Building Artificial Cells Will Be a Noisy Business

Engineers like to make things that work. And if one wants to make something work using nanoscale components—the size of proteins, antibodies, and viruses—mimicking the behavior of cells is a good place to start since cells carry an enormous amount of information in a very tiny packet. As Erik Winfree, professor of computer science, computation and neutral systems, and bioengineering, explains, "I tend to think of cells as really small robots. Biology has programmed natural cells, but now engineers are starting to think about how we can program artificial cells. We want to program something about a micron in size, finer than the dimension of a human hair, that can interact with its chemical environment and carry out the spectrum of tasks that biological things do, but according to our instructions."

Getting tiny things to behave is, however, a daunting task. A central problem bioengineers face when working at this scale is that when biochemical circuits, such as the one Winfree has designed, are restricted to an extremely small volume, they may cease to function as expected, even though the circuit works well in a regular test tube. Smaller populations of molecules simply do not behave the same as larger populations of the same molecules, as a recent paper in Nature Chemistry demonstrates.

Winfree and his coauthors began their investigation of the effect of small sample size on biochemical processes with a biochemical oscillator designed in Winfree's lab at Caltech. This oscillator is a solution composed of small synthetic DNA molecules that are activated by RNA transcripts and enzymes. When the DNA molecules are activated by the other components in the solution, a biological circuit is created. This circuit fluoresces in a rhythmic pulse for approximately 15 hours until its chemical reactions slow and eventually stop.

The researchers then "compartmentalized" the oscillator by reducing it from one large system in a test tube to many tiny oscillators. Using an approach developed by Maximilian Weitz and colleagues at the Technical University of Munich and former Caltech graduate student Elisa Franco, currently an assistant professor of mechanical engineering at UC Riverside, an aqueous solution of the DNA, RNA, and enzymes that make up the biochemical oscillator was mixed with oil and shaken until small portions of the solution, each containing a tiny oscillator, were isolated within droplets surrounded by oil.

"After the oil is added and shaken, the mixture turns into a cream, called an emulsion, that looks somewhat like a light mayonnaise," says Winfree. "We then take this cream, pour it on a glass slide and spread it out, and observe the patterns of pulsing fluorescence in each droplet under a microscope." 

When a large sample of the solution is active, it fluoresces in regular pulses. The largest droplets behave as the entire solution does: fluorescing mostly in phase with one another, as though separate but still acting in concert. But the behavior of the smaller droplets was found to be much less consistent, and their pulses of fluorescence quickly moved out of phase with the larger droplets.

Researchers had expected that the various droplets, especially the smaller ones, would behave differently from one another due to an effect known as stochastic reaction dynamics. The specific reactions that make up a biochemical circuit may happen at slightly different times in different parts of a solution. If the solution sample is large enough, this effect is averaged out, but if the sample is very small, these slight differences in the timing of reactions will be amplified. The sensitivity to droplet size can be even more significant depending on the nature of the reactions. As Winfree explains, "If you have two competing reactions—say x could get converted to y, or x could get converted to z, each at the same rate—then if you have a test tube–sized sample, you will end up with a something that is half y and half z. But if you only have four molecules in a droplet, then perhaps they will all convert to y, and that's that: there's no z to be found."

In their experiments on the biochemical oscillator, however, Winfree and his colleagues discovered that this source of noise—stochastic reaction dynamics—was relatively small compared to a source of noise that they did not anticipate: partitioning effects. In other words, the molecules that were captured in each droplet were not exactly the same. Some droplets initially had more molecules, while others had fewer; also, the ratio between the various elements was different in different droplets. So even before the differential timing of reactions could create stochastic dynamics, these tiny populations of molecules started out with dissimilar features. The differences between them were then further amplified as the biochemical reactions proceeded.

"To make an artificial cell work," says Winfree, "you need to know what your sources of noise are. The dominant thought was that the noise you're confronted with when you're engineering nanometer-scale components has to do with randomness of chemical reactions at that scale. But this experience has taught us that these stochastic reaction dynamics are really the next-level challenge. To get to that next level, first we have to learn how to deal with partitioning noise."

For Winfree, this is an exciting challenge: "When I program my computer, I can think entirely in terms of deterministic processes. But when I try to engineer what is essentially a program at the molecular scale, I have to think in terms of probabilities and stochastic (random) processes. This is inherently more difficult, but I like challenges. And if we are ever to succeed in creating artificial cells, these are the sorts of problems we need to address."

