New Microscope Watches Cells in 3D

Jamie found a story about a new 3D Microscope which creates 3D videos of cells in action. Traditionally scientists have had to choose between high resolution and animation, so no doubt this device will cure the common cold.

Comments

"Cells in action."

[Anonymous Coward]

Sounds hot, hope I can download those videos real soon.

Re:"Cells in action."

[Rob T Firefly]

These must be those "viral internet videos" I've heard so much about.

Re:"Cells in action."

[Nullav]

Don't be ridiculous! Everything was reverse-engineered from Megatron.

The Common Cold

[ComradeSnarky]

If it's cured it won't be common anymore, will it?

Re:The Common Cold

[gEvil (beta)]

Then they'll have to start working on a cure for the uncommon cold...

Re:The Common Cold

[PCM2]

If it's cured it won't be common anymore, will it?

Scientists are already making plans to rename it to the "Pygmalion" family of viruses.

Now I get it.

[tygerstripes]

Ohhhh, I wondered how they did that cool inside-the-body stuff in "House M.D."

Seriously though, this is Big Medicine. I know a couple of guys researching treatments for congenital pancreatic cancer who would kill to get their hands on something like this.

Re:Now I get it.

[Anonymous Coward]

I know a couple of guys researching treatments for congenital pancreatic cancer who would kill to get their hands on something like this. [emphasis mine]

I hope by that you just mean to kill cells.

Re:Now I get it.

[tygerstripes]

You should have seen their research-grant application. It was just a horse's head.

Re:Now I get it.

[pakar]

Ehm... Lets hope not. I don't know about you, but my body is just a bunch of cells.. :)

Send Me One

[sjaguar]

I've got a cold, and could use a cure.

Re:Send Me One

[eln]

Sorry, but there is no cure for a cold. These guys are trying, but it's going to be difficult. The problem with the "common cold" is that it's caused by a whole lot of different viruses, so finding a cure for all of the slightly different variations that are called the "common cold" is difficult.

Of course, if all you had was a fever, the cure is simple and well know: more cowbell.

Re:Send Me One

[sjaguar]

Yes, I know. I'll just sit here and suffer, trying not to spill chicken soup onto the keyboard (again).

You know, maybe I could use some more cowbell.

Re:Send Me One

[Nyago]

From wikipedia:

Schering-Plough are developing an antiviral drug, pleconaril, that targets picornaviruses, the viruses that cause the majority of common colds. Pleconaril has been shown to be effective in an oral form.
Picornaviridae is a family that supersets rhinoviruses and enteroviruses. So it seems that the vast majority of colds could be targeted with a single drug.

Move over YouTube...

[Delusion_]

...here comes FluTube!

even better, Live Pharynx Action!

[UncleWilly]

The worm's mouth is at the top and the thick red band is the worm's pharynx.

Bad summary...

[ed.mps]

...and bad jokes. A little excerpt for those who didn't RTFA:

It can, for example, capture chromosomes spooling during cell division or a cervical cancer cell shriveling up when treated with acetic acid.

Just when we need it !

[o'reor]

That tool comes in handy at a time when SCO Group stockholders need to read the updated SCOX quotes...

http://finance.yahoo.com/q?s=SCOX

Re:Just when we need it !

[Anonymous Coward]

When it gets to a nickle, maybe I'll just buy the whole damned company and turn it into something else... like a tax write-off ;-) or maybe into an application software house doing commercial linux apps that could take it to the desktop in 09...

or maybe just a tax write-off.

a bit disappointing, really

[mweier]

I thought it would have looked a lot more like the animation in Osmosis Jones. Still, with the mentioned possibillities of better displaying cervical cells, I'm sure this will lead to some geeky new trends in pr0n.

Actually buy one

[jabuzz]

Is there a company actually selling these then or is it a one off experimental microscope?

Good job those 1TB hard disks are out, because the storage requirements of these sorts of things is insane. The researchers will be wanting to do things like 24 hour time lapse 3D movies with 60 second frame intervals - repeatedly. I suppose I get to play with ever bigger storage systems :-)

Re:Actually buy one

[halifamous]

This looks a LOT like digital inline holography, but I didn't see in the article what technique they're useing. I did some minor DIH work at Dalhousie University, back in 2004. Last I heard, a couple of the profs there are developing a commercial product.

Cure the common cold?

[CdrGlork]

That's nothing to sneeze at!

Death by light

[G4from128k]

Although the article does not say so, I'd bet that creatures don't live for very long. All of high-resolution imaging systems that I'm familiar with concentrate so much light on the subject matter that the creature dies within minutes.

