What has science done for you?

came across this on xkcd during some late night procrastination yesterday: one of the many reasons why science is so cool. It saves lifes.

Posted in Uncategorized | Tagged , , | Leave a comment

Optogenetics – The Nature Method of the Year 2010

Since 2007 the highly prestigious peer-reviewed journal Nature Methods annually crowns a “method of the year” to give credit to the most remarkable new method that had a wide-ranging impact on the scientific community in the respective year. For 2010 they selected optogenetics.

Huh?

Neuroscientists are more familiar with this method than other scientists as most results so far come from their field. Not being a neuroscientist, I had never heard of optogenetics before. What could it be? As can be inferred from its name, it somehow must combine optics and genetics; it deals with genes and light. My first thought was that it might have to do something with vision and possibly how we perceive light, or maybe developing some novel way of treating vision disorders. Wrong. It actually is much cooler. Optogenetics is the technology of introducing genes encoding for light sensitive proteins into cells and then controlling a specific aspect of the cell by light!

Light sensitive proteins – the optics part

Light sensitive proteins are proteins that perform an action upon exposure to light. You simply shine light on the protein and it does something. Upon this light activation it might for example change its shape or bind to another protein in a cell. A lot of functions in a cell are based on such protein shape changes or binding of different proteins to each other. So upon shining a light on these proteins, they undergo some change that enables them to do some cool stuff. Much like a switch that is controlled by light. Switch the light on –> function on. Switch the light off –> function off. Or the other way round.

Getting the proteins into cells – The genetics part

The central dogma of molecular biology describes the normal flow of information in biology. DNA encodes for RNA encodes for protein. So to stably get the light sensitive proteins into the cells of your interest, you have to get the genes present on a piece of DNA into these cells. One way of how that usually happens is that you isolate that gene of interest from an organism, for example bacteria, then pack it into a virus and infect the target cell you want the protein to be in with that virus. The virus acts like a postal package… you put the interesting gene in it and deliver the virus to the destination, where the package (virus) gets opened and the gene unpacked. The regular cellular machinery in the target cell will then make protein from the introduced gene.

Summary

So what optogeneticists do is they take a special gene from somewhere else, they then might alter it a bit and send it nicely packed into the cell they are interested in. The cell then makes special proteins from this special gene and the special proteins in the cell do some neat little trick when they see light.

Big Deal?

Yes! Big Deal! The little tricks the proteins can do in the light, like changing shape, cuddling together, or moving to a specific part of the cell can make the cell respond in a variety of ways, depending on the exact protein and the cell, and this is where it gets super cool. In neuroscience for example, this can lead to the opening of channels in cell walls, so that molecules can cross these barriers. This in turn can lead to activation of nerve cells and to a coordinated response of the animal. For example researchers could make a mouse with Parkinson’s disease walk regularly, make heart cells beat in response to light or make a fly try to escape whenever you shine a light on it. Here is the Nature Methods video about it.

Advantages over previous techniques – speed, precision, reversibility, invasiveness

What makes optogenetics so valuable is the spatial and temporal control that is possible with the combination of light and genetics as well as its reversibility and minimal invasiveness so that it works even in live animals. Previous methods that are used to study similar phenomena include photocaging (irreversible) or drugs/chemical activation (slower, more invasive). In addition, the speed and the spatial precision with which light can be turned on and off in a lab allows optogenetics to deliver much more defined signals than electric stimuli for example.

Basically, you can give amazingly well timed and defined instructions to cells, a feature that is especially valuable for neuroscience bit also for other areas.

image by greenmelinda

And it gets better

But there is so much more…

For instance, there are several light-sensitive proteins that react to different colors of light.

And you can take the light-sensitive part of one of these proteins and stick it on other proteins to make them light sensitive themselves. And you can do that with the parts that are activated by the different light colors… Now that expands the toolbox immensely.

The light signal can activate or inactivate, depending on how the light-sensitive part gets put on the protein.

The precision with which light can be controlled is amazing. Light can shine on only a part of the cell… and at the same time you can shine light of a different color on another part of the cell. Or you can turn the light on and off in patterns.

The light-sensitive proteins can be made in a way that they would only be present in a specific cell type, but not in others, and only at a specific time of that cell’s life.

Or think about using these tools in naturally transparent organisms like zebrafish…

And, once again: reversible and minimally invasive.

You can have different proteins in different parts of subsets of cells in their native environment reversibly and differentially activated or inactivated by shining light on the cells.

And yes, it gets even better again… scientists are already working on advancing the technique further. For example they try to make proteins that can react to a different color of light, one that can penetrate deeper into tissues like brain for example.

The possibilities for applications of this new technique, especially in combination with other techniques, seem to be endless.

