Medicinal Chemistry - Fusion of Traditional and Western Medicine

A new paradigm has emerged for drug development and patient care. It is a fusion of traditional and modern medicine, or systems and reductionist thinking. In the 21^st century, mathematics, the foundation of modern science, is being used to analyze biological networks to help discover and improve new drugs. In both traditional and modern medicine, it is important to know about the individual components of cells: DNA, RNA, proteins, lipids and carbohydrates, have therefore been described. DNA can code for proteins and different types of RNAs. The former dogmas that DNA codes for mRNA, which codes for proteins and one gene codes for one protein, are only partly right. This does occur, but also pieces of DNA from different chromosomes can be mixed and matched to make millions of different proteins. There are also epigenetic mechanisms and special types of RNA (such as miRNA) that can affect the ability of a gene to be transcribed. There are also mobile genetic elements that can also affect the phenotype. Sugars and carbohydrates can provide fuel and energy through glycolysis and the citric acid cycle, as well as bind to proteins, to affect their properties. Lipids make up the cell membrane and intracellular membranes of internal organelles. Lipids can interact with proteins and carbohydrates. Specific lipids can bind to important proteins, affecting their function. Polyunsaturated omega-3 fats are especially healthy and can help prevent inflammation and resolve its quick appearance.

Drugs are developed in distinct phases. Usually, the drug discovery and development process can be divided into these stages: select a disease, identify a target, find a lead compound, quantify drug-target interactions, determine solubility, pharmacokinetics and toxicity, improve the lead compound, find the best way to deliver the drug to the patient, manufacture the drug, apply to the FDA to do investigational studies, do the clinical studies, apply to the FDA for drug approval, and do post-registration studies. The solubility, pharmacokinetics and toxicity are determined in GLP studies. Similar compounds are tested in the lab and by computer modeling, so structure-activity relationships (SARs) can be developed. Eventually, a new chemical entity (NCE) or investigational new drug (IND) is selected for further evaluation. The optimum method for drug delivery is selected. A manufacturing process is developed and documented according to cGMP. Potential targets include membrane bound receptors (such as GPCRs, tyrosine kinases and intracellular nuclear receptors). Agonists bind to receptors and mimic the action of the endogenous ligand. Antagonists bind to receptors and block the binding and subsequent action of the endogenous ligand. Enzymes, DNA, protein transporters, ion channels and pumps are other potential targets.

Pharmacokinetics is the science of determining how much of the drug reaches the target organs and how much is eliminated at different times after giving different doses, sometimes in various dosage forms. Toxicokinetics is similar to pharmacokinetics, except the earlier one is concerned with toxins, while the latter with medicinal drugs. However, when the dose of a medicinal drug becomes too high, it becomes toxic. So, toxicokinetics is much like pharmacokinetics, but at a higher dose. Important parameters include C_max, the time it takes to reach maximum concentration, T_max, the area under the curve, AUC, bioavailability, clearance, volume of distribution and the half-life for clearance, t_1/2. Physiological based pharmacokinetic models (PBPK) involve a natural way of integrating the individual compound property to physiological properties, providing a rational approach to predict drug like behavior in vivo. Drug metabolism occurs mostly in the liver and intestine. Phase I metabolism adds functional groups (-OH,-SH,-NH₂,-COOH), while phase II involves biotransformation. Phase II enzymes add larger molecules and groups. Drugs can have multiple effects on the proteome, transcriptome, epigenome, metabolome and interactome of cells, tissues and organisms.