Just think of the physics. Most digital sensors need about 10,000 to 100,000 photon to register a full response (i.e, "white") and to see 30 frames per second, that's 300k to 3 million photons per second per pixel. At high resolution a single cell might be 100 pixels by 100 pixels. That means that the poor creature is being hit by 3 to 30 billion photons per second. Even if there's no UV and all heat is removed from the subject, visible light photons in a high enough flux rate will induce various photochemical reactions that damage DNA, denature proteins, and photo-oxidize cellular chemicals. Or to put in another way. consider the amount of light needed to image the average landscape and then concentrate it on a single cell. Even with high-gain amplifiers (= grainy, low-light pictures), the shear concentration of light means the creature doesn't last long.

Re:Death by light

[kebes]

Photo-damage to cells is indeed a concern, but the described technique actually has the advantage that this can minimized as much as physically possible. Many visualization techniques involve either (1) having the cell absorb light, so that you can differentiate different regions based on absorption (may require staining with something sufficiently absorptive), or (2) having something fluoresce, which requires that species to absorb and then re-emit light (typically requires staining or genetic engineering so a target protein is fluorescent). Obviously both (1) and (2) require the sample to actively absorb photos, which means that some amount of photo-heating is unavoidable. Moreover fluorescent molecules often lead to undesired side-reactions and degrade over time (so-called "photo-bleaching"). With fluorescence imaging, you can select an excitation wavelength outside of the absorption bands of everything in solution (especially water!), and thereby minimize photo-heating and photo-damage.

The article says that they are actually imaging the refracted light. Since this technique doesn't require any amount of sample absorption at all, they can use a minimally absorbing wavelength, thereby keeping sample damage to an absolute minimum. In fact since they are measuring refracted light, the technique works best at wavelengths where absorption is as low as possible (but refractive index contrast is as high as possible).

From the description, it doesn't sound like the illumination would be much more intense than what a normal microscope generates. Most cells don't experience significant photo-damage under such illumination conditions.

Some current imaging systems use a raster-scanned focused-laser spot to generate the images. By using high-quality detectors the light-levels can be kept low enough that cell damage is prevented. Thus the technique from the article probably induces less cell damage than currently used techniques. Not to mention that the fact that you don't have to stain or modify the cells eliminates the toxicity (or perturbing effect) or those staining agents.

Re:Death by light

[Compholio]

Although the article does not say so, I'd bet that creatures don't live for very long. All of high-resolution imaging systems that I'm familiar with concentrate so much light on the subject matter that the creature dies within minutes.

Yup, their method doesn't seem to have a very high resolution either (judging from the poor description). I work with a special Two-Photon Excitation Microscope for making 3D images of samples, we avoid bleaching/killing samples by only having a high enough concentration of light at the focal point of the beam and hit the sample with discrete pulses. Granted, you need to raster the beam around in order to form an image - but you get a much better resolution than this (poorly described) microscope and your samples stay alive a lot longer. From the description this microscope is also useless for looking at live tissue of large animals because the images gets "foggy" if the sample is very big - two-photon excitation microscopes do not have this problem. However, using a strong enough beam to penetrate deeply will kill the sample if the exposure time is too long.

Re:Death by light

[kebes]

Some more details about the technique. The writeup on the MIT site has more information. The technique is using laser interferometry:

Feld and his colleagues have been able to image live, untreated cells by using an optical technique based on interferometry: a laser beam passed through a sample is compared with a reference beam of similar wavelength that is not passed through the cell. For example, it takes longer for light to travel through a cell than through, say, water. Researchers can measure that time delay, or phase shift, and then can map the cell and its motions on the scale of nanometers.

This appears to be one of the earlier publications on the technique:
"Cellular Organization and Substructure Measured Using Angle-Resolved Low-Coherence Interferometry", Wax A, Yang C, Backman V, Badizadegan K, Boone C, Dasari RR, Feld MS. Biophysical Journal 82: 2256-2264 (2002).

In the experimental section of that article they say:

Broadband light from a superluminescent diode (superluminescent diode (SLD) (EG&G, Gaithersburg, MD), output power 3 mW, center wavelength 845 nm, full width half-maximal bandwidth 22 nm...

This appears to be one of their more recent publications:
"Quantitative phase imaging of live cells using fast Fourier phase microscopy", Niyom Lue, Wonshik Choi, Gabriel Popescu, Takahiro Ikeda, Ramachandra R. Dasari, Kamran Badizadegan, and Michael S. Feld. Applied Optics, Vol. 46, Issue 10, pp. 1836-1842.

