Making the Micropipette

“Hazards of Mouth Pipetting”

The micropipette, an instrument favored by researchers around the world to measure and move liquids from one container to another and used for everything from forensic analysis to DNA sequencing, was invented by an obscure, 32-year-old German postdoc after a particularly productive two-day tantrum.

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Heinrich Schnitger was born in Lemgo, Germany in 1925. He fought in the Second World War, but was hospitalized with tuberculosis and removed from active duty as a result. The illness probably saved his life. After the war, Schnitger earned a PhD in medicine and began a research position at the University of Marburg.

There, Schnitger busied himself with chromatography, a technique to isolate molecules by flowing liquids through columns and then painstakingly sorting the tiny drops that emerged. At the time, these experiments were done entirely with mouth pipettes. Researchers would suck liquids into a glass tube and then transfer the liquid to another container. But mouth pipettes were fragile, inaccurate, and dangerous.

A 1915 survey of 57 research laboratories found that 40 percent of workplace-related infections were directly linked to mouth pipetting. Decades later, in the 1960s, U.S. Army researchers penned an article entitled, “Hazards of Mouth Pipetting.” Leaving no room for ambiguity, they conclude in all caps: DO NOT MOUTH PIPETTE INFECTIOUS OR TOXIC FLUIDS and USE A PIPETTOR DEVICE FOR PIPETTING.¹

Schnitger viewed mouth pipettes with “great contempt.” In 1957, presumably driven by this pique, he vanished from the laboratory and returned, two days later, “with a self-designed tool to pipette microlitre volumes.” On May 3rd, Schnitger filed a patent entitled, “Device for quick and precise pipetting of small amounts of liquid.” The patent was granted in 1961, and his design had “all the essential features of the modern pipette,” according to a close witness of the invention, including a spring-loaded piston, second spring to shoot out residual liquid, and plastic tip.²

It is nearly impossible to imagine modern biology without the micropipette, which has enabled scientists to manipulate cells with a much higher degree of precision. It was used in the first experiments with recombinant DNA and also, as early as 1968, to determine the sex of rabbit embryos, a necessary precursor to the development of in vitro fertilization. But this tool’s widespread adoption was not inevitable, nor were its features preordained. The micropipette only exists thanks to a long line of scientists and businessmen whose creative iterations, savvy deals, and expensive legal battles shaped the course of modern science.

Like much technology, the development of the micropipette is a story of adaptive radiation. Inventors living in completely different parts of the world each came up with their own ways to move around small volumes of liquid. Many designs failed, other features caught on, and the winners — such as disposable plastic tips and knobs to adjust the micropipette’s volume — were gradually reconfigured into the devices used today.

Although the modern micropipette begins with Schnitger’s exasperation, his own story, sadly, ends in 1964, when he went for a swim in a Bavarian mountain lake and drowned. While this was an untimely end for a great innovator, it is oddly fitting that a man best known for creating a device to move around small volumes of liquid died unable to manage large ones.

The Modern Micropipette

Schnitger’s first micropipette was made from simple parts. He had taken a small metal syringe, similar to those used in hospitals, and added a spring and end stop to it. Schnitger replaced the syringe needle with a plastic tip, which he had crafted from a polyethylene tube, and added a little air pocket to keep liquids from touching the metal pistons and contaminating or corroding the inside of the device.³ To suck up liquid, Schnitger pressed the plunger to the stop, put the tip into the liquid, and then released the plunger. Pressing the plunger again expelled the liquid.

Despite its novelty, Schnitger’s design lacked several features that modern scientists take for granted. The device’s volume could not be adjusted, and the polyethylene tips were too expensive to be disposable, which made them prone to contamination. A solution to these deficits arrived by way of a broad-faced Finn in 1969.

