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Click to edit Master title style THINK.CHANGE.DO Trace elements: As precious as gold for your health Dominic Hare and Blaine Roberts UTS Science in Focus Public Lecture 22 August 2012

First of all, thanks to… UTS: Centre for Forensic Science

Atoms: Building blocks of the Universe • The atoms that make up your body, your house, your brand new car are as old as the universe itself – 14 or so billion years, give or take a few leap years • How atoms interact with each other determines how matter changes • Consider then, that the atoms in your body have experienced an eternity of life experiences, sights, smells, sounds, loves, despairs stretching all the way back to the birth of the cosmos. UTS: Centre for Forensic Science

UTS: Centre for Forensic Science

Chemical properties of atoms • The number of protons determines which element the atom represents – Hydrogen has 1, helium has 2, lithium has 3… • The number of neutrons determines which isotope of the element it represents – Isotopes have the same properties, but have a slightly different mass • The number of electrons orbiting the nucleus determines how the atom will react UTS: Centre for Forensic Science

Electrons and chemical reactions • How electrons interact with other atoms determines what state an atom exists in, and how they react UTS: Centre for Forensic Science

What makes you, you UTS: Centre for Forensic Science

What about the rest? • 0.1% sulfur, potassium, sodium and chlorine • 0.006% iron, or 4.2 grams, equivalent to everyone here relative to Sydney’s population • 0.0001% copper, or 0.072 grams, equivalent to a single grain of rice in 5 buckets of water • 0.000016% iodine, or 0.02 grams, equivalent to one minute every 6 years • 0.0000021% cobalt, or 0.000003 grams, equivalent to one drop of water in an Olympic-sized swimming pool UTS: Centre for Forensic Science

So, how can we possibly measure something that small? UTS: Centre for Forensic Science

Flame tests Potassium Sodium Copper UTS: Centre for Forensic Science

Atomic emission • As the sample heats in the flame, it gets broken down into it’s constituents • Electrons moving around the nucleus take in some of the energy from the flame and jump up to a higher orbital • When these electrons lose energy, they drop back down to their original orbital, emitting light as they go UTS: Centre for Forensic Science

Atomic emission spectra Hydrogen Iron Mercury UTS: Centre for Forensic Science

Emission is great, but… • It often lacks the sensitivity to measure truly trace amounts of something • How can we measure atoms directly? UTS: Centre for Forensic Science

On a lighter note… • Everything weighs something (or, at least officially since July 4, 2012) • Each and every proton and neutron (and even electron) contributes to an element’s mass • If phosphorus has 15 protons… • …and sulfur has 16 protons… • …an atom of sulfur must weigh more than an atom of phosphorus! UTS: Centre for Forensic Science

The ICP: A super-charged Bunsen burner UTS: Centre for Forensic Science

The evolution of the ICP-MS Inductively coupled plasma-mass spectrometers circa 1980s UTS: Centre for Forensic Science

You were talking about the body…? • An ICP-MS gives us a technique that is sensitive enough to be able to measure those minute differences in trace elements in the body • Cutting-edge ICP-MS is capable of detecting down to parts-per-quadrillion, or one centimetre in 50 round trips to the Sun UTS: Centre for Forensic Science

Laser ablation UTS: Centre for Forensic Science

LA-ICP-MS Imaging UTS: Centre for Forensic Science

Imaging Process UTS: Centre for Forensic Science

Imaging Process Ion ICP Detector lenses Mass Ion Spec Cones Data Processing UTS: Centre for Forensic Science

LA-ICP-MS imaging • Each image gives us quantitative spatial information about trace elements, without the need for excision Iron 1mm UTS: Centre for Forensic Science

LA-ICP-MS imaging • We can look at how diseases change trace elements at the micro-meter scale, in situ. Iron 1mm UTS: Centre for Forensic Science

