- I just want to point out that in the '80s and '90s, it usually takes 20 or 25 years for establishing any new technique, but it has tremendously reduced now with the modern technology, with all this innovations and other things. So what can be achieved in 30 years back in the '80s can be achieved in 5 years now. We are living in the fast age, fast world. So it'll not be too far. I will not be surprised if FLASH radiation already enters the clinical trial in about three to five years. I think I will not be surprised.

- [Announcer] This is the ORISE Featurecast. Join host Michael Holtz for conversations with ORISE experts on STEM workforce development, scientific and technical reviews, and the evaluation of radiation exposure and environmental contamination. You'll also hear from ORISE research program participants, and their mentors, as they talk about their experiences, and how they are helping shape the future of science. Welcome to the ORISE Featurecast.

- Welcome to the ORISE Featurecast. As ever, I am your host, Michael Holtz in the communications and marketing department at the Oak Ridge Institute for Science and Education. And I could not be more excited to be talking today to Adayabalam Balajee, the director of the REAC/TS Cytogenetic Biosymmetry Laboratory at ORISE, one of the most amazing assets of the Department of Energy that is managed by ORISE and ORAU, and Dr. Balajee and I had a conversation a few weeks ago about some research that he's doing, and I can't wait to talk about it. I'm so excited. Balajee, welcome once again 'cause you are a returning guest. Welcome once again to the ORISE Featurecast.

- Good morning, Michael. Very, very glad to be here. And also to tell you about the exciting research we are doing currently.

- I'm so thrilled. As you recall, when we were talking about this the other week, I was jumping out of my chair with excitement about the work that you're doing. So, just as background, you are doing some research that is funded through an ORAU-directed research and development grant with Columbia University. And the project focuses on the notion of FLASH radiology for the treatment of cancer. Talk about, in broad strokes, what it is that you're working on.

- FLASH radiation is an emerging new technology that uses ultra high dose rate of radiation. It is really promising. People have done a lot of experimental studies on mice, mini pig and cat. And there are several advantages of this FLASH radiation. First of all, it delivers the dose several hundred folds faster than the conventional radiotherapy. And the most important thing is the normal tissue is spared. So the FLASH radiation is very effective in killing tumor cells, but it spares the normal tissues. So one of the problem in radiotherapy is that conventional radiation causes a lot of acute and late effects to normal tissues. So this is some kind of alleviating that normal tissue effect. So FLASH radiation is going to be the future in my opinion because it delivers the dose in a very short time, and there is no tissue damage, normal tissue damage. So the FLASH scores really high compared to conventional radiation.

- Right. What excites me about this so much is when we talked about this the other week, the idea of treating a tumor with one high dose radiation treatment effectively, and as a cancer survivor, I had 28 doses, micro doses, or smaller doses over a period of time. And of course there were fantastic side effects like blistering and swelling open of orifices that shouldn't be swelling open. And all of those, all of those fun and exciting things. And what I'm hearing about FLASH radiation is you almost eliminate all of that from happening 'cause you're so targeted and so precise in focusing on the tumor with that high dose radiation that you're preserving the non-disease tissue around it.

- Absolutely. So this is what the FLASH radiation does. So they looked at a lot of organs like lung, brain and other organs. So the damage is pretty minimal compared to conventional radiation. For example, with the conventional radiation, lung fibrosis is a common pathological symptom. So FLASH radiation is really effective. So we don't see that lung fibrosis that more frequently than we see with conventional radiation. So there are a lot of benefits. And this is a single fraction radiotherapy compared to multiple fraction conventional radiation therapy. And we don't quite understand how the FLASH radiation differentially acts on tumor cells and normal cells because it kills tumor cells, and the tumor-killing efficiency is comparable to conventional radiation therapy. So there is no compromise, but the normal tissue is spared. So that is what makes FLASH very exciting field to understand how the biological effects are being produced, and how the cells respond to ultra high dose rate. I forgot to mention FLASH radiation delivers ultra high dose rate usually in the range of 40 gray per second. But in the conventional dose rate, it is only one to two gray per minute. And so much radiation is given all in one fraction that seems to be beneficial for the normal tissues, but detrimental to the tumor tissues.