In that paper they say:

The second harmonic of the cw Nd:YAG laser (CrytaLaser, special custom-built module; wavelength 532nm, 500 mW) is used as an illumination source for a typical inverted microscope (Axiovert 100, Carl Zeiss).

The illumination sources are not very intense, but are powerful enough to cause cell damage if they were highly focused. From looking over the papers it doesn't seem that this is the case. For what it's worth, the papers do not mention cell damage as being a concern.

Overall the technique seems to have serious promise. It essentially involves doing laser interferometry on the sample at multiple angles, and reconstructing the 3D image. As they mention in their papers, it has the advantage of interfacing with conventional confocal microscope designs. Thus it could be added as an option on existing setups. It appears to have some exacting requirements (like all holography/interferometry it will be sensitive to vibrations, etc.), but overall seems like the type of thing that could be rapidly built into existing labs and commercial instruments.

Re:Death by light

[WordsAboutMeHere]

Until June, I had been working in a live-cell imaging laboratory for nearly four years. There's a whole list of criteria that will cell proliferation while being grown on a microscope. My lab had (before I arrived) already proven they could grow cells on a microscope stage that would match cells grown in an incubator (ie, number of mitotic events). These like this are important.

A few people have mentioned bits about imaging and I thought I'd kind of list the important ones:

• 'Normal' brightfield
• Phase-Contrast
• Confocal
• DIC, AFM, and others

'Normal' brightfield microscopes are the kind that you'll find in a high school classroom. They work because the sample absorbs light. When they talk about fixing and staining cells, you can use these. Usually cells are transparent and won't attenuate light as it passes through the cell.

Confocal works by exciting a fluorophor with a laser and measuring the emitted photons. Its neat. But you're pointing a laser at a cell.

DIC, AFM and others work on varied principles. AFM is atomic force. They basically poke a cell and measure how it pushes back. But you're poking a cell. DIC are light based but as far as I have seen not extremely popular in the field of live cell imaging for one reason or another.

Phase-Contrast I left till last as its really the only microscope that can be used for live-cell imaging. It works by measuring not how much the light is attenutated, but how much its slowed as it passes through the cell. Basically, a small fraction of light is slowed and difracted as it passes through the sample. The light that passes through unaffected is attenuated after the sample so it and the two groups have approximately the same intensity. Then normal interference will give an image on the detector.

As usual for science articles, it got most of the details wrong. We've had phase-contrast microscopes for over 50 years now. Zernike got the Nobel Prize for inventing them in 1953 http://nobelprize.org/educational_games/physics/mi croscopes/phase/index.html We can use these to measure living cells. We could do drug screening. Nothing the article said was really new and frankly it was rather irritating.

What is exciting though is the fact that this might allow the machine vision guys to be able to reliably segment live-cell image data. Currently this is a problem with no *acceptable* solution. [By acceptable I mean to say, something that has an accuracy over 90-95% for any cell line I give it as well as not using anything like a nuclear stain] Once we get this level of segmentation there is an unlimited number of things we can do:

• Personalized drug screening: Part of your tumor is checked against as many as 96 drug coctail combinations. You get the one that works best. Not the one that works best for 60% of people in a study
• Determining a patients response to radiation. For some cancers, about 50% of people need radiation AND chemotherapy. Chemotherapy can be cancerous (ironic, no?) The 50% of people that DON'T need chemo, still get chemo cause we can't predict if they need it or not, and seeing as the only to find out is to let them get cancer again...
• Primary research in the area of whole-cell systems would grow enormously. Current studies include numbers like 20-30 cells. Your average live-cell experiment will capture as many as 200 to 400 cells. And thats a small one.

Okay

[phoenixwade]

I don't have anything resembling a lengthy commentary - not my field of expertise, but, Damn, That is really cool!

Press Release Science

[LightPhoenix7]

While interesting, the article had several fallacies in it.

For one, cells can be viewed while alive - fixative isn't always necessary. Motility studies, for exmaple, don't actually kill the cells (or sperm). For another, dyes aren't the only technique to view cells - plasmid insertion into bacteria with a fluorescent marker not only allows cells to be seen, but doesn't harm the cell.

Secondly, I find it decidedly inconvenient that this can only view small images. My current research is in bacterial biofilms - living and dead. I haven't had any trouble viewing living biofilms under a fluorescent or confocal microscope. What if you want to study the chemotaxis of groups of cells? Most cells, eukaryote or prokaryote, talk to each other and can respond differentially to external signals.