Coauthors of the paper, "Diversity in the dynamical behaviour of a compartmentalized programmable biochemical oscillator," include Maximilian Weitz, Korbinian Kapsner, and Friedrich C. Simmel of the Technical University of Munich; Jongmin Kim of Caltech; and Elisa Franco of UC Riverside. The project was funded by the National Science Foundation, UC Riverside, the European Commission, the German Research Foundation Cluster of Excellence Nanosystems Initiative Munich, and the Elite Network of Bavaria.

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Cynthia Eller
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A New Laser for a Faster Internet

A new laser developed by a research group at Caltech holds the potential to increase by orders of magnitude the rate of data transmission in the optical-fiber network—the backbone of the Internet.

The study was published the week of February 10–14 in the online edition of the Proceedings of the National Academy of Sciences. The work is the result of a five-year effort by researchers in the laboratory of Amnon Yariv, Martin and Eileen Summerfield Professor of Applied Physics and professor of electrical engineering; the project was led by postdoctoral scholar Christos Santis (PhD '13) and graduate student Scott Steger.

Light is capable of carrying vast amounts of information—approximately 10,000 times more bandwidth than microwaves, the earlier carrier of long-distance communications. But to utilize this potential, the laser light needs to be as spectrally pure—as close to a single frequency—as possible. The purer the tone, the more information it can carry, and for decades researchers have been trying to develop a laser that comes as close as possible to emitting just one frequency.

Today's worldwide optical-fiber network is still powered by a laser known as the distributed-feedback semiconductor (S-DFB) laser, developed in the mid 1970s in Yariv's research group. The S-DFB laser's unusual longevity in optical communications stemmed from its, at the time, unparalleled spectral purity—the degree to which the light emitted matched a single frequency. The laser's increased spectral purity directly translated into a larger information bandwidth of the laser beam and longer possible transmission distances in the optical fiber—with the result that more information could be carried farther and faster than ever before.

At the time, this unprecedented spectral purity was a direct consequence of the incorporation of a nanoscale corrugation within the multilayered structure of the laser. The washboard-like surface acted as a sort of internal filter, discriminating against spurious "noisy" waves contaminating the ideal wave frequency. Although the old S-DFB laser had a successful 40-year run in optical communications—and was cited as the main reason for Yariv receiving the 2010 National Medal of Science—the spectral purity, or coherence, of the laser no longer satisfies the ever-increasing demand for bandwidth.

"What became the prime motivator for our project was that the present-day laser designs—even our S-DFB laser—have an internal architecture which is unfavorable for high spectral-purity operation. This is because they allow a large and theoretically unavoidable optical noise to comingle with the coherent laser and thus degrade its spectral purity," he says.

The old S-DFB laser consists of continuous crystalline layers of materials called III-V semiconductors—typically gallium arsenide and indium phosphide—that convert into light the applied electrical current flowing through the structure. Once generated, the light is stored within the same material. Since III-V semiconductors are also strong light absorbers—and this absorption leads to a degradation of spectral purity—the researchers sought a different solution for the new laser.

The high-coherence new laser still converts current to light using the III-V material, but in a fundamental departure from the S-DFB laser, it stores the light in a layer of silicon, which does not absorb light. Spatial patterning of this silicon layer—a variant of the corrugated surface of the S-DFB laser—causes the silicon to act as a light concentrator, pulling the newly generated light away from the light-absorbing III-V material and into the near absorption-free silicon.

This newly achieved high spectral purity—a 20 times narrower range of frequencies than possible with the S-DFB laser—could be especially important for the future of fiber-optic communications. Originally, laser beams in optic fibers carried information in pulses of light; data signals were impressed on the beam by rapidly turning the laser on and off, and the resulting light pulses were carried through the optic fibers. However, to meet the increasing demand for bandwidth, communications system engineers are now adopting a new method of impressing the data on laser beams that no longer requires this "on-off" technique. This method is called coherent phase communication.

In coherent phase communications, the data resides in small delays in the arrival time of the waves; the delays—a tiny fraction (10-16) of a second in duration—can then accurately relay the information even over thousands of miles. The digital electronic bits carrying video, data, or other information are converted at the laser into these small delays in the otherwise rock-steady light wave. But the number of possible delays, and thus the data-carrying capacity of the channel, is fundamentally limited by the degree of spectral purity of the laser beam. This purity can never be absolute—a limitation of the laws of physics—but with the new laser, Yariv and his team have tried to come as close to absolute purity as is possible.