The first rule of toxicology is that the dose itself is the poison. That is, every substance is toxic if given at a high enough dose. Toxicity testing in animals (preferably rodents) is required for investigational new drugs. The EPA conducts toxicity tests on environmental chemicals through the National Institute of Environmental Health (NIEHS) and the Environmental Toxicology Program (ETP). They give very large doses of test chemicals to rodents to see if they might be harmful to the small portion of humans who are highly susceptible to the test chemical. GLP was formulated by the US Food and Drug Administration (FDA) to regulate non-clinical studies on the safety and possible toxicity of a new compound. The European Organization for Cooperation and Development (OECD) has its own GLP regulations that overlap with the FDA GLP. Every GLP study must have a study director, who writes a study protocol and is responsible for the design, conduct and reporting of the study. Many GLP studies also have principal investigators (PIs). In contract labs that work for the NIEHS, there is a single PI who has overall responsibility for the GLP studies. The PI has the authority to approve all study protocols or any amendments.

To improve the lead compound, chemists can design rational drug. They can systematically alter the structure of the lead compound to yield different compounds that are more effective and present fewer side effects. The structures of compounds drawn in silico can be docked to the target proteins and interaction energies calculated. Databases of biochemical and medicinal interactions can be evaluated using network theory to find new targets for therapy. Computer programs can be used to calculate molecular and quantum mechanical descriptors, which can be correlated to the measured properties in a quantitative structure-activity relationship, or QSAR. Other tools of rational drug design are to model molecular structures and their binding to potential targets, to perform combinatorial synthesis and high throughput screening for any of a number of biological effects. One can also look for the genetic cause of a disease and a way to deliver the correct gene into the patient in gene therapy.

Medicinal chemists try to find ways to induce drugs to the target cell and organ, and not to the rest of the body, and to activate the drug only at the target organ, to make it effective. This can be done with liposomes, synthetic polymers, dendrimers and nanotechnology. Liposomes prepared from polyethylene glycol (PEG) are used to deliver the anticancer agent doxorubicin. Another way to deliver drugs to their specific target is through antibody-drug conjugates and fusion proteins, in which one part (such as the antibody) binds specifically to the target and the other part is released and presents the desired therapeutic effect. An example of this is the drug called trastuzumab emtansine, commonly referred to as T-DM1. There are also recombinant immunotoxins, in which a fusion protein is made that contains a bacterial toxin and a fragment which targets the specific cancer cells being treated. An example is anti- Tac(Fv)-PE38 or LMB-2, which contains a toxin fragment of Pseudomonas endotoxin and a monoclonal antibody against the cell surface protein, CD25, in cancer cells. Radionuclides can also be conjugated to antibodies, such as ¹³¹I-tositumomab (Bexxar) and ⁹⁰Y-ibritumomab tiuxetan (Zevalin), which target the CD20 protein on cancer cells, for the treatment of non-Hodgkin’s lymphoma. Another example that is in development is targeted delivery of small inhibitory RNAs (siRNAs). Fusion proteins consisting of single-chain fragmented antibodies and positively charged peptides can deliver siRNAs into specific target cells.

If a drug formulation is proved to be safe and effective on animals, more must be developed for experimenting on humans. Before this can happen, an Investigational New Drug Application (IND) must be filed with the FDA. FDA has a set of quality controls for drug manufacturing, called current Good Manufacturing Practice, or cGMP. The FDA audits manufacturing organization and has the authority to issue FDA form 483 and a warning letter. Methods used to analyze new chemical entities include UV-Vis and fluorescence spectrophotometry, HPLC and UPLC, ion chromatography, gas chromatography (GC), mass spectrometry (MS), GC-MS, LC-MS, IR and NMR. UV-Vis spectrophotometry measures the absorbance of UV and/or visible light. The wavelengths absorbed depend on the type of compound being analyzed and the amount of absorbance is depends on the amount present in the sample. Fluorescence spectrophotometry measures the emission of light that occurs at a longer wavelength than the light that is used for excitation. Ion chromatography separates and detects ions. Gas chromatography separates molecules in the gas phase and detects them using any of a number of detectors, including MS. Infrared (IR) spectroscopy measures the absorbance of IR light, which provides information about the compound being analyzed. NMR measures the absorbance of radio frequency electromagnetic radiation when organic compounds are placed in a strong magnetic field. It can tell the analyst the number of hydrogen and carbon atoms present in the sample, along with the hydrogens and carbons to which they are bound.

