2015 Nobel Laureate Tu Youyou and Ancient Chinese Medicine

Three researchers shared the recently announced 2015 Nobel Prize for Physiology or Medicine, for their discoveries of therapies against parasites. Microbiologists William Campbell at Drew University in Madison, New Jersey, and Satoshi Ōmura at Kitasato University, Japan, received their share of the award for their discoveries of a therapy against infections caused by roundworm parasites. Chinese pharmacologist Tu Youyou received her share for discovering an anti-malaria medicine called artemisinin.

Tu’s discovery is especially interesting since it happened only because she could read 1,500-year-old Chinese medical texts. It isn’t virology, but it is a good tale. It came about as follows.

In the late 1960s Chinese soldiers, and their Vietnamese allies, were fighting against the United States armed forces in the jungles of Vietnam, where they were being decimated by malaria. Chloroquine and quinine—the main treatments for the disease—were losing their efficacy. Thus, in 1967 Mao Zedong decided that China urgently needed to find a cure for malaria. So, in 1967 he launched a secret research unit for that purpose. In 1969, Tu, then a researcher at the Academy of Chinese Traditional Medicine, became the group’s leader. [The United States too was working on a malaria therapy for the same reason.] See Aside 1.

[Aside 1: Malaria is a life-threatening disease caused by mosquito-borne parasites of the genus Plasmodium. Although malaria is now a preventable and treatable disease, in 2013 it caused an estimated 367,000 to 755,000 deaths, mostly among African children. See the CDC website.]

Tu’s team followed the unusual (by Western standards) route of perusing ancient Chinese texts for clues to historical methods for treating malaria. After screening more than 2,000 traditional Chinese herbal remedies for their effectiveness against malaria, the team came upon a short reference to sweet wormwood, used by the ancient Chinese as an anti-malaria therapy around 400 AD.

In 1972 Tu’s team isolated a compound, artemisinin, from a wormwood plant extract, which seemed to be effective against malaria parasites. Nevertheless, the compound was not effective at eradicating malaria in animals. So, Tu carefully reread the original ancient text, in which she discovered that the secret to the drugs efficacy was to heat the wormwood extract, without allowing it to reach the boiling point. When Tu followed that practice, artemisinin indeed was effective in mice and monkeys. Next, to ensure the safety of the new drug, Tu volunteered to be its first human recipient. Artemisinin still remains the best therapy against malaria.

Tu Youyou, now 84-years old, is the first Chinese woman to win a Nobel Prize. Earlier, in 2011, she won a Lasker prize. Yet, she has neither a medical degree nor a PhD. Instead, she attended a pharmacology school in Beijing and, shortly afterwards became a researcher at the Academy of Chinese Traditional Medicine. She never worked outside of China.

Tu Youyou, now 84-years old, is the first Chinese woman to win a Nobel Prize, awarded for her discovery of an anti-malaria medicine called artemisinin. Tu’s discovery happened because she was able to read ancient Chinese medical texts.

Tu has never won a major award in China, nor is she a member of the Chinese Academy of Sciences. This may be in part because she never received a formal doctoral degree. Moreover, as Tu herself says, “Chinese awards are always given to teams, but foreign awards are different. This honor belongs to me, my team and the entire nation (1).”

Some have commented that Tu’s story points up the need for Western medicine to pay more attention to traditional Asian therapies. Others noted that while alternative medicine has provided some potentially useful leads, it also has been the source of many useless and even harmful treatments. In any case, Tu’s Nobel Prize-winning discovery, linked to her ability to read ancient Chinese texts, is notable.

Reference:

1. http://sinosphere.blogs.nytimes.com/2015/10/09/tu-youyou-nobel-prize-malaria/

ALS (Lou Gehrig’s Disease) and a Human Endogenous Retrovirus

Our last posting was a review of sorts of The Theory of Everything, a movie biography of Stephen Hawking and his wife Jane Wilde (1). Hawking was the first to put forward a cosmology based on an attempt to combine general relativity and quantum mechanics. However, in 1963, before Hawking began his groundbreaking studies, he was diagnosed with the neurodegenerative disease, amyotrophic lateral sclerosis (ALS; commonly known as Lou Gehrig’s disease). He was 21 years old and given a life expectancy of only two years. Even after Hawking become a world-renowned scientist, he was totally dependent on Jane at home.

