Some DNA Basics

This entry is part 1 of 2 in the series "DNA" --

WARNING: Science Content


As with all my posts, I try to include some thought provoking science, as well as interesting water cooler talk.  Good luck.
 

Deoxyribonucleic acid (DNA)

12 Base Pairs of DNA. For those of you not familiar with chemistry, but think you know what an atom is, each stick in this figure represents a bond between atoms. The color of the stick represents the atom that is being bonded to. If the stick line changes from one color to a different color, then you are bonding two different types of atoms together. (i.e. Grey to White = Carbon bonded to Hydrogen) You’ll also notice that some atoms bond to multiple things and others not so many. How many things it attaches to is determined by where it is on the periodic table of the elements. (Don’t worry about this, just appreciate that different atoms bond to different numbers of other atoms.)

There Is a Lot of It.

As we have mentioned before in a different post, there are about 3 billion base pairs of DNA over 46 chromosomes (23 pairs).  This count is for each cell in your body. You have about 70 trillion cells in your body. Yes, that is 70,000,000,000,000 copies of your complete DNA. (For those of you heady in math, that is 210,000,000,000,000,000,000,000 base pairs in your body right now.)

DNA Is a Storage System

DNA is an elegant storage system, and every time that I stop and think about what it is, I marvel at its simple, yet complex nature. The rotating picture to the right is 12 base pairs. The two separate helices are the attachment points of each side of the base, and the base pairs are the flat planes of atoms that connect one helix to the other. (Go ahead and take a moment and convince yourself that there are only 12 base pairs here. I know that you want to!)

The base pair that is in the center is not “technically” bonded. They are held together with a much weaker force than the standard covalent bond.  They are held together with “hydrogen bonding“.  Hydrogen bonding is an electrostatic force that only exists when hydrogen is bonded to a Flourine, Oxygen, or Nitrogen atom.  When hydrogen is taking part in hydrogen bonding, it acts like a strong magnet would if it were fastened to one piece of metal, and another piece of metal got close to it. DNA would be useless without this weak interaction.  It needs to be able to separate easily.  If it were covalently bonded across the base pairs, it would be useless.  (If you look closely at the rotating DNA picture, you will notice that the base pairs are shown with a break between them. The hydrogen bond between them is just strong enough for the base pairs to line up to one another.)

 

A closer look at base pairs

A Closer Look at the base pairs (Thanks to Zephyris on Wikipedia). Each of the four base pairs have names, but to keep it simple, they are abbreviated with the letters A,T,C, and G.  —“A” hydrogen bonds to “T”  — “C” hydrogen bonds to “G” — Also notice that the hydrogen bond between the base pairs is represented by a dashed line. (i.e. Not quite as strong as a regular old covalent bond)

 

DNA Must Break Apart

As a storage system, DNA must continually break apart in order to be read or to be duplicated.  When it is in its double helix form, it is pretty. It is in storage. It just sits there. Hydrogen bonding (which is not nearly as strong as a regular bond) can break apart easily. It can be put together easily. There are two main events that occur with DNA. Copying the DNA strand, and reading the DNA in order to produce the biological machines in the human body that are comprised of proteins.

The following videos describes how the DNA is broken apart and either copied or transcribed.

The Focus of Many Chemotherapy Agents

The main Chemotherapy drugs that are used (at least for Neuroblastoma) focus on the interruption of the copying process. An interruption of the copying process triggers the oncogenes in the cell to cause apoptosis (cell death). While healthy cells have the means and time to do their best job at repairing the cell before sounding the apoptosis alarm, cancer cells are not nearly as patient. When they discover that there is a problem with DNA replication, they will often give up… At least until they assimilate the knowledge of how to repair the DNA or the knowledge of how to keep the chemotherapy drugs out of their cell walls. This adaptation leads to the demise of the effectiveness of chemotherapy drugs in their fight against cancer.

mIBG – We are back on!

This entry is part 3 of 3 in the series "Radiation" --

WARNING: Science Content


As with all my posts, I try to include some thought provoking science, as well as interesting water cooler talk.  Good luck.
 
MetaIodoBenzylGuanidine

MetaIodoBenzylGuanidine


[Prologue]

For those avid followers of all of the science that I have introduced during all of this, you will recognize that this post is a rehash, but an exciting rehash.

Early on, Liam was initially slated to participate in a mIBG (MetaIodoBenzylGuanidine) trial.  The trial wasn’t supposed to happen until after the induction period of chemotherapy.  The catch is that only 80-85% of neuroblastomas absorb mIBG.  This is why fairly soon after diagnoses, while there is still a lot of cancer in concentrated pockets throughout the body, an mIBG scan is given to see if the particular variety of neuroblastoma picks it up. This is done with [123]- mIBG (see below.)

