When radiation misfires...literally

The New York Times has a rather chilling account of how radiation overdose in the treatment of some cancer patients caused deadly side effects leading to death. The entire sobering article deserves to be read. In one case a man's tongue was going to be selectively irradiated; instead his whole face received a blast of radiation that led to a horrible, slow death. Scott Jerome-Parks's story makes for very painful reading. In another case, misguided radiation beams literally cut out a hole in a woman's chest that gradually killed her. This was Alexandra Jn-Charles. Both Mr. Jerome Parks and Ms. Jn Charles died within a month of each other in 2007.

And all this mainly because of computer errors that were not detected by human beings, errors that caused the radiation to be overdosed or misdirected. Seems like one of those classic "technology is a double-edged sword" kind of scenarios with the whole system just becoming too complex for human understanding. In one instance, a wedge in a linear accelerator delivering the radiation was supposed to focus the beam in the "in" position. But the computer that used Varian software- the same software that I used in grad school for operating the NMR spectrometer built by the same company- made a mistake and instead pivoted the wedge to the "out" position, removing the radiation shielding. The mistake was not detected 27 times, leading to acute radiation overdoses in the wrong parts of the body. In the case of the man whose tongue was supposed to be treated, an error in the software failed to save the critical settings for the accelerator which would have focused the radiation to the right parts. The computer repeatedly crashed, leading to the collimator beams being left wide open, and nobody noticed this.

The statistics unearthed by the Times are startling. From 2001 to 2009, more than 600 cases of improper radiation treatment were reported. Out of those, 255 were related to an overdose, while 284 were related to the wrong parts of the body being exposed to radiation. Even in its idealized form radiation has side-effects, so one would assume that doctors and technicians would be deathly serious about operating these protocols. These statistics were collected for New York State, which is apparently supposed to have some of the strictest radiation standards in the country.

What is even more shocking is the lack of transparency due to "privacy laws". Names of the culprits have been withheld, and some of them seem to have been let off the hook with a simple reprimand. St. Vincent's hospital and University Hospital of Brooklyn, where the two accidents had happened, were simply fined a thousand dollars by the city of New York. Some doctors who have participated in the treatments refused to talk to the journalists. There also does not seem to be a single agency responsible for these radiation safeguards. On top of it all there seem to be scant ways for patients to pick beforehand which hospital they would like to receive radiation treatment in, since records of mistakes are not available to the public. The whole shebang sounds appalling.

Now I understand that 600 cases in 8 years is probably small potatoes compared to the total number of cases in which radiation has worked successfully. Nonetheless, the factors responsible for the lapses and the horrendous consequences deserve scrutiny (seriously, death due to "computer error" sounds like something out of a bad science fiction horror movie). For something as serious as radiation treatment for cancer, one would assume that the same kinds of safeguards, fail-safe mechanisms and backup checks would be in place as are used in nuclear reactor safety. What boggles my mind is that there exist no fail safe mechanisms which would simply shut down the system when they detect an overdose. It simply seems that shoddy training, computer error, and lack of accountability are dealing out death and enormous physical and psychological suffering to patients and their families.

Go, learn some linear algebra

When I was taking math classes in college I enjoyed topology, differential equations, calculus and combinatorial math, but somehow could not bring myself to drum up enthusiasm for linear algebra.

If I had picked physics as my major (which I almost did), I would not probably have escaped from the clutches of linear algebra while learning quantum mechanics. As it happened I picked chemistry, and most of the quantum chemistry that was served to me after that was sans linear algebra.

On his blog luysii has an excellent set of notes on linear algebra from a QM class that he audited. As I mentioned on his blog, it's interesting how much one can get away with in QC without linear algebra. Thus, take a look at some classic textbooks- Levine, McQuarrie and the classic Pauling and Wilson- and one can go a long way with very little LA. The only things that you are really required to know are eigenvalues and eigenfunctions, but even then the Dirac notation is usually skipped in elementary QC. About the only QC book I know which utilizes large doses of LA is the sophisticated book by Szabo and Ostlund.

