Quantum microscopy is an emerging technology for achieving comprehensive atomic-resolution imaging of complex molecular structures.
Richard Feynman explained why this goal is important in a 1959 lecture entitled There's Plenty of Room at the Bottom:
What good would it be to see individual atoms distinctly?
We have friends in other fields---in biology, for instance. We physicists often look at them and say, "You know the reason you fellows are making so little progress?" (Actually I don't know any field where they are making more rapid progress than they are in biology today.) "You should use more mathematics, like we do."
They could answer us---but they're polite, so I'll answer for them: "What you should do in order for us to make more rapid progress is to make the electron microscope 100 times better."
What are the most central and fundamental problems of biology today? They are questions like: What is the sequence of bases in the DNA? What happens when you have a mutation? How is the base order in the DNA connected to the order of amino acids in the protein? What is the structure of the RNA; is it single-chain or double-chain, and how is it related in its order of bases to the DNA? What is the organization of the microsomes? How are proteins synthesized? Where does the RNA go? How does it sit? Where do the proteins sit? Where do the amino acids go in? In photosynthesis, where is the chlorophyll; how is it arranged; where are the carotenoids involved in this thing? What is the system of the conversion of light into chemical energy?
It is very easy to answer many of these fundamental biological questions; you just look at the thing! You will see the order of bases in the chain; you will see the structure of the microsome. Unfortunately, the present microscope sees at a scale which is just a bit too crude. Make the microscope one hundred times more powerful, and many problems of biology would be made very much easier. I exaggerate, of course, but the biologists would surely be very thankful to you---and they would prefer that to the criticism that they should use more mathematics.
Other prominent scientists had the same idea even earlier than Feynman. See, for example, John von Neumann's 1946 letter to Norbert Weiner, which can be downloaded from elsewhere on our web site.
Even earlier than von Neumann and Weiner, similar ideas were set forth by Linus Pauling in a 1945 proposal to Warren Weaver at the Rockefeller Foundation. Pauling proposed to create the world's first molecular biology center, emphasizing structural-function studies at the molecular level, and including a strong focus on atomic-resolution microscopy development. (Sadly, historian Lily Kay, who sent us a copy of Pauling's proposal from Rockefeller Foundation archives, has recently passed away. Thank you for helping us, Lily.)
To summarize, quantum microscopy is an emerging science and engineering discipline that seeks to realize Feynman's and von Neumann's and Pauling's vision of comprehensive microscopy by the direct observation of individual spins.
This capability—if achieved—will revolutionize both biology and medicine as thoroughly as the telescope revolutionized astronomy. So we are led to ask, what might an atomic-level description of a cell mean? Will it be a database, a catalog, a taxonomy? Will it be intellectual property, and if so, who can justly lay claim to it? Might it tell stories, and if so, what stories? And who will be telling them? Who will be listening?
For defense analysts, this new frontier will represent new threats and new defense capabilities. For venture capitalists and corporations it will generate new intellectual property cheaply, rapidly, and in unbounded quantities. For biologists and materials scientists it will create new vistas for new theories and observations. For physicians and patients it will will offer transformational hope of effective medical treatments for presently intractable disorders, including global scourges like malaria, tuberculosis, and HIV/AIDS. From these traditional points of view, the objectives of quantum microscopy are those of an ultimate "dual-use" technology.
But it is almost certainly a mistake to imagine the quantum microscopy frontier solely in traditional terms. The truth is, we cannot yet imagine what it will be like to explore this frontier. In his 1994 book Biophilia, biologist E. O. Wilson attempts to envision the new vistas that will open to us:
If I could do it all over again, and relive my vision in the twenty-first century, I would be a microbial ecologist. Ten billion bacteria live in a gram of ordinary soil, a mere pinch held between thumb and forefinger. They represent thousands of species, almost none of which are known to science.
Into that world I would go with the aid of modern microscopy and molecular analysis. I would cut my way through clonal forests sprawled across grains of sand, travel in an imagined submarine through drops of water proportionally the size of lakes, and track predators and prey in order to discover new life ways and alien food webs. All this, and I need venture no more than ten paces outside my laboratory building.
The jaguars, ants, and orchids would still occupy distant forests in all their splendor, but now they would be joined by an even stranger and vastly more complex living world virtually without end. For one more turn around I would keep alive the little boy of Paradise Beach who found wonder in a scyphozoan jellyfish and a barely glimpsed monster of the deep.