New drugs are investigated in the following steps: pre-clinical, phase I, phase IIa, phase IIb, phase IIIa, phase IIIb, launch new FDA-approved drug and phase IV, post market surveillance.

The pre-clinical phase is used to prove the scientific principle behind the drug, perform 28 day toxicity studies in two species, identify a suitable formulation, prepare sufficient material, perform an Institutional Board review, prepare protocols and documents for Phase I. Phase I measures the absorption, distribution, metabolism and excretion (ADME) safety and tolerability in healthy human subjects, except in emergencies, such as treating terminally ill cancer patients for whom all standard therapies have been tried already. Phases IIa tests the efficacy of the IND and its ADME in patients and IIb establishes the dosage and regimen for Phase III. Phase III is the large scale clinical trial that determines the efficacy and find out side effects. After getting FDA approval and launching the new drug, the market must be monitored so that all side effects and complaints are saved and studied. Also, additional applications for the drug might emerge as it is used on patients with more than one condition that needs to be treated.

There are many important drugs that inhibit enzymes. They include drugs to prevent heart attacks, pain relievers, antibiotics to cure bacterial infections, chemotherapeutic drugs to help cure cancer, anti-malarial drugs, sleeping pills, medicines for high blood pressure, and drugs to treat diabetes, asthma, HIV, seasonal flu, fungus infections, parasitic worm infections and osteoporosis. Enzymes that are inhibited by FDAapproved drugs include acetylcholine esterase, AChE; cyclooxygenase; enzymes that catalyze a key reaction in the synthesis of bacterial cell walls; the protein-RNA complex of the 30S subunit of the bacterial ribosome; bacterial DNA-gyrase; topoisomerase; bacterial tetrahydrofolate reductase; a reductase that catalyzes the synthesis of mycolic acids in Mycobacterium tuberculosis; angiotensin-converting enzyme, or ACE; renin; type 5 phosphodiesterase (PDE-5); farnesyl pyrophosphate synthase; inosine-5’-monophosphate dehydrogenase (IMPDH); calcineurin; HIV reverse transcriptase; fungal enzymes; pyruvate-ferridoxin oxidoreductase; aromatase; topoisomerase; BCR-ABL tyrosine kinase; the proteasome,; histone deacetylase,; thymidylate synthase; viral neuraminidase, viral thymidine kinase; L-amino acid decarboxylase; xanthine oxidase; and dipeptidyl peptidase- 4 (DPP-4). Drugs are being developed that bind to allosteric sites on enzymes, partially inhibiting them and causing fewer side effects than drugs already developed that target active sites.

There are many important drugs that bind receptors. Morphine, codeine, heroin and fentanyl bind to opioid receptors. Barbituates, zolpidem and diazepam bind to GABA_A receptors. Varenicline binds to nicotinic acetylcholine receptors; Tiotropium bromide binds to the M₃ muscarinic acetylcholine receptor. Tamsulin binds α1aadrenergic receptors in the prostate; bronchodilators bind to β₂-adrenergic receptors. Ramelteon binds to the melatonin receptor and lets the patient sleep. Memantine binds to the NMDA subset of glutamate receptors. Montelukast sodium is a synthetic antagonist of a cysteinyl leukotriene receptor. Loratadine blocks the binding of histamine to its receptor. Prostaglandin analogs, such as latanoprost decrease intraocular pressure by binding to prostaglandin receptors. Ranitidine binds to the histamine H₂ receptor. Glipizide binds to K⁺ ion channels in the β cells of the pancreas. Pioglitazone is an agonist of the peroxisome proliferator-activated receptor-γ, or PPARγ. Atenolol binds competitively to the β-adrenergic receptor and blocks the binding of the natural ligands, adrenaline and noradrenaline. Calcium ion channel blockers like Amlodipine decrease contractions of the heart and dilate the arteries, lowering blood pressure. Clopidogrel bisulfate prevents the formation of blood clots by inhibiting the binding of ADP to its platelet receptor. Estrogens and progestins bind to estrogen receptors and progesterone binds to its receptor. Oxytocin binds to G-protein coupled receptors (GPCRs). Calcitriol binds to the Vitmin D receptor. Raloxifene is a selective estrogen receptor modulator. FY720 binds to the sphingosine-1-phosphate receptor. Vaccine adjuvants bind to toll-like receptors. UK-427857 (Maraviroc^TM) binds to the CCR5 receptor, preventing the binding of HIV.