Yet LA matters and as luysii demonstrates, there is a generality and elegance to it. There is at least one key LA theorem which is mandatory knowledge in QC. When you are learning about the variational principle (which is used to find approximations to the ground state energy of a system), you derive the so-called secular equation by utilizing a very important LA theorem; that a set of linear homogeneous equations has a non-trivial (non-zero) solution if and only if the determinant of the coefficients is zero. Further on, matrices also come into play in important ways when you are learning about the calculation of transition states, normal modes, and energy minima in molecular mechanics. In the latter exercise you have to calculate the Hessian matrix and then diagonalize this monstrosity (thank god for computer programs).

Perhaps it's not surprising that QC can go a long way without much linear algebra. QC is an application of QM to problems of chemical interest, and the whole reason why the Schrodinger formulation of quantum theory became hugely more popular than the equivalent Heisenberg matrix formulation was that it was more tractable to applications (essentially plug in the correct expression for the potential energy) and couched in the more familiar 19th century language of differential equations. If you wish to know about matrix mechanics take a look at Max Born's excellent book "Atomic Physics"; I had to give up on that particular section.

But even the great Erwin's celebrated paper introducing his equation was titled "Quantization as an Eigenvalue Problem". Maybe it is worth even for a "quantum engineer" (as the late Wolfgang Pauli once somewhat derisively called Enrico Fermi) to learn some linear algebra.

How much chemistry can we wring out of the universe?

Chemiotics II (luysii) had a very interesting post on his blog about the number of proteins of a given length that can be constructed from the entire mass of the earth. Comparing the masses of amino acids to the mass of the earth, he demonstrated that all the earth's mass will be pretty much exhausted with all combinations of a protein that's only 41 amino acids long, which is peanuts as far as your typical protein goes. Such calculations have great relevance for the origin of life if we are to understand the design and evolution of biomolecules.

One can ask similar questions about crystals or small organic molecules. For the latter one can similarly show that the number is much more than the number of atoms in the universe. But most naturally occurring organic molecules have a preponderance of certain fragments like benzene rings. Similarly, there are only a certain rather small number of symmetry groups for crystals. Therefore it seems that in reality, we are dealing with modular units which are much smaller in number (although still quite large) rather than the bare individual units which compose proteins/small molecules/crystals. Thus once these modular units evolved, natural selection probably worked on them instead of trying out possible combinations of their individual atoms. Also remember that natural selection can work on a population of individuals- any kind of individuals- if one of them shows even the slightest advantage with respect to replication. In case of sequences of amino acids, such replicative advantages could arise from several features; stability, charge distributions that could serve to protect the sequences from aqueous hydrolysis or attract one sequence to another, or conformational flexibility that could serve to effect flexibility in the functions of the sequence. Any one of these features could serve to "fix" a particular sequence or group of sequences in a pool of sequences.

In case of proteins for instance, one should ponder how many of the many possible sequences considered could be energetically favored. Some sequences that pit bulky or similarly charged amino acids next to each other could be disfavored by steric and electrostatic factors. Also in case of proteins, the conservation of 3D structure relative to sequence must have been a boon for natural selection. For instance, there's an enormous number of sequences that can fold up into alpha helices (although certain amino acids are favored and others are disfavored) or sheets (where amino acid preferences are not as pronounced). Thus one gets the feeling that natural selection could have some flexibility in designing sequences that would fold into energetically favored secondary structural motifs. However this would not work as well for the active sites of enzymes, where very specific amino acids need to be located in very specific positions in order to effect catalysis. But even here, certain amino acids such as histidine and lysine are interchangeable in terms of their acid-base catalysis roles.

A particularly interesting case that comes to my mind is that of amyloid. Once thought to be the province of only proteins like ß-amyloid, it has now been extensively shown (most notably by Christopher Dobson of Cambridge University, for instance see Nature Chemical Biology 5, 15 - 22 2009, doi:10.1038/nchembio.131 ) that virtually any protein can form amyloid under the right conditions. Amyloid may have been evolution's dream, since it could have tremendous flexibility in picking sequences and coercing them to form amyloid-like structures under the right conditions. As work in which I participated demonstrated (Biochemistry, 2008, 47 (38), pp 10018–10026, DOI: 10.1021/bi801081c), the simplest of changes in conditions like temperature and pH are enough to drastically modulate the architecture of amyloid assemblies.