Thirdly, even if you can view these cells, only in very specific instances will it give clues about functionality. Sure, that's better than nothing, but it's not the miraculous panacea that the article describes. The mechanics of drug interaction are much more complex than can be determined by simply looking at a cell.

Finally, from a research standpoint, I have to ask how much this costs. Is the cost-benefit ratio really that good that spending large amounts of money to get this is worth it? Especially considering how in reality it has such a limited usage? I would tend to assume no. There may be some very useful things you can do with this, but it just seems like much more of a toy than anything.

Re:Press Release Science

[CensorshipDonkey]

For one, cells can be viewed while alive - fixative isn't always necessary. Motility studies, for exmaple, don't actually kill the cells (or sperm). For another, dyes aren't the only technique to view cells - plasmid insertion into bacteria with a fluorescent marker not only allows cells to be seen, but doesn't harm the cell.

What's interesting about this is the cell organelle contrast. Yes, you can view living cells without exogenous contrast. No, not many good techniques exist which can show internal structure very clearly, in vivo, with no exogenous contrast. Differential interference contrast (DIC) is nice (Interactive Java Tutorial demonstrating this common technique).

Secondly, I find it decidedly inconvenient that this can only view small images.

I chose to respond to these comments to shed some light on the science. This, however, is just plain argumentative, short-sighted, etc etc. On a topic more accessible to the general public it would be obvious flamebait.

Thirdly, even if you can view these cells, only in very specific instances will it give clues about functionality. Sure, that's better than nothing, but it's not the miraculous panacea that the article describes. The mechanics of drug interaction are much more complex than can be determined by simply looking at a cell.

I agree, it's an excellent tool, but it will take a long time before it is fully utilized, and it does not cure cancer by itself. However, when fluorescence confocal microscopy came out, it had (and still does) many more problems. And yet, it revolutionized so many fields it would be impossible count them.

Finally, from a research standpoint, I have to ask how much this costs. Is the cost-benefit ratio really that good that spending large amounts of money to get this is worth it? Especially considering how in reality it has such a limited usage?

This should cost anything more than a good confocal microscope once the technology is refined. Most departments have at least one of those for common usage among labs (same for mass spectrometers, etc). In fact, it's one of the cheaper instruments I can think of, and extremely easy to maintain.

Re:Press Release Science

[CensorshipDonkey]

http://www.microscopyu.com/tutorials/java/dic/bias retardation/index.html

That's the link I failed to format properly, to an interactive Java tutorial demonstrating the power of DIC (Differential interference contrast).

Re:Press Release Science

[kebes]

The presented technique does indeed have limitations--sample thickness being a major one. However the fact that it requires no sample prep (e.g. staining) seems like a big advantage. For many studies, having video of the 3D structure of a cell will be irrelevant compared to what more traditional techniques can tell you (e.g. labeling a protein and using fluorescent to monitor its localization). However for other studies, realtime 3D visualization may be very useful (e.g. cellular dynamics). I agree that it's not the cure-all that the article hypes it to be... but I can see it becoming useful for a number of research topics.

As to how difficult it is to get working... The papers indicate that it can be fitted onto a conventional confocal microscope. However because it is an interferometry technique, things like vibrations must be minimized. So it's probably a bit finnicky, but I any research lab with experience in optics could build one if they really wanted to. The technique uses off-the-shelf technology, so commercial instruments (probably sold as add-ons to existing microscopes) could easily be built. I'm not an expert in the field, so I can't predict whether there would be a strong demand for such an instrument.

(Note: I've used various microscopies in my research, but not on biological samples, so please correct any mistakes I've made in that regard.)

Re:Press Release Science

[LightPhoenix7]

What's interesting about this is the cell organelle contrast. Yes, you can view living cells without exogenous contrast. No, not many good techniques exist which can show internal structure very clearly, in vivo, with no exogenous contrast. Differential interference contrast (DIC) is nice (Interactive Java Tutorial demonstrating this common technique).

Organelle contrast, and being able to see the organelles is interesting, but I don't think that it's as useful as the article describes. In very specific circumstances, it may give hints as to what is going on, but that's it. It's like looking at a computer program as it's running, and saying you'll be able to figure out the code. You may be able to do it in some instances, but those are very limited.

I chose to respond to these comments to shed some light on the science. This, however, is just plain argumentative, short-sighted, etc etc. On a topic more accessible to the general public it would be obvious flamebait.

Perhaps, perhaps not. The article makes a point to mention that it can't take very large or thick images. That's quite a difficulty for people studying anything thicker than a single layer or two of cells. There's a lot of stuff out there that is more than that.