Cheers, to the method of the year,

loveforscience

Posted in science | Tagged , , , | 1 Comment

The most beautiful experiment in biology – The Meselson-Stahl experiment

Here is the example of scientific beauty I promised last week. Most people will agree right away that the Mona Lisa is a great painting. You don’t need to study it in depth to realize that, though it might be worth a second glance to appreciate more of its beauty. As is true with most art. The same however is true for science. Let’s look at what some call biology’s most beautiful experiment:

The golden era of DNA research

It was published in 1958, in the golden era of DNA research. Oswald T. Avery had just shown some years ago that DNA is the hereditary material, and a mere 5 years ago (just yesterday in scientific terms) Jim Watson and Francis Crick published their famous paper on the structure of DNA. Along with their model that shows the double helical DNA molecule consisting of two antiparallel DNA strands (that means that the two strands lie “head to toe” to each other) they also developed an idea how the DNA, our genetic material, might be copied. They concluded their paper with the famous sentence that “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”, one of the most famous sentences in science for all the understatement it contains.

The problem

However, their suggested mechanism of DNA replication was not the only one out there. Various influential scientists suggested 3 different theories; future Nobel Prize winners were championing one or the other. The whole world was discussing whether DNA would get replicated in a conservative, a semi-conservative or a dispersive fashion (ok, rather a few expert scientists and not the whole wide world, but still…). Conservative replication means that one double stranded DNA molecule would stay together all the time and would produce a copy of 2 new strands. Semi-conservative replication means that the strands would separate during replication and both daughter molecules would contain one of the original strands and a new complementary strand. Finally, dispersive replication means that the original strands would get broken up into smaller pieces that get individually copied and then the two daughter molecules would each contain a mixture of old and newly synthesized pieces of DNA. No one could come up with a working experiment to prove one or the other up to 1958.

Image modified from the original image by Adenosine,

The idea

The stroke of genius that Matthew Meselson and Franklin Stahl came up with to solve this problem is beautiful in its simplicity. They were aware that they had to find a way to distinguish the old strands from the newly made ones. DNA can be readily detected by UV light but you cannot distinguish between freshly made and old DNA. When they realized that you could float different things in solutions of a different density, the idea for their experiment was born. It is based on the same principle that allows us to float in the water of the Dead Sea between Jordan and Israel but not in regular seawater.

The water of the Dead Sea contains much more salt than other seas. Thus water from the Dead Sea has a higher density than our average water and we can float on it. Meselson and Stahl adopted the same principle for their experiment and developed a technique called density gradient centrifugation. Basically, they put salty water in a centrifuge and spun it at very high speeds. The high-speed centrifugation forms a gradient in the salty solution with a higher density at the bottom of the tube, as the heavy atoms will gradually move there. Any molecule placed in the solution will eventually end up at the region that has the same density as the molecule itself.

What was left before starting the experiment was to find a good salt with the right density for DNA (they found Cesium Chloride to work well) and a good way to make one sample of DNA heavier than the other one. After some trial and error they succeeded at labeling DNA with a heavier isotope of nitrogen,15N . All that is important here is that this makes the DNA molecule significantly heavier than regular DNA containing the usual 14N isotope, as DNA contains a lot of nitrogen. They also had access to a shiny new ultracentrifuge in which you they could separate the heavy from the light DNA and take a picture of the samples while spinning them in the centrifuge.

Ingenious!

They reasoned the following: If we grow bacteria in a solution containing only the heavy nitrogen and none of the regular one, after a while, all the DNA in the bacteria will contain almost exclusively heavy nitrogen. If we then take them out of this growth medium and into a regular one containing the regular nitrogen, all newly made DNA will contain only the light nitrogen. Let’s separate the DNA molecules that we obtain from the bacteria after several generations of bacterial growth on our density gradient (a generation is the time the bacteria need to double). We should observe bands of DNA on the pictures at the density of the DNA molecules. Lighter DNA should float higher than heavier DNA, this we can quickly confirm with control heavy and light DNA. Depending on the patterns of heavy and light DNA we will observe in the experiment, we should be able to distinguish between the different models of DNA replication.

Can you tell how?

The result

The result was clean as a whistle. At the start of the experiment before shifting to the regular medium, they saw only one band of DNA on the pictures of their density gradient. It consisted exclusively of heavy DNA as no growth in the regular medium had occurred yet. After one bacterial generation they still only observed one band although at a lower density in the gradient (i.e. higher up!), about half way between control heavy and control light DNA! This means that DNA replication cannot be conservative, as conservative replication would lead to two distinct bands, one consisting exclusively of heavy DNA and one exclusively of light DNA. But that still leaves options 2 and 3. Yet another round of bacterial growth gave the final answer: They now saw two distinct bands, one at the density of the control light DNA and one at the intermediate density from last round. This excludes dispersive replication as a mechanism as dispersive replication would have resulted in yet another single band at a density between the control light DNA and the control heavy DNA.