- I know part of the research involves how that works, but, again, as a cancer survivor that, it blows my mind, the prospect of one treatment rather than 28 fractions of radiation over time. And not only are you preserving healthy tissue, and reducing side effects, but for folks who are getting this treatment, the barriers to treatment have to be reduced at some level. I mean, I'm thinking in my case, 28 sessions of radiation, for some people, that could be a barrier to getting complete treatment, If you have to go to a cancer treatment center 28 times over the course of seven or eight weeks if you have transportation issues or you have to work or you have to... I mean, I worked while I was in treatment, and had an understanding workplace based on where I worked that it wasn't an issue for me to leave work to go get treatment. But that may not be the case for some people. So the fact that you can target the tumor with one ultra high dose has such incredible potential on so many levels.

- Michael, I just want to emphasize that the FLASH radiation is not yet there. So only one patient was treated. He was having T-cell acute lymphoma way back in 2018 in Switzerland. So he was the only patient to receive FLASH radiotherapy. He's doing absolutely fine, and they have not reported any normal tissue damage in that patient. But still, lot of studies have to be done before we take this to the clinic.

- Yeah, yeah, absolutely. I realize. I'm very excited. But we have to temper, we have to temper the enthusiasm with the fact that much research still needs to be done-

- Yes, yes.

- to ensure that it's safe and it's effective, and as you say, the patient is doing fine, making sure that that doesn't change, that healthy tissue isn't ultimately impacted, all of those things.

- Yes. I just wanted to point it out that people should not think that it is already there in their clinic, but it is not. So, yes. We have to do a lot of experiments. So I'm quite excited with this 40 RT per gram in general because we have done a lot of projects in the past. So we looked at bio tissue, bio prints of humans. Basically you make bio prints that mimic the tissues, and we also compared the physical dosimetry with the bio dosimetry using cell phones. And we already published that manuscript. And this one is really exciting. We are doing this with Columbia University Medical Center. So they have actually modified Clinac accelerator to produce the FLASH rates. Just to tell you what we are actually doing. So we are using the peripheral blood lymphocytes as the model system. And we irradiate the lymphocytes with the conventional dose rate, which is actually one gray per minute. And we also use two dose rates of FLASH. One is 50 gray per second, the other one is 600 gray per second. So we are trying to understand how cells respond to this ultra high dose rate. And we are also looking at the DNA damage by looking at chromosomes. So we are looking at different types of chromosome elaborations to see is there any difference between the FLASH and the conventional dose rate. And we are also using a number of cancer cell lines and then the cell lines which are compromised for DNA repair. So we are interested in checking out the role of radio sensitivity in potentiating the effects of FLASH because there are some people who are inherently radiation sensitive. So how those people will respond if they are subjected to FLASH for radiation therapy. So it's quite exciting. So the field is evolving, but like I said, a lot of things to be learned. We don't know anything about this. I also want to mention here, in the past, we did the extremely low dose rate of gamma rays. So we have in the south campus that delivers 20 milli gray per minute, which is really low. So the conventional dose rate is one gray per minute. So this is only 20 milli gray per second. So what we observed with the low dose rate of gamma rays, the chromosomal aberrations are reduced because when you give low dose rate, the exposure time is enhanced. So you will do this a couple of hours, two or three hours instead of 20 minutes. So because of this prolonged exposure time, the cells have the time to remove the lesions or repair the lesions. So the cells, more and more cells survive, thereby the chromosomal aberration is reduced. So what is interesting now with the FLASH radiation, we see the exact phenomenon. So the conventional dose rate produces lot more chromosomal damage than the FLASH radiation with both the dose rates, 50 gray per second and 600 gray per second. So we get reduced yield of chromosomal aberrations, which is consistent with the FLASH effect. Like I said before, it kills efficiently the tumor cells, but it spares the normal cells. So that is exciting. But we have to do a lot more. Columbia University is looking for all this protein biomarkers. So if we can get FLASH-responsive biomarkers, which we can use for patient care, to follow that up. So how are the effects? So how many effects are the downstream effects? We are talking about the acute and late effects. So if we have suitable protein biomarkers, we can actually monitor those effects for the long term. But another advantage of FLASH, I can keep going on FLASH.

