Meeting Unmet Medical Needs – Genomic Medicine by Dr. Kalyan and Dr. Hima
Panel Discussion: 2 – Realizing the Promise of Personalized Medicine
Moderated by Dr. Hima
The panel members included: Dr. Samatha Tulla, an Internal Medicine Specialist and Diabetologist; Dr. Dilip Nandamuri, Diabetologist at Yashoda Hospitals; Dr. M. Nithin Reddy, Endocrinologist at AIG Hospitals; and Dr. Vishwanath Gella, a Consultant Clinical & Interventional Pulmonologist.
Dr. Hima started the second panel discussion by thanking all the panelists for gracing the stage and accepting the invitation to come over and talk a little bit about personalized medicine. She introduced all the physicians who have been actively incorporating personalized medicine into their practice and saw what their perspective was on the floor and what was happening right now. The discussion was expected to be a little opposite to the previous discussion from the oncologists, and everyone was quite enthusiastic because oncology is going at a rapid pace but the other specialties are also not that far behind.
Personalized Medicine in Practice
There are a lot of drugs already coming in and a lot of active research going on. The most important thing Dr. Hima wanted to know from everyone was to start by asking Dr. Dilip about his experience practicing personalized medicine, doing genomic analysis, and using those inferences for patients in his practice.
Dr. Dilip is known as one of those progressive physicians who has incorporated personalized medicine at the level of internal medicine at a much earlier stage compared to some of the other physicians. Dr. Dilip started by thanking Dr. Hima and Dr. Kalyan for organizing this discussion. He has started using this since the time Dr. Hima and Dr. Kalyan started it in 2019, but around 2020, he started using pharmacogenomics from Dr. Kalyan and Dr. Hima, and from his experience, he has done pharmacogenomics for quite a few patients. It is very helpful for a few of the patients, but what he observed is that for certain patients, there are a lot of medications that are not working and had to be removed after they were doing better than when they were using them.
Pharmacogenomics in Treatment Process
The medications were changed according to pharmacogenomics, sugar control, and other parameters, after which the quality of life improved, and over a period of time, it was also learned that in India, there were a lot of people with Clopidogrel resistance, which is the most commonly used anti-platelet medication. The drug was being used for a couple of his patients, but they were getting recurrent strokes, after which they did a pharmacogenomics report to find out that it was not working and changed to other medicines and are doing much better now. Dr. Dilip also says that it’s a bit of a chicken-and-egg situation, as the drug is not a big molecule and also a very cost-effective molecule, but to find out that it is not working is an expensive step even though the situation may not be a permanent one.
Current Indian Pharmacogenomic Landscape
The doctor also says that unless we do pharmacogenomics in a lot of patients, we won’t know what’s happening in the Indian population, and right now we may say it is costly, but unless we do it, we won’t get the data, which is very important to help the patients in the future. It may sound costly for a while, but when everybody starts using it, their cost will come down, and we will have a lot of information that will benefit patients a lot in terms of cost and decreased complications in the future. Another thing that he understands is that, over a period of time, as generations are changing and all genetic modifications are leading to cancers and lifestyle diseases, genes change, which means that a simple physician’s or layman’s understanding is that genes change and if he has a patient with a chronic or cardiac disease, strokes, etc., and identifies the problem in their siblings and next generation, changing the lifestyle can lead to modification in those genes also. If this can be done over the next few generations, we can reduce the incidence of chronic diseases and their complications, as well as cancer. This is a very long project to do and also costly right now, but if you start doing it, then that’s the thing.
Benefit of Digital Health Records
The doctor also agrees with Dr. Chinnababu about digital health records, which not only tell about disease patterns but also the risk factors in certain populations and how to modify them with computers and AI. These are the different applications we are trying to develop and will have a great impact on how we deal with healthcare and quality of life. The doctor also mentions that the system is evolving from the early days when it started out as general medicine and was called “individualized medicine” to now being personalized, and the next would be precision medicine and then targeted drugs for specific people, which is what we are dealing with and hence we have to catch up with the situation. Right now, a lot of people don’t do genetic testing for pharmacogenomics or genetics, but once we start things, we’ll have a lot of knowledge that will be helpful for patients.