Reconstructing iron in the mouse brain UTS: Centre for Forensic Science

Three-dimensional imaging UTS: Centre for Forensic Science

Where are we going now? UTS: Centre for Forensic Science

Trace elements: As precious as gold for your health Dominic Hare and Blaine Roberts UTS Science in Focus Public Lecture 22 August 2012

Periodic Table

Abundance in the Universe

What are the Biological Elements of Life? Lipids Protein Carbohydrates DNA

Central Dogma of Biology Lipids = membranes Carbohydrates = energy Proteins = function

Proteins equal Function “ Pretty much anything a cell does, a protein does it. ” – P. Andrew Karplus 3D crystal structure of antioxidant enzyme Cu, Zn Superoxide Dismutase

Human Genome -23 chromosomes ~ 22,000 genes -30-50% of proteins use metal to function Examples; Hemoglobin(Fe), Ferritin (Fe), Matrix metalloprotease (Zn), Xanthine Oxidase (Mo) ….etc.

Vitamin and mineral Supplements *Daily value not established We know that many minerals are essential but don ’ t know how much, why in most cases.

Diseases caused by mineral Deficiency Hemochromotosis Anemia (Fe, Cu) Acrodermatitis enteropahtica (Zn) Menke ’ s disease Wilson ’ s disease (Fe) (Cu)

Malnutrition Zinc deficiency one of the most common deficiencies in the world Over 2 Billion people are estimated to be deficient in zinc. -Decreased wound healing -Impaired immune function -Impaired growth and neurological development -Aggressive behavior

Alzheimer’s disease Alois Alzheimer Auguste Deter • Although named after Alois the disease was describe previously by Fischer, Bonfiglio, Perusini. • Accounts for 50-80% of dementia. • Average patient lives 8 years but can be up to 20 years. • Projected cost of $20 Trillion dollars over the next 40 years.

Alzheimer’s Pathology • Pathology begins 10-15 years before disease symptoms arise (Braak 1996) • Disease pathology begins in the neocortex and and progressively spreads through the cortex. • Massive neuronal loss >50%. Amyloid Plaques Fe, Cu, K, and Rb are altered in AD Brain.

Amyotrophic Lateral Sclerosis

Zinc-deficient SOD hypothesis for ALS • Zinc deficient SOD hypothesis – Without zinc, copper is reduced ~3000x faster than Cu,Zn-SOD (Estevez, AG et al.) – Many SOD mutants have a reduced affinity for zinc (Crow, JP et al.) e - Ascorbate Cu +1 Cu +1 O=O • - + NO • O=O Cu +2 Cu +2 ONOO - Purified SOD Apoptosis Zinc- Cu,Zn deficient Estevez, A. G., Crow, J. P., Sampson, J. B., Reiter, C., Zhuang, Y., Richardson, G. J., Tarpey, M. M., Barbeito, L. & Beckman, J. S. (1999). Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science 286, 2498-500. Crow, J. P., Sampson, J. B., Zhuang, Y., Thompson, J. A. & Beckman, J. S. (1997). Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite. J Neurochem 69, 1936-44.

Measuring Global Metalloprotein Changes with Liquid Chromatography-ICPMS Agilent HPLC 1200 Agilent 7700 ICP-MS Output Size exclusion column (Agilent BioSEC 4.6x300mm) Vt Vo Decreasing MW

Measure Protein Metal Status Directly Metalloproteomics = measure of metal bound to protein Cu,Zn- Thyroglobulin, SOD, 660kDa 32kDa Vit B12 Ferritin , 440kD Conalbumi a n, 75kDa Catalas V e, t 256kDa Thyroglobuli n aggregate

Application of Metalloproteomics

Each island is a different Zn-Protein The Zn metalloproteome

Micronutrient Information Center For more information on minerals and vitamins in health and disease please visit the Linus Pauling Institute Micronutrient Information Center. (http://lpi.oregonstate.edu/)

Summary -Proteins are important for cellular function -Metals are important for protein function -Deficiencies in minerals can manifest in many ways -Little is know about the role of minerals in disease -Metalloproteins play pivotal roles in normal cellular function and in disease pathologies.