Another important class of proteins that make good targets for drugs is the class that contains transporters, carriers and ion pumps. There are several drugs that affect ion pumps, carriers and transporters. Ezetimibe (ZetiaTM) inhibits the absorption of dietary cholesterol in the small intestines. Stomach acid is produced by one type of H⁺/K⁺ ATPase. The drugs called Omeprazole (PrilosecTM) and Prevacid inactivate it. Atovaquone and Proguanil act by inhibiting electron transport. Ion pumps are also important in multidrug resistant (MDR) bacteria and cancer cells. Ivermectin (StromectolTM) is a broad spectrum antiparasitic agent that acts by opening glutamategated chloride channels in invertebrates. MDR in cancer involves simultaneous resistance to several different, unrelated anticancer drugs. An efflux protein, P glycoprotein, or PgP, pumps out anticancer drugs. There are several other drugs, called MDR converters that inhibit the action of PgP.

Microtubules are also possible targets for therapy. They participate in many cellular processes, including transport and cell division. There are two classes of microtubule drugs, microtubule inhibitors (vincristine and vinblastine, which are alkaloids from the Madagascar periwinkle, also known as the Catharanthus roseus, and once known as Vinca rosa), approved by the FDA in 1963 and 1965, and stabilizers Taxol (Paclitaxel) and Taxotere (Docatexel) approved in 1992, and 1996, respectively. Also, there are two semi-synthetic derivatives of vincristine, called vindesine and vinorelbine, which are also microtubule inhibitors. Another class of microtubule-acting anticancer drugs contains the epothilones. Epothilones A and B are naturally occurring 16-membered macrolides, which are produced by the myxobacterium Myxococcus xanthus or Sorangium cellulosum. Another natural product that acts on tubulin is called eribulin. It was isolated from the Pacific sponge and it inhibits the polymerization of tubulin. The root bark of the Combretum caffrum tree is the source of combretastatin, which another natural inhibitor of tubulin polymerization. Another drug that binds to microtubules is called Maytansine. It disrupts microtubule assembly.

Some drugs target DNA. One of the most important is called either adriamycin or doxorubicin. Mitomycin is activated in liver cells and adds an alkyl group to bases, causing DNA to cross-link, which kills the cancer cells. Another alkylating agent is Ifosfamide, which is used to treat testicular cancer, breast cancer, lymphoma, cervical cancer, bone cancer, soft tissue sarcoma, osteogenic sarcoma, and ovarian cancer. Carboplatin (Paraplatin^TM) is a chemotherapeutic agent for treating cancer. Bleomycin (Blenoxane^TM) is a member of a family of glycopeptide antibiotics produced by Streptomyces verticillus. It damages deoxyribose in DNA, causing the strand to break. It is used to treat testicular cancer, along with head and neck cancer. There are also antimetabolites and nucleosides that are FDA-approved anti-cancer agents. They include 5- azacytidine, 5-fluorouracil, 6-mercaptopurine, allopurinol, calcium leucovorin, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, pentostatin and thioguanine Vitravene is an antisense drug that binds to mRNA that is produced by a gene coded by the cytomegalovirus (CMV), which causes CMV retinitis.