Genetic Testing (For Families)
Dr. Hima agrees with Dr. Dilip and feels he is absolutely right about epigenetics. She also believes that screening not only the patient but also the patient’s family would be beneficial. For example, cardiomyopathy has a lot of evidence where you can actually screen the family and help them prevent such dangerous conditions, which is definitely something that adds value.
Pharmacogenomics in Diagnosis and Treatment
The next question was posed to Dr. Vishwanath, Dr. Hima’s senior at Gandhi Medical College. He has been practicing pharmacogenomics and is also part of the study coming up at his institution.
Dr. Vishwanath feels that pharmacogenomics is quite expensive, but everyone needs it and we need to know which drugs the patients respond well to. The next point was to know his experience with the pharmacogenomics aspect of being a critical care specialist and a pulmonologist. Dr. Vishwanath says that our knowledge in pharmacogenomics and personalized medicine is in its early stages and that he has been using it for the last year since his interaction with Dr. Hima almost a year ago. He feels that there are two kinds of indications, especially in pulmonary medicine, when it comes to personalized medicine. One is about the utility of genetic testing in a particular diagnosis to understand why a particular disease is happening, and the second is about the response to the treatment.
Pharmacogenomics in Optimizing Drug Therapy
One example is interstitial lung disease, mainly idiopathic pulmonary fibrosis, where a common cause is smoking. Patients with it have no smoking history; thus, the most frequently asked question is why they developed it despite never smoking. In this case, the doctor mentions that there are some variants like MUC-5 and TOLLIP that are known to be associated with some familial causes of idiopathic pulmonary fibrosis. In these conditions, sometimes, in addition to the regular anti-fibrotic, a drug called N-acetyl cysteine will be helpful.
Similarly, there are numerous bronchial cases. Sometimes patients develop post-infective and post-viral bronchiectasis because of tuberculosis or any viral infection in childhood, but a lot of patients who come without any previous history of viral infections or tuberculosis develop bronchiectasis. Hence, it is very important to identify what the reason is. Some of these patients may have primary ciliary dyskinesia, an inheritable disease, so there is a need to counsel the patients specifically regarding family planning and other things due to its inheritable nature and future generations being susceptible to suffering from it. The therapeutic aspect can be seen in cases like asthma, where it was seen that some of the patients do not respond to the regular corticosteroid inhalers, where pharmacogenomics can be used.
A recent review of the literature revealed that some of the glucocorticoid receptors actually do not respond to the inhaled corticosteroids because of some polymorphisms in the glucocorticoid receptor gene, and we are just trying to escalate the treatment with biologics, which is likely to be a never-ending affair. Instead, if we can find the reason for this non-response, in addition to the non-compliance of the inhalers and triggers like anxiety, etc., for the glucocorticoid receptor polymorphism mutations, there might be some new molecules that might help us in overcoming the resistance.
More Pharmacogenomic Studies Needed for Pulmonology
Hence, Dr. Vishwanath says that the field is very promising, but we need more data, especially in the diagnosis of familial pulmonary fibrosis or bronchiectasis, and in understanding treatment responses and how we can modify those responses. Dr. Vishwanath also says pharmacogenomics is being used when initiating Azathioprine to understand if its metabolism is influenced by Thiopurine Methyltransferase, and people who have its deficiency tend to have a lot of side effects because of myelosuppression. Little literature is also available about resistance to mycophenolic acid due to certain mutations where pharmacogenomics can be used to predict response. The field is also slightly underutilized, so have cautious optimism for patients who are not responding and see why they are not responding.
Dr. Hima thinks there need to be more studies and more patients need to be enrolled, and we can’t really give that cost to the patient because that’s going to be very expensive.
Diagnosis & Treatment Stress of Common Complex Diseases
Dr. Nitin, an endocrinologist who uses pharmacogenomics, presented the following topic. The discussion was about Dr. Nitin’s experience with the problem of personalized medicine and internal medicine, where the conditions are mostly called “common complex diseases.” Disorders, in which many conditions will have at least 100 gene variants that may be responsible for causing the disease, and determining whether a person is predisposed to a certain condition or not, or what drugs work for him, are not easy tasks to incorporate, even for the physician.
