As discussed in previous articles on dietary guidelines and reversing aging, science is a process of continuous improvement1,2. As scientists learn more about nutrition, they change their recommendations about diet. Unfortunately, some people take this to mean that we are just guessing or that we don’t know what we are doing. In contrast, most professional scientists realize that science almost never comes up with a final answer. All we can do is develop ideas (hypotheses) that can be tested. The hypotheses can be modified based on the test results and then tested further. In the process, we usually discover things we never even imagined. This causes us to ask more questions, formulate new hypotheses and gain a new level of understanding. This is not just a mind game being played to amuse us. This process can have life and death consequences. Previous advice on nutrition (eat very little fat) turned out to be wrong or at least oversimplified (consume more omega-3 fats and fewer saturated fats). So, the discerning, thoughtful reader will realize that even the most up-to-date guidance can be misleading. Thoughtful people will continue to read scientific articles on diet and nutrition, so they can make the most intelligent choices possible.

As we learn more about aging, we try to find better ways to live longer and healthier. This month I am giving another example of how pharmaceutical science also continues to improve. There was a time when new prescription drugs were developed based on their ability to make an observable positive change, such as providing immunity to a disease. For example, Edward Jenner observed that milkmaids who had previously had cowpox did not catch smallpox later. Even though he did not know that the human immune system exists, he introduced the first successful vaccine. Similarly, many traditional medicines were developed based on similar observations and an oral tradition of teaching. However, many of the traditional medicines did not work when tested with modern, rigorous scientific methods. Many traditional remedies have been shown to be unsafe and ineffective. This led many scientists to believe that it was more important to find the single root cause of a disease and target it. The single root cause (such as a defective protein) became the therapeutic target.

So, pharmaceutical scientists started trying to discover what happens when an illness emerges. For example, several genes that code for specific proteins can be mutated and then cause cancer. These are called oncogenes and oncoproteins. Scientists have used the best technologies and methods available to identify proteins that cancer cells need to stay alive, to grow and to spread throughout the body. Clinical trials have begun on some of the more promising new chemical entities (NCEs) that target these proteins. However, a recent study used the new technology called CRISPR to show that these proteins are not required for cancer cells to live after all3. Still, if the drugs prove to be safe and effective in curing cancer with no adverse side effects, does it really matter if we don’t know exactly how they work? So, the goals of this article are:

1) to give examples of drugs that were approved by the US Food and Drug Administration (FDA) and other governments’ organizations without knowing how they work
2) to give examples of drugs that were approved for treating one disease, but later found to be effective in treating other diseases
3) to describe the recent study that used CRISPR to show that some anticancer drugs currently being tested were designed using false therapeutic targets3.

This application3 shows how the gene editing technology called CRISPR is being used to develop new prescription drugs. In a previous article in the Wall Street International magazine, I described briefly what CRISPR is and how it is being used to develop new foods4. It has also ben used to change a gene in viable human embryos, resulting in live births, despite being illegal and unethical5,6.

Drugs that were approved without knowing how they work

One of the best examples is the over the counter drug – aspirin. It had been used safely and effectively for over 100 years before its mechanism of action was determined. Similarly, metformin was developed based on its similarity to a natural product, galegine (Galega officinalis) that had been used in herbal medicine in medieval Europe7. It “was not designed to target a particular pathway or disease mechanism. It was established as a safe and effective therapy before detailed mechanistic studies became possible” 7. Thalidomide is another striking example. It was originally approved by several government agencies (but not the FDA) to treat morning sickness before laws required that NCEs be tested for teratology (birth defects) before being approved. Unfortunately, it caused severe birth defects and was removed from the market in the United Kingdom in 1961. However, after much more research, thalidomide was approved by the US FDA to treat leprosy and multiple myeloma (cancer of plasma cells in the bone marrow). This happened only after the FDA and other governments’ organizations had established protocols for testing the possible toxicities of NCEs before they could be considered for approval. Now that such protocols and laws exist, NCEs can be tested for their ability to affect the phenotype rather than a specific mechanism of action. So, screening NCEs for their ability to kill a pathogen (virus, bacteria, intestinal worms, etc) or cancer cells or heal diseases (the phenotype) as opposed to their effects on any specific gene (genotype) is still quite effective in developing safe prescription drugs. Still, whenever possible, pharmaceutical scientists do try to find a mechanism of action for many drugs, including anticancer drugs.

