Smash Notes
Eric Betzig
Episodes
Notes
632nm · Diffraction Limit, Microscopy, and Cell Biology | Eric Betzig on…
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Why Does Eric Betzig Call Biology the Last Frontier?
Eric Betzig says biology is the last frontier. He studies it at the last stage of his career and says he is never going to be a biologist. Mystery sits everywhere, and people understand so little that biology is still in the pre-Kepler era and the phlogiston era. So many things people think they know are bullshit. Biology is the final frontier because it is the most complex matter in the known universe.
A virtual cell, the goal people say they want now, will take generations, if not eons, if it ever happens. The missing piece is enough mechanistic understanding. Eric Betzig says people do not grasp how big the mystery is. Asked whether there is a SpaceX of biology and where a biologist shou
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Why Does Eric Betzig Call Bell Labs Impossible to Copy?
Eric Betzig says copying Bell Labs is literally impossible. Full immersion is an immutable law of how the human brain works. Any distraction pulls the mind off the problem it is supposed to work on. Putting up a building like Bell Labs and having people work even 50-hour weeks is not enough.
In his era most of the men had stay-at-home wives and worked 16 hours a day, seven days a week. Eric Betzig says the wives deserve Nobel Prizes as much as the men who received them, because the work would not have happened without the wives. The arrangement is a unicorn now. People are not expected to have a stay-at-home wife and work 16 hours a day, seven days a week. Most people do not want to work ev
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Why Did Bell Labs Line Every Lab Down One Hall?
Eric Betzig says Bell Labs turned out 12 Nobel Prizes from one institution because scientists were left to do science all the time. Shannon worked that way. Hamming worked that way. Bell refused separate chemistry, physics, and mathematics departments, because advances happen at the interface between disciplines.
In the physical research division where Eric Betzig worked, 100 PIs were all called members of technical staff. A new hire and a Nobel Prize winner faced the same limit: one postdoc and one technician. Empires were banned, so people collaborated. Everyone shared one corridor of a massive building, labs on both sides of one straight line. Lunch meant walking past 50 other people, an
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Why Does Eric Betzig Say Nuclear Beats Wind and Solar?
Eric Betzig says the right long-term answer on energy is nuclear, and he has no doubt about it. Nuclear will be scalable. Done right, it is by far the cheapest method, because the costs come down to energy density. Energy density is materials, and materials are cost. The energy density of nuclear is orders of magnitude better than hydrocarbons, which are orders of magnitude better than wind and solar. Anybody who expects wind and solar to replace hydrocarbons is, he says, completely delusional.
In the pandemic, when it was difficult to do much, Eric Betzig went down two rabbit holes. One was nuclear space propulsion. Musk had talked about Mars, and he looked at using Starships for people wh
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Why Can't Dyes Show a Thousand Proteins at Once?
Eric Betzig says a label with a truly narrow emission line would let a microscope watch a thousand proteins at once, because each spectrum would stay narrow. Fluorophores do not give that line. He puts the width at about 50 nanometers of emission spectra, and the excitation spectra are just as broad.
He still lets the bands overlap and then unmixes them. The lasers turn on and off for each one, and multiple cameras each watch one spectral band. He has also looked for help from plasmonics and little silver resonators. Nothing useful has come up. Delivery is a pain, the sample is no longer in a vacuum, and nearby electric fields cause stark shifts that perturb the lines.
He treats a caged io
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How Fast Does Eric Betzig Need Microscope Data?
Eric Betzig says microscopes get better all the time, and he keeps an ear out for anything new that comes along. One microscope coming online now will be more performative than anything they have had before. His best estimate is they will need on the order of 20 to 50 petabytes by the time the work is done. He wants that data in two years instead of 15 years, and he wants an order of magnitude more out of the scopes.
They are building scopes that take multi-well plates and will be automated for perturbation experiments. Betzig says the optics still have to be clever. For the last eight years, most of what he has been doing is mixing optics he already knows. He takes pieces off the shelf, co
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What Comes First From Eric Betzig's Cell Observatory?
Eric Betzig says the first thing from the cell observatory is robust segmentation, and segmentation would be valuable in many contexts. Once segmentation is robust, identifying cell types is trivial, and a lab can ask the interesting biological questions, including off-target effects in pharma.
Betzig estimates the cell observatory would take $50 million. The group is developing biological reagents, knocking in fluorescent proteins and dozens or hundreds of tags across cell types, and the microscopes to take the data are already in hand. Zebrafish is the model because the fish is transparent, a vertebrate, and 70 percent genetically homologous with humans. To the extent the match is recapit
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Why Did Eric Betzig Call the 2014 Nobel Premature?
Eric Betzig argues that most single-molecule super-resolution has not revealed much of anything, and that most super-resolution in general has not either. Even back in 2014, he felt it was incredibly premature to give a Nobel Prize for the work.