Exploring the Role of Precision Medicine in Diabetes Diagnosis
According to Dr. Nitin, diabetes is on the rise, and we have seen an increase in the number of young cases of diabetes in the last decade. India is the global capital for diabetes, so there is a need to ensure that we are on top of the new advances that come with diabetes management. Dr. Nitin mentions some original work of Dr. Mohan’s Institute in this segment that ensured that they recognized diabetes phenotypes such as insulin resistance, insulin deficiency, or a combination of the two.
This makes the job easy, and that’s where precision medicine is needed because of the presence of multiple agents in managing diabetes with different types of insulin, etc., and selecting the right one where genetic testing becomes important. The doctor also says that this is an evolving phase, and more and more data will keep on accumulating. He also says that, as of now, there is no mention of the usage of pharmacogenomics in the guidelines. But his institute has been enrolling patients since last year, as part of a specific study that is currently in progress, and part of the next step is to collect the data and then look at the phenotypic changes.
He claims that they are planning to make the necessary treatment changes to the individual, and then follow them up the line, and then look for the improvements that are happening. The doctor and his colleagues also feel that there is a lot of scope in this segment because many people, especially at the place where he practices, are diagnosed with diabetes and wanted to know the reason for getting diabetes. People were curious as to why they had diabetes even if their parents did not, and if they would develop diabetes in the future, and if so, how severe it would be. They also wanted to know when and what should be done to prevent it, and there are no answers at this time.
Use of Pharmacogenetics in Diabetes Treatment
As a result, the doctor believes that pharmacogenomics and genetics will be of great assistance in this area, where diabetes is prevalent in almost every household these days.
Dr. Hima also agrees with it and adds that pharmacogenomics is still evolving for all of the internal medicine specialty conditions, but still, the data is definitely out there and we can start incorporating it and seeing how patients are responding to diabetes specifically and also for screening protocols, and also if the patients are prone to microvascular complications, nephropathy, etc., and the future is quite right for that now.
Predictive Medicine in Endocrine Disorders
Dr. Samatha, an expert in personalized medicine, was the next speaker. She not only uses it from a pharmacogenomics perspective, as most doctors do, but uses it as a whole for her patients with regard to screening, diet, and other modalities as well. Dr. Hima asks her about her experiences, how it’s going, and how patients are responding.
Dr. Samatha starts by saying that she will stay away from the spectrum of oncology, diagnosis, and pharmacogenomics in favour of predictive medicine, as there is no use for decoded genomics without proper actionable evidence. As a result, predictive medicine is used, and the clients who walk into her clinic have metabolic disorders or metabolic syndromes such as obesity, diabetes, and hypertension. The majority of them are middle-aged men and women, and the majority of them are in pre-diabetes or post-pandemic syndromes, where they are sedentary most of the time and have high LDL values. Dr. Samatha says that as part of the screening, there are multiple omics that come into play when it comes to precision medicine.
Genomic Biomarkers in Predictive Medicine
The top one is genomics; the second is looking for biomarkers of metabolism, which describe what is happening. Most of the tests look for serum D3 levels and serum B12 levels, which do not give their exact values. And very little is known about intracellular B12 levels, so that is where markers of metabolism come into the picture, which could be vitamins, minerals, lipids, carbs, and fats. Even she didn’t initially have this knowledge of testing for CoQ10 and alpha lipoic acid, and now these tests are not currently available in Hyderabad, but Dr. Samatha sends them to Bangalore or Mumbai.
These tests are beneficial because many patients have very non-specific symptoms and believe that physicians have a difficult task determining where to place the diagnosis, or that a patient may not have a diagnosis, and that is the most common problem. As a result, he believes that physicians should consider what is happening with carbohydrate metabolism, whether it is a problem with nutrients, hormones, or detoxification, and where the patient is falling; all of these aspects should be covered and incorporated into a treatment plan.
Nutrigenomics and Personalized Diets
Hence, when it comes to prescribing, it has changed over the years for Dr. Samatha. For the past three to four years, she used to prescribe medicines directly, but now her first prescription is a diet plan or a nutritional plan. That is the way going forward, as all physicians should learn to modify their diet first, and that is where the biggest answer comes and treatments start changing. So, when she receives the comprehensive genome analysis from GenepoweRx, she looks into nutrigenomics and how she can influence nutrition plans using genetics in the report. One finding from the few patients she tested was that 60 to 70% of them had this APOE2 gene variant that makes them unsuitable for keto diets or high-fat diets, so she called Dr. Hima and inquired about the data on the APOE2 variant in India because she sees the majority of her patients on keto diets for metabolic syndromes like diabetes, hypertension, etc.