Meselson-Stahl experiment

Image by LadyofHats

DNA replication is semi-conservative! Jim Watson and Francis Crick who had proposed the semi-conservative model had been right (again).

This discovery was so important for biology because it focused the thinking of many bright minds on the right mechanism of DNA replication rather than having their attention divided. It provided the basis for many more in-depth discoveries on the replication machinery and the molecular players involved.

All it took was one very simple and elegant experiment to solve the mystery of the mechanism of DNA replication that had been elusive before. I don’t know wheter it is the most beautiful biology experiment of all time, but it sure is an example of true scientific beauty.

Cheers,

loveforscience

the original 1958 paper in PNAS

Posted in science | Tagged , , , | Leave a comment

On Science, Art and Beauty – An artist’s soul in a scientist and vice versa

I very well remember a situation during the first two years of my PhD-thesis when a then good friend was confiding to me that she thought she would never be a good scientist, that she would much rather do something artistic and express herself through creating beauty. Well, we had a few drinks, talked about life in general and science, art and beauty in particular and in the end I could convince her that good science is a beautiful art and that scientists are much like artists in many aspects. She went on doing science and by now holds an advanced degree in science, is working in a beautiful city and is a more successful scientist than me. She also is very much into art; I spent many good hours in museums with her and she loved putting her creativity into different types of artistic projects outside of work; and I love using her as an example of how similar artists and scientists are. And they are! After all, both are often portrayed as rather peculiar personalities, either very introverted or very extroverted.

Artists are without any doubt creative. They create beauty through their work. They hold the power to make other people happy simply by having these people experience their creations. By looking at their beautiful pieces of work people become happy… truly, science has a long way to go before hoping to achieve something similar, right? Wrong! So wrong. The evidence is right out there. In the eyes of so many children in scientific museums everywhere, in their expressions when looking at a dinosaur skeleton or listening to someone explaining them a concept of nature. They grasp the beauty of nature. And they are happy. Understanding a scientific experiment can create happiness. (On a side note, also seeing an experiment work for the first time and answer the question the scientist was asking creates happiness for the scientist, much the same as finishing artwork creates happiness for the artist… unfortunately both happen not nearly often enough.)

Some science might very well need a complicated explanation to understand its merits, but then so does some artwork that is not readily accessible to everyone. But there are some classic pieces of art, both in science and in art itself, where beauty is evident and all it takes to understand either one is just a few minutes. But before looking at what is (arguably) the most beautiful paining and the most beautiful experiment in biology in the next post, let me finish the thought on artists and scientists.

Scientists are creative in their work as well. Same as artists, they use the tools they have learned to master to create new things. For artists those tools range from simple to complex (brush or chisel to digital high speed camera, and let’s not forget the body of dancers), just as they do for scientists (Bunsen burner or pipet to cyclotron). As a lot of creativity (and often training) is necessary to create fine works of art, so is it necessary to design experiments and create scientific setups that will answer the question the scientist is asking.

Another important similarity between artists and scientists is dedication. Both spend countless hours, weeks and months on their projects, trashing unsuccessful trials, restarting at the beginning. Both know the frustration of work slow proceeding, the feeling of being stuck and both face failure. Not every scientist is successful and has to abandon hopes for his/her career, neither is every artist. Yet, artists and scientists alike know the feeling of joy of completing an “own” piece of work and both know the feeling of late night work…. How bad it feels to bury an idea at 2 am but also how amazing it feels to complete it after a night in the studio/lab. Neither science nor art knows regular working hours.

Finally, besides creativity, another major force driving artists and scientists alike is curiosity. The difference is just what the curiosity is directed at. Artists are often very curious about themselves, about their feelings and emotions and their art is a way of expressing these emotions. Scientists on the other hand often direct their curiosity to the things around them – how does this work, what is that made of… very similar to a child taking things apart to see what is in them and trying to put them back together from the small pieces.

In my opinion what artists and scientists both are all about is creativity and curiosity as driving forces matched with dedication to not throw in the towel all the time. With these traits they will create beauty in the end. Artist’s traits, to be sure. But no less so for scientists. As artists love to see the beauty in their work, so do scientists love to see the beauty in the experiments they designed. Beauty in a beautiful science experiment though might not be as obvious as the beauty of a beautiful painting. The beauty of a science experiment very often lies in its elegance and simplicity.

I’ll try to show that with “biology’s most beautiful experiment” in the next post…

And for those who are still not convinced that scientists are true artist (and don’t live in Ivory towers but do know pop culture), have a look at this hilarious parody from the Zheng lab 😉

Cheers,

loveforscience

Posted in Philosophy, Science and Beauty | Tagged , , , , , , | 4 Comments