You don’t get these types of news everyday, where you can feel adrenaline rushing in veins and communicating with your brain. Yes, finally you can write not only write but say it louder…here is the women in science. It’s not just a metaphor or motivational phrase anymore. I woke up one morning and learned that, two great women with most fertile neurons got noble prize in chemistry for their outstanding contribution towards simplifying methods of gene editing. Although there are many tools available for the manipulating genome. But what separate the discovery of Emmanuelle Charpentier and Jennifer A. Doudna from others is the feasibility of the genome editing technique.
Emmanuelle Charpentier and Jennifer A. Doudna have won the 2020 Nobel Prize in chemistry for the development of a method for genome editing, CRISPR–Cas9 . I could not believe that after Marie Curie, née Sklodowska groundbreaking discovery of radium and polonium for which she was awarded Noble prize in 1911. Here, these are the women who won this most prestigious award and what more not shared with any man.
CRISPR literally means clustered regularly interspersed short palindromic repeats. It is bacterial defense mechanism against attacking viruses i.e bacteriophages. What bacteria does it stores virus genetic information (the ones who have attacked bacteria already) with CRISPR-associated proteins or famously called as Cas. Cas are group of enzymes which is very effective in chopping the DNA. So what happens, already stored viral genetic information (CRIPSR sequence) is converted in to guide RNA. These guide RNA form a complex with Cas (there are many types of Cas, but Cas9 is the most commonly used) to find complimentary sequence in the attacking viral DNA. Once Cas system recognize target sequence, it snips the DNA at that location. Using this interesting system bacteria diffuse viral genetic information and protect themselves.
Doudna got her Ph.D. in the lab of Jack Szostak at Harvard Medical School in 1989 and then worked as a postdoctoral fellow in the lab of Noble Prize Winner Thomas Cech at University of Colorado Boulder. Then she started as an assistant professor at Yale University, there she met her lab manager Kaihong Zhou, who has been with her from past 20 years. Doudna credits her success to Zhou. Doudna says “I owe tremendous amount for what we have been able to achieve”. Although when Doudna hired Zhou she was unable to see common scientific grounds in her resume, but she thought of giving her chance. And since then there is no looking back. When in 2001 UC Berkeley offered her an impressive position, it was only Zhou from her laboratory who moved with her to west coast. Doudna has an impressive research profile including CRISPR, RNA interference and translational control. Although Zhou was really interested in Doudna RNA interference work, but she thinks it was interpersonal relationship which was the key driving factor for working together. Doudna describe their relationship very cutely as a pea in a pod. Doudna and Zhou relationship is an exemplary colleague collaboration where women is having all praise for each other. This type of relationship not only make lab environment supportive but also conducive for research.
Doudna has always been interested in RNA biology. RNA is not just a spaghetti like strings. Apparently, they are structurally organized and behave like proteins. Doudna has resolved crystal structure of a large domain of the protozoan Tetrahymena ribozyme. Her interest for RNA and structure biology led her to investigate the crystal structure of the hepatitis delta virus ribozyme, that helped to resolved how virus could replicate itself by hijacking host cell machinery.
It is around mid 2000s, when Doudna lab was working on gene regulation by small RNA molecules, idea of CRISPR strike her mind. It immediately came to her radar, as she hypothesized that CRISPR is kind of RNA interference used by small bacteria organisms to evade virus infection. Her lab became the torch bearer to see if there is any evolutionary connection between bacterial and mammalian system in harnessing RNA to regulate genetic information.
Normally, bacteria has three different type of RNA –mediated system for destructing invading virus DNA. These systems are called as endonucleases or CRISPR-associated Cas. It was one day Doudna and her postdoctoral fellow Martin Jinek were discussing some data, when this revolutionary thought came to their mind that if they can generate a single chimera RNA from CRISPR. This chimera can still guide Cas9 to complementary sequence in DNA. This can be an effective way of introducing mutation in gene. They wondered, if they can do so then they will have simple yet effective system of gene editing or manipulation. Both of them looked at each other faces and said “if we could get this work in other cells, it would be a very good tool”. And that was the turning point.
Doudna laboratory started exploring type II system, when Emmanuelle Charpentier asked her at a conference that it would of interest to her to work together to investigate what is the exact function of Cas9. Type II Cas9 system is of great interest, as type 1 and III Cas system uses variety of endonucleases.
Charpentier received her degree in Biochemistry in 1991 from Pierre and Marie Curie University, now part of the Sorbonne University. She earned her PhD in 1995 from Institut Pasteur, where she explored the genetic and molecular mechanisms behind antibiotic resistance. She started her research group at University of Vienna in Austria. Later on, she worked as associate professor at Umeå University from 2009 to 2014. She is director at the Max Planck Institute for Infection Biology in Berlin since 2015 and also in 2018, founded an independent research unit, the Max Planck Unit for the Science of Pathogens.
Emmanuelle Charpentier and Jennifer A. Doudna share corresponding authorship of 2012 science (https://science.sciencemag.org/content/337/6096/816) paper which showed bacterial Cas9 attacks bacteriophage genome ( a type of virus). Investigators demonstrated the proof of their hypothesis in this paper. In vitro studies suggested that chimeric RNA could be rationally designed, and logically can target any complementary DNA sequence.
This discovery gave investigators a chance to do science with clinical implications. Like Doudna group is exploring if CRISPR/Cas9 system can be used make changes in correcting neurological disorders like Huntington’s disease. Until now, scientists have exploited CRIPSR to edit genes in almost anything they can get in their hands: human cells, zebrafish, fruit flies, mice, worms and rhesus monkeys.
One of the best used of CRISPR was explored in 2019 for treating sickle cell anemia. The technique was used to restore fetal hemoglobin in cells removed from bone marrow, these cells corrected for hemoglobin were reinserted in order to compensate for defective one. Until now, treatment appears to be successful.
Although genome editing is still a controversial topic, when it comes to editing genes in germline. DNA editing can be done both at somatic and germline level. Somatic cells gene editing seems to appear safer, whereas germline gene editing is debatable. Germline gene editing leads to heritable changes in embryos, which prevents them from having deadly disease because of mutation (Notoriously labeled as genetically engineered babies).
However, beside this little controversy, CRISPR/Cas9 has far more reaching benefits, not only helping us understand molecular biology, but also for advancement of therapies to treat human disease. Doudna says she sees CRISPR as a futuristic gene therapy, but there are some roadblocks. Investigators have to work on fine tailoring the editing system, so that gene editing can be done only in specific cells not in all. Doudna says her heart breaks when she gets email from someone who has a loved one suffering from deadly genetic disorder and wondering if CRIPSPR can help….although it’s too early to say, but HOPE IS STILL THERE.
Both brilliant biochemists are evenly going to share the academy award money i.e. 1.1 million dollars.
Today on international day for girl child, I would like to end on a very positive note, as I see the future of women in science flourishing beautifully. Moreover, people are changing their mind set. I sincerely believe if we all can start helping each other in growing, we can make a big difference. Doudna set a beautiful example how she motivated, praised her lab manager Zohu. I feel more and more women should come together and help each other. Women have divine powers as mentioned in this beautiful shloka from Svetashvatra Upanishad.
त्वं स्त्री त्वं पुमान् त्वं कुमारः त्वं कुमार त्वं जीर्णः दण्डेन वञ्चसि। त्वं विशतोमुखः जातः॥
Thou art the woman and Thou the man; Thou art a boy and again a young virgin; Thou art yonder worn and aged man that walkest bent with thy staff. Lo, Thou becomest born and the world is full of thy faces