EDUCATING THE IMMUNE RESPONSE. Andrea Califano is President of the Chan Zuckerberg Biohub New York. He is the Clyde and Helen Wu Professor of Chemical and Systems Biology at Columbia University Irving Medical Center, and also holds appointments in the Departments of Biochemistry & Molecular Biophysics, Biomedical Informatics, and Medicine.

The Chan Zuckerberg Biohub Network of scientific institutes is supported by and partners with the Chan Zuckerberg Initiative to help researchers cure, prevent, or manage all diseases by the end of the century.

You can listen to the podcast of this interview here.

Andrea Califano, what is the aim of the Chan Zuckerberg Biohub Network?

Our goal is pursue grand scientific challenges on a 10- to 15-year time horizon to bring us closer to understanding the mysteries of the cell and how cells interact within systems. The CZ Biohubs are located in San Francisco, Chicago, and New York, and have a novel funding model that allows top scientists to dedicate themselves 100 percent to addressing the basic science challenges necessary to achieve these goals, without repeatedly applying for grants. With at least ten years’ funding we are able to focus and create a dream team to solve a specific problem.

Do you think a century-long goal is quite a long time? 

We also have shorter term goals, which in the Biohub that I run in New York are to re-engineer the human immune system. This kind of research is already ongoing in bits and pieces in some foremost labs around the world, but there’s no example other than this Biohub of a concerted effort where you create a team of scientists that work together to try and solve that problem. The three universities we work with – Columbia University, Yale University and The Rockefeller University – have stellar people who were all super excited about participating. Our goal is to detect and potentially treat diseases that the immune system has not been originally trained to detect and cure by natural evolution. We are trying to take over where natural evolution has stopped. That means pretty much anything that happens to us after we’re about 20 years old.

“We are trying to take over where natural evolution has stopped.”

Andrea Califano, what do you mean by natural evolution stops?

Our immune system is shaped to defeat most of the challenges that we encounter before we enter our reproductive age. As a species, what happens after reproduction is no longer very important, because it’s no longer a shaping force in modelling the organism’s genetics. The problem is that it also takes a very long time – about 200,000 years – to fix the genetics that give us certain types of functional traits in a population. The reproductive age for the human species about 200,000 years ago was probably between 15 and 20 years old, so our immune system has been shaped to defend against the things that happen before that age. Wound healing and infectious diseases were the major killers of humanity, and those are indeed exactly the two things that the immune system knows how to handle best.

Now that we are living longer, are you saying we want these immune cells to fight different diseases later on?

The immune cells defend against an infection by detecting certain types of messages on the surface of bacteria or viruses, and then creating an inflammatory response so that they recruit other immune cells to that site to participate in killing the foreign object. What they are not trained to do, yet, is to sense other types of signals that are generated by cells that, for instance, are associated with Parkinson’s or Alzheimer’s, or the types of cancer that are able to evade the initial immune response. We’re trying to engineer these cells so that they can now recognize the signals which they are not trained to recognize yet, and then activate exactly the same mechanism that they could have used in order to kill bacteria in the case of cancer, or prevent inflammation in the case of diseases that are inflammatory or neurodegenerative. It’s all about teaching the immune cells how to get to a particular site where there is a problem in one of our organs.

And then the immune system would defend us all by itself?

The immune system is the natural defense about pretty much anything that can go wrong with our body. When you cut yourself, the major system in our body that takes care of that is the immune system. It not only participates in wound healing and in repairing your own tissues, but also prevents foreign pathogens from getting into your body and kills them on the spot. It is the only set of cells in the human body that can pretty much go anywhere in our body to keep us healthy.

Is one of your major goals getting the immune system to prevent any illness right at its start, before it becomes a full-blown disease? 

Yes. For instance, by the time that cancer is typically detected, it already has about a billion cells. Wouldn’t it be wonderful if we could detect cancer when it has 100 cells? You would be able to treat it without requiring complex surgeries or treatments that are often ineffective when the tumor has grown too large, especially when it’s progressed to metastatic disease. Similarly, there are now drugs that can help alleviate some of the progression and symptoms of both Alzheimer’s and Parkinson’s, but they are ineffective if you use them when the disease is already in full-fledged flare. Instead, we could start administering those drugs at the moment the disease is in its initial phases.

How do you plan to do that?

Using cell engineering, we are designing novel technologies that allow us, for instance, to identify every single cell in the human body that an immune cell gets in contact with. Once you know that, you can figure out how to read the behaviour of that cell and then figure out whether it’s doing the right thing or if it’s doing something abnormal. That is already being done, for example to fight cancer using CAR-T therapy. CAR-T therapy modifies an immune cell, a T cell, so that it can recognize an antigen that is on a cancer cell. Once you do that then this allows these cells to start killing cancer cells. We’re doing the same thing, but instead of using a mechanism that can recognize the signal emitted by a cancer cell, we are using something that could recognize the signal emitted by Alzheimer cells or  Parkinson cells, etc.. We’re generalizing a concept that has already been used in cancer to do many more additional things.