- That's okay. No, please do.

- Another distinct advantage is that the patients are getting only a single fraction unlike the conventional one, and there is very minimal, I won't say there is absolutely no normal tissue damage, but there will be some degree of normal tissue damage, but that'll be very minimal. So what it saves is from the long-term following up of the patients because you don't have severe normal tissue damage. So the long-term follow up may not be necessary for FLASH radiation therapy compared to the conventional radiation therapy. So that is a distinct advantage, is it's a single fraction and the normal tissue is spared, so you don't need to follow up the patients for a long time for the stochastic health risk like cancer. So again, secondary cancer.

- Yes. And again, that's exciting to me as a survivor who had radiation treatment, who is still doing my annual visits with my radiation oncologist to check for those secondary signs of cancer as a result of treatment. And again, realizing we are... It's early days, but biomarkers and precision medicine is really the next frontier of cancer research and cancer treatment. And it is just exciting to be talking with you about work that you're doing with Columbia University Medical Center. As we're talking about the frontiers of medicine, it's exciting to know that as a company who has a history in the cancer space, that we're still on the frontier. We are still, we're still on the leading edge of cancer treatment and knowledge of how cancer works and how treatment can happen.

- So by working on FLASH, we can also find more about the cancer cells, how they behave differently from normal cells. So I always talk about the differential effects. Like I said, it kills tumor cells but does not kill normal cells. So we don't understand the mechanistic basis for the differential effects of FLASH. So we have to do a lot more experiments. So that could be less DNA damage and more resistance to ultra high dose rate because it's just a single fraction. So there are, there are a lot of things to be resolved to understand the mechanistic basis, how it actually functions, why it selectively kills tumor cells. So that is our main interest. So we are doing a lot of studies on cancer cells and also normal cells. But the pilot project is just one year, so we cannot do too much. But with the data we generate from this pilot grant so we can get more funding from federal agencies to pursue this exciting field of research. So there is no doubt that it is going to be a very powerful radiotherapy technique in the future, but we have to cross so many hurdles on the way just trying to find out how this FLASH works on cancer cells.

- And, Balajee, this is not your first research in the cancer space. I mean, you've done lots of research and experimentation in the cancer space. I guess my question, as I completely pause and stop, is has that always been an interest for you? I mean, obviously from a research perspective you've been doing it, so there's definitely interest there.

- No, actually. Ever since I graduated, I started focusing on DNA repair. So many people know, "Oh, what is DNA repair?" So we are exposed to a lot of things on a daily basis. So if I tell you the kind of, the DNA lesions we encounter every day, it'll blow your mind. So hundreds and thousands of DNA lesions that are being generated on a daily basis because of our metabolism. So we all have a very efficient DNA repair system that takes care of all these lesions. So they repair the lesions, they remove the lesions, and some cells die and the new cells come. So it's a fascinating field. So that's why I have been really, really very much interested in understanding the DNA repair because with the aging, the DNA repair also declines. The DNA repair efficiency is really high when you are young, but with the age, it declines. So cancer was known to be a, known to be an age-associated disease.

- Yes.

- Because in general, I'm not talking about that childhood cancer, so that, it's a different story,-

- Absolutely.