Osmo Suovaniemi grew up in a farming family from Kihniö, Finland, a tiny town on a small lake one-and-a-half hours north of Tampere, the nearest mid-sized city. He studied medicine by day and worked in research labs at the University of Helsinki by night. While mouth pipetting one night in the lab, Suovaniemi “almost swallowed a piece of rat’s brain,” according to a 2014 review. After tinkering with syringes, springs, and screws, Suovaniemi assembled a micropipette with a knob on top to adjust the volume inside—no mouth-suction required.

Suovaniemi filed a patent application on his adjustable micropipette in 1969, at the age of 26, and founded a company to produce the devices.⁴ His work is little-known outside Finland, and the design didn’t catch on, in part because it lacked a numerical gauge to display volumes, which hampered its precision.⁵ 

Shortly after making his adjustable micropipette, Suovaniemi made a second pipette that could move multiple liquids around at once; it was the first multichannel pipette. Interestingly, Suovaniemi didn’t attribute his inventions to diligence or tireless ambition, but quite the opposite. “I’m extremely lazy by nature,” Suovaniemi once told an interviewer, so “I created a pipette with nine channels.” His multichannel pipette, with tips arranged in a 3 x 3 grid, was patented in 1969. 

In 1972, another micropipette breakthrough came from Warren E. Gilson, a bald, ruddy-cheeked medical professor in Wisconsin. With help from his son Robert, and several scientists at the University of Wisconsin, Gilson used a screw mechanism to adjust the travel of the piston, thus changing the volume of liquid. A gauge on the pipette’s side displayed the position of the screw. The pipette also had a locking ring on top that could be set to keep volumes from shifting by accident.

Gilson’s pipette design is still sold by his eponymous company, which is led by a third-generation family member. In 1974, Gilson’s French collaborator, Eric Marteau D'Autry, changed the finger hook design and added a tip ejection mechanism. The result was the first recognizably modern micropipette — a device made by a French-American duo, based on earlier designs by German and Finnish scientists.

The D’Autry-Gilson micropipettes were sold across Europe, but rights to the United States market were bought by Kenneth Rainin, a young California businessman. Rainin was born in Cleveland, Ohio in 1938, later joined the Army, and got his start selling science equipment in Boston. At the age of 25, Rainin founded the Rainin Instrument Company, which distributed Gilson’s pipettes and other laboratory supplies.

Although Rainin became rich selling Gilson’s pipettes, he also went on to build his own pipette empire that he later sold to the Mettler-Toledo corporation, in 2001, for more than $290 million in cash and stock. Rainin ordered a custom-made, 62-meter-long motor yacht with English country-home decor and mahogany paneling.

Rainin had skills outside of business, too. He made many improvements to the micropipette, including the addition of an electronic display to make it easier to see the set volumes, and “quick-set” controls so that scientists didn’t need to twist the pipette several times to move from a small volume to a large volume. Rainin also modified the Gilson design so that it fit better in the hand, and reduced the strength required to eject the plastic tips.⁶ More comfortable micropipettes were a welcome improvement; a 1997 study that surveyed 80 scientists who used a pipette for more than one hour per day found that 90 percent of them reported hand or elbow disorders.

As evidenced by Rainin’s ergonomic refinements on Gilson’s base design, micropipette companies operated in relative harmony for several decades. But then, an issue with the Rainin-Gilson contract saw the two companies run headlong into an expensive legal battle, and all equanimity was dashed.

Rainin was Gilson’s exclusive distributor in the United States. Under the terms of their distribution contract, Rainin was supposed to promote Gilson’s products. But after Gilson’s patent for the adjustable pipette expired in 1991, Rainin saw an opportunity to introduce a competing line of pipettes and market them to American scientists. 