Here Wilson has set forth a noble vision, and yet even so visionary a thinker as Wilson did not foresee in 1994 the rich world of RNA regulation of eukaryotic gene expression; a world that seems to be at least as rich as the world of DNA and proteins; a world which quantum microscopy will open even wider, and which is at present almost entirely unexplored.
Thus, we now realize that each cell in the human body itself comprises an ecology, containing many tens of thousands of molecular species, such that each cell is at least as rich in biological meaning as the macroscale ecosystems that Wilson and his colleagues already embrace so passionately. One of the challenges that quantum microscopy brings to humanity is for us to comprehend and embrace these cellular ecosystems with the same passion and respect that we have for our planetary ecosystem.
In sharp contrast to the romance of quantum microscopy's goals, day-to-day life on the frontiers of quantum microscopy is decidedly unglamorous. For example, the present focus of our UW QSE Group is on getting biospecimens into our prototype quantum microscope, and observing their quantum noise properties. This unglamorous work recapitulates the early history of electron microscopy, in which specimen preparation and system integration issues proved to be even bigger challenges than getting the fundamental physics right.
The tension between quantum microscopy's romantic goals and the disciplined pursuit of these goals is the essence of quantum system engineering.
Note added: For all you engineers, there are ~10^14 atoms in an ordinary human cell, compared to ~5x10^11 stars in the Milky Way. So each cell in the human body is made, quite literally, of a galaxy of atoms. And by a remarkable numerical coincidence, the number of cells in the human body is about the same as the number of atoms in a cell. Thus every human being can invoke Walt Whitman in saying "I am large, I contain multitudes." Exploring this biological galaxy-of-galaxies is the 21st Century's new frontier of biology and medicine.
Creating practical technologies that perform at or near these ultimate levels - the levels imposed by the fundamental laws of quantum mechanics, thermodynamics, relativity, causality, atomic theory, and information theory - is what defines quantum system engineering as an objective discipline.
Examples of practical quantum system engineering (QSE) include established technologies like the Glocal Positioning System (the RAND corporation has published a fascinating GPS history) and atomic clocks, emergent technologies like the gravity wave interferometers being built by LIGO, VIRGO, TAMA, GEO 600, and LISA, as well as future technologies like quantum computing devices.
To the best of our knowledge, the first person who defined themselves professionally as a quantum engineer was John Bell. We believe that many more engineers will follow in Bell's steps during the 21st Century.
Is quantum system engineering less exciting than fundamental quantum research? In a recent essay, MIT engineers John Guttag and Paul Penfield, Jr. reflect that
Life on the frontier is exciting. Research thrives where there is ambiguity, where much is unknown; overturning a major principle or law is considered a success, an accomplishment worthy of distinction. The disruptive, somewhat chaotic, character of frontier life is one we engineers relish.
But most institutions in a civilized society need stability and predictability. Consider what happened to America's western frontier. Civilization arrived and brought with it law and order. For better or for worse, the frontier became a more predictable and less exciting place.
Is it our turn now? Our scientific and engineering frontier is of critical importance to America. Must our frontier become "civilized?" History suggests that it must. In fact, it is already happening.
As William Wulf, president of the National Academy of Engineers, said in his well-known essay An Urgent Need for Change: "Engineering is design under constraint". Wulf goes on to remark:
Engineering is not just applied science. To be sure, knowledge of nature is one of our working constraints. But it is not the only one, not the hardest one, and almost never the limiting one.
Quantum system engineering, therefore, may be defined as "system design under quantum constraints".
How does one become a quantum system engineer? For students, one path is to click here!
By combining the above three ideas, we can hope to create a technology for achieving:
The following explanation covers just the basics of MRFM. For a more extensive historical and technical overview, please consult our MRFM White Papers or IBM's excellent MRFM page. You may also wish to view our MRFM animations, from which the following pictures are taken.
A cantilever with a magnetic tip (center) approaches a sample positioner (entering from below). A radio-frequency coil (left) modulates the sample spins, and a fiber-optic interferometer (top) detects the resulting cantilever motion.
The tip-sample region, with resonant slices. Slices closer to the tip have higher resonant frequency. Note that the magnetic slices reach into the sample, allowing nondestructive subsurface 3D imaging.
Close-up of a resonant slice. Protein data bank entries 1GGI, 1CAO, and 1TSR are shown for scale.
