Cristina Deptula on San Francisco State University’s Personalized Medicine Conference 6.0

Personalized Medicine 6.0: Emerging Frontiers in Diagnostics and Treatment

Tailoring treatments for different patients based on their genetics represents an emerging technology that could streamline medicine and reduce costs while maintaining quality of care. San Francisco State University’s Department of Biological Sciences’ sixth annual personalized medicine conference, organized by department head Dr. Michael Goldman, and held at the South San Francisco Conference Center on Thursday, May 30th, explored various successes and ramifications of this approach to biomedical science.

Dr. Kimberly Popovitz, CEO of Genomic Health, served as a keynote speaker. Her talk emphasized potential cost savings and health benefits for many cancer patients who will now be able to confirm that their diseases are slow-growing and less dangerous, and thus skip painful, invasive treatments. Some people will also discover sooner that they require urgent interventions, and in these cases, personalized medicine could save their lives.

‘Cancer’s becoming a chronic disease in this country,’ Popovitz said. While this is good for patients whose lives can be prolonged, the lengthy treatments are expensive. Also, currently, many people are over-treated for prostate, colon and some forms of breast cancer, receiving chemotherapy and radiation even when they are likely to experience normal lives without these measures. Yet, no physician or patient wishes to skip out on a treatment that could prove life-saving, even in rare cases, especially when they could be accused of letting someone die for financial reasons.

The more detailed understanding of a person’s cancer subtype and individual genetic makeup made possible through genomic sequencing and analysis can increase the likelihood that he or she will receive appropriate and timely care. Popovitz and others hope this will make a difference in the lives of the 1.6 million people diagnosed with cancer every year in the USA.

Currently researchers seek to understand which genes are associated with better or worse health outcomes, so they can provide this information to oncologists and patients to help them make better informed treatment decisions. Scientists are also studying RNA, a form of DNA that functions within cells to build proteins, and identifying genes whose action contributes to disease processes and which could be targets for new drug therapies.

The human genome provides so much information that, according to the conference speakers, physicians, including oncologists, might get confused and need guidance about how to interpret the data.

For this technology to move forward, we will need more research and more detailed predictive models. Popovitz and others emphasized that the complexity of the science is a major factor holding back progress on cancer cures. ‘People wonder why we spend so much time and money on this, and we still don’t have a cure yet. Well, we’re working on it, and it takes awhile because it’s just that hard!’

Dr. Popovitz ended her segment on a note of cautious optimism. Although it has taken a long time for the field to move forward, both technically and in the eyes of decision-makers who choose whether to approve studies and pay for treatments, Genomic Health’s technologies are now in use in countries around the world.

Next, Dr. Jorge A. Leon, of Leomics Associates, discussed the future of the field of molecular diagnostics, as related to other conditions as well as cancer.

Dr. Leon pointed out that it’s cheaper and easier in the long run to sequence a patient’s entire genome than to test for the presence of particular alleles, or forms of certain genes. Whole genome sequencing has become much more accurate, faster, cheaper, and simpler.

Cancerous cells within a patient’s tumors can mutate and develop resistance over time to chemotherapy drugs. Molecular diagnostics could also allow oncologists to identify which drugs would be effective in each patient before starting treatment.

‘It’s no longer impossible to think about sequencing the whole genome of an individual cancer,’ Dr. Leon asserted.

Data storage and information processing power requirements could be addressed through cloud computing. And, also by harnessing some of the region’s information technology expertise, drawing upon the software knowledge of Silicon Valley.

Dr. Leon, and several other presenters, discussed other factors which influence our DNA. These include epigenetic changes in gene regulation and expression due to our environment, substances in the environment which can affect DNA, spontaneous somatic mutations, and the genetic makeup of the bacterial species living symbiotically within our bodies. Personalized medicine hopes to account for all of these factors eventually within its models.

 

Applied Medical Genomics: Breakthroughs and Next Steps

A panel presentation followed these talks. Dr. Christos Petropoulos of Monogram Biosciences spoke first, outlining his firm’s research into identifying strains of HIV and hepatitis virus resistant to common treatments.

