What have HIV and hepatitis C treatments, Tamiflu and breast cancer treatment got to do with particle physics?

The main theme of this post is to say “science for the science’s sake” makes more sense than “art for the art’s sake,” a French slogan in 19^th century.  We cannot be always sure where the pursuit of science may lead us to.  Science is to seek ‘truth’, to understand the nature; thus pursuit of it can never go wrong.

The difficulty to convince you that pursuit of gravitational waves will benefit mankind     

Why do we have to concern ourselves with the gravitational waves (so-called “ripples in spacetime”) that were caused by the merger/collision of the two colossal black holes, leaving behind a single black hole some 50 times heavier than our sun.  This event happened about 3 billion light-year away and some 3 billion years ago.  For better perspective of how far away it is, it takes sun lights 8 minutes 20 seconds to reach us, traveling at speed of light.

This is almost like a science fiction.  Accordingly it would be difficult for me to argue that gravitational waves matter.  But, it does matter, otherwise its observation/detection won’t yield three Nobel Prizes in physics this year.

Why particle physics matters?  It gave us synchrotron.

I have lost track of how many particle physicists who have been decorated with Nobel Prizes in physics. What is the use to study subatomic particles? Atom has long been not indivisible; but to know atom is composed of leptons (electron, muon and tau, not interacting with strong nuclear force, thus staying outside the nucleus) and quarks (interacting with strong nuclear force, thus found inside the nucleus, such as proton and neutron). Let’s not forget the force-carrying particles, bosons, that produced the 2013 Nobel Prize in physics.

All the subatomic particles are discovered by using particle accelerators or so-called Super Collider.  Synchrotron is a device/technology that is evolved from super collider; it gives off light of such brilliance that it illuminates molecular structures or ‘sees’ the details of it.

Using x ray crystallography to learn the molecular structures is the road to Nobel glory

Using X-ray crystallography (think about it like a CT scan for molecules) to unravel the molecular structure has helped 40 some laureates (and 29 prizes) to get the Nobel Prizes.  Some of the works have been done with the help of synchrotron, complementing to x-ray crystallography.

Synchrotron is a better tool when the molecule of interest cannot be crystallized or has to be studied in the presence of liquid.  Simply put, the synchrotron is to accelerate electrons in a circular path (see photo below), not to crush them to find subatomic particles, but to let them emit the most brilliant light possible, and use the light to 'see' the details of the molecules, almost down to the atomic level.

Dr. Ramakrishnan showed four synchrotron centers in his Nobel Lecture

Ribosome structure: Synchrotron propels the advance of basic science research

V. Ramakrishnan, in his 2009 Nobel Lecture for unraveling the structure of ribosome, (upon which genetic codes of DNA was translated into amino acid sequence to make proteins) said “It was made possible by many technical developments, not least the development of synchrotron radiation sources. . .”

RNA polymerase II and transcription: Synchrotron made it possible for Roger Kornberg’s Nobel glory

Arthur and Roger Kornberg are one of the few father and son (William Henry Bragg and William Lawrence Bragg; Niels Bohr and Aage Bohr) or mother and daughter (Marie Curie and Irene Joliot-Curie) who’re Nobel laureates:  All in the family.

The elder Arthur Kornberg was so honored by his discovery/isolation of DNA polymerase, leading to our understanding of DNA synthesis (I read his memoir, For the Love of Enzymes, twice, about 20 years apart).  The younger Roger Kornberg followed the father’s footstep and figured out RNA polymerase II structure almost down to atomic resolution, using the synchrotron technology.  His research was mostly done at Stanford Synchrotron Radiation Laboratory, located at the Stanford Linear Accelerator Center and also at the synchrotron light source, located at the Lawrence Berkeley National Laboratory.  (This info is proudly presented at the Department of Energy (DOE) online page as both synchrotron facilities are funded by DOE.)

Roger Kornberg (then 12-year old) was in Stockholm in 1959 when his dad was awarded the Nobel Prize.  He is the boy sitting on the left in the family photo [see above] taken then and there.  I am so glad that Arthur Kornberg lived to see his son also to get the Nobel Prize in 2006; he passed away one year later.

father & son: Arthur and Roger Kornberg at the 2006 Nobel Prize press conference

Structure based drug design

Applied science, of which clinical medicine is one, reaps what the basic science research has sown.  The structure based drug design is made possible by using synchrotron technology; the examples abound, the resultant drugs have been in clinical use for nearly 20 years.

HIV and hepatitis C protease inhibitors

The success of using protease inhibitors in treating HIV was applied to hepatitis C treatments, resulting in an even more stunning success.  HIV and hepatitis C viruses replicate by growing a long protein chain that must be cut into smaller pieces to work.  Protease, like a scissor, does the cutting; so by blocking this cutting will prevent the replication of viruses.

The first HIV protease inhibitor (Invirase) hit the market in 1996.  Thankfully viral protease is different from human protease, blocking the viral protease will not block the human one.

Synchrotron technology is used to figure out the viral protease structure down to the atomic resolution, including the active site of this enzyme, so a blocker/inhibitor can be designed.

The story of Herceptin (trastuzumab), a breast cancer drug, making of which was helped by synchrotron

EGFR is a receptor that sits on cell surface, transmitting signals into the cell to make it grow and divide.  HER2 (or HER2/ErbB2 or HER2/neu) is a member of EGFR family.  Overexpression of HER2 (which means the number of receptors increases from normally 20,000 to up to 2 million on each cell surface) is found in 20–30% (some say 25-30%) of breast cancers, and correlates with more aggressive behavior and a poorer prognosis.  Dr. Dennis Slamon (the son of a WV coal miner, a W&J graduate) from UCLA made this important discovery.

This is why HER2 is targeted in making drugs to treat breast cancer.  Art Levinson and Axel Ullrich (from Genentech) successfully cloned HER2 gene, which makes HER2 receptor.  The process involved synchrotron technology.  One needs to know the structure before elucidation of its function.

Axel Ullrich made the first mouse antibody to HER2 receptor that didn’t work as it was rejected as a foreign invader, until it was “humanized” (fusion of a mouse antibody with a human antibody, chimeric) in 1992.  The clinical trial went on from 1992 to1998 when FDA approved it for breast cancer patients who are HER2-positive (overexpression).

Tamiflu: Synchrotron is used to design a drug against influenza virus

Influenza virus has an enzyme, neuraminidase, that cuts the sialic acid which is found in a glycoprotein of the surface of human cell, thus releases new virions.  Tamiflu blocks the cutting action of this enzyme, preventing new viral particles (virions) from being released.

Elucidation of neuraminidase structure was done with the help of synchrotrons.

Radiation therapy also uses accelerator-based technology

Certain radiation therapies for cancers are made possible by using accelerator-based technology.  I do not know enough to elaborate.

The project that led to the detection of gravitational waves was funded by the National Science Foundation that spent $1 billion over the fore decades.  It was managed by Dr. Barry Barish (one of the three Nobel laureates in physics this year) who was also the director of the Super Collider that would have been the world’s largest particle accelerator (proposed by President Reagan) until it was canceled by the Congress that got cold feet.  The best U.S. particles physicists flocked to CERN in Switzerland.

Like Churchill, the scientists would say, “Give us the tools, and we’ll finish the job.”