MRFM signals arise when spins in a sample are modulated by an applied radio-frequency field, precisely as in conventional magnetic resonance imaging. Only spins within a thin resonant slice are affected; the spins closer to the tip are in too strong a field for resonance, while spins farther from the tip are in too weak a field. The thickness of the slice is described by Bloch-type equations; the stronger the gradient of the magnetic field, the thinner the resonant slice.
The spins within a resonant slice are detected by force microscopy, by virtue of the magnetic force between the spins and the nearby tip, which excites the cantilever into motion which is detected by the interferometer. As in conventional magnetic resonance, there are many different ways to modulate this tip-sample interaction: cyclic saturation, adiabatic inversion, spin echos, and pulse inversion have all been demonstrated in the context of MRFM, for both nuclear and electron spins.
Also, although tips, cantilevers, and interferometers have been fabricated separately with the required ultrasmall dimensions, they have not yet been fabricated and operated conjointly, particularly at ultralow temperatures.
From an engineering point of view, systems integration is emerging as the single biggest challenge in MRFM. All the above subsystems must operate together, reliably, with performance near the limits dictated by quantum mechanics, thermodynamics, and information theory.
The required levels of design sophistication, system reliability, and documentation are therefore becoming similar to those of "Big Science" projects like LIGO and the Sloan Digital Sky Survey, even though MRFM devices themselves are small.
As quantum microscope technologies continue to improve, and as larger scientific resources are committed, the diverse missions of its sponsors must be recognized and respected.
Among the more sobering mission-related issues in quantum microscopy are:
Whether quantum microscopy works or not -- but sooner if it does work -- humanity must make progress toward resolving these issues.
Meeting these challenges is opening tremendous new frontiers, with wonderful opportunities for scientific discovery, humanitarian achievement, and wealth creation.
The Biological Warfare Convention represents humanity's nearest approach to a consensus on these difficult issues. A list of signatory nations is available. It is heartening to see how many nations have signed this treaty, but it is sobering that many of these nations are presently war-torn and/or unstable.
On a hopeful and inspirational note, the heroic conquest of yellow fever by Major Walter Reed and colleagues of the US ARMY Medical Corps-- some of whom died of yellow fever in the course of their research -- reminds us that some of the greatest medical advances have occurred under a military aegis.
The ongoing AIDS crisis is evidence that the age of devastating global pandemics is not yet over. All nations and all people recognize their common interest in defeating these enemies of humanity.
Gen. George C. Marshall articulated perhaps the most compelling and enduring strategic vision of the missions that quantum microscopy might help serve. Marshall's 1947 Marshall Plan Speech speaks to us today as strongly as ever:
I need not tell you gentlemen that the world situation is very serious. That must be apparent to all intelligent people. I think one difficulty is that the problem is one of such enormous complexity that the very mass of facts presented to the public by press and radio make it exceedingly difficult for the man in the street to reach a clear appraisement of the situation. Furthermore, the people of this country are distant from the troubled areas of the earth and it is hard for them to comprehend the plight and consequent reactions of the long-suffering peoples, and the effect of those reactions on their governments in connection with our efforts to promote peace in the world.
From Marshall's 1953 Nobel Prize speech:
I would like to discuss ... the problem of the millions who live under subnormal conditions and who have now come to a realization that they may aspire to a fair share of the God-given rights of human beings. Their aspirations present a challenge to the more favored nations to lend assistance in bettering the lot of the poorer. This is a special problem in the present crisis, but it is of basic importance to any successful effort toward an enduring peace. The question is not merely one of self-interest arising from the fact that these people present a situation which is a seed bed for either one or the other of two greatly differing ways of life. Ours is democracy, according to our interpretation of the meaning of that word. If we act with wisdom and magnanimity, we can guide these yearnings of the poor to a richer and better life through democracy.
We must present democracy as a force holding within itself the seeds of unlimited progress by the human race. By our actions we should make it clear that such a democracy is a means to a better way of life, together with a better understanding among nations. Tyranny inevitably must retire before the tremendous moral strength of the gospel of freedom and self-respect for the individual, but we have to recognize that these democratic principles do not flourish on empty stomachs, and that people turn to false promises of dictators because they are hopeless and anything promises something better than the miserable existence that they endure.