Approved drugs found to be useful in treating other diseases

Some drugs that were approved by the FDA and other governments’ regulatory agencies for treating one disease have been shown to be safe and effective in treating other diseases. Two excellent examples are statins8,9 and metformin10-12. Statins were developed based on their ability to lower cholesterol13. At the time, it was thought that the human circulatory system was like indoor plumbing. If blood flow became blocked with too much cholesterol, it would cause high blood pressure, cardiovascular diseases and stroke. Further studies have shown that statins also lower the concentration of triglycerides in the blood. They can also help prevent cancer by inhibiting angiogenesis it in a critical tissue – the lymph nodes14,15. Lymphangiogenesis is important because the lymph nodes are the first places where metastasis occurs in most epithelial cancers and malignant melanomas. In addition, malignant tumors need lymphatic blood vessels to grow13,16. So, statins can help prevent metastasis and help cure cancer. That is, simvastatin (Zocor®) is sometimes combined with traditional chemotherapy to cure some types of cancer16. It may also slow the growth of an especially deadly form of cancer – malignant melanoma16. Statins also prevent heart attacks. They improve endothelial function, increase the stability of atherosclerotic plaques, decrease oxidative stress and inflammation and inhibit the thrombogenic response8. They also have beneficial effects on the immune system, central nervous system, and bones8. Metformin (also known as Glucophage®) is the first line treatment for type-2 diabetes, or T2D10. Metformin is also quite useful in preventing T2D in people who are pre-diabetic. It also reduces the incidence of cancer and mortality, while helping people retain proper cognitive function. It may be able to extend the lifespan and possibly even slow down the aging process10,17. So, statins and metformin are two excellent examples of how pharmaceutical science and medicine are continuously improving. As scientists develop better tools, we hope that public health improves. For example, the new genetic editing tool called CRISPR is being used to improve livestock and seafood production, create better animal models of diseases, help in the development of improved vaccines and new prescription drug, and possibly eventually eradicate malaria4,18. It may also become one of the key technologies that will be part of the fourth industrial revolution (along with artificial intelligence, robotics, nanotechnology, information technology (IT) and big data) 19,20.

CRISPR has shown that several anticancer NCEs were designed using the wrong therapeutic targets

CRISPR is being used to help develop new drugs by identifying the best therapeutic targets for treating or curing diseases20. A recent study used CRISPR to show that several NCEs were designed using the wrong therapeutic targets21. These targets were proteins that were thought to be needed for cancer cells to survive and/or proliferate. They were identified using the best technologies available at the time. However, CRISPR gene editing showed that ten NCEs that are either in the preclinical stages of development or undergoing clinical trials were designed using the wrong therapeutic targets. Moreover, CRISPR editing identified the actual target for one of the NCEs (OTS964). It is a protein called CDK11 that is important in several cellular processes, but its role in cancer is unknown. Still, several drugs that target CDK11 have been approved by the FDA for treating cancer. So, CRISPR is quite useful in identifying the true therapeutic targets for treating cancer and in understanding more about the biology of cancer.

In conclusion, science is a process of continuous improvement. Even though we may not know exactly how some prescription drugs work, clinical trials can show that they do extend the lifespan of patients and often cure deadly diseases. To the patient who has been diagnosed with cancer and his or her loved ones, all that matters is if the drug works and has few (if any) adverse side effects. However, to future patients and dedicated pharmaceutical scientists, learning more about cancer biology can potentially save lives and improve the quality of life. Still, science should not be used as a dogmatic religion. It seldom provides complete answers to questions. Instead, each new answer tends to raise at least ten new questions. Science is a process of continuous improvement. It gives us at least partial answers to important questions, but seldom ever gives final, definitive answers. Most professional scientists are life-long students and teachers. We are always trying to learn more and convey what we learn to others. It’s about the journey – not the destination. A wise person readily admits that we all need peer reviews because we could be proven wrong in light of new data.