- but cancer, in general, occur with the age. So when you age, your DNA repair deficiency declines, so your body is more susceptible to develop cancer because the immune response goes down because of the falling DNA repair efficiency. So it's all interrelated. And also the aging. So DNA repair has got a vital role in aging because the DNA repair declines and then the aging... So the DNA repair declines and the age increases. That's an inverse proportion between DNA repair and the aging, and also any genetic diseases, you can name it. I mean, the cancer is the one which was believed to be an age-dependent phenomenon. So that's why I'm really interested in understanding the DNA repair efficiency and also deficiency, and how the DNA repair deficiency leads to premature aging. So we have some syndromes that have deficient DNA repair system. Because of the DNA repair deficiency, the aging accelerates in those syndromes. So premature aging syndromes. So it's all very fascinating to me. And there are five genes that actually are responsible for the aging process, and mutations in those five genes, I don't want to go too deep into science. So these five genes are helicases, so they actually unwind the DNA and RNA. So they're pretty important. So if you have mutations in those genes, then it'll lead to premature aging. And, of course, all these premature aging syndromes are also susceptible to cancer. So there is a link, you see. So the DNA repair deficiency can lead to premature aging and also can lead to cancer susceptibility. So I was fascinated during my graduation days, and then I said, "Oh, I should pursue in DNA repair." And then I actually diverged into radiation biology, which is also equally exciting. And my future goal is to find out how radiation causes cancer. So, yeah. During the REM course and Arm course and HP physics course, we contacted REAC/TS. I always tell that radiation is a double edged sword. So you can use radiation for curing cancer, but it can also cause cancer as a stochastic effect. I mean, not immediately though, but several years later on after the exposure. So our main goal is to characterize some of the chromosomal changes. So the chromosomal changes, which are often known as translocations. So the translocations are responsible for the carcinogenic events. So if you ask me, the chromosomal translocations cause cancer or the cancer progression causes chromosomal translocations, I cannot answer because it's a chicken or egg thing. So what we would like to do is we would like to characterize those chromosomal translocations that are specifically induced by radiation exposure. So if we get some kind of fingerprint so we can actually predict. So if a cancer patients receive radiation therapy, of course the chances of getting secondary cancers are very remote. So probably 5 to 10% of the cancer patients who received radiotherapy can get secondary cancers. But still. So we would be interested to characterize those chromosomal translocations, and use them as fingerprints for predicting the cancer risk. And also early on. Radiation causes cancer after 20 or 25 years. It's a very slow process. But if you can catch these translocations much earlier, we can actually avoid or mitigate some of this, or you can delay the carcinogenic events. So we can actually, we can actually predict the risk. That's what I'm saying.

- Okay.

- So cancer risk, you can predict early on, and you can take proper precautions. I mean, it is unavoidable. I mean, it's a genetic basis, so you can do very little, but you can prolong the initiation of cancer.

- You said a minute ago that cancer, traditionally, is a function of aging. It's something that tends to happen as DNA repair gets less and less. We're seeing some cancers at younger and younger ages. Is that a function of... And I realize there is much research to be done in this area as well, but could that be a function of DNA repair issues that are starting earlier potentially?

- Yeah. I mean, those childhood cancers could be hereditary because they are born with certain genetic mutations. So there are many oncogenes that have been mapped in the human genome. You might have heard retinoblastoma, and there are a lot of the breast cancer susceptibility gene, one and two. There are a lot of oncogenes. So they play an important role during the childhood, but they are also important for DNA repair. Most of these oncogenes are also DNA-repair genes, and tumor-suppressive genes also. So if children are born with certain specific mutations in DNA-repair genes, designated DNA-repair genes, then the cancer incidence will be accelerated. Like I said, in case of premature aging syndrome, if we have mutations in those five genes, RecQ helicases, five RecQ helicases. So it is, So the premature aging is accelerated. So the system is down. You have reduced the DNA repair efficiency because you have mutations in important genes. So it may lead to the onset of cancer very early on. But for adults, we call this as sporadic cancers and familial cancers. Familial cancers are hereditary and sporadic cancers, I think, we acquire during our lifetime. So decline in DNA repair efficiency, and also our lifestyle. Smoking causes lung cancer, but not in all. But if some persons are predisposed, they may get lung cancer. So like that, there are a lot of genetic factors that go wrong when we age because it is systemic process. And during the process of aging, your DNA repair declines, probably you have accumulated some somatic mutations in some genes. So all this accelerate the cancer instance.

