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Archive for January, 2014

This article appeared in symmetry on Jan. 7, 2014.

Accelerator technology could be key to developing an effective treatment for a type of brain tumor currently considered incurable.

Accelerator technology could be key to developing an effective treatment for a type of brain tumor currently considered incurable.

One of the most common and aggressive types of malignant tumor originating in the human brain is called a glioblastoma multiforme. Patients diagnosed with this kind of tumor are told they have, on average, a little more than a year to live.

Because standard treatments, including surgery and radiation therapy, cannot completely eradicate glioblastomas without fatally damaging the surrounding healthy tissue, these tumors are considered incurable. But Narayan Hosmane, a boron chemist from Northern Illinois University, is working with a team of scientists from Fermilab to try to rid them of that classification.

The group is exploring the capabilities of an experimental treatment called Boron Neutron Capture Therapy. The key to making BNCT work, they think, could lie in particle accelerator technology.

Daniel Silbergeld, a University of Washington neurosurgery and neuropathology professor based at UW Medical Center and Harborview Medical Center in Seattle, operates on more than 200 tumors in a year, at least half of which are glioblastomas.

“Our goal is to help that person live as long as possible and as well as possible,” Silbergeld says. “We never know how well an individual is going to do.”

Silbergeld, who is an affiliate of Seattle Cancer Care Alliance, says patients who undergo aggressive therapy tend to be the ones who live longer.

Here’s an overview of how BNCT works: A medical professional injects into the patient’s bloodstream a tumor-seeking compound containing non-radioactive boron. Normally, blood does not come in contact with the brain, thanks to a bodily structure called the blood-brain barrier. But due to the relatively low molecular weight of the compound, and the fact that tumors often compromise the blood-brain barrier anyway, the drug can bypass this membrane and enter the glioblastoma, which is filled with blood vessels. The drug accumulates there and in some of the surrounding tissue.

Next, scientists send a beam of neutrons through the patient’s brain. Compared to other elements, boron (specifically, boron-10) is one of the best at capturing neutrons; because of the structure of its nucleus, it acts like a specialized, larger-than-average baseball mitt. When a neutron is caught, the boron atom fissions into two particles called an alpha particle and a lithium ion. These particles, due to their relative heaviness, deposit a lot of energy locally—in this case, in the cancer cells. The deposited energy is equivalent to a hefty dose of radiation to the tumor, meant to eradicate it.

So far, the most successful BNCT trials have yielded results that are about the same as standard therapies. The technique has been attempted around the world for decades and has even reached clinical trials in Japan.

But, until now, researchers have generated their beams of neutrons using nuclear reactors. Patients at research facilities, such as MIT’s Fission Converter Beam, or hospitals, such as the Helsinki University Central Hospital, would lay with their heads positioned directly against a nuclear reactor that generates neutrons by a fission chain reaction. Hosmane and the group from Fermilab have another idea.

They think they can improve results by creating epithermal neutrons using higher energy beams from a linear particle accelerator instead, says Tom Kroc, head of neutron therapy at Fermilab. In the past, Fermilab’s fast neutron therapy facility used beams of 66 million electronvolts. While BNCT trials would not require nearly that much energy, the capabilities are much higher than the 2 million electronvolts or less that reactors provide.

Low-energy neutrons have more of a propensity for causing boron atoms to fission; however, they cannot penetrate tumors located deep within the brain, Kroc says.

“With the neutrons from the reactors, they can only treat tumors that are about 2 centimeters deep,” Kroc says. “Our hope is that since we have a higher energy beam we will be able to treat tumors that are deeper.”

He says they must “try to find some sweet spot,” slowing down their beam just enough to penetrate deeply while also giving the boron atoms a fighting chance at fission.

An added benefit of using a particle accelerator instead of a nuclear reactor could be the reduced amount of security required at treatment facilities, Kroc says. And, while treatments using a reactor took a number of hours to complete in the past, the use of an accelerator could speed up a patient’s visit to about 10 to 20 minutes.

In addition to changing the way the neutron beam is generated, the NIU-Fermilab team is working to improve the way the boron is administered.

“The biggest challenge is to get that boron into the tumor,” says Jim Welsh, chief medical coordinator for the development of BNCT at Fermilab.

Hosmane is in the process of getting approval for a different compound that he hopes would work in a similar way, but more effectively. For example, Welsh says, to get to the tumor, some of the compounds would emulate the function of amino acids, which are able to bypass the blood-brain barrier using special carrier proteins. But for now, the team’s efforts are still mostly ground-level.