1 Smith, R.E. Historical Differences in Dietary Guidelines. Continuously Improving Dietary Guidelines. Wall Street International, 24 October 2019.
2 Smith, R.E. Can Aging Be Reversed? Wall Street International, 24 October 2019.
3 Lin, A. et al. Off-Target Toxicity Is a Common Mechanism of Action of Cancer Drugs Undergoing Clinical Trials. Science Translational Medicine, Volume 11, Article eaaw8412, 2019.
4 Smith, R.E. Using CRISPR Gene Editing to Create New Foods. Wall Street International, 24 May 2019.
5 Li, J-R. et al. Experiments That Led to the First Gene-Edited Babies: The Ethical Failings and the Urgent Need for Better Governance. Journal of the Zhejiang University – Science B (Biomed & Biotechnology), Volume 20, pp. 32-38, 2019.
6 Scott, C.T. and Selin, C. What to Expect When Expecting CRISPR Baby Number Four. The American Journal of Bioethics, Volume 19, pp. 7-9, 2019.
7 Rena, G. et al. The Mechanisms of Action of Metformin. Diabetologia, Volume 60, pp. 1577-1585, 2017.
8 Liao J.K. and Laufs, U. Pleiotropic Effects of Statins. Annual Reviews of Pharmacology and Toxicology. Volume 45, pp. 89–118, 2005.
9 Oesterle, A. and Liao, J.K. The Pleiotropic Effects of Statins – From Coronary Artery Disease and Stroke to Atrial Fibrillation and Ventricular Tachyarrhythmia. Current Vascular Pharmacology, Volume 17, pp. 222-232, 2019.
10 Smith, R.E. Metformin (Glucophage) May Extend Lifespan. Wall Street International, 24 August, 2018.
11 Schulten, H.-J. Pleiotropic Effects of Metformin on Cancer. International Journal of Molecular Sciences, Volume 19, Article 2850, 2018.
12 Pratticizzo, F. et al. Pleiotropic Effects of Metformin: Shaping the Microbiome to Manage Type 2 Diabetes and Postpone Ageing. Ageing Research Reviews, Volume 48, pp. 87-98, 2018.
13 Smith, R.E. Medicinal Chemistry – Fusion of Traditional and Western Medicine, 2nd ed. Bentham Science, Sharjah, U.A.E., 2014.
14 Smith R.E. Medicinal Chemistry – Fusion of Traditional and Western Medicine, 3rd ed. Bentham Science, Sharjah, U.A.E., 2015.
15 Schulz, M.M.P. et al. Phenotype-Based High-Content Chemical Library Screening Identifies Statins as Inhibitors of in vivo Lymphangiogenesis. Proceedings of the National Academy of Sciences, Volume 109, pp. E2665-E2674, 2012.
16 Mazzone, M. and Begers, G. Regulation of Blood and Lymphatic Vessels by Immune Cells in Tumors and Metastasis. Annual Reviews of Physiology, Volume 81, pp. 535-560, 2019.
17 Soukas, A.A. Metformin as Anti-Aging Therapy: Is It for Everyone? Trends in Endocrinology & Metabolism, Volume 30, pp. 745-755, 2019.
18 Enzmann, B.L. and Wronski, A.W. How CRISPR is Accelerating Drug Discovery. Genetic Engineering & Biotechnology News, Volume 39, Number 1, pp. 84-86, 2019.
19 Schwab, K. The Fourth Industrial Revolution. Geneva, Switzerland: World Economic Forum, 2016.
20 Fellmann, C. et al. Cornerstone of CRISPR-Cas in Drug Discovery and Therapy. Nature Reviews Drug Discovery, Volume 16, pages 89-101, 2017.
21 Lin, A. et al. Off-target Toxicity Is a Common Mechanism of Action of Cancer Drugs Undergoing Clinical Trials. Science Translational Medicine, Volume 11, Article eaaw8412, 11 September, 2019.