In 2004, Gilson filed a lawsuit against Rainin, accusing Rainin executives of “a campaign to disparage Gilson's Pipetman products and route customers to their own competing product lines.” A Wisconsin court “granted Gilson's motion for judgment as a matter of law and held that Rainin and Mettler-Toledo breached their obligation to use their best efforts to market and sell Gilson's Pipetman products,” according to reporting in NBC News. A jury awarded Gilson $500,000 in damages, far less than the $8 million Gilson had initially sought. But the jury’s decision wasn’t the only blow dealt to Rainin: The company also lost their exclusive license to sell Gilson pipettes in the United States, which cost Rainin an estimated $19 million in lost revenue.

As Gilson and Rainin competed for large chunks of the micropipette market, other businesses popped up to profit from their disposable tips.

The first micropipettes used custom-made Teflon tips, which had good chemical resistance and high accuracy, but were too expensive to regularly dispose of. The German company that first licensed Schnitger’s 1957 invention, Eppendorf, also made the first disposable polypropylene tips. Disposable plastic tips helped scientists avoid some cross-contamination but couldn’t always be used in sensitive experiments because liquids produce small amounts of aerosols that get sucked into the pipette body and then seep into subsequent samples. In 1986, Eppendorf scientists added a filter at the top of each pipette tip to block such aerosols.⁷

Rainin’s company, seeking to boost profits, also launched their own line of narrow-tapered tips that could only be used on Rainin micropipettes. Their logic was akin to those of the razor blade companies: sell the pipette for a few hundred dollars and tips for $20 per box. Over time, they assumed, the vast majority of profits would come from selling the tips. In the early 2000s, though, a company called USA Scientific found a way to make Rainin-compatible tips without using Rainin’s patents. Rainin sued them, albeit unsuccessfully, and USA Scientific still sells Rainin-style tips.

And that’s the making of the modern micropipette. For roughly three decades, the invention was iterated upon and refined by German, Finnish, American, and French inventors. Some of these inventors were driven by profit, and others just didn’t want to aspirate the brains of a rat. Their collective efforts culminated in an indispensable tool for modern biology and medicine.

Adaptive Radiation

A typical PhD student in the biosciences will use about 200,000 pipette tips over the course of their research.⁸ Hospitals and medical labs use even larger quantities of tips for diagnostic tests. This was starkly highlighted in 2020, when demand for COVID testing, coupled with a low supply of polypropylene resin after Texas power outages temporarily closed plastic manufacturing plants, caused the Great Pipette Tip Shortage. 

Pipette tip manufacturers were backordered for months, and sometimes years, as queues for COVID tests, newborn genetic screening, and other diagnostic tests lengthened. A single PCR-based diagnostic test requires about ten pipette tips, and more than a million of these tests were performed every day by October 2020. Scientists bartered with other scientists for tips, tried their luck with sketchy resellers, or gambled with washing and reusing tips.

But as the adage asserts: necessity is the mother of invention. Just as the first microplate, a flat plate with little wells on top to hold liquids, was invented by a Hungarian scientist as a replacement for plastic tubes after an influenza epidemic led to a manufacturing shortage in Hungary in the early 1950s, the recent pandemic spurred similar innovations in micropipette and tip designs.

A chemistry lab in Connecticut invented a COVID-19 diagnostic kit using 3D-printed micropipette tips and a smartphone app. Chemists in Okayama, Japan developed paper-based analytical devices that don’t have to be loaded with a micropipette at all. Eppendorf launched a line of pipette tips made from biologically-derived propylene gas, ostensibly to help curb plastic waste. While the supply chain corrected itself, ultimately relieving the pipette tip shortage, times of need or specialization are often moments where innovation is especially active.

The basic micropipette design used in laboratories today has remained largely the same since the mid-1970s, when D’Autry and Gilson made their adjustable version. But innovations have continued to the present. In 2018, a bioengineering team in Chicago open-sourced blueprints for a 3D-printed, adjustable micropipette. A highly precise micropipette that dispenses tiny volumes as small as 0.1 microliter, with a variation of just 0.6 percent, was developed the same year. And in 2014, a Japanese team invented a micropipette that can pick up individual cells through a thin, glass tube.