These findings were published in a paper titled, "High-coherence semiconductor lasers based on integral high-Q resonators in hybrid Si/III-V platforms." In addition to Yariv, Santis, and Steger, other Caltech coauthors include graduate student Yaakov Vilenchik, and former graduate student Arseny Vasilyev (PhD, '13). The work was funded by the Army Research Office, the National Science Foundation, and the Defense Advanced Research Projects Agency. The lasers were fabricated at the Kavli Nanoscience Institute at Caltech.

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Monday, April 7, 2014
Center for Student Services 360 (Workshop Space)

Planning Session for the Fall 2014 Teaching Conference

Wednesday, April 23, 2014
Beckman Institute Auditorium

The Art of Scientific Presentations

Wednesday, April 2, 2014
Beckman Institute Auditorium

Juggling Teaching at a Community College and Research at Caltech

Everyone Starts Small: How Metals Learn to Behave

Watson Lecture Preview

On Wednesday, February 12, Assistant Professor of Aerospace Dennis Kochmann will explain how controlling a material's complex structural details from the atomic scale up can affect its behavior in everyday life. The talk begins at 8:00 p.m. in Caltech's Beckman Auditorium. Admission is free.

Q: What do you do?

A: We study the mechanics of materials. Specifically, we're making computer models that start with collections of individual atoms, and we're trying to extend those models all the way up to the scale of visible objects. We also have a lab where we make new materials and test them to see if they behave the way the models predicted. And eventually, once we have that understanding, we'll try to go back downward—if we want a material with certain properties, how do we make it?

Most innovation nowadays depends on new materials. In energy, in space travel, in biomedicine, many of the challenges involve finding a material that can meet certain conditions or that we can use in an extreme environment. It used to be that whenever you needed a specific material, you would tell your colleagues, "I want a material that has this and this and this property," and they'd look in various handbooks and try to find something that met your conditions. Nowadays we do it online, but it's basically the same process. In the future, we want to be able to tell our computer, "Okay, I want this and this and this," push a button, and an hour later the material is delivered to you. We're far away from this, of course.

It's much more complicated than just looking at the periodic table and throwing atoms together. Getting something on the atomic level is just one challenge. We also need to bridge the scales from atoms to the visible, macroscopic scale that we can see with the naked eye. There are many, many levels in between. Atoms form crystals. The crystals have defects. The defects arrange into networks. So if you put any material under a microscope, as you zoom in closer and closer you'll find that on each level there's a very specific pattern. These very specific structures and the things going on at each level are what give the material its unique properties.

 

Q: What gets you excited about this?

 

A: Well, as any researcher would say, it's doing something nobody has ever done before. In our case, making new, peculiar materials, or materials with extreme properties.

For example, we are designing materials that are pretty boring under ambient conditions, but if you tweak the temperature or the electric field the material suddenly gets 100 times stiffer and 100 times better at damping out vibrations. So you can control these properties with the push of a button. Usually, stiffness and damping are mutually exclusive. On the atomic scale, if you want something stiff and strong you need a perfect crystal. If you want high damping, there must be mechanisms at the microscale such as crystal defects that somehow absorb energy. Materials that do both are of great interest in applications such as aerospace—airplanes and spacecraft need materials that can withstand extreme conditions while absorbing vibrations, because there's a lot of vibration going on in them.

 

Q: How did you get into this line of work?

A: Before I went to college, this was absolutely not my goal. I started playing classical music on the organ when I was a teenager, and so I was trying to decide between music and chemistry. Then someone told me that engineering was a safer career, so I ended up in majoring in mechanical engineering. I wanted to be a design engineer, but by coincidence I was offered a job in solid mechanics, which is the mechanics of materials. By yet another coincidence I ended up at the University of Wisconsin–Madison, where I worked with Roderic Lakes and Walter Drugan—pioneers in the design of extreme materials. So as is often in life, it was many small events and little coincidences.

 

Q: Do you still play the organ?

A: I do. I'm very lucky. There's a church up in Altadena that lets me go up there every Friday morning for two hours and practice.

 

Q: Do you plan on giving a recital any time soon?

A: [laughs] No.

 

Named for the late Caltech professor Earnest C. Watson, who founded the series in 1922, the Watson Lectures present Caltech and JPL researchers describing their work to the public. Many past Watson Lectures are available online at Caltech's iTunes U site.

