Professor Scott Manalis, Massachusetts Institute of Technology
This week, Scientists at MIT have announced that they have developed the world’s smallest scales – even capable of measuring the weight of a single bacterium.
To explain how it works, we spoke to Scott Manalis, who leads the Nanoscale Sensing group at the Center for Bits and Atoms at the Massachusetts Institute of Technology.
Chris - Thank you for joining us on the naked scientists, what was the point of doing this?
Scott - Well, we wanted to have a very sensitive way to weigh bio-molecules and cells underwater for biosensors and application to biology and diagnostics.
Chris - So how does it actually work, and why can’t we already do that?
Scott - Well, the scale consists of a tiny piece of silicon in the shape of a cantilever. Imagine walking out on a springy diving board, you would be bouncing up and down at some frequency. As soon as you jump off that diving board, it will vibrate much quicker. The difference in frequency between when you were on it and after you jumped off corresponds to your mass.
But imagine if you wanted to do the same thing underwater, all the water would impede the vibration of the diving board. So what we have done is to put the water inside the diving board, so we can float all the objects we want to weigh through the inside of it. On the outside is a vacuum, so the ‘diving board’ can vibrate very efficiently.
Chris - So the water is passing through a very tiny tube embedded inside that diving board and carrying with it the thing that you want to weigh?
Scott - Exactly, picture the tube as a U shape, and so the water flows all the way out to the end and then back out to the base again. The object, for instance a cell, would pass through that U shaped tube.
Chris - So, apart from bacteria, what sorts of things could you weigh with this and what sorts of applications would you see it having?
Scott - Essentially, we could weigh anything that could fit inside that tube down to a detection limit that’s about equal to a femtogram, so 10-15th of a gram (0.000000000000001 grams!).
We envisage applications for being able to identify specific cells; for example in HIV diagnostics a very important one is to be able to count CD4 cells. We believe this has the potential to do this, although we have a lot of additional steps we must solve in the lab to be able to get there.
Chris - How do you know that there’s only one cell going through at a time? How do you account for the fact that cells might stick together or clump, and a clump would weigh more than just a single cell?
Scott - There’s two things we have to do; one is we make the concentration such that the cells are dilute enough that the probability of there being two in the channel at the same time is unlikely. Clumping is always a problem that one must think about and that has to be addressed by adjusting the right types of buffer conditions, the salt solution, to make sure that they don’t do that. That takes some thought beforehand to know how to do that.
Chris - The human body is absolutely heaving with bacteria and not all of them are bad for us. If you have a combination of bacteria, but you’re just looking for nasty bacteria, how can you be sure you wouldn’t diagnose someone with an infection caused by just the good ones?
Scott - Yes, that is the key question. In fact, when we weigh these bacteria, just using the mass alone it would be very difficult to know what type of bacteria it is, so we must do more that just weigh.
There are a number of possibilities; One is to coat the interior walls of the U Tube to make them sticky with certain types of antibodies that are specific for the bacteria that you want to see, which will then stick to the tubes. You can also use nanoparticles that are functionalised with antibodies that are specific for these bacteria. These nanoparticles would then make certain bacteria heavier. Finally, we can also measure the mass density of these cells, and this may be a way to differentiate different types of bacteria or perhaps even the viability of the bacteria, but this is something we must explore.
Chris - How big is the tube that runs around the inside of the diving board-like vibrating see-saw that you described?
Scott - Right now, the way we make it it’s about a few hundred microns long, so maybe 3 or 4 times the width of a hair. The thickness is between 3 and 10 microns, depending on our devices, so the thickest one we have is about the thickness of a white blood cell.
Chris - But that’s still significantly bigger than a bacterium, so will your machine be fooled if the bacteria goes around the corner and ends up further towards the outside edge of the tube than towards the inner edge, would that not cause a considerable error in your measurements.
Scott - Yes, absolutely, that would cause an error, but the error is very small because of the dimensions of the ‘diving board’ the error in that is actually very small, and works out to not be significant.
Chris - And finally Scott, how much does E. coli weigh, per bacterial cell?
Scott - Good question, it weighs 100 femtograms. Another way to think about this is it’s the weight of a gold particle that’s only a few hundred nanometers in size.
Chris - So how many zeros after the decimal point before you get to some numbers for the E. coli weight?
Scott - Well, in grams, you would need to have 13 zeros after the decimal point, so 10-13 g or 0.00000000000001 grams would be the weight of a single E. coli cell.