Prof. Caroline Bartucci says that when she entered her first chemistry class at the university, something ignited. “I thought molecules were like humans,” she says. “Each of them has its basic rhythm, but they can also be very relaxed in the company of some people, and very active or explosive in the company of other people.
Sometimes a molecule can ignore everyone in the room, except for one molecule that it sees on the other side and it is attracted to it like a missile. And sometimes there is a molecule that has high potential, but it needs another molecule that will help it release it from it. “
The enthusiasm for chemistry was not self-evident to her. As the daughter of a nuclear physicist father, science has always been present at home, but before choosing him as a career she rebelled twice: once when she preferred Harvard over MIT to which the father belonged, “and in which I also had a tuition waiver,” she said, In undergraduate music. Her parents have already vetoed this.
“I had a musician cousin, but he couldn’t make a living from it and ended up working at a bank,” she says. This was probably a severe warning enough for her to enroll in chemistry studies. To the delight of the family, she did not choose a third area in which she excelled as a girl – football.
The candies that ignited an idea
In one of her biology classes, she came across an image that influenced her career.
The lecturer noted that the cells in the human body are like M&M candy – wrapped in sugar. At the time, the advertisement “M&M, melts in the mouth but not in the hand”, made it very clear even to those who were not students of biology or chemistry that the hard candy shell protects the sensitive inner part. But why do our body cells contain so many sugars? No one knew then exactly.
Bertucci also did not really intend to solve the riddle, all she said she wanted was to synthesize new molecules, meaning to focus more on chemistry, but still the question remained in her head. Since it was difficult at the time to find a place to do a doctorate in organic chemistry, she continued to skip between chemistry and biology for a few more good years.
A new field of research was born
The development by which it is especially known today is called bioorthogonal chemistry. In fact, it is a method of studying the chemistry of living cells, without harming them or altering their activity. It can be said that Bertucci, now a researcher at Stanford University, invented a kind of velcro glue of chemistry: two molecules that know how to stick to one side of everything and everything to the other. As a result, everything can be eradicated very accurately.
Once the world learned to stick with this method, it became clear that there was no end to its applications. Bartucci herself founded seven start-ups, and additional companies were established on the basis of the method she developed, which actually became a scientific field in its own right. She is also feared to be nominated for the Nobel Prize. Soon, she will receive the Wolf Prize in Israel, which is considered a prophet of the Nobel.
“What I wanted to do in the lab was to simulate how the sugars change as they go through different processes in the cell. To do that, I wanted to do an imaging of the sugars on the cell, and I was looking for a molecule that I could detect but only react to the sugar I want to explore and nothing else. Lots going on in the animal cell, and I was looking for a molecule that would not react with anything other than my sugar.
“So we started a long process of cataloging all the drugs in the world, to understand what reacts with what and what does not react with what. Our goal was to create something that does not exist in nature, a man-made substance that has very specific reaction capabilities, more than is usually found in nature.
“We developed a substance called Azide, three nitrogen in a row, and it can react with alkaline substances, especially those we have developed. That is, we have found two rare substances that can react very selectively with each other.”
This discovery opened up a whole world of possibilities in the study of substances such as sugars, fatty acids, nucleic acids (DNA and RNA) and neurotransmitters, which until then had been difficult to find a way to bind to substances that could be seen in tests or imaging devices. Proteins have antigens that bind to them, so they are relatively easy to study, but they do not bind to other substances in the cell. Today even some of the antibody-based tests use its method.
“Since then, we and other researchers, as well as commercial companies, have been finding new materials that meet this definition of a very specific, very delicate connection that does not impair cell activity, to certain molecules in the cell. These are materials that can be measured or observed. This is what we did between 1996 and 2006. About”.
The jungle of the immune system
In 2008, Bartucci founded Redwood, its first company based on the technology it developed. The company’s product connects an antibody that knows how to bind to certain proteins in cells and a drug that you want to insert into those cells, and is currently in clinical trials. It was followed by Enabled Biosciences, which uses this tool to bind substances in the body that can indicate the existence of a disease. “We use it to identify diabetes. This is a test that already exists in the market, and now the company is developing an oral test for HIV,” she says.
Another company, Paleon, is based on another discovery by Bartucci, regarding the role of sugars in a cancerous process, and is related to the same sugar that envelops m & m and cells. But while candies are wrapped in simple sugar, our cells are wrapped in molecules that bind very complex sugars to them.
Bertucci likens it to a forest growing on the mantle of each of the cells, each sugar being a kind of tree or shrub or flower, which look different from each other. “Long chains of sugars move from side to side on your cells, like a forest in the wind,” she says. In a normal cell, the same thick forest of sugars Which we mentioned earlier looks like a tidy garden compared to the jungle that surrounds a cancer cell. Why does the cancer cell grow in a jungle? Bertucci claims that this is how the cancer cell manages to deceive the immune system and prevent it from eliminating it.
One of the breakthroughs in cancer treatment in recent years has been the understanding that if we deprive cancer of the ability to deceive the immune system and if we increase the activity of the immune system against it, it will already be able to treat the problem itself without having to kill the cancer directly. After all, it routinely kills cancer cells.
“How do immune system cells recognize if the cell is cancerous? They cling to the cell, curl up in its lap, and then taste a little (that is, part of the cell is digested inside the immune system cells). That way they know if it has good taste or bad taste,” says Bartucci. . But if the cell is wrapped in the wild sugar jungle, the cells of the immune system will think it actually tastes pretty good. Bartucci’s solution was intuitive and simple: mow the lawn, prune the trees. She developed in the lab, then trades to Paleon, an enzyme that removes excess sugars from the cell. Now the immune system can taste the real cell, and it will understand that it is cancer.