Dr. Samatha believes that, while keto diets work very well by turning off and shutting down insulin, which produces fantastic results, there are some side effects that occur because most of them are consumed through nutritional apps, etc. And after getting the data, she found that about 60 to 70 percent of the South Indians do have this variant, was very cautious, and now very seriously looks into what nutrition she actually puts patients on. The second most important aspect she talks about is the sudden cardiac deaths that are happening in the country right now; hence, she looks into fitness genomics, which is also part of comprehensive genomics or GenepoweRx total, and in that case, certain deficiencies are looked for that can put them at risk for certain cardiac deaths.
She also believes that fitness genomics, in addition to pharmacogenomics, can help assess whether patients are suitable for high-intensity workouts, which are very good for all of these metabolic syndromes or diabetes, by looking for gene variants that may affect them. She says that predictive medicine is going to be the future in the coming two or three years.
Role of Epigenetics
Dr. Samatha says that when it comes to the process of disease prediction, the disease risk that is done as part of the comprehensive testing gives the risk score and risk severity based on the variance that exists, and that we must incorporate epigenetics so that their age, other risk factors, and lifestyle can give an appropriate assessment score. Without genomics, we are falling short, but the genetic risk assessment score is adding up. Sometimes, it is found that a patient is actually at low risk according to their lifestyle, but their genetics put them at higher risk.
But again, Dr. Samatha feels that not every person who has a genetic variant for a particular disease is going to develop that disease and says we should outsmart our genes with exercise, nutrition, and keeping the disease away. Therefore, through the prediction of disease risk through genetics, situations could change, with epigenetics being the key factor.
Dr. Hima concurs, saying that in internal medicine, it’s not just pharmacogenomics and screening protocols that give the edge for ensuring that patients are put on evidence-based diets, but also telling them to eat according to their genes, etc., that will help them, and also feels that, surprisingly, quite a lot of our Indian population are not really fit for those kinds of heavy, high-intensity workouts that are happening these days.
DNA Testing for Fitness Genomics
Dr. Vishwanath also talks about his own experience. He said that after he got his genetic testing, he found one variant that said that he should not do intense workouts and suggested moderate exercise. Whenever he used to go for intense exercise, he used to get tired immediately, but after that advice, he shifted to a moderate kind of exercise and thinks that nutrition and fitness genomics are something very promising, and a lot of people would benefit from it.
Dr. Hima says that fitness genomics and nutrigenomics are for the patients to understand, but the bottom line is that they are just metabolism variants that we are looking at, and they all have a physiological process behind them.
Dr. Dilip spoke and said that he also had a similar experience post his genomic report and that his diet and exercise schedule has changed, but he has stopped high-intensity workouts after a recommendation. Dr. Dilip also suggests not to assess if the patient can afford the test and medications by looking at their attire, the way they talk, or how they come and try recommending them; it would be surprising to know how many people would want to do it, so he suggests giving them the option and allowing them to take the call.
Whole Exome Sequencing: A Must-Do One-Time Test
Dr. Vishwanath feels that the tests are also cost-effective with the Whole Exome Sequencing being included in them, although some of the medicines being used are more expensive. Dr. Hima says that this is a one-time test, and doing it once will suffice.
Dr. Samatha finally discussed one commonly asked question, which she addressed: “Don’t patients get anxious when they get a complete genome sequencing, and are they not afraid to get their disease prediction?” Dr. Samatha mentions a research article published in the Journal of Clinical Genomics that says that people who get the genetic screening done have far better adherence to their treatment than people who are not screened, so that notion of becoming anxious is no longer there.
Application of Whole Exome Sequencing in Patient Treatment
The second question she addressed was regarding doctors and whether her treatment changes after she gets genetic screening done for her patient. She again mentions a study published in the New England Journal of Medicine that says that seventy percent of the time, the physician is going to change the screening protocol, like follow-ups, or even change the treatment protocol after getting the genetic screening done. She feels that it is very promising and thinks we should all start using genetic screening for patients.