Human disease is generally a consequence of complex interaction between our genes and the environment. Traditionally, medical research focuses on creating therapies to treat specific diseases.
This can be very effective. Individual therapies can have universal benefits across the whole population: look at immunisation against specific pathogens, or how new antiviral medication has helped control the spread of HIV/AIDS.
However, many diseases defy simple drug solutions and strategies for population therapeutics. In our increasingly sophisticated and impatient society, there’s more demand than ever on biomedical research to develop therapies across a broad range of clinical conditions.
Genetic and environmental factors mean diseases can have very different trajectories over different people’s lives. Considering these factors can reduce the chance of catastrophic events that cause accelerated disability or premature death.
Some people may respond well to a certain therapy while others might react adversely, or not at all. Bioinformatic data analysis helps clinicians work out a person’s likely response to medication and how urgent it is to intervene.
Personalised or precision medicine uses genomic and biological data to find the best therapeutic option.
This is rather different to symptom-only clinical diagnosis that doesn’t take that broader information into account.
First, a consulting clinician needs to submit a patient’s e-health record to an informatics centre for detailed analysis. The centre then uses worldwide health and genomics data to identify the diagnostic cluster group a patient belongs to.
This is used to compute a diagnosis and the probable best treatment options, which the clinician receives as summary data.
When combined with the patient’s molecular diagnostic information from pathology tests and specific patient examination, this data enables the clinician to determine personalised therapies that maximise likely benefit while reducing the chance of adverse events and failure.
Letting the gene out of the bottle
So how can we make all this happen? The genomic and patient history data banks are already being built.
But we need detailed bioinformatics analyses to turn large amounts of complex data into useful information for busy clinicians. The outcomes of diagnosis and treatment then need to be verified and fed back into these data banks.
There’s a role for the private sector to enter this space and help provide the needed specialist bioinformatics advice. Since the goal is to improve patients’ lives and reduce primary health care costs, government can also play a part.
Insurance policies and their coverage of therapy will need to be revised to ensure equal access to these new precision medicines. The overall economic benefits to the community will drive these transformations in the health industry.
Experts are connecting this data with gene-edited and genomic screens to develop and repurpose drugs and identify clusters of patients likely to benefit from them.
The microbiome is rapidly being incorporated into medical diagnostics and therapeutics as we increase our understanding of its association with disease.
In the past, this aspect of patient variance hasn’t been considered critically for many conditions.
For example, anti-tumour immunity responses have been very clearly associated with microbiota changes in mice. Specific microbial strains can significantly boost immune responses to tumour cells and restricted tumour growth.
Similarly, the composition of patient’s gut microbiome can influence the success of cancer immunotherapy. Studies are underway that combine immune checkpoint therapy (ani-PD1 therapy) with oral doses of certain bacteria or fecal matter from other patients who responded well to this treatment. There is interest in adding this information into the data sets for personalised therapy.
As genomics adopts new advances for identifying and confirming the role of gene signalling pathways in diseases, new drugs will be discovered and personalised medicine will evolve.
For example, large patient-donated samples of stem cells derived from adult tissue (induced pluripotent stem cells, or iPSCs) are being analysed to find out how various diseases respond to different drugs.
Similarly, researchers are designing personalised cell therapies for regenerative medicine by using iPSCs from individual patients or rare donors. These studies are entering clinical trials for numerous conditions including blindness, spinal cord injury, diabetes, heart disease, Parkinson’s disease and cancer.
It’s now possible to generate stem cells from adult tissue that are the equivalent to primitive embryonic stem cells. These iPSCs make it possible to gene-edit very specific genomic designs, dramatically increasing the effectiveness of cancer-destroying white blood cells.
The success of immune therapies has impacted the present approach to cancer therapeutics. Three particularly exciting developments are monoclonal antibodies, checkpoint inhibitors and chimeric antigen receptor technologies (CAR-T).
