A typical bacterial genome comprises greater than 4,000 genes, which encode the entire proteins that the cells must survive. How do cells know simply how a lot of every protein they want for his or her on a regular basis capabilities?
Gene-Wei Li, an MIT affiliate professor of biology, is attempting to reply that query. A physicist by coaching, he makes use of genome-wide measurements and biophysical modeling to quantify cells’ protein manufacturing and uncover how cells obtain such exact management of these portions.
Utilizing these strategies, Li has discovered that cells seem to strictly management the ratios of proteins that they produce, and that these ratios are constant throughout cell varieties and throughout species.
“Coming from a physics background, it’s shocking to me that these cells have developed to be actually exact in making the correct amount of their proteins,” Li says. “That statement was enabled by the truth that we’re capable of design measurements with a precision that matches what is definitely occurring in biology.”
From physics to biology
Li’s dad and mom — his father, a marine biologist who teaches at a college in Taiwan, and his mom, a plant biologist who now runs a science camp for highschool college students — handed their affinity for science on to Li, who was born in San Diego whereas his dad and mom had been graduate college students there.
The household returned to Taiwan when Li was 2 years outdated, and Li quickly turned eager about math and physics. In Taiwan, college students select their school main whereas nonetheless in highschool, so he determined to check physics at Nationwide Tsinghua College.
Whereas in school, Li was drawn to optical physics and spectroscopy. He went to Harvard College for graduate faculty, the place after his first 12 months, he began working in a lab that works on single-molecule imaging of organic programs.
“I spotted there are quite a lot of actually thrilling fields on the boundary between disciplines. It’s one thing that we didn’t have in Taiwan, the place the departments are very strict that physics is physics, and biology is biology,” Li says. “Biology is loads messier than physics, and I had some hesitancy, however I used to be glad to see that biology does have guidelines that you may observe.”
For his PhD analysis, Li used single-molecule imaging to check proteins known as transcription components — particularly, how shortly they’ll bind to DNA and provoke the copying of DNA into RNA. Although he had by no means taken a category in biology, he started to be taught extra about it and determined to do a postdoc on the College of California at San Francisco, the place he labored within the lab of Jonathan Weissman, a professor of mobile and molecular pharmacology.
Weissman, who’s now a professor of biology at MIT, additionally skilled as a physicist earlier than turning to biology. In Weissman’s lab, Li developed strategies for learning gene expression in bacterial cells, utilizing high-throughput DNA sequencing. In 2015, Li joined the school at MIT, the place his lab started to work on instruments that could possibly be used to measure gene expression in cells.
When genes are expressed in cells, the DNA is first copied into RNA, which carries the genetic directions to ribosomes, the place proteins are assembled. Li’s lab has developed methods to measure protein synthesis charges in cells, together with the quantity of RNA that’s transcribed from totally different genes. Collectively, these instruments can yield exact measurements of how a lot a specific gene is expressed in a given cell.
“We had the qualitative instruments earlier than, however now we are able to actually have quantitative data and find out how a lot protein is made and the way essential these protein ranges are to the cell,” Li says.
Utilizing these instruments, Li and his college students have found that totally different species of micro organism can have totally different methods for making proteins. In E. coli, transcription of DNA and translation of RNA into proteins had lengthy been recognized to be a coupled course of, that means that after RNA is produced, ribosomes instantly translate it into protein.
Many researchers assumed that this may be true for all micro organism, however in a 2020 examine, Li discovered that Bacillus subtilis and lots of of different bacterial species use a different strategy.
“Numerous different species have what we name runaway transcription, the place the transcription occurs actually quick and the proteins don’t get made on the similar time. And due to this uncoupling, these species have very totally different mechanisms of regulating their gene expression,” Li says.
Li’s lab has additionally discovered that throughout species, cells make the same proportions of sure proteins that work collectively. Many mobile processes, reminiscent of breaking down sugar and storing its vitality as ATP, are coordinated by enzymes that carry out a collection of reactions in a specified sequence.
“Evolution, it seems, provides us the identical proportion of these enzymes, whether or not in E. coli or different micro organism or in eukaryotic cells,” Li says. “There are apparently guidelines and rules for designing these pathways that we did not know of earlier than.”
Mutations that trigger an excessive amount of or too little of a protein to be produced could cause quite a lot of human ailments. Li now plans to research how the genome encodes the principles governing the proper portions of every protein, by measuring how modifications to genetic and regulatory sequences have an effect on gene expression at every step of the method — from initiation of transcription to protein meeting.
“The following degree that we’re attempting to give attention to is: How is that data saved within the genome?” he says. “You’ll be able to simply learn off protein sequences from a genome, however it’s nonetheless unimaginable to inform how a lot protein goes to be made. That’s the following chapter.”