Personalized medicine is designed for the specific genetic, epigenetics and environmental properties of the individual and their diseased cells. Eventually, new technologies will enable people to take a drop of blood from their fingertips, analyze it at home and send it to a central computer. The data will be analyzed and compared to the individual’s genome and epigenome. It may also be able to predict whether a patient will respond well to a medicine. People with different genotypes and phenotypes can metabolize drugs differently. The HIV viral genome is always changing, and resistance testing can help doctors choose the drug that will best match the virus and suppress it. The development of new biomarkers through advanced genomic, proteomic, metabolomic and imaging technologies has a very high priority because they can improve diagnosis, and define disease subsets. Clinical trials are being modernized by automating the trials and managing the data. Instead of just making the medicine specific for the DNA that a person is born with, it can also be made specific for a type of cancer. This is being done by developing monoclonal antibodies, which will bind to receptors that are specific for a particular type of cancer. Some of them are even parts of FDA-approved medications. Most can’t kill cells by themselves, but they can still bind to cancer-specific antigens and deliver drugs that are covalently attached to the monoclonal antibody. Thus, there is much research required to bind drugs to monoclonal antibodies, so that the drug only reaches the target organ.

Cancer is the rapid, unregulated and pathological growth (proliferation) of abnormal cells. Even when cancers occur in the same part of the body, they can be very different diseases. When tumors become malignant, their threat depends on their ability to modify surrounding cells to form new blood vessels (angiogenesis) and other supporting cells. The typical American diet that leads to obesity can make people more susceptible to cancer. The human papilloma virus, hepatitis B and T cell leukemia virus type 1 can cause cancer of the cervix, liver and leukocytes (leukemia). Tyrosine kinases regulate many cellular processes which can contribute to cancer development and progression. KRAS is the oncoprotein that is most commonly activated in human cancer. RAS is one of the most commonly mutated genes in human cancers. Oncogenes code for oncoproteins, which are upregulated in cancer. Another important oncogene is PI3K, which codes for the enzyme PI3K (phosphoinositide 3-kinase). The enzyme PTEN (phosphatase and tensin homolog) catalyzes the opposite reaction, so it is a tumor suppressor and the gene coding for it is downregulated in cancer. Human epidermal growth factor (hEGF, or HER), vascular endothelial growth factor, or VEGF, and the PI3K/AKT/mTOR (mammalian target of rapamycin) survival pathway are all important therapeutic target in many cancers. Cancer stem cells could be good targets for new drugs that will prevent the recurrence and metastasis of tumors. Also, induced pluripotent stem cells could be used to screen drugs to see if they will be effective in treating each individual patient.

Heart disease is the biggest killer in the world. Its major cause is obesity or metabolic syndrome, which can also lead to diabetes and stroke-the third leading killer (after cancer) and the most frequent cause of disability in the world. All of these involve imbalances in energy metabolism. Early symptoms of metabolic syndrome include excessive weight, high blood pressure, elevated blood glucose and elevated levels of lipids, especially low density lipoprotein (LDL). People who have two or more of these symptoms are at a higher risk of developing heart disease, stroke and type 2 diabetes. Childhood obesity is such a big problem that it will probably mean that this generation will be the first to have a shorter life expectancy than their parents. Ischemic strokes need to be treated as soon as possible, so it is very important to take a stroke victim to a hospital as soon as possible, so the blockage can be removed and blood flow can be continued properly. Drugs such as aspirin, clopidrogel and dipyridamole can be given to prevent more clots from forming by preventing blood platelets from aggregating. If the patient can get to a hospital soon enough, tPA, or tissue plasminogen activator, can be given. When blood flow to the heart is interrupted, it causes a myocardial infarction, or heart attack. The most common cause is a blockage in the coronary artery that is usually caused by the rupture of an atherosclerotic plaque.