“We need to learn more about mechanisms that we can harness to generate universal therapies.”

Andrea Califano, do you use artificial intelligence to help you?

Yes. A lot of what has been done in immunology so far has been by intuition and careful assembling of clues that can then be used to formulate hypotheses. It’s a process that is quite complex, very much trial and error, and to some extent, serendipity. For everything that we discovered in immunology, there’s a hundred things that did not work out. We’re trying to turn the laws of that discovery process to our advantage, so that when we go to the lab and formulate a hypothesis, the probability that the hypothesis will be validated is around 80 percent. You do that by using computational models based on machine learning or AI that can actually simulate or model what the cell is going to do when it encounters a certain stimulus or is perturbed by a drug. Once you have that model, you can predict the solution to the problem you’re trying to solve.

At the end of the day, will all this be detected easily for patients by simple blood tests?

The goal is to create what we call a cellular endoscope. An endoscope is a minimally invasive device that allows you to go inside our body and detect if there’s anything wrong, without major surgery. For instance, you could use it to look at your stomach or your intestine, but there are some places where you can’t go. For example, you can’t go to the brain or to the pancreas with a regular endoscope. With a cellular endoscope one could  instruct the cells to go to a specific site and to report back on what they’ve seen – allowing for very complex diagnostics in a minimally invasive manner. The idea is that we’re creating cells from your own body, or cells that are compatible with your body, that could be injected into circulation and be able to go to any organ on demand and report back what they have seen there and whether there’s anything abnormal. We’re trying to figure out all the different pieces of this puzzle that we have to put together to reach that point. It will probably be reached in the next ten years.

Are the resultant treatments going to be very expensive?

The first therapies we will generate will probably be personalized and more expensive, but we hope to eventually use universally engineered cells, rather than cells from a specific individual, to expand the impact of the therapy. We have put so much emphasis on the basic science of immunology because we need to learn more about mechanisms that we can harness to generate universal therapies.

Not every population has the same medical problems. Is your center in New York because New York is multi-ethnic?  

Typically the studies that were done until about 30 years ago were mostly done in white male populations. Almost no children were enrolled in these studies, there was a significant imbalance of women, and they were not ancestrally diverse. About 30 years ago, we started to realise that the ability of disease to manifest in humans depends on the background genetics of our bodies, and those are obviously very strongly linked to ethnicity. The genetics of an African-American in the United States is quite different from the genetics of, say, an American of Asian descent or of an American of European descent. In Africa, there is probably the largest diversity even within one continent. Mapping the genetic genealogy of Africa has been one of the major efforts that have gone on in the last 30 years. In fact, African American women tend to be much more likely to get a more lethal form of breast cancer than white women, and there has to be a careful investigation into why there are these differences. That can only happen if you can do studies in populations that are multiethnic and really representative.

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“For Alzheimer’s and Parkinson’s, we are certainly hoping to accomplish being able to detect them at a stage where they are still treatable.”

Andrea Califano, is the process of detection the same for everybody or does it change according to what you just said?  

We want to know the most universal mechanism of detection. If you studied only, say, African-American population, or only a white American population, you may find things that you can detect that are very useful, but they may not carry across to the other ethnicities. But if you study them all together, you can distill the most generalizable principle. Because of the partnership with the three universities, we have the opportunity to engage a diverse population. By studying diverse populations around New York, we will make sure that the mechanisms that we try to target are as universal as possible. 

By harnessing the immune system will cancer, Alzheimer’s or Parkinson’s become treated almost like the flu is today?

For cancer, that’s definitely a very strong possibility. For Alzheimer’s and Parkinson’s, we are certainly hoping to accomplish being able to detect them at a stage where they are still treatable, in terms of really delaying the full onset of the disease, because, once that is settled in, it’s very hard to treat. There are no drugs, at least no drugs yet, to invert the progression of Alzheimer’s.

These illnesses also sometimes touch very young people, did they always exist?

Yes, but the problem is that we live a lot longer now. Cancer has always existed. One of the reasons older people develop cancer is that evolutionarily the immune system has not been trained to see it past the reproductive age. We’re starting to see a lot more cancer because people live longer. If people died when they were 20, you would see very little cancer. Now they are 85 on average, and some live until 105 or even 120. When you live that long, there is the probability that some of the cells in your body may go awry.

The human being is not programmed to live very long unless artificially helped? 

We are programmed to live just as long as it takes to have children. Everything else is a bonus. It’s extra time, I would say. That’s the way natural evolution works.

Andrea Califano, thank you very much.

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