This invention relates to your research into sugars, but not to bioorthogonal chemistry.
“When we did the feasibility study in the lab, we created the ‘lawn mower’ using bioorthogonal chemistry, but in the meantime the company has found it easier to genetically engineer a cell that expresses the two parts of the ‘mower’ together, instead of performing a complex chemical process to synthesize it. It is true to say that it was easier, but the company invested a lot in creating a process that would later be more commercially efficient. “
Pharmaceutical companies are changing access to proteins
If a cancer cell is characterized by a shell of “sugar forest” different from that of a healthy cell, perhaps it happens in other diseases as well. This is an increasingly science-based approach, and another Bertucci company, Intervenn, has already developed an artificial intelligence system that attempts to decipher how sugars bind to proteins in the cell.
“We have developed a blood test to diagnose ovarian cancer, and another test that tests whether cancer patients will respond to drugs based on immunotherapy, because we do not want to give people drugs that are not helpful to them, because that is what happens today. However, people who can benefit from these drugs do not receive them.
“We know how to map all the proteins in the blood, all the sugars that are attached to them and the points where the sugar is attached. It turns out that this profile changes almost every change in the body. Today it is cancer, but later it can also be relevant to a variety of oncology Or aging. “
Today science is passionate about proteomics, mapping all the proteins in the human body. “So glycoproteomics (protein and sugar mapping) is like the exponential version – more sensitive and accurate, but also so much more complicated – of proteomics,” says Bartucci.
Another Bartosi company, Lycia, uses the same idea of connecting things, but in a completely different direction: it develops a molecule that is on the one hand an antibody that binds to protein on the cell envelope and on the other a substance that labels the protein as “recyclable”, then sent to the recycle bin. . “This is part of a change that the pharma industry is going through, which until today knew how to block proteins to prevent their biological activity, and today is already thinking in the direction of destroying them completely,” says Bartucci. If the protein blocking analogy is a key and a lock, here it is a complete destruction of the lock. Nothing will be able to enter through it anymore.
How did you manage to set up so many companies?
“I already have enough experience in this, I recognize the things that have an application. Usually I try to get some kind of feasibility in the lab, and then sometimes the student leading the project wants to set up the company, or be its VP of technology, or people come to me saying ‘I read about this invention of yours, do you agree we will purchase it? The university owns the patent, sometimes it also invests in the company. “
The father who was looking for medicine for his daughter
Bertucci tells of an application she received from the father of a girl who had a genetic disease. The father, Matt Wilsey by name, resigned from his job to investigate the daughter’s illness, and indeed located the relevant gene and realized that it was related to the synthesis of sugars in the body. “So he called me, and of course I was very impressed with him. He is a force of nature, he raised all the money for us. We found that the enzyme that is lacking in these patients lowers sugars from proteins in the healthy body, and in patients it does not.” “The company’s discovery is also relevant to cancer.”
What does he think about the fact that after all his work now it’s a cancer company?
“He is happy because it can lift society, but God forbid we do not abandon patients with the rare disease and intend to treat them with real genetic therapy. Our intention is to put a healthy gene into all their brain cells because their main problem is neurological.”
it is not dangerous?
“Genetic therapy has already reached clinical trials, and so far no reason has been found to think it is unsafe.”
In the field of cancer, the blockade of that enzyme can put the cells under stress, which is of course a desirable thing when it comes to a cancer cell.
Academics usually do not get rich from inventions
According to Bartucci, her companies already have several hundred employees, but in the meantime she has not yet become rich from them. “Academics rarely get rich from inventions, and only one of my companies, Redwood, has made an exit. It could take another 10-15 years. Meanwhile, companies only consume money. For me, getting rich is not the story. I want to see my science come out. I always believed “That’s important. My whole career has been about putting sugar research into biology. If we can do that, we’ll have better drugs.”
What in your career do you think allowed you to do everything you do today, seemingly with zero effort.
“So not at zero effort. If you look at my Twitter account, you will see that I write a lot about the small failures and everyday embarrassments of the scientist’s life.”
Indeed, her popular Twitter account receives responses such as “Look – geniuses are just like us.” “But I think two things that built me were instances where I was landed into a task that seemed beyond my size, and I had to succeed in it. For the first time as a research assistant, I was forced to use a device I did not understand. “They would not let me do it, so I have to somehow get there. That’s how I was prepared for the evil where my doctoral supervisor was diagnosed with cancer.”
Doctoral students were given the option to start all over again with another supervisor or finish the doctorate on their own. Bertucci was one of those who chose to end without guidance. Today this would probably not have been possible, but this period prepared her for her next role, as a researcher in her own right.
“Another process I went through was a disillusionment with the thought that the students I teach would be my replicas, with the same level of ambition and the same interests,” she says. There were researchers who worked with her and left the lab in frustration, and Bartucci decided she must change her management style. Today she is considered one of the excellent mentors of the university. “It’s hard to find someone who has a bad word to say about her,” said Prof. Christina Wu, a Harvard researcher who completed her post-doctoral dissertation.
Prof. Caroline Bartucci
personal: 55 years old, married to a woman and mother of three
Current position: Professor of Chemistry at Stanford University and Researcher at the Howard Hughes Institute. Has established a large number of start-ups based on its inventions
education: Bachelor of Chemistry from Harvard University, Internship at Bell Laboratories, Ph.D. in Chemistry from the University of Berkeley, Post at the University of San Francisco and then returned to a position at Berkeley before being recruited to Stanford
Something else: As a student she also seriously studied music and played in the rock band Bored of Education with Tom Morello, who went on to join the band Rage Against the Machine