ALS has been a poorly understood and incurable disease, involving the death of neurons that control voluntary movements, speech, and breathing. The illness is usually fatal within three years of the onset of symptom, thus accounting for Hawking’s grim initial prognosis. Now, new evidence, from a research team at the NIH, headed by Avindra Nath, shows that a human endogenous retrovirus, HERV-K, likely plays a key role in the pathology of ALS (2).

Endogenous retroviruses probably arose millions of years ago, when retroviruses first began inserting their provirus (DNA) genomes into the genomes of germ line cells (see reference 3). Astonishingly, eight percent or more of the human genome is comprised of retroelements. Most of these are defective because of the accumulation of numerous mutations over time. Nearly nothing had been known with certainty about their relevance to human disease, although they had been implicated in a variety of illnesses, including cancer, inflammatory disorders, and neurodegeneration.

The new NIH study was prompted by several earlier observations. First, ALS can present as a rare complication in AIDS patients. Second, the ALS symptoms of at least some of these AIDS patients were alleviated by anti-retroviral therapy against their HIV infections. Third, reverse transcriptase activity was detected in the blood of some ALS patients. Fourth, despite an extensive search for exogenous retroviruses in ALS patients, none has ever been detected.

HERV-K, like other retroviruses, has three major structural genes, gag, pol, and env, which encode the viral capsid protein, reverse transcriptase, and envelope proteins, respectively. Nath and co-workers detected transcripts of each of these genes in postmortem brain tissue samples from ALS patients, thus implying that the entire HERV-K genome was expressed in these patient samples. No significant expression of other HERVs was detected in these patient samples. Nor was HERV-K expression detected in brain tissue from healthy individuals, nor was it seen in brain specimens from Alzheimer’s and Parkinson’s disease patients.

ALS patient samples were immunostained for the HERV-K env protein in order to identify the cell types in which the endogenous retrovirus was expressed in those individuals. Env was detected only in large pyramidal neurons in the cortex, and in anterior horn neurons of the spinal cord.

Next, the entire HERV-K genome and env alone were transfected into human neuronal cell cultures to evaluate whether HERV-K expression might be neurotoxic. Env alone, as well as the entire HERV-K genome, caused a decrease in cell numbers and a retraction of axons. Thus, the HERV-K env protein alone causes neurotoxicity and neuronal death in vitro.

The authors then assessed whether the HERV-K env protein might be neurotoxic in vivo; first by in utero electroporation of the env gene into embryonic mouse brain, and then by generating env-expressing transgenic animals. Expression of the HERV-K env in vivo indeed caused degeneration of motor neurons. And, as in ALS patients, only those motor neurons in the transgenic mice that control movements were damaged. Moreover, the transgenic animals developed progressive motor dysfunction, and 50% of the animals died by 10 months of age. The authors note that the mechanism by which the HERV-K env protein leads to neuronal injury is not yet known.

More than 12,000 Americans are currently living with ALS, and there is not yet any effective treatment for them. The current study offers hope that antiretroviral therapy, similar to that used to treat AIDS patients, might benefit at least some individuals suffering from this tragic illness. Be on the lookout for follow-up studies to this report, which are sure to occur.

Lou Gehrig’s iconic speech, July 4, 1939.
“Today I consider myself the luckiest man on the face of the Earth…”

References:

1. “The Theory of Everything,” Posted on the blog September 15, 2015

2. Wenxue Li, Myoung-Hwa Lee, Lisa Henderson, Richa Tyag, Muzna Bachani, Joseph Steiner, Emilie Campanac, Dax A. Hoffman, Gloria von Geldern, Kory Johnson, Dragan Maric, H. Douglas Morris, Margaret Lentz, Katherine Pak, Andrew Mammen, Lyle Ostrow, Jeffrey Rothstein and Avindra Nath. Human endogenous retrovirus-K contributes to motor neuron disease, Science Translational Medicine, 7:307ra153 (2015).

3. Howard Temin: In From the Cold, Posted on the blog December 14, 2013.