Infectious diseases can be caused by worms, protozoa, fungi, bacteria, viruses and even proteins (prions). Organisms, viruses and prions can be classified by their infectivity, or their ability to enter, survive and multiply in a host. There are seven classes of viruses, based on their DNA or RNA. By number, 90% of the cells in the human body are bacteria. Even though our lives depend on symbiotic bacteria, it is important that they stay in their proper places in our human bodies, or ecosystems. By the mid-1980s strains of S. aureus emerged that were resistant to common antibiotics. The most common bacterial disease is tuberculosis, caused by the Gram positive bacterium called Mycobacterium tuberculosis. Fungi, protozoa and multicellular organisms are eukaryotes and some of them are pathogenic. Multicellular parasites include four species of Schistosoma, a flatworm which causes schistosomiasis, which is second in importance only to malaria, with hundreds of millions infected worldwide. In addition to schistosomiasis, helminths can cause ascariasis, dracunculiasis, elephantiasis, hookworm, lymphatic filiaruasis, onchocersiasis, and trichuriasis.

Inflammation can be a cause or a symptom of many diseases. When controlled, it is also an important part of maintaining good health. Reactive oxygen substances (ROS) are produced as part of normal, healthy aerobic metabolism, such as electron transport in the mitochondria of cells. Many foods, spices, herbs and dietary supplements contain antioxidants that can destroy ROS and prevent diseases, including arthritis, cancer, heart disease, stroke and brain diseases. Some important dietary antioxidants include vitamins A and E, oleic acid, polyunsaturated fats, omega-3 fats, resveratrol and polyphenols. Inflammation is a significant factor in many diseases, including arthritis, cancer, diabetes, heart disease, stroke, Alzheimer’s disease, hormonal diseases, osteoporosis, inflammatory bowel disease, pelvic inflammatory disease, and many others. Smoldering inflammation is a relatively low level of inflammation that occurs in diseases such as obesity, type-2 diabetes, asthma, and atherosclerosis. In many cases, these diseases of inflammation can be prevented by avoiding obesity, trans fats and saturated fats that are in the typical fast food diet consume by many people in the USA. Instead, unsaturated fats are much better. Omega- 3 fats can be taken as dietary supplements such as fish oil and flaxseed oil. They are also present in fatty fish, such as salmon. Omega-3 fats are also very important in the brain, where they play an important role in cognitive function and behavior. Inflammation plays an important role in all stages of atherosclerosis and cardiovascular disease. Inflammation is also an important factor in stroke.

The fertility cycle in women is controlled by a cascade of events, which are initiated by protein and steroid hormones. These hormones create signals between the hypothalamus, the pituitary gland and the ovaries. Oral contraceptives contain an estrogenlike drug, ethinyl estradiol. It is combined with any of a number of progestin derivatives. Progestin-only pills are available for women who are breast feeding and those who are unable to tolerate estrogens. There is also an emergency contraceptive to prevent pregnancy after unprotected intercourse, called Plan B. One form consists of two pills, each containing 0.75 mg of levonorgestrel. Mifepristone is a synthetic steroid that is used for the termination of pregnancy up to the 49^th day of gestation. It has been tested as a morning after pill to prevent pregnancy when taken within 12 hours of unprotected intercourse. It is also used in combination with another drug called Gameprost to terminate pregnancies between weeks 13 and 24. In the USA, levonorgestrel is the preferred emergency contraceptive. It can prevent a pregnancy up to 72 hrs after unprotected sex or contraceptive failure. Oxytocin and prostaglandin E₂ are also available to induce labor by stimulating uterine contractions. Some women take hormone replacement therapy, in which a low dose of one or more estrogens (conjugated equine estrogens) and a progestin are given. Another approach is to increase the consumption of soybeans and foods made from soybeans (such as soy milk).