When this scan was performed on Liam back in September, there had been problems and the scan was not performed right away.  The doctors and hospital staff were having difficulty stabilizing Liam.  In fact, that first session in the hospital lasted over 21 days.  He had been started on  a fantastic chemotherapy drug called Topotecan (which is a TopoIsomerase I inhibitor that is so darn cool, it deserves its own post and I will not discuss it here.)  The problem was that Liam was spiraling out of control while he was on it. He started having trouble breathing, and he ended up with a plural effusion (yep… that was a bad couple of days. Click here for the post from that day).  After all was said and done, the mIBG scan was pushed off until he was admitted for chemo round 2.

When the [123] mIBG scan was finally performed, it came back negative. We were bummed, but the chemo seemed to be going so well that we really didn’t give it much thought. Liam was feeling better.

After 6 rounds of chemotherapy, a follow up PET scan was performed. No cancer showed up on the scan. He had a remarkable response, and we thought we were doing pretty well.  In reviewing all that had happened over the course of 6 rounds of chemo, I wondered if most of the cancer had vanished just after the first round of chemotherapy.  If it did, it would have skewed the mIBG test to a negative result.

Looking back at the sudden improvement after round 1- the plural effusion (now believed to be caused by cancer dying his lungs) and all of the immediate weight loss (now believed to be the cancer dying in his abdomen)…. he looked normal for the first time in months; I contend that the Topotecan chemotherapy made most of the cancer disappear quickly.  His response even astonished his doctors.

Now that the cancer has come back,  it was suggested by the doctors at CookChildren’s that we look one more time at the mIBG.  So, we did, and it gave a positive response to mIBG.  It can clearly be seen in the left tibia and the pelvis.

mIBG Liam 24July2015

123-mIBG Scan of Liam on 24July2015. His neuroblastoma has soaked up the mIBG compound, and due to its radioactivity is exposing the film. His trouble spots in his left leg and pelvis can clearly be seen.

So what does this mean? It means that we now have a really awesome tool in our tool chest to fight this. It won’t cure the neuroblastoma, but hopefully we can knock it down and coupled with other therapies, we can get this disease under control for Liam.  This is an option that a week ago we did not have.

[End of Prologue]

So, how does it work? It turns out that Neuroblastoma has a strong affinity for mIBG in about 85% of cases.[1] In a very high percentage, the Neuroblastoma cells will take this compound up while the normal cells will not. This is called ‘selectivity’. (i.e. the Neuroblastoma soaks this compound up selectively over normal cells).  mIBG in itself, however, doesn’t do anything. It is taken into the cell, and then is excreted from the cell at a later time.  This means that the Neuroblastoma cells are not sensitive to the compound. 

A clever and ingenious pupil of chemistry can already see what to do next.  Swapping out the Iodine atom on this compound with the radioactive version  makes this molecule very useful.


[123]-Iodine

123 Iodine will decay by electron capture to form 123 Tellurium which will then emit a Gamma ray with an energy of 159 keV. This is useful for imaging.  This is like having an x-ray performed, but rather than having an x-ray source shining high energy light through Liam, the light will be generated inside him!  Since this radioactive atom is attached to a compound which is only selective to Neuroblastoma, Gamma rays (like x-rays) will be generated only at the Neuroblastoma sites.  With the correct detector, the Neuroblastoma will light up like a Christmas tree.


[131]-Iodine

If 131 Iodine is used, different results will be observed.  131 Iodine decays in the follow two manners (statistically a 90% Beta(-) Decay and a 10% Gamma decay):

(Beta(-) Decay ~90%) {^{131}_{53}\mathrm{I}} \rightarrow \beta + \bar{\nu_e} + {^{131}_{54}\mathrm{Xe}^*}  + 606 keV 

(Gamma Decay ~10%) {^{131}_{54}\mathrm{Xe}^*}  \rightarrow {^{131}_{54}\mathrm{Xe}} + \gamma  + 364 keV

The Beta(-) decay produces a very energetic electron and an Antineutrino which have a tissue penetration of about 0.6 to 2 mm. This is enough energy to destroy cells. (i.e. a cell sized atomic bomb) So in essence, this gives a pathway for the mIBG, which is very selective to the Neuroblastoma, to blow up the cells (and leave the good cells alone).


This mIBG scan that was performed today only involved 123 Iodine for gamma ray imaging (see above images). This indicates all of the places that the Neuroblastoma is, with a few exceptions. There are false readings in some of the places like the thyroid (which regulates Iodine containing compounds).    In the coming weeks, it’ll be time to bring out the [131] Iodine and give this cancer the radioactive punch it deserves.

  1. According to NationWideChildrens.org “…Roughly 80-85% of neuroblastomas will absorb MIBG. There are really 2 ways in which MIBG treatment is used. In both methods, the MIBG chemical is attached to an iodine molecule that has been made radioactive. The radioactivity can be either a low-dose or a high-dose…. ”