Technological progress often proceeds as a linear series of advances: the vacuum tube, then the transistor, then the microchip. But the history of pipettes reveals a subtler story.

Even before Schnitger made the piston-driven micropipette in 1957, other inventors had proposed unique ways to measure, or move, small volumes of liquid. Some of these ideas worked, but did not catch on. For example, in 1953, two American inventors, James W. Brown and Robert L. Weintraub, filed a patent for an adjustable pipette with a removable tip. The device dispensed tiny drops of liquid via the spinning of a wheel on one end, and it could be used with one hand. But Schnitger’s plunger mechanism ultimately won out.

Path dependencies also shaped the development of the modern micropipette; one refinement often set the course for subsequent ones. Multichannel pipettes today are designed around the 96-well plate, for example, which was itself copied from the Hungarian 72-well format. If scientists had adopted the 72-well format, multichannel pipettes today might look very different.⁹

Nearly all biological research requires the ability to transfer precise volumes of liquids, which makes it interesting to speculate about what might have happened if the micropipette was invented a few years earlier or later.¹⁰ The scientists who deciphered the genetic code and discovered the principles of gene expression in the late 1950s and early 1960s performed their experiments mostly with mouth pipettes. This makes their feats more impressive, but adjustable micropipettes would have greatly accelerated their work. Likewise, the groundbreaking experiments on DNA sequencing in the mid-1970s, which kickstarted the field of genomics, would have been difficult to achieve without micropipettes.

The micropipette’s history is a reminder that simple tools can have a large impact. Even a task as straightforward as transferring liquid from one tube to another can be accomplished by many different mechanisms, some of which are vastly superior to others. And so it’s worth considering: What is something you do, day after day, that is arduous or bothersome? Do you have a subtle itch or a pressing need to make it easier?

If the answer is yes, consider spending a couple of days making improvements to the process, as a frustrated Schnitger did in 1957. Simple solutions to widespread problems can alter the course of scientific history.

Footnotes

1. Today, researchers have mostly heeded this advice, and only use mouth pipettes in niche cases where they need both hands free.
2. Eppendorf, a German medical supply company, purchased an exclusive license. The company made at least two models by 1961; one to pipette 1 microliter volumes (smaller than a grain of salt) and another for 25 microliter volumes.
3. This feature was essential; Schnitger’s first micropipette was used to transfer formic acid, a chemical that reacts with metal to form hydrogen gas.
4. Suovaniemi is 80 years old and remains chairman of the board of his company, Biohit OYJ.
5. The Finnpipette brand, sold by Thermo Fisher, derives from Suovaniemi’s design. But I’ve never seen one of these pipettes in person, and their market share (at least in America) is a small fraction of other manufacturers.
6. Rainin pipettes received the highest overall score in a 2010 study that asked twenty-one scientists to rate the comfort and usability of ten different micropipettes. Scientists collectively rated Rainin pipettes highest for “hand and arm comfort,” as well as its “lower tip ejection force, lower blowout force, and pipette balance in the hand.”
7. Eppendorf scientists were inspired by filters designed to protect scientists who used mouth pipettes to transfer infectious materials.
8. An estimated ten boxes of 96 tips per week, with 50 working weeks per year over a 5-year period, comes out to 240,000 tips. And five years is a generous estimate for completion of a PhD in the biosciences.
9. The number 96 has several advantages, including the fact that it has many integer factors, which makes it simple to evenly divide the plate for experiments.
10. Polypropylene was not produced at a large scale until the mid-1950s, and so a different (and likely inferior) material would have been required to make the plastic tips.

Metacelsus is a PhD student who researches synthetic biology, stem cells, and reproductive development. He also writes the blog De Novo.

This article was published on January 2, 2024.

Cite this essay: Metacelsus. "Making the Micropipette." Asimov Press (2024). DOI: https://doi.org/10.62211/2u7d-jwms