The first year of life is critical in brain development, for the total brain volume doubles, as measured by MRI. This is when the brain is most susceptible to damage by genetic defects and environmental insults. It is also the time in which therapeutic intervention can have its maximum effect. A principal component of the nervous system is the neuron. Neurons are arranged in networks and circuits. The normal human brain has many local regions, or centers, and many pathways between them. The autonomic nervous system is organized into three divisions: the sympathetic, parasympathetic and enteric. Their maintenance activities are primarily performed without conscious control or sensation. The sympathetic and parasympathetic nervous systems work to maintain a type of balance. They have opposite effects on the body. The sympathetic division is used in actions requiring quick responses. The parasympathetic division is used in actions that do not require immediate reaction. Messages are sent to and from neurons in the form of primary messengers, called neurotransmitters. L-DOPA is used to treat Parkinson’s disease, which affects about 1% of the population over 65. Alzheimer’s disease (AD) is the most common neurodegenerative disease. Phenobarbital, carbamazepine, valproic acid and its sodium salt, gabapentin, ethosuximide, lamotigrine, and tiagabine are anti-epileptics. Diazepam, buspirone, β-blockers, tricyclic antidepressants and monoamine oxidase inhibitors treat anxiety disorders. Currently the first-line treatment is either SSRIs or SNRIs. The four main classes of antidepressant drugs are MAOIs, TCAs, SSRIs and SNRIs.

The immune system recognizes and defends us against internal threats caused by invading organisms and pathogens. The innate immune system recognizes bacteria, fungi and other organisms, breaks them down, identifies a characteristic protein on them (an antigen) and attaches it to the surface of specific cells, which present it to the adaptive immune system for destruction. The adaptive or acquired immune system acts once then it is stimulated by the innate system. The adaptive immune response is initiated by specific interactions between antigen loaded, mature dendritic cells and naïve CD4⁺ T cells in the lymph nodes. The five families of immune cells are: phagocytes, granulocytes, natural killer (NK) cells, lymphocytic T-cells and lymphocytic B-cells. The four major classes of immune system mediators are chemotactic agents, cytokines, C-reactive protein and antibodies. A fifth class of immune network mediators comprises the small molecules, including neurotransmitters, such as L-DOPA and catecholamines. Risk factors for autoimmune diseases include exposure to man-made chemicals. Benlysta (belimumab) is approved for treating lupus erythematosus. AIDS is caused by the retrovirus HIV. Currently, a mixture, or cocktail of antiretroviral drugs is given in what is often called highly active antiretroviral therapy, or HAART. Microbes in the intestines and lungs (acquired from the environment) keep rare invariant natural killer immune cells from triggering autoimmune diseases.

An extremely important part of disease prevention is vaccination, which improves the immune response to a particular disease. Vaccines save lives and prevent deadly diseases that used to take millions of lives, especially the ones of infants. Vaccines can be made from dead or inactive organisms or viruses. Vaccines can also contain “live” attenuated viruses. The tetanus and diphtheria vaccines contain inactivated toxic compounds. Children should be vaccinated against hepatitis B, hepatitis A, diphtheria, tetanus, pertussis, polio, Pneumococcus, measles, mumps, rubella, rotavirus, human papilloma virus (HPV), Meningococcus, Orthomyxoviridae (flu virus) and varicella (chicken pox).

The five major food groups include cereals, vegetables, fruits, dairy, meat (and meat substitutes), and fats, oils and sweets. A lack of folic acid causes birth defects, such as spina bifida, which leaves the victim severely disabled. Folic acid is also found in multi-vitamin supplements, which are recommended for pregnant women. It is better to eat many types of fish, than to eat red meat. If at all possible, mother’s should be encouraged to breast feed their babies. The best-selling, most interesting and controversial dietary supplements are multi-vitamins. The American Medical Association (AMA) does not recommend them. Instead, the AMA recommends getting your vitamins and minerals from a healthy, balanced diet. The National Institutes of Health maintains several pages on their website that have fact sheets on many dietary supplements. The NIH has an office of dietary supplements. It provides information on the use and safety, nutrient requirements, database resources, news and research. However, it is the FDA that has regulatory responsibility for dietary supplements, as dictated by the dietary supplement health and education act, or DSHEA, passed in 1994. The DSHEA indicated that the dietary supplement manufacturer is responsible for ensuring the safety of a dietary supplement before its marketing, but the FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market. The popular dietary supplement, açaí, will make you gain weight – not lose weight. Another supplement, myo-inositol, may prevent lung cancer in smokers.

