South Korea is a botulinum toxin (botox) powerhouse. There are only four companies in the world that have successfully commercialized Botox, but Korea has three: Medytox, Daewoong Pharmaceuticals and Hugel. Moreover, six to seven others have secured the strain a core component to dive into the Botox market for product commercialization. There is also a rumor in the finance sector that about 16 other Korean companies are trying to startup a Botox business.

The Botox market is estimated to be 5 trillion won ($4.42 billion) worldwide and 100 billion won in Korea.

It is promising that the market is growing but there is a problem: Botox is a high risk pathogen and biological agent that can be used as a biological weapon. Storage, separation, cultivation and control of Botox strain must be reported to regulatory bodies due to many risks involved with the strain, and international transfer of this biological substance is strictly restricted.

The Korean government insists there is no problem because Botox is under tight control, but experts wonder why there are around 10 companies just in Korea alone that have been trying to commercialize Botox over the last two to three years.

A Botox industry insider who asked for anonymity said, "Botox companies are known to have achieved an operating profit of 40% on average. Once companies have strains that allow them to produce Botox permanently, they can easily penetrate into the market, therefore, everyone wants to know how they can secure botulinum strains."

Maeil Business Newspaper has reported if botulinum strain control needs improvement and how the strain`s origin and transfer route can be tracked with Next Generation Sequencing (NGS). Health Journal of this week presents a meeting between Paul Keim, world-class Botox expert and Professor of Northern Arizona University, and Wonjong Jang, Head of Korean Biological Safety Association and Professor of Konkuk University Medical School. Professor Keim visited Korea for the first time as a speaker for the Federation of Korean Microbiological Societies International Conference held on Oct. 11-12.

He is legendary when it comes to tracking botulinum strain with DNA sequencing and also for finding the suspect responsible for 9/11 Anthrax Attack. Professor Keim and Professor Jang had the following conversation.

- People are concerned that around 10 companies in Korea only are preparing for commercializing botulinum strains.

▶Professor Jang: Botox is strictly controlled in Korea compared to other countries and five government ministries are in charge. As a microbiologist, I am surprised that so many Korean companies have successfully developed strains for commercialization despite the fact that serotype A, botulinum-producing strain is very rare in nature and it takes a long time to develop the botulinum strain separated from nature into commercial strain.

▶Professor Keim: It is important to prevent the leakage of botulinum strains because there is a lot of information on how to weaponize them. Even the smallest amount of high risk biological agent can be fatal and you must strictly control it no matter how low the chances of leakage might be. For safer control, you need double/triple-tiered system such as physical security control, cybersecurity and internal staff control. US has established a system that lets researchers or other relevant employees take psychological test to verify their emotional stability and prevent a person from handling strains at his/her discretion. I think Canada even monitors banking records of the relevant employee`s spouse.

- Korea has 66 Grade 3 facilities capable of producing biological weapons, which is a lot compared to other countries like Singapore, etc.

▶Professor Jang: The number is relatively high, but this is how we could handle so many samples quickly and safely during the MERS outbreak. Botulinum strains are controlled through various regulatory acts such as INFECTIOUS DISEASE CONTROL AND PREVENTION ACT, ACT ON THE CONTROL OF THE MANUFACTURE, EXPORT AND IMPORT, ETC. OF SPECIFIC CHEMICALS AND CHEMICAL AGENTS FOR THE PROHIBITION OF CHEMICAL AND BIOLOGICAL WEAPONS, FOREIGN TRADE ACT, TRANSBOUNDARY MOVEMENT, ETC. OF LIVING MODIFIED ORGANISMS ACT. By law, Grade 1 and 2 facilities must be reported to the government for operation and Grade 3 and 4 facilities must be approved. Botulinum toxin-producing strains and Botox manufacturing technology are protected as national core technology, and high risk testing requires pre-approval from the government. It is impossible for someone to produce a material for terrorism from an authorized facility.

- Some people say that all the Korean Botox companies at commercialization stage should submit NGS data of their strains. If the government had NGS data, would it help them trace and control the strains in case something happens?

▶Professor Keim: Yes, absolutely. They should of course do that. NGS is inexpensive and simple. There is no reason not to do it. Genome sequencing has significantly improved since the Human Genome Project, and NGS has become a tool to analyze and understand human and microbes easily at a cheap price. We can find results more easily and quickly with this kind of technology. In the US, if FDA approves, it will be required to submit different types of data for clarifying the source of strains, and submit NGS data. Stricter requirements apply to new found strains.

▶Professor Jang: Early this year, a bill regarding reporting high risk pathogens (botulinum strains, etc.) and biological agents separately, and submitting genetic information during production stage were proposed for safety purposes. If all the organizations or companies owning the strains were to submit their strains` genetic information to the government, it could discourage them from researching. However, others say that making it a requirement to submit genetic information like NGS is reasonable because production safety and product safety are important at commercialization stage. Like US, we need to receive NGS data during the MFDS approval stage but it`s not a requirement yet.

- Professor Keim, tell us about the time when you worked with FBI during 9/11 Anthrax letter attack.

▶Professor Keim: At the time, I also was one of the suspects. Hundreds of researchers were on the list, because Ames strain used in the attack is only used in laboratories. We asked 16 labs with Ames strain throughout the US, including 2 foreign labs in the country to send us all the strain samples being stored or used. We narrowed down the ones similar to what was used in the attack and we found DNA signature. Then, we were able to confirm that the anthrax came from a strain culture flask for animal testing at USAMRIID and this is how we found the suspect. This is what drove the regulations to be tighter in US (if there is a bioterrorism with botulinum toxin, all the organizations, labs and companies holding the strains are on the investigation list and anyone who has access to the strains is on the suspect list).

- Do you have any tips for Korean regulatory bodies, companies or researchers in terms of how they can safely use high risk biological agents like Botox?

▶Professor Jang: The government needs to think how it can stop malicious bioterrorism and keep the research and commercial production regulations tight. However, government protection and safety/security control should be implemented to an extent which commercial value of product is unharmed and R&D is not undermined. The government also needs to inform anxious people that biological agents are controlled with systemic safety approach.

▶Professor Keim: A few days ago, it was announced during Federation of Korean Microbiological Societies International Conference that Burkholderia pseudomallei was discovered in Australia millions of years ago and spread to Southeast Asia and other regions. This gathered a lot of attention from Korean researchers. They have been investigating for decades how pathogens evolve and spread, and this recent result forms the backbone of epidemiological data and can contribute to medicine development. Biosafety and biosecurity are crucial for handling high risk pathogen or biological agent. I wish we could study and discuss together after establishing a system to manage research safely.

By Shin Chan-ok and Minu Kim

[ⓒ Pulse by Maeil Business Newspaper & mk.co.kr, All rights reserved]