 

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Douglas Smith
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In Our Community
Friday, March 14, 2014
Avery Dining Hall

Workshop: Comedy as a Teaching Tool

Caltech's "Secrets" to Success

Everyone who really knows Caltech understands that it is unique among universities around the world. But just what makes Caltech so special? We've asked that question before, and the numbers don't tell the full story. So, is it our focus? Our culture? Our people?

The UK's Times Higher Education magazine recently tackled the topic, asking more specifically, "How does a tiny institution create such an outsized impact?" Caltech faculty share their perspectives in the cover story of the magazine's latest issue.

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Nanoscale Materials and Big Solar Energy: An Interview with Harry Atwater

As a high school student during the oil crisis of the 1970s, Harry Atwater recognized firsthand the impact of energy supply issues. Inspired to contribute to renewable energies, his research at Caltech today works to develop better thin-film photovoltaics—cheaper, lighter, more efficient alternatives to the bulky cells now used in solar panels.

In addition to his individual research interests in photovoltaic cell development, Atwater is also part of a collaborative effort to advance solar energy research at the Joint Center for Artificial Photosynthesis (JCAP)—a U.S. Department of Energy (DOE) Energy Innovation Hub. JCAP, which is led by a team of researchers from Caltech and partner Lawrence Berkeley National Laboratory, aims to develop cost-effective fuel production methods that require only sunlight, water, and carbon dioxide.

Atwater, who serves as the project leader for the Membrane and Mesoscale Assembly Project at JCAP, recently chatted with us about his research, his background, and why he came to Caltech.

What originally drew you to Caltech?

It was the opportunity to pursue my area of research. I felt that Caltech was the best research environment I could [be in] for mixing fundamental science and engineering technology. Caltech is very developed in its orientation toward engineering and technology, and its connection to technology in many areas like aerospace, photonics, communications, semiconductors and chemistry. It is a great combination—an institutional focus on fundamentals but also a focus on applying those fundamentals to engineer new technologies.

What are your research interests?

My research is at the intersection of solar energy and nanophotonic materials. Nanophotonic materials are materials and structures in which the characteristic length scale of the material is less than the scale of the wavelength of light—meaning that they're so small that they must be visualized with something that has a wavelength much smaller than that of visual light. Half of my research group is focused on the fundamentals of nanophotonic materials. These materials could form the building blocks of a chip-based optical device technology for improved imaging in computing, communications, and for the detection of chemical and biological molecules.

The other half of my group is focused on improving solar energy. We are investigating several approaches to creating very low-cost and ultrahigh-efficiency thin-film photovoltaics, which are an alternative to, and the future of, today's solar cell panels. In our design, we use thin layers of semiconductors for absorbing sunlight. The Joint Center for Artificial Photosynthesis (JCAP) fundamentally focuses on using semiconductor photonic materials and devices to create fuel from solar energy, so it's a really good match for our work.

How do these semiconductors you're working with make thin-film photovoltaics cheaper, thinner, and more efficient?

Most materials cost nearly the same amount when you just think about them on a price-per-atom basis. What makes materials expensive or cheap is the cost of the synthesis and processing methods used to make them with sufficient purity and perfection to enable high performance. Much of what we do is aimed at either designing new syntheses that can yield high-performance materials in a scalable low-cost fashion or designing new structures and devices whose performance is robust against use of impure or defective materials.

How did you first get interested in your field?

I would say that my interest in solar energy dates back to the first big energy crisis in the 1970s, when I was a high school student. I grew up in Pennsylvania, and I remember my school was shut down for a few weeks in the wintertime because there literally was no oil to heat the burner. I thought then that addressing supplies of energy was an important problem. It made a big impression on me. But at that point, I hadn't really thought about how I could contribute to a solution.

But then in graduate school, I got interested in things at the intersection of physics and electrical engineering, which is really where my work lies. As a graduate student at MIT, I began to focus on developing new technologies for thin-film solar cells. At MIT, I worked in one of the first nanostructure fabrication labs in the country, where it became apparent to me that we could make nanostructures and characterize their properties.

You were among the first scientists to study these nanostructures. What was that like?

Nowadays "nano" is sort of pervasive in the ether—nanomaterials are not unusual. At that time, it was as invisible to the general public as the Internet. It became obvious to me that there was a lot of opportunity to use nanofabrication principles and techniques to make new optical materials. Later, around 2001, we ended up playing a pretty significant role in starting another new field called plasmonics, which studies the behavior of the excitations created by light in metals. This new field led to the first serious and widespread efforts to make these kinds of optical devices and optical materials out of metals.