Thus, while there was potentially an infinite pool of possibilities to design proteins from, as evolution proceeded, I think that the funnel of possibilities became narrower and narrower as the units needed to achieve optimum design became more tailored and building-block like. It's a very interesting question to contemplate the details of this matter.

A biochemical parody of Bryan Adams

For some reason when I was in high school Bryan Adams was big, and we used to listen to his songs all the time. These days I find many of his songs too sappy, but I still love some of the melodies and find myself going nostalgically down memory lane when "Summer of '69" or "Everything I Do" or "Cloud Number Nine" wafts on to the air from somewhere.

So yesterday I happened to be looking at a particularly ravishing picture of dihydrofolate reductase (DHFR) and Adams's "Have You Ever Really Loved A Woman" randomly started playing on my iPod and Bam! The two topics meshed together in an ungodly union. So here is my tribute to Bryan Adams with profound apologies...an ode to that perfect protein which we can only covet. The original version is copied first to mitigate the trauma that will follow.

HAVE YOU EVER REALLY LOVED A WOMAN

To really love a woman
To understand her - you gotta know it deep inside
Hear every thought - see every dream
N' give her wings - when she wants to fly
Then when you find yourself lyin' helpless in her arms
You know you really love a woman

When you love a woman you tell her
that she's really wanted
When you love a woman you tell her
that she's the one
she needs somebody to tell her
that it's gonna last forever
So tell me have you ever really
- really really ever loved a woman?

To really love a woman
Let her hold you -
til ya know how she needs to be touched
You've gotta breathe her - really taste her
Til you can feel her in your blood
N' when you can see your unborn children in her eyes
You know you really love a woman

When you love a woman
you tell her that she's really wanted
When you love a woman
you tell her that she's the one
she needs somebody to tell her
that you'll always be together
So tell me have you ever really -
really really ever loved a woman?

You got to give her some faith - hold her tight
A little tenderness - gotta treat her right
She will be there for you, takin' good care of you
Ya really gotta love your woman...

Then when you find yourself lyin' helpless in her arms
You know you really love a woman
When you love a woman you tell her
that she's really wanted
When you love a woman
you tell her that she's the one
she needs somebody to tell her
that it's gonna last forever
So tell me have you ever really
- really really ever loved a woman?

Just tell me have you ever really,
really, really, ever loved a woman? You got to tell me
Just tell me have you ever really,
really, really, ever loved a woman?


HAVE YOU EVER REALLY LOVED A PROTEIN

To really love a protein
To understand her - you gotta know her deep inside
Hear every helix - see every sheet
N' give her energy - when she wants to jiggle
Then when you find yourself staring helpless at her domains
You know you really love a protein

When you love a protein you tell her
that she's really conformationally correct
When you love a protein you tell her
that she's catalytically perfect
she needs somebody to tell her
that her half-life?s gonna last forever
So tell me have you ever really
- really really ever loved a protein?

To really love a protein
Let her hold your high-affinity binders-
til ya know how she needs to be crystallized
You've gotta mass spec her - really sequence her
Til you can feel her atoms in your spectrometer
N' when you can see the unformed hydrogen bonds in her pockets
You know you really love a protein

When you love a protein
you tell her that she's really evolutionarily conserved
When you love a protein you tell her that she's peptidase-digestion preserved
she needs somebody to tell her
that her fold will always hold together
So tell me have you ever really -
really really ever loved a protein?

You got to give her some metal ions - hold her co-factors
A little pH-control - gotta treat her ionization state right
She will be there for you, takin' good care of your ligands
Ya really gotta love your protein...

Then when you find yourself staring helpless at her PDB coordinates
You know you really love a protein
When you love a protein you tell her
that she's really conformationally correct
When you love a protein you tell her
that she's catalytically perfect
she needs somebody to tell her
that her half-life?s gonna last forever
So tell me have you ever really
- really really ever loved a protein?

Just tell me have you ever really,
really, really, ever loved a protein? You got to tell me
Just tell me have you ever really,
really, really, ever loved (that helical, sheety, hydrogen bondalacious) protein?

Almost back

I have been in Tasmania for the last three weeks visiting family, enjoying sunny weather while my home in the northeast faced the wrath of the Norse gods. Back next week for a new year of chemical bloggity bloggings.

Happy New Year