Sequencing the viral genomes seems a faster and cheaper strategy than the current technology of cell-based infectivity assays, where researchers observe directly whether a patient’s viral strains infect cells. However, genomic sequencing will take more knowledge and proficiency with tools than we now have. His company’s using emulsion PCR, a faster way to replicate DNA for observation, and sequencing by synthesis, a more effective way to identify variant viral strains.

However, many questions remain, including how to determine a threshold for how much resistant virus within a patient’s body should indicate a change in treatment.

Dr. Jonas Korlach of Pacific Biosciences talked next, again pointing to the need to consider factors beyond just DNA in these types of analyses. Integrating genetic, epigenetic (environmentally triggered changes in gene expression), protein, metabolite, and clinical databases would prove an enormous, but potentially greatly useful, project.

Someday in the future, this type of data might be accessible through iPhone applications, making our phones critical diagnostic tools. But today, researchers seek ways to improve the accuracy of laboratory results. Dr. Korlach pointed to an example of the limitations of our technology from UC Davis researcher Dr. Paul Hagerman, who works on fragile X syndrome. This condition leads to severe and permanent mental and physical issues for children, and results from inheriting excessive repeats of a certain DNA sequence, CGG.

To determine a person’s risk of passing on Fragile X syndrome to their children, researchers count the numbers of CGG repeats in the relevant DNA region. However, some people’s set of CGG repeats is interspersed with AGG codons (groups of three bases signifying a particular amino acid). These AGG codons significantly reduce the risk of transmitting the condition, yet often go undetected when geneticists count the number of repeats.

Dr. Korlach pointed out that there are 10,000 regions of possible nucleotide sequence repeats in the human genome. Many of these could well be medically important, including those within introns (regions of DNA on the genome not coding for particular proteins).

That, in addition to possible genomic effects from the DNA from the three pounds of bacteria co-existing inside our bodies, and from the bacteria we encounter every day, highlights the need for further data collection and research.

‘Personalized medicine needs comprehensive biology,’ said Dr. Korlach, advocating for epidemiological tools such as population statistics to be applied to this intensive genomics research project.

Next, Dr. Frank Ong, of Illumina Inc. talked about his company’s form of noninvasive prenatal testing for trisomies, extra chromosomes leading to conditions such as Down’s syndrome. Some fetal DNA makes its way into a mother’s blood during pregnancy, from apoptosis (programmed and natural cell death) within the placenta. This can be examined as a preliminary way to rule out certain conditions or refer mothers for further tests.

He, also, closed with a call for computer science, engineering, and business professionals to consider lending their skills to this emerging field.

‘Biology does not have all the answers,’ he said.

Dr. Ong and others then mentioned a project to sequence the DNA of foodborne pathogens, such as salmonella, to determine how and why some strains are more virulent and figure out how to avoid them.

Also, while molecular genomics remains quite expensive, some technologies developed through this technology can translate into forms affordable for developing countries. Bacterial DNA observation is one area where this has been possible.

 

What Personalized Medicine Can Mean for Patients: Therapy In Action

After lunch, Stanford’s Dr. Atul Butte, physician, scientist and entrepreneur, spoke. He discussed the case study of Steve Quade, a forty year old healthy white man with a family history of aortic aneurysm and sudden, unexpected death, as an example of the power of personalized medicine.

Mr. Quade discovered that he did indeed have a genetic predisposition to coronary artery disease, and his doctor suggested he take statins. However, he did not.

Here Dr. Butte joked that there was no genetic method yet to find the best way to encourage patient compliance with treatment.

Dr. Butte described the process of identifying potential health risks from a patient’s genome, which was surprising. High school students scanned and searched through academic literature to curate the data, and identify alleles linked to specific diseases. Placing this data into the common medical statistics format of a likelihood chart made it easier for physicians to comprehend and refer to when discussing these matters with patients.