I agree, it's an excellent tool, but it will take a long time before it is fully utilized, and it does not cure cancer by itself. However, when fluorescence confocal microscopy came out, it had (and still does) many more problems. And yet, it revolutionized so many fields it would be impossible count them. This should cost anything more than a good confocal microscope once the technology is refined. Most departments have at least one of those for common usage among labs (same for mass spectrometers, etc). In fact, it's one of the cheaper instruments I can think of, and extremely easy to maintain.

I wanted to combine these two points, because they're similar. You are correct in that everything has problems when it comes out, and costs large amounts of money. However, except in all but a few circumstances, I don't think that there's much of a tangible benefit to buying this. It certainly won't happen for a lab that might only have one or two projects benefiting from this. That's a cost-benefit ratio. Of course, as you stated, only time will tell what sorts of applications this could use.

Re:Press Release Science

[jotok]

Oi, Dr. Stickinthemud. All of those are valid questions but come on, this is cool even if it doesn't yet apply to every area of research or is several hundred times the size of your grant :)

Anyway, chemotaxis is fascinating to me. Have you read any Brian Goodwin?

Article figure somewhat mislabeled

[Ichoran]

The worm shown in the picture in the article is probably about 200 microns long, not 1 mm--the one shown is recently hatched, not an adult. You can tell because adult worms do not have a pharynx that takes up nearly half the length of the body. Also, in adults you'd be able to see reproductive structures (including eggs).

Re:Article figure somewhat mislabeled

[zalas]

Yes, you are correct. I took a look at the original article which actually had a scale bar for the image and it amounts to roughly 200 micron. The linked article is kind of scant on details, so here's a more detailed writeup: http://www.sciencedaily.com/releases/2007/08/07081 2173253.htm

Re:Article figure somewhat mislabeled

[Anonymous Coward]

Good catch, +1 geek cred!

Re:Article figure somewhat mislabeled

[Speedracer1870]

Thanks guy! This is some great stuff.

full of patches and security vulnerabilities, no?

[aapold]

lol I bet it doesn't work and everyone uses it uninstalls it and bunch of unsecured applications that are mess of...

oh, microSCOPE.

never mind.

3D movies of living cells

[rpiquepa]

I have to admit that the results obtained with this new kind of microscope are spectacular. You'll find additional references and images of a cervical cancer cell taken using this new imaging technique on this ZDNet post.

Re:3D movies of living cells

[Anonymous Coward]

"rpiquepa". A preferred link to primidi.com. A link in your post to a ZDNet blog.
Roland Piquepaille, is that you?

I have a real question, not trolling. Rife micro..

[hot soldering iron]

I've read some (pseudo) scientific articles about a Dr. Rife who worked for the Carl Zeiss company and supposedly developed a UV microscope that appears to have combined principles of holography and optical hetrodyning to shift the frequency into the visual spectrum.

http://en.wikipedia.org/wiki/Royal_Rife

Various sites (enthusiasts/nutballs) claim that using it, he was able to isolate various living organisms, including a cancer-causing virus , and kill them with electromagnetic wave harmonics.

What I'm really wondering is: Are there any Optical microscopes using these principles? Or is it technically unfeasible?

Re: New Microscope Watches Cells in 3D

[tuzo]

These Microsoft watches are just another attempt to lock everyone in to proprietary technology and squeeze out true innovation!

Cmdr Taco...Dumbass

[Anonymous Coward]

The "common cold" is caused by a virus, not a cell. Good luck imaging a virus with an optical microscope. And the common cold was cured in the 50's. It's called interferon. It's extremely cheap to produce. But the profit margins are so high for it's use with autoimmune and other disorders that the drug companies refuse to provide it as a cheap over the counter cold cure.

Engineering hot, thinking not

[InternationalCow]

If these guys need laser interferometry to understand why the acetic acid test works, I am not sure whether they should be the ones to decide how to use this really cool new toy. The test works because squamous cell carcinoma of the cervix behaves a bit like skin - it no longer acts as a non-keratinizing mucous squamous epithelium but will form proteins that are normally present in skin. Application of acetic acid (try it on your own skin if you don't believe this :)) will denature these and cause white discoloration. Duh.Other acids will work, too, but tend to be a tad too corrosive to use on a cervix.

Microsoft is making watches with IBM Cell chip?!?

[Anonymous Coward]

What time is it again?

Sony?

[MadCatMk2]

Will sony try to sell blu-ray to them as well? The image could need some improvement lol. I'm just kidding :P