- Gotcha. That makes perfect sense. I know time is running a little bit short, but I know that you are doing some speaking about your research coming up in Munich, I believe, and-

- Yes.

- elsewhere.

- Yes. So we submitted an abstract for an oral presentation at the ConRad, that is 25th Nuclear Defense Conference, Nuclear Medical Defense Conference in Munich. So that is going to be held from May 8th through 11. So our presentation was accepted. So I will be presenting some of the results we got from the FLASH radiation. So this is a collaborative work between us and Columbia University Medical Center, and a few researchers from Columbia University Medical Center also will be attending that conference, so I'm quite excited.

- That is exciting.

- So, yeah. I also sent the abstract to International Conference on Radiation Research. It is called ICRR. So the conference will be held in Montreal in August. So I don't know the result now because they are actually reviewing the abstracts. So if the abstract is selected for presentation, I will also present at the ICRR conference.

- Gotcha.

- Yes.

- Well that's exciting, and I know that those opportunities, hopefully, lead to additional funding, and all of that because I know that beyond the pilot project, you, and I'm certain your research fellows at Columbia University Medical Center would love to keep going.

- Oh, yes, yes. Conferences are the best platforms for networking because you meet, and after hearing your lecture, they come to you and then discuss more. And then probably it may also lead to fruitful collaborations in the future. So I love to go to conferences and present the talks because that is the only way of connecting to people, so I always like that.

- Awesome, awesome. Well, Balajee, thank you so much for spending this time with me, and talking about your ODRD project with Columbia University Medical Center, and the promise that FLASH radiation holds. It's, again, early days, but things sound really exciting. And I'm thrilled as ever to have the opportunity to talk to you about the work that you're doing.

- Yeah. I just want to point out that in the '80s and '90s, it usually takes 20 or 25 years for establishing any new technique. But it has tremendously reduced now with the modern technology, with all this innovations and other things. So what can be achieved in 30 years back in the '80s can be achieved in 5 years now. We are living in the fast age, fast world. So it'll not be too far. I will not be surprised if FLASH radiation already enters the clinical trial in about three to five years. I think I will not be surprised because, yeah, people are working on this because they see the potential. So it is fantastic. I mean, it's good for the cancer patients, and it is cost effective because you are going to get only one time treatment, and then it saves the anxiety and stress for the cancer patients. So if you have to go for 30 or 35 fractions compared to one, you can imagine. So they'll be all very relieved. And then the time, you save so much time, like you said. So you are working, and then you have to break and then go for the treatment and then come back. You are fatigued. And all the side effects probably will not be there after FLASH radiation therapy. So I feel really excited to get to the bottom of this. At least I can do alone, I cannot do alone, but, yeah, that's why the collaboration helps.

- Right, right. And the health equity issue too of one treatment can be more readily available to everybody as opposed to, again, 28, 35.

- Yeah. Because when you do conventional radiation therapy, it takes 25, 30 minutes or something like that. And then you can only treat a certain number of patients on a given day. So, yes. Because more and more people can get treatment really fast because it's just a single fraction. So that must be appealing to a lot of people, including the insurance, healthcare insurance companies. It's also cost effective.

- I wouldn't

- It is good for the patients and good for others as well.

- Right. Absolutely. Thank you so much again for this conversation. I really appreciate your time.

- Oh, no, no problem, Michael. It's a pleasure. So, hopefully, I made some sense about FLASH radiation, and thank you very much.

- Thank you.

- I really appreciate this opportunity.

- Thank you again. Have a great day.

- Yeah. Okay, Michael. Bye.

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