He also reminded conference attendees not to ignore the effects of environmental toxins on the body and human genetics. As he mentioned, the set of all the toxins we’re exposed to over our lifetime could be considered the human ‘toxome,’ perhaps as influential as the genome.

A current research project known as  the National Health and Nutrition Examination Study (NHANES) surveys environmental factors for disease. Scientists are also using the approaches of molecular genetics to look at the effects of the environment on human health.

‘Do you want to change the genome?’ Dr. Butte asked. ‘Change behavior and the environment.’

Near the end of his talk, he mentioned that with our decentralized heath care system in the USA, researchers often do not know how many people have a particular disease, unless it is contagious. Except for Kaiser, our hospital systems do not coordinate record-keeping, and this has hampered population genetics and epidemiological research.

Next, Dr. Mark Sliwkowski, distinguished staff scientist with Genentech’s department of research oncology, explained the molecular mechanisms behind new breast cancer drugs, such as herceptin.

Nearly three million women within the United States have been treated for breast cancer, and nearly forty thousand die per year. Younger women are more likely to have a particular form of cancer known as HER positive, where a gene known as HER codes for a protein that works together with another substance to signal for the continued growth of tumors.

New-ish drug Herceptin prevents tumor growth by binding to the substances within the cell, known as ligands, to stop them from coming together to produce their signal. Although Herceptin has proved fairly successful in slowing cancer, 5,000 women still die per year from HER positive breast cancer.

Researchers now have developed another drug for breast cancer, Kadcyla, which inhibits microtubule formation within cells. Cytotoxic, Kadcyla kills tumor cells and seems more potent than Herceptin, although it has only undergone a small clinical trial. It also leads to more months without progression of the disease in patients, and creates fewer side effects than Herceptin.

 

Legal and Financial Ramifications of Personalized Genomics: Industry Perspectives

Next up was a panel on legal issues involved with personalized medicine. Dr. Hank Greely, of Stanford’s Center for Law and the Biosciences, spoke first.

Dr. Greely advocated for policies encouraging and facilitating corporate investment in research and development, including stronger patent protections.

‘In order to meet today’s stringent regulatory requirements concerning evidence for the safety and efficacy of these therapies’, he said, ‘we must spend a lot of money developing them.’ And the biotech companies seek return on their research investments.

Dr. Greely then went on to highlight the unexpected drama of coding, where new therapies receive classifications determining the level of government health and safety regulation they will be subject to, and whether public or private insurers will cover them. Companies must pay to test their therapies and prepare for them to undergo the complex coding process.

Next, Dr. Michael Shuster, partner at Fenwick and Est LLP, discussed patent law in relation to personalized medicine. He brought up some basic categories of things which cannot be patented under American law: the laws of nature (i.e. no one can own gravity), products of nature (animals, plants, fungi) and abstract ideas and mental processes.

Dr. Shuster brought up a few examples from case law relevant to the science at hand. Isolated DNA molecules were once ruled unpatentable as a product of nature, and methods of screening cancer therapeutics were seen as a law of nature. Techniques for comparing and analyzing DNA sequences can also be seen as an abstract idea, although the courts reversed themselves on that decision.

Finally, he reminded us that genes were not currently under discussion for potential patenting, just molecules.

Finally, Paul Sheives, JD, of the Biotechnology Industry Organization, spoke enthusiastically about what was needed to advance the field.

He pointed out, once more, the need for improved accuracy and validity of the genomic screening procedures, and warned that this would not be easy to accomplish.

“Have you read War and Peace? How about the whole Bible? Or the Lord of the Rings?” he asked. “Imagine reading each of these a thousand times. That’s how many characters we’re going to have to analyze if we look at all of our DNA base pairs.”

Also, he sees a need for scientists to educate doctors and patients about the meaning of the genomic findings. People need to understand the concept of absolute and relative risks, so they will not panic with slight risk increases or avoid needed tests and health measures because of a small decrease.

Communication will serve as a major part of this education. “Personalized Medicine?” Sheives said, echoing the theme of the conference. “That’s usually thought of as talking to people, seeing them as human. Genomics is only part of that.”