“It’s beyond the early stage, but I’d say it’s still in the experimental and exploratory stage,” Welsh says.

Silbergeld’s colleague, Radiation Oncologist Jason Rockhill, is well versed in BNCT research. He says that, beyond getting enough boron to the target cell, an added challenge is to then inflict enough cellular damage to destroy the cancer.

“BNCT is a really cool idea, but it’s complex,” Rockhill says.

He estimates that, between drug development and gaining access to the proper type of accelerator, getting to the point of clinical trials is likely to take much time and effort—plus upwards of multiple millions of dollars.

If Welsh’s team pulls together proper funding, receives access to Fermilab’s linear-accelerator-derived neutron beam facility and purchases the necessary computer software, they could start pursuing clinical trials in a few years, Welsh says.

Fermilab is the only place in the United States considering using linear accelerator-based neutrons for BNCT and would be the only lab using the new drugs being developed at NIU.

“There is so much potential,” Kroc says. “The questions are still unanswered as to whether we can make it work, and I want to see it through to its conclusion.”

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In the philosophy of science, realism is used in two related ways. The first way is that the interior constructs of a model refer to something that actually exists in nature, for example the quantum mechanical wave function corresponds to a physical entity. The second way is that properties of a system exist even when they are not being measured; the ball is in the box even when no one can see it (unless it is a relative of Schrodinger’s cat). The two concepts are related since one can think of the ball’s presence or absence as part of one’s model for how balls (or cats) behave.

Despite our and even young children’s belief in the continued existence of the ball and that cats are either alive or dead, there are reasons for doubting realism. The three main ones are the history of physics, the role of canonical (unitary) transformations in classical (quantum) mechanics, and Bell’s inequality. The second and third of these may seem rather obtuse, but bear with me.

Let’s start with the first, the history of physics. Here, we follow in the footsteps of Thomas Kuhn (1922–1996). He was probably the first philosopher of science to actually look at the history of science to understand how science works. One of his conclusions was that the interior constructs of models (paradigms in his terminology) do not correspond (refer in the philosophic jargon) to anything in reality. It is easy to see why. One can think of a sequence of models in the history of physics. Here we consider the Ptolemaic system, Newtonian mechanics, quantum mechanics, relativistic field theory (a combination of quantum mechanics and relativity) and finally quantum gravity. The Ptolemaic system ruled for half a millennium, from the second to seventeenth centuries. By any standard, the Ptolemaic model was a successful scientific model since it made correct predictions for the location of the planets in the night sky. Eventually, however, Newton’s dynamical model caused its demise. At the Ptolemaic model’s core were the concepts of geo-centrism and uniform circular motion. People believed these two aspects of the model corresponded to reality. But Newton changed all that. Uniform circular motion and geo-centrism were out and instantaneous gravitation attraction was in. Central to the Newtonian system was the fixed Euclidean space time geometry and particle trajectories. The first of these was rendered obsolete by relativity and the second by quantum mechanics; at least the idea of fixed number of particles survived–until quantum field theory. And if string theory is correct, all those models have the number of dimensions wrong. The internal aspects of well-accepted and successful models disappear when new models replace the old. There are other examples. In the history of physics, the caloric theory of heat was successful at one time but caloric vanished when the kinetic theory of heat took over. And on it goes. What is regarded as central to our understanding of how the world works goes puff when new models replace old.

On to the second reason for doubting realism–the role of transformations: canonical and unitary.  In both classical and quantum mechanics there are mathematical transformations that change the internals of the calculations[1] but leave not only the observables but also the structure of the calculations invariant. For example, in classical mechanics we can use a canonical transformation to change coordinates without changing the physics. We can express the location of an object using the earth as a reference point or the sun. Now this is quite fun; the choice of coordinates is quite arbitrary. So you want a geocentric system (like Galileo’s opponents), no problem. We write the equation of motion in that frame and everyone is happy. But you say the Earth really does go around the sun. That is equivalent to the statement: planetary motion is more simply described in the heliocentric frame. We can go on from there and use coordinates as weird as you like to match religious or personal preconceptions.  In quantum mechanics the transformations have even more surprising implications. You would think something like the correlations between particles would be observable and a part of reality. But that is not the case. The correlations depend on how you do your calculation and can be changed at will with unitary transformations. It is thus with a lot of things that you might think are parts of reality but are, as we say, model dependent.

