounts of DNA resulted in huge leaps in genetic research in a variety of fields from evolutionary biology to forensics to medicine.
Although the reaction is straightforward, requiring only a few ingredients, it is incredibly time-consuming to perform by hand. Because different steps of the reaction take place at different temperatures (hence the name “thermal cycling”), scientists performing the reaction were required to stand at the lab bench for several hours, moving the sample back and forth between water baths of different temperatures. While they loved the technique, scientists were eager for an automated machine that could perform the reaction for them.
“Son of Son of Cycle” is very similar to the second prototype PCR machine “Son of Cycle,” consisting of a control box (with the digital display) and a reagent box (with wells on top for sample tubes where the reaction took place). Sample tubes containing all the reagents necessary for the reaction were placed in the wells on top of the reagent box. The duration of the cycle would be programmed using the control box and the changes in temperature occurred through Peltier devices for thermoelectric heating and cooling. Like “Son of Cycle,” “Son of Son of Cycle” utilized heat-stable enzymes, chemicals used to speed up the reaction. (Early on, enzymes that were not heat-stable were used in PCR. Because they were degraded at high temperature, new enzyme had to be added with every cycle.) This prototype was an improvement over the previous prototype because it incorporated more Peltier devices, allowing for a greater number of samples in a single run. It also used a different path for airflow, resulting in a more efficient cooling system.
overall: 55.3 cm x 33 cm x 55.8 cm; 21 3/4 in x 13 in x 21 15/16 in
This object, affectionately referred to as “Mr. Cycle,” was the first prototype automated PCR machine or thermal cycler. Its robotic machinery is contained in a beige plastic housing. One side of the housing features a rainbow colored “California Dreamin’” sticker. It’s not known who applied the sticker to the prototype, but it may be a reference to the location of its creation or the “surfer dude” personality of the PCR process’s inventor.
The machinery consists of a liquid handling arm that slides up and down and a drawer portion. The drawer portion houses three blocks (from front to back): sample block, reagent block, and tip magazine. The sample block has four black hoses attached to it. The other ends of the hoses are attached to solenoid valves on the top of the machine. In operation, these solenoid valves would also have been attached to water baths via hoses. The water baths were not collected.
PCR, short for polymerase chain reaction, was a revolutionary laboratory technique developed by Kary Mullis at Cetus Corporation in 1983. PCR acts like a photocopier for genetic material, working on principals similar to nature’s own method for replicating DNA. With the reaction, scientists can take a single portion of DNA they wish to study and amplify it into millions of copies in only a few hours. This simple technique for creating large amounts of DNA resulted in huge leaps in genetic research in a variety of fields, from evolutionary biology to forensics to medicine.
Although the reaction is straightforward, requiring only a few chemicals, it is incredibly time-consuming to perform by hand. Because different steps of the reaction take place at different temperatures (hence the name “thermal cycling”), scientists performing the reaction were required to stand at the lab bench for several hours, moving the sample back and forth between water baths of different temperatures. While they loved the technique, scientists were eager for an automated machine that could perform the reaction for them.
Engineers at Cetus developed the “Mr. Cycle” prototype by modifying a Pro/pette (see object 1994.0031.01), an instrument that the company had previously created to be used for liquid handling. The tray on the front held the sample and could slide back and forth. When slid to the front, the sample tray would rest in a water bath. The black hoses brought water from baths of different temperatures (not pictured) as necessary. When slid to the back, the sample could be injected with new enzyme, a chemical used to speed up the reaction, that had to be added once during a cycle. These two features—water baths and the need to add enzyme during each cycle--would be phased out in all future prototypes (see object 1996.0166.02) and commercial models. The water baths were replaced first with Peltier devices for thermoelectric heating and cooling and later, in commercial models, with electric heating and refrigeration units. The enzyme problem was solved by isolating a heat-stable form from bacteria which live in geothermal hot springs. Previously, the enzyme had to be replaced in each cycle because it would degrade in the high-heat step of the reaction.
Currently not on view
from Roche Molecular Systems, Inc., through Thomas J. White, Ph.D.
overall: 50 cm x 66 cm x 46 cm; 19 11/16 in x 26 in x 18 1/8 in
This machine is an automated DNA/RNA synthesizer, Model 394 from Applied Biosystems, Inc. It was on the market from 1991 to 2007. DNA/RNA synthesizers can produce short single strands of nucleotides known as oligonucleotides. These “oligos” can be linked together to create longer strands of DNA or RNA. Synthetic DNA or RNA is used by researchers both to study how genes work and for the purposes of genetic engineering and PCR (see object 1993.0166.01). Often it is easier to make a stretch of DNA or RNA with a synthesizer than it is to isolate that same stretch of DNA or RNA from a natural source. Synthetic oligos can also be created with slight changes from the naturally occurring forms, allowing researchers to study the impact of modifying the molecule.
The ability to synthesize oligos has been around since the late 1950s, when Har Gobind Khorana discovered a method to make them in the lab using solution phase chemistry. In the 1960s, Robert Letsinger devised a method for assembling oligos using solid phase chemistry, which constructs the oligo by linking its chemical building blocks onto a polymer bead scaffolding. This advance, along with slight adjustments to Khorana’s original protocol, simplified the reaction to the point where the first automated machines to perform oligo synthesis could be built in the late 1970s. At the time, however the reaction relied on very unstable chemicals that had to be prepared by a highly trained chemist just before the machine could be run.
By the 1980s further adjustments to the reaction made it possible for someone without a great deal of experience in chemical preparation to operate the machines, opening up their use to a wider audience and increasing their commercial viability. Applied Biosystems marketed these simpler to use machines starting in 1989. This object, Model 394, was the second wave of Applied Biosystems’s DNA/RNA synthesizers. It consumed chemicals more efficiently than the previous model and could synthesize up to four oligos at one time.
“Gene Synthesis Demystified.” Czar, Michael J., J. Christopher Anderson, Joel S. Bader, Jean, Peccoud. Trends in Biotechnology. 27 February 2009 (2):63–72.
Manual for DNA Synthesizer Models 392 and 394, Applied Biosystems, Inc.
“A Short History of Oligonucleotide Synthesis.” Hogrefe, Richard. TriLink BioTechnologies. http://www.trilinkbiotech.com/tech/oligo_history.pdf