 

International Genomics and Biotechnology Investment

Next, a final panel celebrated regional investment in biotechnology, within the Skane region of southern Sweden which a small delegation at the conference hailed from, and locally within South San Francisco.

Moderator Andrew Copestake, CEO of Swedish Biomimetics 3000, illustrated the cost savings potential of personalized medicine through a French study through their National Cancer Institute. By not over-treating slow-growing, non-lethal cancers, the nation recently saved $69 million euros.

However, this type of success will require an unprecedented level of cooperation among the chain of healthcare institutions. Researchers within the United States hope to facilitate a similar type of collaboration.

Later, Stefan Johansson, CEO of Sweden’s Invest in Skane association, encouraged those present to visit and work within the country’s Oresund region, near Denmark. This former shipyard, now a working and living area, has now become a hub for biotech investment. The locale offers a proton and electron accelerator, a ‘science village’ full of biomedical companies, vodka, food, arts and media.

Research in progress at Sweden’s firms includes work on drug delivery, healthier aging, using the Internet to enhance patients’ access to health information, and enhancing the immune system. They seek to translate systems biology into clinical care, and enjoy beaches, sun, and golf, as the region’s supposedly unusually warm for Scandinavia.

Sweden also offers affordable hydropower, which benefits biotech firms, and England and other European countries offer tax credits for research and development.

Next, Michael Lappen, economic development coordinator for the City of South San Francisco, reminded us that they were the epicenter for product development, education, and surfing (down the Peninsula). South San Francisco is actively developing infrastructure and science and math education to encourage corporate and startup biotech investment.

Lappen said that companies will go wherever there are skilled workers with backgrounds in relevant particular fields, so we maintain our economic edge by supporting education. He said that outside of Sweden and the San Francisco Bay Area, Munich, Boston, San Diego, Singapore and parts of Shanghai were developing into biotechnology centers.

 

Genomics, Patient Care and Cancer: Concluding Keynote

Lastly, Dr. Carl Borrebaeck of Lund University’s CREATE Health program discussed new methods for personalized, and earlier, detection of pancreatic cancer in a final keynote.

One hundred people in the USA die per day of pancreatic cancer, and only three to four percent of people diagnosed with it live more than five years after diagnosis. Diabetics, those with a family history of pancreatic cancer, and others are at greater risk, but many people come down with the cancer for no apparent reason.

Dr. Borrebaeck pointed to the emerging development of a blood-based test for pancreatic adenocarcinoma. Through improved planar well microarrays for analyzing multiple blood samples, scientists in Lund, Sweden are closer to being able to distinguish whether a patient has cancer or just pancreatitis. Early treatment can go a long way to save lives for those who do have cancer.

Currently scientists investigating pancreatic cancer receive an overwhelming amount of information from the tests we have, and seek to identify peptide motifs, the signs of the presence of a few major protein groups.

He also discussed protein profiling for breast cancer. Researchers examined tumors from 52 patients, identifying 49 proteins associated with certain grades of breast tumors. These techniques enabled higher-resolution classifications.

Researchers hope to continue by uncovering the biology behind cancer’s progression from one grade to another.

‘This assay technology is not a replacement for a pathologist, it’s a tool for them.” Borrebaeck said.

Sweden possesses a repository of genetic cancer data from their relatively homogeneous population, and his group takes part in a worldwide collaboration with researchers in Tianjin, China, Oxford, Madrid, and elsewhere. They’ve also made inroads and connected with the Pancreatic Cancer Action Network, and are trying to stay on top of resistance by developing several antibodies for the same antigen. 

Overall, the conference reflected the promise, and challenges, of new technology, and left us in an upbeat mood. Near the end, over wine, cheese, and various sweet and savory snacks, undergraduate students presented quite professional research work on a host of posters. And, gauging from the conversations among the departing attendees, this sixth annual event will inspire continuing work in a variety of science and technology fields.

 

For more information, please contact San Francisco State University’s Dr. Michael Goldman, dnamed@sfsu.edu