However, material assistance alone is not sufficient. The most important thing for the world today in my opinion is a spiritual regeneration which would reestablish a feeling of good faith among men generally. Discouraged people are in sore need of the inspiration of great principles. Such leadership can be the rallying point against intolerance, against distrust, against that fatal insecurity that leads to war. It is to be hoped that the democratic nations can provide the necessary leadership.
At the United Nations 2003 HIV/AIDS Plenary Colin Powell has conveyed the urgency of the modern-day AIDS crisis in words not less eloquent than Marshall's:
AIDS has left 15 million orphans, and unless we stem the tide, that number will swell to 25 million by the end of this decade. The vast majority of these children are likely to live without emotional support, without the barest of physical necessities, and without any prospects for the future.
Unless we act effectively, these precious children are likely to perish in the same cycle of disease, destitution, despair and death that took the lives of their parents.
The appalling statistics do not begin to describe the magnitude of the destruction wrought by AIDS. AIDS is more devastating than any terrorist attack, any conflict or any weapon of mass destruction. It kills indiscriminately, and without mercy.
As cruel as any tyrant, the virus can crush the human spirit. It is an insidious and relentless foe. AIDS shatters families, tears the fabric of societies, and undermines governments. AIDS can destroy countries and destabilize entire regions.
Gen. Powell is referring to recent AIDS statistics, from which "it is clear that the epidemic is still in its early stages."
The statistics are such that the human mind cannot easily bear to contemplate them:
The following passages are quoted from mission statements of the institutions that sponsor MRFM development:
To ensure that the spread of biological weapons is minimized, and the threat from existing systems is effectively countered.
To uncover new knowledge that will lead to better health for everyone.
To promote the progress of science and to advance the national health, prosperity, and welfare.
To lead in the creation, development and manufacture of the industry's most advanced information technologies.
Traditionally, all of these missions have been well-served by the scientific community's committment to an open, enduring scientific literature.
This picture was generated using the public-domain program POV-Ray. It was created partly for fun, for use as a screen saver within our MRFM group. High-resolution versions are available in the GIF format from our MRFM Graphics Directory.
This picture represents a serious attempt to explain, within one picture, what we are doing and what we hope to achieve. The students are three of our own UW MRFM students, and they are wearing virtual-reality glasses because they are accessing an imagined whole-cell database of directly observed biomolecular structures. The imagined year is (roughly) 2010, and the quantum microscope technology described in our MRFM White Papers is fully on-line.
The structures these students are holding are real human proteins. Left-to-right, they are: (1) a human antibody gripping a fragment of the HIV envelope protein GP120, (2) a protease bound to the human amyloid protein whose accumulation is implicated in Alzheimer's disease, and (3) the DNA-binding protein P53 whose mutation is strongly associated with tumor malignancy.
In this imagined world of 2010, molecular biology has become -- at least partially -- an observational discipline, and it has therefore acquired some of the traits of traditional observational disciplines like astronomy, geology, and field ecology.
On the illustrated scale of one angstrom to one centimeter, a human eukaryotic cell is about one kilometer in diameter. The box in the background labeled "TERA" is a terabyte database containing all the nontrivial atomic coordinates within a single human cell. The database was created by scanning a single cell systematically, layer-by-layer, in a manner similar to the way today's Sloan Digital Sky Survey is scanning the sky. The database contains on the order of one hundred million biological molecules, each observed in exact (but static) relation to its neighbors.
The box in the background labeled "PETA" is a petaflop computer; this computer animates and annotates the molecules database, and allows the students to interact with the database by walking around within the cell while directly observing it, in a manner similar to the way that field ecologists interact with the ecosystems they study, and astronomers interact with the Sky Survey database.
In this imagined world of 2010, molecular biologists, cell biologists, geneticists, ecologists, physicists, chemists, and computer scientists all share a common ambition: to survey, catalog, and curate a global database containing all structures of all molecules of all living organisms. Needless to say, this is a large database, of order one exabyte (10^18 bytes). For comparison, the number of words ever spoken in all history by all human beings is of order 5 exawords.
This database is represented by the globe labeled "EXA" in the right-hand corner. This database will be created once and only once in human history, so it will be best if we make it easy and natural to interact with, and if we can arrange for it to share some of the same beauty as the living world it represents.
How long would such a comprehensive database take to create? How many people would contribute to it? How much would it cost? Who would own it? What would it be used for? What would it mean to us?
These questions are becoming increasingly urgent as technical progress in MRFM makes the feasibility of comprehensive quantum microscopy increasingly evident.