Monoclonal antibodies are a fascinating breakthrough. Antibodies are protective proteins in the immune system that attack “foreign” substances like viruses and bacteria. To do this, they recognise and latch onto proteins called antigens.
Thanks to genomics, we can now identify antigen markers specific to an individual cancer. This lets us design specific therapeutic antibodies to bind to and kill tumour cells. These are called “monoclonal antibodies” because they come from identical, cloned immune cells.
The precision sequencing of tumour DNA in patients’ blood is a very rapidly expanding area of diagnostics. It’s revealing important variations within cancers traditionally considered to be of a single cancer type. This allows us to design specifically targeted therapies that transform patients’ lives.
Personalised cancer vaccines are also rapidly evolving. These make use of dendritic cells: tree-shaped cells that present antigens to the immune system and instruct it to make antibodies and disease-fighting white blood cells.
Scientists make cancer vaccines by taking the patient’s own dendritic cells and activating them with synthesised molecules (peptides) that are based on the specific gene mutations in the patient’s tumour.
No two people’s tumours are identical: their likely malignancy and spread vary considerably. Additionally, the rapid growth of tumours means that multiple gene mutations in tumour-starting genes (oncogenes) can develop.
Inheritance, mutation, and environmental influence can cause abnormalities in oncogenes and their regulation, which in turn causes cancer. Since each situation is unique, personalising therapy makes a lot of sense. Checkpoint inhibitor therapy is another exciting area of research.
Tumours sometimes use the immune system’s own regulators to protect themselves from it. Molecules called checkpoint inhibitors block these regulators and activate the patient’s immune system to hunt down and destroy cancers. This is particularly effective against melanomas.
In the blood
The most effective therapy for B cell blood cancers is CAR-T therapy. This involves genetically engineering tumour-recognising proteins called chimeric antigen receptors (CAR) into a patient’s own white blood cells. These CAR-T cells are multiplied in the lab then infused back into the patient.
When the CAR-T cells recognise and bind to the cancer cells in the patient, they signal the immune system to kill the tumour. CAR-Ts are incredibly effective at targeting a patient’s own specific tumour type, and are being studied for a wide range of cancers.
Presently, CAR-T therapy involves recovering and genetically manipulating the patient’s own white blood cells. However, cancer patients’ immune systems have often been impaired by long and debilitating chemo- or radiotherapy. This can make it hard to get enough cells for successful treatment.
“Off-the-shelf” CAR-T therapy is emerging as a useful alternative. By removing the major transplant barrier genes in donor cells, or choosing rare donors who are compatible with a high proportion of the population, doctors can use healthy cells that haven’t been subjected to chemo. This is also cheaper, because you don’t have to manufacture a unique product for every individual patient.
Unfortunately, precision medicines often cost many hundreds of thousands of dollars for any treatment. While there may be tolerance for expensively funding a few patients with rare diseases, the cost of mass precision medicine will be onerous for present health budgets.
The present health system won’t be able to provide public funding and insurance for these treatments unless major changes are implemented. We need to remember that keeping people healthy also has economic benefits. Helping patients meet the increased costs of these personalised therapies is an investment that will drive down the long-term costs of disease care.
The other great challenge is in training clinicians to use major data resources. That means collecting and interpreting individual patient information to make better diagnoses and therapeutic recommendations.
Our community’s health will increasingly be a partnership between patients, consulting clinicians and therapeutic providers. These relationships will be different to what we’re used to. Patients’ decisions and data inputs will have a bigger role than ever before.
All these changes are already happening. Medical practice, public health, government, health insurance and the community need to come together to be ready for them. It’s up to us to create an economically rational, emotionally comfortable and socially just health care system for all.
Professor Alan Trounson FTSE
Alan Trounson PhD LLD is a world-renowned expert in stem cell research and one of the pioneers of IVF. Elected a Fellow in 2014, he is an Emeritus Professor at Monash University and Distinguished Scientist at the Hudson Institute of Medical Research. Professor Trounson is also the CEO of Cartherics, an immune stem cell cancer therapy company.