Finally we come to Bell’s inequality as the third reason to doubt realism. The idea here goes back to what is known as the Einstein-Podolsky-Rosen paradox (published in 1935). By looking at the correlations of coupled particles Einstein, Podolsky, and Rosen claimed that quantum mechanics is incomplete.  John Bell (1928 – 1990), building on their work, developed a set of inequalities that allowed a precise experimental test of the Einstein-Podolsky-Rosen claim. The experimental test has been performed and the quantum mechanical prediction confirmed. This ruled out all local realistic models. That is, local models where a system has definite values of a property even when that property has not been measured. This is using realism in the second sense defined above. There are claims, not universally accepted, that extensions of Bell’s inequalities rule out all realist models, local or non-local.

So where does this leave us? Pretty much with the concept of realism in science in tatters. The internals of models changes in unpredictable ways when science advances. Even within a given model, the internals can be changed with mathematical tricks and for some definitions of realism, experiment has largely ruled it out.  Thus we are left with our models that describe aspects of reality but should never be mistaken for reality itself. Immanuel Kant (1724 – 1804), the great German philosopher, would not be surprised[2].

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[1] For the relation between the two type of transformations see: N.L. Balazs and B.K. Jennings, Unitary transformations, Weyl’s association and the role of canonical transformations, Physica, 121A (1983) 576–586

[2] He made the distinction between the thing in itself and observations of it.

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No cream, no sugar

Monday, January 6th, 2014

My first visit to CERN was in 1997, when I was wrapping up my thesis work. I had applied for, and then was offered, a CERN fellowship, and I was weighing whether to accept it. So I took a trip to Geneva to get a look at the place and make a decision. I stayed on the outskirts of Sergy with my friend David Saltzberg (yes, that David Saltzberg) who was himself a CERN fellow, and he and other colleagues helped set up appointments for me with various CERN physicists.

Several times each day, I would use my map to find the building with the right number on it, and arrive for my next appointment. Invariably, I would show up and be greeted with, “Oh good, you’re here. Let’s go get a coffee!”

I don’t drink coffee. At this point, I can’t remember why I never got started; I guess I just wasn’t so interested, and may also have had concerns about addictive stimulants. So I spent that week watching other people drink coffee. I learned that CERN depends on large volumes of coffee for its operation. It plays the same role as liquid helium does for the LHC, allowing the physicists to operate at high energies and accelerate the science. (I don’t drink liquid helium either, but that’s a story for another time.)

Coffee is everywhere. In Restaurant 1, there are three fancy coffee machines that can make a variety of brews. (Which ones? You’re asking the wrong person.) At breakfast time, the line for the machines stretches across the width of the cafeteria, blocking the cooler that has the orange juice, much to my consternation. Outside the serving area, there are three more machines where one can buy a coffee with a jeton (token) that can be purchased at a small vending machine. (I don’t know how much they cost.) After lunch, the lines for these machines clogs the walkway to the place where you deposit your used trays.

Coffee goes beyond the restuarants. Many buildings (including out-of-the-way Building 8, where my office is) have small coffee areas that are staffed by baristas (I suppose) at peak times when people who aren’t me want coffee. Building 40, the large headquarters for the CMS and ATLAS experiments, has a big coffee kiosk, where one can also get sandwiches and small pizzas, good when you want to avoid crazy Restaurant 1 lunchtimes and coffee runs. People line up for coffee here during meeting breaks, which usually puts us even further behind schedule.

Being a non-drinker of coffee can lead to some social discomfort. When two CERN people want to discuss something, they often do it over coffee. When someone invites me for a chat over coffee, I gamely say yes. But when we meet up I have to explain that I don’t actually drink coffee, and then sit patiently while they go to get a cup. I do worry that the other person feels uncomfortable about me watching them drink coffee. I could get a bottle of water for myself — even carbonated water, when I feel like living on the edge — but I rarely do. My wife (who does drink coffee, but tolerates me) gave me a few jetons to carry around with me, so I can at least make the friendly gesture of buying the other person’s coffee, but usually my offer is declined, perhaps because the person knows that he or she can’t really repay the favor.

So, if you see a person in conversation in the Restaurant 1 coffee area, not drinking anything but nervously twiddling his thumbs instead, come over and say hello. I can give you a jeton if you need one.

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