He says the prize came because the work broke a limit, but anyone who knew optics would know the limit is not fundamental in the same way the uncertainty principle is fundamental. It was a practical limit circumvented by a trick: localize to better precision than the wavelength. In his opinion, the first real hit, and the one that led to ICON, came when the work stopped looking at dead and fixed samples. Dead and fixed samples were used because the
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How Did Eric Betzig Get the Science Data So Fast?
Eric Betzig says the method was obvious the moment violet light switched the molecules on. He and the other experimenter knew it worked, then raced.
Within less than a month they plated thin cryo-sections instead of a whole cell, so the sample stayed two-dimensional and out-of-focus light from the third dimension stayed off the picture. The slices ran through lysosomes. They had only a 10-milliwatt laser, so they worked around the clock and babied a cheap microscope whose focus drifted. It was November and cold, in an old dark room converted for the work. They kept the effort quiet in a big lab full of postdocs and graduate students, who called the two old guys the gruesome twosome. Within
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How Fast Did Bell Labs Flip From Papers to Fruit?
Eric Betzig hated science and hated academia, then realized he missed doing science and wanted a way back. He left Bell Labs in 95 and reconnected with his best friend as the lab's culture flipped from pure papers to work meant to help the bottom line.
The monopoly that funded Bell Labs broke up in 84. Support lasted through the mid-90s, then leadership pushed the lab to contribute to AT&T, including the purchase of National Cash Register. Betzig started in 88. In 90 a friend told him technology did not matter at Bell and the only thing that mattered was how many letter papers he published. Two years later, after the National Cash Register purchase, Bell Labs research head Arno Penzias, who
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Why Did Eric Betzig Leave His Father's Company?
Eric Betzig says he is a good scientist, a horrible businessman, and an even worse salesman. He cannot make people feel comfortable. Raising money from philanthropy runs into the same wall, because he comes across as too crazy. Even philanthropists who claim they are risk-tolerant do not want to look stupid.
After six years he apologized to his dad for wasting a couple million dollars of his money. The company was still doing fine. His dad wanted his son to take over the business someday. Eric Betzig calls his dad the inverse of him: people-friendly, able to make everybody feel comfortable and like him. He was never going to fill his dad's shoes, and he did not want to. He still saw himself
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Why Did Eric Betzig's Part Inspector Get Turned Off?
Eric Betzig built an inspector with about 30 cheap CCD cameras set all around a part. It measured every piece coming off the machine in a fraction of a second, to sub-pixel precision on an edge or a hole, and rejected any part that missed the blueprint tolerances.
He put one on a machine shipped to New York, and it started rejecting parts. Eric Betzig places the specs in the era of GE and Jack Welch's Six Sigma push. He says Six Sigma means precision like 10 to the minus 6, a level nobody can achieve. The old method used a coordinate measuring machine to check only some parts. As long as the parts bolted onto the axle, the result was good enough. Companies wrote tolerances so tight that eve
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How Did Eric Betzig See Single Molecules?
Eric Betzig says one of the two experiments he did at Bell, which led to the idea for the Nobel Prize, made him the first person to see single molecules at room temperature. He localized their positions to about a 50th of the wavelength of light.
He did the work with near field microscopy. He knew the energy distribution inside the near field aperture, fit a profile to the light, and placed the molecule much better than the width of the aperture, the same way the center of a Gaussian can be found much better than the width of a Gaussian. Two facts proved a single molecule. The molecule bleaches all at once: it is there and the next instant it is gone. Fluorescent molecules are dipoles, so t
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Why Did Eric Betzig Leave Science for His Dad?
Eric Betzig says the scales fell off his eyes early. He did not just leave Bell Labs, and he did not just leave Nearfield. He left science, and he was done with it. He went to work for his dad.
His dad worked for a machine tool company in Michigan, home of the big three in the auto industry, and the industry was producing millions of cars a year. The volume means millions of brake calipers a year, and Eric Betzig says you may need to make a million intake manifolds a year. A thousand guys each on a milling machine cannot turn out the parts. Computer numerically controlled machines existed, but they were not robust enough to produce a million parts a year. Where his dad worked, the company d
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Why Did Eric Betzig Pivot From Super-resolution?
Eric Betzig pivoted from super-resolution because chemical fixation makes nanoscale structure artificial. Regular optical resolution can tolerate the damage. Super-resolution shows artificiality.
Betzig starts with cultured cells because they are the easiest, and palm is where the work had to start. Super-resolution began on single culture, and at first on dead cells chemically fixed so they are not wiggling. The techniques were slow at first and remain slow in many cases today, so a sample wiggling and moving fast blurs. The cell is chemically locked in place and then imaged. The fixation protocols started with electron microscopy and are incredibly perturbative to the ultrastructure at th