Many new phenomena emerge at higher levels of organization. One possible emerging problem is the likelihood that the virus that causes the flu in birds or pigs will mutate to a form that can easily infect and kill people. As global warming continues, several tropical diseases could appear in colder regions. Global climate change is projected to significantly increase the range conducive to the transmission of both dengue and yellow fevers. Another possible problem is the re-emergence of the poliovirus or smallpox virus, even though these diseases have almost been eradicated. Scientists are creating new, genetically altered life forms, to what some consider an emergent solution, while others consider this genetic engineering to be a terrible problem. It is also known as genetic modification (GM), biotechnology, gene splicing and recombinant DNA technology. Nanotechnology has the potential to turn relatively inactive molecules into potent drugs. Another technology that could provide many medical benefits is stem cell technology. Another emergent problem is a shortage of certain medicines. This can happen if a major producer has problems in manufacturing and has to stop for a while, or if there is not enough profit to be made. As a result, patients are experiencing unacceptable delays in receiving 210 different medicines for cancer, Parkinson’s disease, schizophrenia, osteoporosis and organ failure.

The most common second messenger is Ca²⁺, which is stored in the type of endoplasmic reticulum (ER). Some of the other important second messengers include IP₃ and diacyl glycerol (produced by the hydrolysis of phosphoinositides), arachidonic acid (produced by the hydrolysis of phospholipids that have arachidonoyl on carbon number 2 of the glycerol backbone), ceramide, eicosanoids, lysophosphatidic acid, NO (nitric oxide), cAMP and cGMP. The most common type of receptor is the G proteincoupled receptor (GPCR). Protein kinases can catalyze the addition of a phosphate to another protein or even to themselves and affect signal transduction. Another class of G proteins is called the small GTPases. Nuclear receptors (NRs) play key roles in growth, development and homeostasis. Lipohilic natural hormones diffuse past the cell membrane and bind to receptors located in either the cytosol (type I NR) or the nucleus (type II NR). The IP₃ receptor, or IP3R is a membrane-bound complex of glycoproteins. It is a Ca²⁺ channel that is activated by IP₃, which is a secondary intra-cellular messenger. Inter-and intracellular communication can be considered as a network that contains many items (nodes) that have about one to thousands of connections. The most widely connected nodes are called hubs. Probably, the major genetic hub in human and many other mammalian cells is the gene TP53 which codes for the protein p53. About 50% of all human cancers have one or more mutations in p53 that alter DNA transcription.

In systems biology, the basic, fundamental unit is the cell, not the atoms and molecules in the cell. Many new properties emerge when atoms, molecules and ions are organized in a living cell.

The functions of a cell do not depend on just the properties of the individual molecules, but also their interaction. Autopoiesis means self-production. It is a network of production processes, in which the function of each component is to participate in the production or transformation of itself and also the other components in the network. The production processes are circular. Life is a cyclic process that produces the components of a living system.

Based on the autopoietic theory of life, the biosphere of Earth is often considered as a living system. Bacteria can be taken as the catalysts that maintain the atmosphere in its present state, far from equilibrium, but stable, like homeostasis in a cell, organ or organism. Networks permeate living systems. Living systems and the internet are examples of a type of network called a scale-free network. These networks are dominated by a few well-connected nodes, called hubs. Most nodes in the network have a few connections, but a small number of nodes has a seemingly unlimited number of connections. In the scale-free network that is in living cells, there are many levels of organization. Each of them can be viewed as a network. There is a network of genes, a metabolic network, a regulatory network and a cellular network.