Do you have any hobbies or interests outside of your research?

I'm an avid soccer player, and I play weekly with the graduate students. Until my kids got to an age when I started embarrassing them, I was coaching them every week. That's what I like to do for fun.

Atwater joined the Caltech faculty as an assistant professor of applied physics in 1988, becoming an associate professor in 1994 and a professor in 1999. Now the Howard Hughes Professor of Applied Physics and Materials Science, Atwater has many roles on campus and beyond. These include serving as the director of the Resnick Sustainability Institute, the director of the Department of Energy's "Light-Material Interactions in Energy Conversion" Energy Frontier Research Center (LMI-EFRC), and most recently as the editor-in-chief of a new research journal, ACS Photonics.

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1+1= 3, or How I Learned to Stop Worrying and Love Holistic Circuits

Watson Lecture Preview

In a matter of a few decades, silicon chips have transformed the way we live, taking us from typewriters, landlines, and turntables to computers, cell phones, and MP3 players (which by now, are in your cell phone anyway). Today, with the continued development of complementary metal oxide semiconductor (CMOS) technology, literally billions of transistors can be placed on a tiny, inexpensive chip and customized to perform all sorts of marvels. Developing these technologies and exploring potential applications keeps Ali Hajimiri, Thomas G. Myers Professor of Electrical Engineering at Caltech, and everyone in his lab busy. Hajimiri will lecture on integrated circuits and their applications in our daily lives as part of the Earnest C. Watson Lecture Series on Wednesday, January 29, 2014, at 8 p.m. in Caltech's Beckman Auditorium. Admission is free.

What kind of research do you do?

I'm interested in crafting hardware devices for a range of applications, from communications, radars, and sensors to projection, imaging, and medical technologies. My focus is really on coming up with new solutions to interesting problems, using the underlying circuit and device technology we are now capable of developing.

What do you find most exciting about what you do?

Creating something that didn't exist, making a difference. That is what making a difference is—creating something new. In a way it's like having a crystal ball to look into the future, except for the fact that you're making the future.

What is special about today's circuit technology?

CMOS is basically a low-cost technology that's used for making microprocessors. You can have a tiny chip, smaller than your fingernail, and there's a whole city on there. Our chips are manufactured through a lithography process, which basically means that they are made layer by layer. It's like photography, but in the other direction: instead of taking a negative and enlarging it, we take a stencil and make it very tiny.

What can you use these circuits for?

On the commercial side, our lab developed a technology for power amplifiers that go into cellular phones. These chips are smaller, cheaper, and better than those that came before, and now they are in hundreds of millions of cell phones worldwide. We've also developed the world's first radar-on-a-chip. It's an entire self-operating radar system with the antennas and everything on a chip smaller than a dime. It's intended for automotive applications. Eventually it should be able to prevent automobile collisions because your car will automatically detect when, for example, another car is cutting you off, and it will brake or steer your car away.

One of the greatest things about CMOS technology is that these circuits can be made in volume at a very low cost, maybe a dollar or two. This is especially important for medical devices. You can make an amazing diagnostic device, but if they cost $100,000, there won't be very many people who will end up using them. With CMOS, a variety of medical devices can be made available very widely.

When you're coming up with these ideas, are you thinking in terms of a problem you would like to solve, or are you looking at a chip and imagining what you could do with it?

Both. The way I describe it to my students is that you want to expand in both directions. You want to start with the relevant problems, but you also want to say, "These are the technologies that I have at my disposal. What can I do with them?"  They are like two trees, one that goes down and the other that goes up. The multiple branches at some point start meeting each other. When they connect, you've got a way to link an application to a device.

How did you get into this line of work?

My background is in electrical engineering. But even as a boy, I really liked making stuff. When I was in kindergarten, I used to pound rocks and pebbles and stir up different combinations of them. I made cement, essentially. A couple of years later, I invented a device for avoiding afternoon naps. I really didn't like taking afternoon naps, so I made an alarm that I put under the carpet, and when my mom stepped on it, I would hear it buzz, and I could immediately pretend to be asleep.

How long did it take her to catch on?

For some reason she always avoided stepping on that spot.  I think she must have been on to me.

Writer: 
Cynthia Eller
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